1. What is autoimmunity? What are the autoimmune diseases?

In normal individuals, the immune system allows a host to distinguish between self and non-self tissue and to defend itself against foreign pathogens. A disturbance in this balance results in autoantibody production and autoimmune disease. Autoantibodies may be organ and non-organ specific. Examples of organ-specific antibodies include antithyroid and anti-smooth-muscle antibodies. Non-organ-specific antibodies are the antiphospholipid antibodies (anticardiolipin antibody [ACA], lupus anticoagulant [LA]), antinuclear antibodies, and antihistone antibodies (see Table Autoimmune diseases and associated autoantibodies).

Autoimmune diseases include the antiphospholipid syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis, and idiopathic thrombocytopenic purpura (ITP), which is also known as autoimmune thrombocytopenia. Thyroid disease and diabetes are discussed elsewhere.

Table Autoimmune diseases and associated autoantibodies

Autoimmune Disease Associated Autoantibodies
Antiphospholipid syndrome ACA, LA
Systemic lupus erythematosus ANA, anti-DNA, anti-SSA, anti-SSB, ACA anti-SM
Myasthenia gravis Anti-acetylcholine receptor antibodies
Rheumatoid arthritis Rheumatoid factor
ITP Antibody to antigens on platelet glycoproteins (IIb-IIIa or Ib-IX)

ACA = anticardiolipin antibody; LA = lupus anticoagulant; ANA = antinuclear antibody; SSA = skin-sensitizing antibody; ITP = idiopathic thrombocytopenic purpura.

2. What are LA, ACA, and anti-beta-2 glycoprotein antibody?

LA and ACA are antiphospholipid antibodies (non-organ-specific autoantibodies) that bind to the negatively charged phospholipids found in all cell membranes. Both LA and ACA have been associated with thrombosis and adverse pregnancy outcomes. Beta-2 glycoprotein I is an abundant plasma glycoprotein that enhances the binding of antiphospholipid antibodies to phospholipid. Although it has been reported that the presence of anti-beta-2 glycoprotein antibodies may be more specific markers for the medical complications of the antiphospholipid syndrome, their use in this regard is still investigational. The role of treating pregnant women with isolated elevations of anti-beta-2 glycoprotein is unknown.

3. What are the implications of antiphospholipid antibodies in pregnancy?

Antiphospholipid antibodies have been associated with arterial and venous thrombosis, recurrent pregnancy loss, thrombocytopenia, fetal growth restriction, preterm birth, and preeclampsia.

The presence of these autoantibodies when there is no other underlying disease is suggestive of a primary antiphospholipid syndrome (APS). When the antibodies are present with other diseases such as the collagen vascular or rheumatic diseases (e.g., SLE), a secondary APS is suggested. The diagnosis of APS is made after specific clinical and laboratory criteria are met.

4. How is LA detected in plasma?

LA is detected by using a phospholipid-dependent clotting assay (e.g., activated partial thromboplastin time, kaolin clotting time, or dilute Russell viper venom time). In all of these assays, phospholipid is used as a template for the cofactors and enzymes of the clotting cascade. If LA is present, it binds to the phospholipid, interferes with the clotting cascade, and prolongs the time for clot formation. Other factors can result in prolonged clotting times, including medications and clotting factor deficiencies.

If the presence of LA in plasma is suspected, a mixing study should be performed for confirmation. In this test, the suspected plasma is mixed with normal plasma. If the prolonged clotting time is due to the absence of a factor, the clotting time will be normal; if it remains prolonged, then LA is present. The addition of excess phospholipid to the plasma should correct or shorten the clotting time in the presence of LA.

5. How is ACA detected?

Use a standardized, enzyme-linked immunosorbent assay (ELISA) that detects the anionic phospholipid cardiolipin for the detection of ACA. The antibody levels are reported in a standard nomenclature: GPL = immunoglobulin G, MPL = immunoglobulin M, APL = immunoglobulin A. All values are reported as negative, low, medium, or high positive. Only the medium- to high-positive GPL and MPL are used for the diagnosis of APS.

6. How is the diagnosis of APS made?

In 1998, an international conference of experts convened and proposed criteria for the classification of APS. One of the primary goals of the conference was to standardize the classification to facilitate studies of treatment and causation. Diagnosis of APS is confirmed if at least one of the clinical and one of the laboratory criteria are met.

Clinical Criteria

Vascular thrombosis: One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by imaging or Doppler studies, or by histopathology, with the exception of superficial venous thrombosis. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

Pregnancy morbidity:

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

(b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or

(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Laboratory Criteria

ACA of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart, measured by a standardized enzyme-linked immunosorbent assay for beta-2 glycoprotein I-dependent anticardiolipin antibodies

LA present in plasma, on two or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society of Thrombosis and Hemostasis, in the following steps:

(a) Prolonged phospholipid-dependent coagulation demonstrated on a screening test (e.g., activated partial thromboplastin time [aPTT], kaolin clotting time, dilute Russell viper venom time, dilute prothrombin time, Textarin time)

(b) Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma

(c) Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid

(d) Exclusion of other coagulopathies.

