18 Autoimmune Disease in Pregnancy

Katherine Latimer

Donna Neale

Autoimmune disease is characterized by the production of antibodies against selfantigens. One of many medical mysteries is how the fetus, that is genetically partially foreign to the mother, implants and survives a pregnancy.

PATHOPHYSIOLOGY

Cytokine Milieu during and after Pregnancy

During pregnancy, the immune system undergoes several changes to allow the mother to carry the fetus.

Traditional teaching suggests that pregnancy reflects a switch from the normal predominant proinflammatory (T helper 1 [T_h1]) state to an antiinflammatory (T helper 2 [T_h2]) state. It is this switch that is thought to protect the antigen-distinct fetus from being rejected by its mother. More recent study suggests that the immune changes in pregnancy are not so simplistic but represent a constant interplay between the proinflammatory and anti-inflammatory systems. Because of these changes in the maternal immune profile, autoimmune diseases can present and behave very differently during various times of the pregnancy than in the nonpregnant state. Furthermore, the switch back to the predominant proinflammatory state in the postpartum period can affect disease activity during this time. Clinical applications of these changes help explain exacerbations in T_H2-driven diseases such as systemic lupus erythematous and improvement in T_H1-driven diseases such as rheumatoid

P.235 arthritis, multiple sclerosis, and autoimmune thyroiditis during pregnancy with increased “flaring” in the postpartum period.

Autoantibodies in Pregnancy

Maternal immunoglobulin G (IgG) crosses the placenta, not immunoglobulin M (IgM) or immunoglobulin A (IgA).

COMMON MANAGEMENT CONCERNS

• Care should be taken at the initial prenatal visit to outline baseline function/disability, recent history, and symptoms of flares. Ideally, patients should have stable disease or remission prior to embarking on pregnancy. Whenever there is a concern for the presence of anti-Ro, anti-La, or antiphospholipid antibodies, titers should be checked. C3/C4 levels may also be helpful. Patients should be asked about flare symptoms at each visit. Generally, patients exhibiting one autoimmune disease should be carefully evaluated for others because these frequently coexists.

• Anti-Ro and anti-La antibodies are found frequently in patients with systemic lupus erythematosus and Sjogren disease and occasionally seen in scleroderma and mixed connective tissue disorder (MCTD). If present, fetal echocardiography should be performed at 22 weeks' gestation. M-mode with PR interval measurements should start at 16 to 18 weeks' gestation and repeated weekly to assess for possible fetal heart block. If it is found, maternal dexamethasone administration may be helpful to protect the fetal cardiac tissue from further damage.

• Baseline renal function should be determined because many autoimmune diseases affect the kidney. For instance, systemic lupus erythematosus, scleroderma, MCTD, and vasculitis can cause renal insufficiency. Renal crises during pregnancy carry high morbidity and mortality. Patients at risk should be carefully evaluated early in pregnancy with 24-hour urine protein and creatinine for baseline function.

Pregnancy Complications

• Several autoimmune diseases put patients at increased risk for intrauterine growth restriction (IUGR) including systemic lupus erythematosus, scleroderma, MCTD, dermatosytis/polymyositis, antiphospholipid syndrome, and autoimmune bullous disease. An ultrasound should be performed every 4 weeks following the anatomy ultrasound. In the presence of IUGR, serial fetal Doppler ultrasonographic studies should be performed.

• Increased risk of preeclampsia: These patients should have baseline 24-hour urine collection for total protein and creatinine clearance, even in the absence of known renal disease. Serial samples should be collected at least in every trimester in highrisk patients.

• Increased risk of stillbirth: Antenatal testing is normally initiated at 32 weeks of gestation, unless there is evidence of maternal/fetal compromise prior to this time.

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• Increased risk of premature birth: Betamethasone/dexamethasone should be administered to patients with poor fetal testing results or worsening maternal disease before 34 weeks.

