Antiphospholipid Antibody Syndrome and Pregnancy

Background: Antiphospholipid syndrome (APS) is a recently recognized autoimmune condition that may manifest with fetal loss, thrombosis, or autoimmune thrombocytopenia. Women with these clinical features should be tested for lupus anticoagulant (LAC) and anticardiolipin (aCL) antibodies; most patients with APS have both LAC and aCL immunoglobulin G (IgG) antibodies. The diagnosis of APS requires the presence of both clinical and biological features.

Systemic lupus erythematosus (SLE) is a chronic systemic disease with diverse clinical and laboratory manifestations. LAC (and aCL) predisposes to clotting in vivo, predominantly by interfering with the antithrombotic role of phospholipids (PLs); therefore, it is associated with clinical thrombosis, not bleeding. The antiphospholipid (aPL) autoantibodies bind moieties on negatively charged PLs or moieties formed by the interaction of negatively charged PLs with other lipids, PLs, or proteins.

aPL antibodies belong to the large family of antibodies that react with negatively charged PLs, including cardiolipin, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, and phosphatidic acid.

Pathophysiology: The biologic effects mediated by the human aPL antibodies include (1) reactivity with endothelial structures, which disturbs the balance of prostaglandin E2/thromboxane production; (2) interaction with platelet PLs, with consequent up-regulation of platelet aggregation; (3) dysregulation of complement activation; and (4) interaction of aPL with phosphatidylserine exposed during trophoblast syncytium formation, which raises the possibility of a more direct effect of these autoantibodies on placental structures.

In patients with primary APS, the presence of the 3 aCL isotypes plus LAC has been associated with a higher number of recurrent spontaneous abortions compared with other possible combinations of aCL isotypes.

The association between aPL antibodies and particular human leukocyte antigen (HLA) alleles and HLA-linked epitopes has been reported in studies of patients with lupus erythematous (eg, HLA-DR7, HLA-DR4). The HLA-DR3 phenotypes seem to predispose to the formation of aCL antibodies and antinuclear antibodies (ANAs), but this has not been confirmed in patients. However, particular HLA alleles associated with recurrent miscarriage have not been reported.

Animals immunized with aCL or with the cofactor beta-2 glycoprotein I (b2GPI) develop clinical manifestations of APS, including fetal loss, thrombocytopenia, and neurological and behavioral dysfunction, along with elevated levels of aPL antibodies.

aCL antibodies bind to b2GPI, or a complex formed by this b2GPI is a platelet adhesin glycoprotein and cardiolipin. Exposure of endothelial cells to anti-b2GPI antibodies and their corresponding peptides leads to the inhibition of endothelial cell activation, as shown by decreased expression of adhesion molecules E-selectin, intercellular adhesion molecule, and vascular cell adhesion molecule and of monocyte adhesion.

In vivo infusion of each of the anti-b2GPI antibodies into BALB/c mice followed by administration of the corresponding specific peptides prevents the peptide-treated mice from developing experimental APS. These fascinating results suggest that the use of synthetic peptides that focus on neutralization of pathogenic anti-b2GPI antibodies represents a possible new therapeutic approach to APS.

Passive transfer into naive mice of inherently heterogeneous aPL antibody populations, either affinity-purified or as part of whole immunoglobulin fractions, from humans with APS or autoimmune mice has been shown to induce growth retardation and fetal loss.

Frequency:

• In the US: SLE occurs in approximately 120 cases per 100,000 population and causes pregnancy complications in approximately 45 cases per 100,000 pregnant population. The aPL antibodies account for 65-70% of cases of venous thrombosis. In women with venous thrombosis in unusual sites (eg, cerebral portal, splenic, subclavian mesenteric veins), aPL antibodies are detected in approximately 2% of patients with nontraumatic venous thrombosis. This is a rate similar to that of several inherited conditions of hypercoagulability such as antithrombin III deficiency and protein C deficiency. Approximately 22% of women with APS have had venous thrombosis and 6.9% have had a cerebrovascular incident (over a median follow-up period of 60 mo); 24% of thrombotic events occurred during pregnancy or the postpartum period. The rate for thrombosis or stroke is 5-12%. These observations suggest that women with documented APS should not take estrogen-progestin combination oral contraceptives.

Mortality/Morbidity:

• APS increases the risk for maternal and fetal morbidity and fetal mortality in pregnancy. The rate of fetal loss may exceed 90% in untreated patients who have APS. Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al.

• APS is one of the major causes of thrombosis and its complications in women. SLE, transient serologic abnormalities, skin lesions, and congenital heart block are affected by APS. The true neonatal lupus dermatitis, a variety of systemic and hematologic abnormalities, and isolated congenital heart block are associated with APS.