7. What are the indications for testing for antiphospholipid antibodies (APA)?

The American College of Obstetricians and Gynecologists has adopted a list of indications for testing for APA.

Obstetric indications include: otherwise unexplained fetal death or stillbirth; recurrent pregnancy loss (three or more spontaneous abortions with no more than one live birth, or unexplained second- or third-trimester fetal death); severe pregnancy-induced hypertension at less than 34 weeks of gestation; and severe fetal growth restriction or other evidence of uteroplacental insufficiency in the second or early third trimester.

Medical indications include: nontraumatic thrombosis or venous or arterial thromboembolism; stroke in an individual less than 50-55 years of age; autoimmune thrombocytopenia; transient ischemic attacks or amaurosis fugax in individuals younger than 50-55 years of age; livedo reticularis; hemolytic anemia; SLE; or a false-positive serologic test for syphilis.

8. How is APS treated during pregnancy?

Patients who are diagnosed with APS using the previously mentioned strict clinical and laboratory criteria are candidates for treatment. Traditional regimens have included prednisone, prophylactic or therapeutic heparin, and low-dose aspirin. Current recommendations include prophylactic heparin in divided subcutaneous doses with low-dose aspirin daily in those who have had a prior fetal death or recurrent pregnancy loss. Women who have experienced a prior thrombosis or stroke may be candidates for therapeutic heparin dosing. In women who have APS without a prior history of pregnancy loss or thrombosis, the best management is uncertain. All patients receiving heparin therapy should be counseled on the adverse effects, including bruising, bleeding complications, osteoporosis, and heparin-induced thrombocytopenia.

Recently, the use of low-molecular-weight heparin (LMWH) has been more common, although experience is limited during pregnancy. LMWH is produced through an enzymatic breakdown of unfractionated heparin. It has no effect on aPTT; therefore measurement of anti-factor Xa levels may be necessary. LMWH has a longer half-life than unfractionated heparin, resulting in questions surrounding its use with epidural anesthesia.

Key points: antiphospholipid antibody syndrome

  • The effects of antiphospholipid antibodies on pregnancy are increased venous thromboembolism, thrombocytopenia, preterm birth, and preeclampsia.
  • The diagnosis of APAS is made if a patient meets at least one laboratory and one clinical criteria of the disease.
  • During pregnancy women with APAS generally are treated with low-dose aspirin and prophylactic heparin; women with a history of thromboembolic disease may be placed on therapeutic heparin.

9. How is SLE diagnosed?

SLE is a multisystemic disease in which tissues and cells are damaged by autoantibodies and immune complexes. Several drugs can cause a syndrome that resembles SLE, including procainamide, hydralazine, and methyldopa. After excluding drug-induced SLE, the diagnosis is made when 4 of 11 criteria are present at any time during the course of disease. The 11 criteria are:

  • Malar rash
  • Discoid rash
  • Photosensitivity
  • Oral ulcers
  • Arthritis
  • Serositis
  • Renal manifestations (proteinuria)
  • Neurologic manifestations (seizures, psychosis)
  • Hematologic disorder (e.g., hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia)
  • Immunologic manifestation (positive LE cell preparation, anti-ds-DNA or anti-SM antibodies, or false positive VDRL [test for syphilis])
  • Antinuclear antibodies (abnormal titers of ANA)

10. Describe the course of SLE during pregnancy.

Ninety percent of SLE occurs in women of child-bearing age; therefore, its occurrence during pregnancy is common. Pregnancy is not thought to affect the long-term prognosis of lupus. However, flares may increase during pregnancy and the puerperium. The effect of SLE on pregnancy is dependent on the disease activity. Mild disease generally has a good prognosis, but active disease-especially active renal disease and maternal hypertension-have been associated with fetal loss, premature birth, and intrauterine growth restriction.

It is generally recommended that prior to planning a pregnancy, a woman with lupus should be without a flare for at least 6 months. Patients who do become pregnant will have their disease activity monitored by measuring levels of total serum complement. In addition, these patients should have ultrasounds to follow fetal growth, and antenatal testing should be initiated between 28 and 32 weeks.

11. What is neonatal lupus?

Neonatal lupus is defined by two criteria: the presence of maternal antibodies to the 52-kD SSA/Ro, 60-kD SSA/Ro, or 48-kD SSB/La ribonucleoproteins; and the presence of heart block or a transient skin rash. Neonatal lupus may also be associated with hepatic and hematologic abnormalities. Only the development of heart block is permanent and results in significant morbidity and mortality. Available treatment includes oral corticosteroids, which may slow the progression of the heart block, and postnatal pacemaker placement.

12. What is rheumatoid arthritis (RA)? What is its course during pregnancy?

RA is a chronic, multisystem disease characterized by a persistent inflammatory synovitis involving the peripheral joints in a symmetric distribution. The synovial inflammation can cause cartilage destruction and bone erosions that result in joint deformities. Women are affected more frequently than men, and the prevalence increases with age.