MEDICATION CONSIDERATIONS DURING PREGNANCY

Generally, immunosuppressive medications are the cornerstone therapy for autoimmune disease. The need for medications in pregnancy must be balanced against fetal affects. Breast-feeding may be contraindicated based on the immunosuppressant medications mothers resume postpartum.

• Glucocorticoids such as prednisone and methylprednisolone are often first-line therapies. They are generally considered safe in pregnancy.

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically limited during pregnancy after the first trimester up to 32 weeks given the concern for fetal renal agenesis, premature closure of the fetal ductus arteriosus, and oligohydramnios. If used during pregnancy, consider short pulse courses.

• Low-dose aspirin (81 mg) can be used safely in pregnancy.

• Immunosuppressant azathioprine and antimalarial hydroxychloroquine are used for a variety of autoimmune conditions and are generally considered relevantly safe.

• The monoclonal antibody rituximab and immunosuppressant mycophenolate are less commonly used due to limited safety data.

• Cyclophosphamide is an alkylating agent used to treat severe vasculitis and other autoimmune disorders. It should be avoided in the first trimester due to risk of congenital anomalies.

• Methotrexate should not be used during pregnancy. It is an antimetabolite/antifolate drug associated with spontaneous neural tube defects, abortion, and other significant congenital anomalies. Patients on methotrexate prior to conceiving should begin folate supplementation prior to becoming pregnant.

• Antihypertensives: When autoimmune disease is associated with hypertension, the need for medications should be reevaluated in the context of pregnancy. If possible, patients on angiotensin-converting enzyme (ACE) inhibitors, which have fetal renal effects, should be transitioned to alternatives such as labetalol, nifedipine, hydralazine, or methyldopa.

DISORDERS COMMONLY ENCOUNTERED IN PREGNANCY

• Systemic lupus erythematosus (SLE) is a multisystem, chronic autoimmune disease that commonly affects women in their 20s and 30s. Symptoms can include arthritis, photosensitive rash, alopecia, mucocutaneous lesions, renal insufficiency, Raynaud phenomenon, pulmonary involvement, gastrointestinal (GI) disease, neurologic symptoms, pericarditis, and hematologic effects. Autoantibodies involved include antinuclear antibodies (ANAs), anti-Ro, anti-La, anti-Sm, anti-dsDNA, and antiphospholipid antibodies.

• Lupus is associated with poor obstetric outcomes including IUGR, prematurity, stillbirth, and spontaneous abortion.

• Disease should be inactive for at least 6 months prior to pregnancy.

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• One third of patients experience flares during pregnancy, which should be treated with hydroxychloroquine, low-dose prednisone, pulse intravenous (IV) methylprednisolone, or azathioprine. High-dose prednisone and cyclophosphamide should only be used in severe flares when necessary.

• Distinction between a flare versus preeclampsia (PEC) may be difficult, as both can result in proteinuria, thrombocytopenia, hypertension, or hyperuricemia. Transaminitis supports PEC. Generally, during a lupus flare, complement levels will be decreased. Red blood cell casts may be present on urinalysis.

• Neonatal lupus syndrome is rare, characterized by skin, hematologic, and other systemic lupus lesions and sometimes by congenital heart block appearing up to a month after birth. Subsequent pregnancies carry up to 25% recurrence risk.

• Antiphospholipid syndrome

• Antiphospholipid (APL) antibodies interfere with coagulation, thrombus formation, and complement pathways.

• Diagnosis requires the presence of at least one of the clinical criteria in Table 18-1 and testing positive for lupus anticoagulant, anticardiolipin antibodies (IgG and IgM), or anti-β2-glycoprotein I antibodies (IgG and IgM) on two separate occasions at least 12 weeks apart. Notably, 1% to 5% of healthy individuals may test positive for APL antibodies.

• Gravidas are at increased risk for venous or arterial thrombosis, IUGR, fetal loss, preeclampsia, and pregnancy-induced hypertension.