• APS is also associated with infertility and pregnancy complications such as spontaneous abortions, prematurity, and stillbirths. Fetal deaths at or beyond 20 weeks' gestation may be attributed to APS involvement, and aPL antibodies are found in 10-15% of women at high risk for fetal growth restriction.

Sex: The female-to-male ratio is 9:1.

Age: Newborns of women with SLE may develop lupus syndrome. This predominantly affects reproductive-aged women (ie, 15-55 y).

Treatment
Medical Care: Pregnant women with APS are considered high-risk obstetric patients, and medical care is instituted with this in mind. If a chromosomal abnormality is found, genetic counseling is recommended.

• Intravenous immunoglobulin (IVIG): Infused immunoglobulins may modulate aCL antibodies levels by 3 mechanisms.
  • Antiidiotypic antibodies may be present in the IVIG preparation. These antiidiotypic antibodies may bind autoantibodies to form idiotype-antiidiotype dimers, resulting in neutralization of autoantibody effects.
  • Antiidiotype antibodies may bind and down-regulate B-cell receptors, resulting in a decrease in autoantibody production.
  • Antiidiotype antibodies might bind receptors of regulatory T cells, resulting in suppression of lymphokine production and decreased activation of autoantibody-producing B cells.

• Landry-Guillain-Barré-Strohl syndrome (LGBSS) of acute inflammatory demyelinating polyradiculoneuropathy
  • Patients usually present with progressive bilateral and symmetrical muscle weakness accompanied by mild sensory symptoms, including paresthesia, numbness, and tingling. The disease can progress to involve the respiratory muscles, resulting in respiratory failure. Two thirds of the patients have a history of viral-like infections 1-3 weeks prior to the onset of symptoms.
  • Recently, CMV infection has been incriminated as a potential etiologic agent in some pregnant patients presenting with LGBSS.
  • Acute inflammatory demyelinating polyradiculoneuropathy is a rare disease with an incidence of approximately 1-1.5 cases per 100,000 LGBSS cases per year. LGBSS is exceedingly rare in pregnancy.

• Obstetric care
  • Patients should be counseled in all cases regarding symptoms of thrombosis and thromboembolism and should be educated regarding and examined frequently for the signs or symptoms of thrombosis or thromboembolism, severe PIH, or decreased fetal movement.
  • In patients with poor obstetric histories, evidence of PIH, or evidence of fetal growth restriction, ultrasonography is recommended every 3-4 weeks starting at 18-20 weeks of gestation.
  • Human chorionic gonadotropin (hCG) values may suggest early prognosis of the pregnancy outcome in the first trimester. If hCG levels are increasing normally (ie, doubling every 2 d) in the first month of pregnancy, a successful outcome is predicted in 80-90% of cases. However, when the increases are abnormal (ie, slower), a poor outcome is predicted in 70-80% of cases.
  • In patients with uncomplicated APS, ultrasonography is recommended at 30-32 weeks of gestation (ie, to evaluate uteroplacental sufficiency).
  • Low molecular weight heparin (LMWH) may be used in APS and pregnancy (replacement of unfractionated sodium heparin).
  • Importantly, counsel the patient regarding potential adverse effects of heparin. Heparin-induced osteoporosis occurs in 1-2% of cases.
  • Drugs such as chloroquine and cytotoxic agents are not recommended during pregnancy, and patients should stop taking these drugs several months prior to becoming pregnant.
  • Warfarin may be substituted for heparin during the postpartum period to limit further risk of heparin-induced osteoporosis and bone fracture.
  • Splenectomy during the early second trimester or at the time of cesarean delivery may be considered in patients refractory to glucocorticoid therapy.

• Nonobstetric care
  • Immunosuppressive agents are recommended for patients with SLE with secondary APS.
  • Thromboprophylaxis is recommended.
  • Patients should be evaluated for renal disease, (glomerulonephritis, N-stage disease), anemia, and thrombocytopenia.

  Proposed Management for Women With aPL Antibodies

  Feature	Management
  	Pregnant	Nonpregnant
  APS with prior fetal death or recurrent pregnancy loss	Heparin in prophylactic doses (15,000-20,000 U of unfractionated heparin or equivalent per d) administered subcutaneously in divided doses with low-dose aspirin daily Calcium and vitamin D supplementation	Optimal management uncertain; options include no treatment or daily treatment with low-dose aspirin
  APS with prior thrombosis or stroke	Heparin to achieve full anticoagulation (does not cross the placenta)	Warfarin administered daily in doses to maintain International Normalized Ratio of 3 or greater
  APS without prior pregnancy loss or thrombosis	No treatment or daily treatment with low-dose aspirin or daily treatment with prophylactic doses of heparin plus low-dose aspirin Optimal management uncertain	No treatment or daily treatment with low-dose aspirin Optimal management uncertain
  Preeclampsia	IVIG at 400 mg/kg/d for 5 days monthly Additional therapy is heparin plus low-dose aspirin	Not applicable
  LGBSS	High-dose IVIG at 400-1500 mg/kg/d for several days	IVIG at 400-1500 mg/kg/d for several days
  aPL antibodies Without APS
  LAC or medium-to-high level of aCL IgG	No treatment	No treatment
  Low levels of aCL IgG, only aCL IgM, or only aCL IgA Without LA, aPL, or aCL	No treatment	No treatment

• Note the following:

• The medications shown should not be used in the presence of contraindications.
• Close obstetric monitoring of the mother and fetus is necessary in all cases.
• The patient should be counseled in all cases regarding symptoms of thrombosis and thromboembolism.