RA generally improves during pregnancy, probably due to the elevated cortisol levels that are present. In those patients who require treatment, steroids and analgesics may be used. Other drugs include paracetamol, aspirin, gold, chloroquine, sulfasalazine, penicillamine, and immunosuppressants such as azathioprine.

13. What is myasthenia gravis? What is its course during pregnancy?

Myasthenia gravis is characterized by a reduced number of acetylcholine receptors at the neuromuscular junction. This results in weakness and fatigability of the muscles. Muscle weakness generally starts with the cranial muscles. Diplopia and ptosis are common complaints, as is facial weakness. Speech and swallowing may be affected, and the muscle weakness can generalize to the limb muscles.

During pregnancy and the puerperium, relapses and remissions are variable. Management during pregnancy should be the same as in patients who are not pregnant. Treatment includes the use of anticholinesterase medications, immunosuppressive agents (e.g., glucocorticoids, azathioprine), thymectomy, and plasmapheresis. Intrapartum issues that must be addressed include the use of regional anesthesia over general anesthesia and the avoidance of muscle relaxants. Do not use magnesium sulfate, because it may precipitate a myasthenic crisis. Some patients may require assistance during the second stage of labor to have a successful vaginal delivery.

Key points: autoimmune disease in pregnancy

  • Fetal effects of lupus include fetal congenital heart block, which is associated with maternal anti-SSA and anti-SSB, and neonatal lupus due to transplacental antibody passage.
  • Women with myasthenia gravis should not receive magnesium sulfate.
  • ITP may be treated with steroids, IVIG, splenectomy, and, for immediate but temporary resolution, platelet transfusion.
  • The main fetal risk of maternal ITP is intracranial hemorrhage, but there is no consensus about how to safely minimize or avoid this risk.

14. What is neonatal myasthenia?

Neonatal myasthenia is a transient disorder and occurs in about 10-15% of infants born to myasthenic mothers. The infant may show signs of a weak cry, respiratory difficulties, and weak movements. The symptoms generally become apparent within the first 72 hours after birth. Infants can be treated with anticholinesterase drugs.

15. What is ITP?

ITP (autoimmune thrombocytopenia) is an autoimmune disorder in which IgG antibodies are directed to platelet antigens. These immune complexes are then sequestered and destroyed in the reticuloendothelial system, especially the spleen. During pregnancy, the disorder places the mother at risk for hemorrhage postpartum, and because IgG antibodies can cross the placental barrier, the fetus is at risk for thrombocytopenia.

16. How is the diagnosis of ITP determined?

The diagnosis of ITP is one of exclusion, and the differential diagnosis of thrombocytopenia should include laboratory error, SLE, antiphospholipid syndrome, HIV infection, drug-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and diffuse intravascular coagulation. During pregnancy, other possible causes of thrombocytopenia include preeclampsia and gestational thrombocytopenia. Most women with ITP have a history of easy bruising and menorrhagia. Currently, the use of assays that measure antiplatelet antibodies are not recommended for the routine evaluation of possible ITP, and a bone marrow biopsy may be required to diagnose the disorder.

Confusion can occur during pregnancy because gestational thrombocytopenia, which occurs in 5% of pregnancies, may lead to platelet counts as low as 80,000/μL. Gestational thrombocytopenia is a benign condition that has no maternal or fetal affects.

17. What are the maternal management issues of ITP during pregnancy?

Management during pregnancy should take into consideration both the mother and fetus. The goal for maternal therapy is to minimize the risk of hemorrhage. Generally, maternal platelet counts above 50,000/μL are not treated. As platelet counts fall below 50,000/μL in the second trimester, prednisone may be started. In those cases refractory to prednisone, intravenous immunoglobulin (IG) can be used. Platelet transfusions are a temporary measure to control hemorrhage. Transfused platelets have a shortened life span because of the presence of antiplatelet antibodies.

Splenectomy results in remission in 80% of cases. It can be performed during pregnancy and is generally reserved for women who have not responded to steroids or intravenous IG.

18. What are the fetal considerations in the management of ITP?

The main fetal risk is that of intracranial hemorrhage (ICH). IgG antiplatelet antibodies cause maternal thrombocytopenia and cross the placental barrier, resulting in fetal thrombocytopenia. There is no correlation between maternal and fetal platelet counts. Although there is only a 1% risk of fetal ICH due to ITP, this low risk has led to concern and controversy about the mode of delivery. Many have recommended cesarean section for women who have ITP. Others have recommended that fetal platelet counts be determined prior to allowing vaginal delivery. If the fetal platelet count is > 50,000/μL, then vaginal delivery may be allowed.

Suggested methods of assessing fetal platelet counts have included fetal scalp sampling and cordocentesis. Fetal scalp sampling often incorrectly diagnoses low fetal platelets, and cordocentesis may have a complication rate up to 5%. A recent decision analysis suggests that cordocentesis is preferable to fetal scalp sampling. Currently, the optimal intrapartum management remains controversial.

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