• American College of Obstetricians and Gynecologists expert's opinion on pharmacologic management

differs by patient history. During the antepartum period and 6 weeks postpartum, women with:

ξ History of thrombosis should receive prophylactic heparin

ξ No history of thrombosis should receive clinical surveillance or prophylactic heparin

P.238 ξ Recurrent pregnancy loss should receive prophylactic heparin and low-dose aspirin

• Neonatal thrombosis attributable to APL antibodies is rare.

• Autoimmune thyroid disease

• Graves disease involves thyroid-stimulating antibodies that bind the thyroidstimulating hormone (TSH) receptor, causing hyperfunctioning and potential thyrotoxicosis.

• Hashimoto thyroiditis involves destruction of the thyroid by autoantibodies, such as antithyroid peroxidase antibodies. Despite transplacental transfer of autoantibodies and rare reports of effects on fetal thyroid function, most maternal autoantibodies do not result in fetal thyroid dysfunction. Untreated maternal disease can have significant consequences (see Chapter 13.)

• Type 1 diabetes—See Chapter 13.

• Rheumatoid arthritis is a chronic polyarthritis of unclear etiology characterized by morning stiffness and decreased range of motion in affected joints. Diagnosis is based on symptoms and lab findings such as rheumatoid factor, anti-cyclic citrullinated peptides (anti-CCP), or elevated erythrocyte sedimentation rate (ESR). During pregnancy, symptoms improve in 50% to 90% of patients; however, up to 90% will experience flares postpartum, particularly in the first 3 months. No obvious adverse fetal effects are known. Need-based treatment includes NSAIDs, low-dose acetylsalicylic acid (ASA), glucocorticoids, and potentially hydroxychloroquine.

• Sjogren syndrome is a chronic inflammatory disorder with diminished lacrimal and salivary gland function and potential extraglandular symptoms. Autoantibodies involved commonly include Ro, La, ANA, rheumatoid factor (RF) and potentially Sm, ribonucleoprotein (RNP), anticardiolipin, and lupus anticoagulant. Treatment of dry mouth involves diet modifications, regular hydration, and regular dental care. Artificial tears can be given for dry eyes. Extraglandular symptoms may require immunosuppressive therapy.

• Scleroderma (Sc) is a chronic, inflammatory disorder with nearly universal dermatologic involvement including skin hardening or sclerosis. Patients have varying degrees of pulmonary fibrosis and hypertension, renal insufficiency, GI dysmotility, cardiac, and musculoskeletal effects.

• Pregnancy has no clear impact on flares. However, morbidity is high when renal crises occur. There is an increased risk of hypertension and IUGR.

• Pregnancy exacerbates GI dysmotility. Proton pump inhibitor (PPI) may be helpful.

• When present, perineal/cervical involvement impacts vaginal delivery and may increase risk of shoulder dystocia.

• Skin symptoms are managed with antihistamines and lotion.

• DermatomyositisZpolymyositis: Myositis-specific autoantibodies are believed to contribute these inflammatory myopathies. Diagnosis is aided by elevated muscle enzymes, electromyelogram, and confirmed by biopsy. Treatment involves glucocorticoids and/or azathioprine. Dermatomyositis (DM) has characteristic skin changes, of which 15% are associated with a malignant tumor. There is an increased risk of IUGR and

perinatal death. Active disease is associated with worse outcome.

• Mixed connective tissue disease is an autoimmune disease associated with anti-U1 ribonucleoprotein (RNP) that is characterized by a combination of symptoms of SLE, Sc, rheumatoid arthritis, and myositis. Other autoantibodies sometimes associated with the condition include anti-dsDNA, Sm, and Ro. Presentation is

P.239 highly variable with patients with predominant Sc or myositis-like features generally having a worse prognosis. Treatment is tailored to features of illness, including autoantibody management as mentioned earlier. SLE features are typically steroidresponsive, whereas Sc-like features are not.

• Myasthenia gravis is characterized by IgG-mediated damage to acetylcholine receptors or muscle-specific tyrosine kinase at the neuromuscular junction resulting in contractile muscle weakness of the face, oropharynx, eyes, limbs, and respiratory muscles.

• Crisis can be life-threatening, particularly with oropharyngeal or respiratory involvement, and is more likely in the first trimester and postpartum period.

• Suspected infections should be treated promptly to decrease risk of crisis.

• The gravid uterus increases baseline fatigue and difficulty breathing.

• Labor is possible because smooth muscle is unaffected. Fatigue with expulsive efforts in the second stage may necessitate operative delivery.

• Magnesium sulfate can precipitate a crisis, and phenytoin worsens weakness. Seizure prophylaxis typically involves levetiracetam or valproic acid.

• Pyridostigmine, an anticholinesterase, is used in treatment, as well as glucocorticoids and azathioprine. Plasmapheresis or intravenous immunoglobulin (IVIG) may be needed for crisis.

• Both treatment and maternal antibodies can pass transplacentally. In rare instances where fetal movement is inhibited, the contracture syndrome arthrogryposis multiplex congenital develops. Transient neonatal symptoms are noted in 10% to 20% of infants following delivery.

• Multiple sclerosis is an autoimmune disease of the central nervous system characterized by demyelination, inflammation, and axon degeneration. Various cell types including T_h17 and inflammatory T and B cells have been implicated. The disease exists in relapsing-remitting and progressive forms. Neurologic symptoms such as weakness and visual and sensory loss vary depending on the tissues involved.

• The Pregnancy in Multiple Sclerosis (PRIMS) study suggests that patients have fewer relapses during pregnancy and tend to flare postpartum.

• Women with bladder involvement may be more prone to urinary tract infections (UTIs).

• Methylprednisolone intravenously can be used for treatment of acute attacks. Limited data suggest that continuing use of natalizumab and glatiramer acetate during pregnancy is safe. Similarly, patients taking interferon beta have a slightly lower birth weight and increased incidence of preterm birth without increased risk of anomalies.

• Immune thrombocytopenic purpura—See Chapter 20.

• Autoimmune hemolytic anemia

• Cold agglutinin disease is caused by IgM (rarely IgA or IgG) antibodies against polysaccharide components of the red blood cell. Symptoms are prominent in cold temperatures. Rapid hemoglobin drops may result in miscarriage or stillbirth. Fetal effects are rare because the antibody is normally IgM, which does not cross the placenta. Treatment is supportive, including warm clothing. In severe cases, rituximab is used. Plasmapheresis is rarely necessary. If transfusion is necessary, fluids should be warmed.

• Warm agglutinin disease is due to IgG antibodies and may be associated with SLE, viral infection, connective tissue disease, or immune deficiency. When IgG antibodies cross the placenta, fetal effects are usually mild. Maternal treatment options

P.240 include glucocorticoids and azathioprine. Splenectomy can lead to remission, and IVIG is used for refractory cases. Neonates will transiently be Coombs-positive and rarely require transfusion or plasmapheresis.

• Autoimmune neutropenia is characterized by granulocyte-specific antibodies and an absolute neutrophil count (ANC) less than 1,500 cells∕μL. It is commonly developed in childhood with remission in adulthood.

T ransplacental passage of antibodies from affected gravidas has been documented. The transient effect on neonates is mild; however, severe infections may occur.

• Vasculitic syndrome involves damage to blood vessels, often through immune complexes. Relatively rare in pregnancy, information is limited to small cases series and reports.

• Polyarteritis nodosa (PAN) is a necrotizing vasculitis involving small- and mediumsized arteries that is characterized by neuropathy, hypertension, GI disorders, and renal failure. Treatment consists of glucocorticoids, cyclophosphamide, and ACE inhibitors. During pregnancy, this regime must be reevaluated (see medications discussed earlier). Thirty percent of cases are associated with hepatitis B and require antiviral treatment. Although rare, PAN can be devastating when identified in pregnancy, with morality rates greater than 50%.

• Wegener granulomatosis is a necrotizing granulomatous vasculitis with pulmonary, ear/nose/throat, and renal involvement. Treatment includes corticosteroids, cyclophosphamide, rituximab, or azathioprine.