Surgical Care:

• Cardiac valvular surgery is recommended in patients with severe aortic regurgitation as a result of APS.

• Splenectomy is recommended in patients with the chronic form of idiopathic thrombocytopenic purpura and is associated with remission in approximately 75% cases.

• Thromboprophylaxis is recommended for any abdominal or orthopedic surgery.

• Manage thrombotic or hemorrhagic complications. Be aware of associated thrombocytopenia, and employ laboratory methods of perioperative anticoagulation monitoring in the setting of prolonged clotting times.

Consultations:

• The patient should be informed about potential maternal and obstetric problems, including fetal loss, thrombosis or stroke, PIH, fetal growth restriction, and preterm delivery.

• In women with APS and one or more prior thrombotic events, lifelong anticoagulation with warfarin may be advisable to avoid recurrent thrombosis.

Medication
In women with well-recognized obstetric APS, anticoagulant prophylaxis is recommended during pregnancy and the postpartum period. Pregnant women with APS are considered at risk of thrombosis and pregnancy loss. Data suggest low-dose aspirin and heparin (either unfractionated heparin or LMWH) are the treatments of choice for prevention of pregnancy loss in pregnant women with APS and previous pregnancy losses. Pregnant women with APS and a history of thrombosis but no pregnancy loss only require treatment with heparin. Treatment is optional for patients with no history of pregnancy loss or thrombosis.

Drug Category: Heparin compounds -- Unfractionated IV heparin and fractionated SC LMWH are the 2 choices for initial anticoagulation therapy. Warfarin therapy may be initiated in the postpartum stage.

These are used in the treatment or prophylaxis of clinically evident intravascular thrombosis. Special precaution should be exercised in obstetrical emergencies or massive liver failure.

LMWHs may also be used. Similar to unfractionated heparin, LMWHs are a class of anticoagulants termed glycosaminoglycans. LMWHs are derived from unfractionated heparin but have smaller, more standard average masses than heterogeneous unfractionated heparin.

Unlike standard heparin, LMWHs have higher specificity for factor Xa and have fewer effects on platelet activity. As a result, LMWH may cause bleeding less often, while still retaining anticoagulant effects. LMWHs may be associated with less risk of heparin-induced osteoporosis.

Drug Name	Heparin, unfractionated -- Indicated to decrease risk of thrombosis and pregnancy loss in pregnant women with APS. Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.
Adult Dose	APS with prior fetal death/recurrent pregnancy loss: 15,000-20,000 U/d SC divided q12h plus low-dose aspirin APS with prior thrombosis or stroke: Adjusted dose heparin SC q12h to maintain aPTT within target range APS without prior pregnancy loss or thrombosis: 15,000-20,000 U/d SC divided q12h (treatment optional)
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hemorrhage, monitor aPTT, adjust dose accordingly; caution in severe hypotension and shock; heparin-induced osteoporosis

Drug Name	Enoxaparin (Lovenox) -- Indicated to decrease risk of thrombosis and pregnancy loss in pregnant women with APS. Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Adult Dose	APS with prior fetal death/recurrent pregnancy loss: 40 mg/d SC plus low-dose aspirin APS with prior thrombosis or stroke: 1 mg/kg SC q12h APS without prior pregnancy loss or thrombosis: 40 mg/d SC (treatment optional)
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; major bleeding, thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated or LMWH; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; heparin-induced osteoporosis; monitor target anti-Xa levels, adjust dose accordingly

Drug Category: Antiplatelet agents -- Randomized controlled trials demonstrate improved fetal survival when pregnant women with APS and prior pregnancy losses are treated with low-dose aspirin plus heparin compared with low-dose aspirin alone.

Drug Name	Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin) -- Antiplatelet effect indicated to decrease risk of thrombosis and pregnancy loss in pregnant women with APS. Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. Used in low dose to inhibit platelet aggregation and improve complications of venous stasis and thrombosis.
Adult Dose	1-2 mg/d PO for antiplatelet effect; not to exceed 325 mg/d (low-dose aspirin)
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma; due to association of aspirin with Reye syndrome, do not use in children (<16>
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in third trimester with full-dose aspirin; may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants