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. This chapter aims to review common autoimmune diseases encountered during pregnancy, including their management concerns and medical therapies.
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 [TH1]) state to an antiinflammatory (T helper 2 [TH2]) 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 TH2-driven diseases such as systemic lupus erythematous and improvement in TH1-driven diseases such as rheumatoid
arthritis, multiple sclerosis, and autoimmune thyroiditis during pregnancy with increased “flaring” in the postpartum period.
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). Notably, even in the presence of transplacental transfer of antibodies, fetal sequelae vary widely from no harm to permanent disability due to patient-dependent differences in antibody titer, specificity, and avidity as well as fetal factors such as antigen distribution, blocking, or inhibiting factors. Following delivery, the newborn’s titers of maternal autoantibodies drop quickly over a period of 1 to 3 weeks; therefore, neonatal disease is often limited.
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 Sjögren 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. Patients with significant, known renal disease (serum creatinine, SCr > 2.5 mg/dL) are generally advised against becoming pregnant.
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.
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. In most cases, it is discontinued at 36 weeks; however, in high-risk pregnancies such as symptomatic antiphospholipid antibody syndrome, it can be continued throughout the entire 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. Active lupus nephritis poses the greatest maternal risk.
Disease should be inactive for at least 6 months prior to pregnancy.
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.
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