• Takayasu arteritis is a vasculitis that affects large vessels including the upper aorta and its branches. Surgery prior to pregnancy may improve survival. Most case series report good fetal outcomes; however, the incidence of maternal adverse events varies widely. Baseline function, abdominal aorta involvement, and prenatal care may explain these differences. Hypertension poses significant risk and should be managed aggressively. Invasive monitoring may be necessary.

• Henoch-Schonlein purpura is a small vessel vasculitis characterized by abdominal pain, hematuria, purpura, and arthritis that is more common in childhood. Treatment is supportive, and pregnancy outcomes are generally favorable.

• Behςet disease is a systemic vasculitis characterized by uveitis and oral and genital ulcers. Disease is usually stable during pregnancy; early miscarriage rates are higher.

• Autoimmune bullous disease

• In pemphigus vulgaris, IgG antibodies against desmoglein result in intraepidermal bullae on the skin and mucous membranes. Its milder variant, pemphigus foliaceus, does not have mucous membrane involvement. Therapy includes systemic glucocorticoids and occasionally azathioprine. Refractory cases are treated with rituximab and IVIG.

• In bullous pemphigoid (BP), IgG antibodies against hemidesmosomes in the basement membrane result in subepidermal bullae. When onset occurs during pregnancy, the condition is called pemphigoid gestationis or herpes gestationis. Exacerbations can occur postpartum and in subsequent pregnancies. Maternal treatment includes topical corticosteroids and antihistamines. Systemic therapy is used for refractory cases.

• Fetal deaths have been reported in women with high antibody titers. Therefore, rising titers should prompt aggressive maternal treatment.

• Due to risk of stillbirth, prematurity, and IUGR, antenatal testing may be indicated.

• Neonatal bullous disease occurs in 3% to 40% of infants. Treatment is supportive because lesions resolve as maternal antibodies degrade.

• Autoimmune hepatitis has a heterogeneous presentation ranging from asymptomatic to liver failure. Autoantibodies present include antinuclear (ANA), antiactin

P.241 (AAA), and anti-smooth muscle (ASMA) in type 1 and anti-liver/kidney microsomes (ALKM-1) and anti-liver cytosol (ALC-1) in type 2. Healthy pregnancy outcome is possible, although there is an increased risk of prematurity, low birth weight, and stillbirth. Common treatment options include glucocorticoids and azathioprine.

TABLE 18-1 Clinical Criteria for Diagnosis of Antiphospholipid Syndrome

Vascular One or more clinical episodes of arterial, venous, or smal l vessel thrombosis in any thrombosis tissue or organ

Pregnancy One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th morbidity week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus

One or more premature births of a morphologically norma l neonate before the 34th week of gestation because of eclampsia or severe preeclampsia or features consistent with placental insufficiency

Three or more unexplained consecutive spontaneous pregnancy losses before the 10th week of pregnancy, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

Adapted from American College of Obstetricians and Gynecologists. Practice bulletin no. 132: antiphospholipid syndrome. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120(6):1514-1521.

SUGGESTED READINGS

American College of Obstetricians and Gynecologists. Practice bulletin no. 132: antiphospholipid syndrome. Obstet Gynecol 2012;120(6): 1514-1521.

Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv2011 ;66(10):639-653.

Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 2007;29(2):95-113.

Cunningham FG, Leveno KJ, Bloom SL, et al., eds. Connective-tissue disorders. In Williams Obstetrics, 23rd ed. New York, NY: McGraw-Hill, 2010.

Cunningham FG, Leveno KJ, Bloom SL, et al., eds. Neurological and psychiatric disorders. In Williams Obstetrics, 23rd ed. New York, NY: McGraw-Hill, 2010.

Hoftman AC, Hernandez MI, Lee KW, et al. Newborn illnesses caused by transplacental antibodies. Adv Pediatr 2008;55:271-304.

Seo P. Pregnancy and vasculitis. Rheum Dis Clin North Am 2007;33(2):299-317.