eMedicine Specialties > Obstetrics and Gynecology > Medical Problems in Pregnancy

Antiphospholipid Antibody Syndrome and Pregnancy

Author: Teresa G Berg, MD, FACOG, Associate Professor, Program Director, Director of the Perinatal Diagnostic Center, Department of Obstetrics and Gynecology, University of Nebraska Medical Center
Contributor Information and Disclosures

Updated: Aug 11, 2008

Introduction

Background

Recognized for its associated thrombosis in the 1950s, antiphospholipid syndrome (APS) and lupus anticoagulant (LAC) are associated with pregnancy complications that include fetal loss, fetal growth restriction, preeclampsia, thrombosis, and autoimmune thrombocytopenia. It is characterized by an autoimmune process that is separate in many women from systemic lupus erythematosus (SLE) and other connective tissue diseases. Diagnosis requires clinical and laboratory findings with the clinical criteria being the primary method of diagnosis. Women with the clinical features should be tested for LAC and anticardiolipin (aCL) antibodies; most patients with APS have both LAC and aCL immunoglobulin G (IgG) antibodies.

APS is classified as primary or secondary depending on its association with other autoimmune disorders. Primary antiphospholipid syndrome is diagnosed in patients demonstrating the clinical and laboratory criteria without other recognized autoimmune disease. Secondary antiphospholipid syndrome is diagnosed in patients with other autoimmune disorders such as SLE.

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

LAC and aCL predispose to clotting in vivo, predominantly by interfering with the antithrombotic role of PLs; thus, it is associated with clinical thrombosis, not bleeding. The aPL autoantibodies bind moieties on negatively charged PLs or moieties formed by the interaction of negatively charged PLs with other lipids, PLs, or proteins.

For related information on pregnancy, see Medscape's Pregnancy Resource Center.

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 neurologic 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.

See Medscape's CME activity, Mechanisms of Disease: Antiphospholipid Antibodies -- From Clinical Association to Pathologic Mechanism.

Frequency

United States

Women have been reported to account for approximately 80% of patients with APS.

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 and mesenteric veins). The aPL antibodies are detected in approximately 2% of patients with nontraumatic venous thrombosis. 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.

SLE occurs in approximately 120 cases per 100,000 population and causes pregnancy complications in approximately 45 cases per 100,000 pregnant population. 

Mortality/Morbidity

APS is one of the major causes of thrombosis and its complications in women. Arterial and venous thrombosis are both reported. Coronary artery occlusions are reported in patients with APS. Previous thrombosis in the face of the diagnosis of APS has been documented to have a rate of recurrence of 25% per year if untreated.

Maternal morbidity

Thrombosis, especially in patients with APS and a history of thrombosis is a major concern. Morbidity may also be associated with anticoagulation in patients treated with heparin or low molecular weight heparins in pregnancy. Women with APS have an increased incidence of preeclampsia, which is frequently prior to 34 weeks’, and severe preeclampsia requiring premature delivery. 

APS is also associated with infertility and pregnancy complications such as spontaneous abortions, prematurity, and stillbirths.

Maternal mortality

Mortality rates during pregnancy are not well characterized. Multiorgan failure has been described during pregnancy by Asherson¹ and during postpartum by Kochenour.²  

Perinatal Morbidity

aPL antibodies are found in 10-15% of women at high risk for fetal growth restriction. Neonatal morbidity and mortality may be influenced by indicated preterm delivery for maternal severe preeclampsia or fetal growth restriction.

Neonatal lupus dermatitis, a variety of systemic and hematologic abnormalities, and isolated congenital heart block have been associated with APS and SLE.

Perinatal Mortality

Fetal deaths at or beyond 20 weeks' gestation may be attributed to APS involvement. 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.³

Sex

Most cases of APS (80%) are in women.

Age

APS is predominantly diagnosed in reproductive-aged women (ie, 15-55 y). This is similar to other autoimmune states.

Clinical

See Medscape's CME activity, Mechanisms of Disease: Antiphospholipid Antibodies -- From Clinical Association to Pathologic Mechanism.

History

The “International consensus statement for the diagnosis of antiphospholipid syndrome” was published in 1999 by Wilson et al.⁴  This serves as a set of criteria similar to the criteria for the diagnosis of other autoimmune disorders. Diagnosis of antiphospholipid syndrome (APS) requires at least 1 clinical and 1 laboratory criterion.

Clinical criteria

Vascular thrombosis 

• One or more clinical episodes of arterial, venous, or small-vessel thrombosis, occurring within any tissue or organ

Complications of pregnancy

• One or more unexplained deaths of morphologically normal fetuses at or after 10 weeks’ gestation
• One or more premature births of morphologically normal fetuses at or before 34 weeks’ gestation
• Three or more unexplained consecutive spontaneous abortions before 10 weeks’ gestation

Laboratory criteria

• Anticardiolipin antibodies - Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on 2 or more occasions at least 6 weeks apart
• Lupus anticoagulant - Lupus anticoagulant antibodies detected in the blood on 2 or more occasions at least 6 weeks apart, according to the guidelines of the International Society on Thrombosis and Hemostasis

Physical

APS is primarily a diagnosis based on clinical history and laboratory data. Some physical findings may be associated with primary APS, but patients with secondary APS are more likely to have findings on physical examination.       

•  Thrombosis or stroke - Possible residual neurologic findings
• Cutaneous manifestations
  • These may include digital cyanosis, livedo reticularis, digital gangrene, and leg ulcers. The cause of these features remains otherwise unexplained.
  • Other features related to cutaneous manifestations, with a cause that remains unexplained, include transient ischemic attacks or amaurosis fugax, positive result from the Coombs test, hemolytic anemia, chorea, and chorea gravidarum.
  • Discoid rash (ie, erythematous raised patch with keratotic scaling and follicular plugging) is a criterion. Older lesions may be atrophic. Again, the cause remains unexplained.
  • Photosensitivity with an unexplained cause is another criterion.

The following are physical findings that should be considered secondary to other autoimmune disorders and an appropriate evaluation should be undertaken.

• Arthritis: Patients may have nonerosive arthritis involving 2 or more peripheral joints, and the cause cannot otherwise be determined.
• Serositis: This may be (1) pleuritis or pleural effusion or (2) pericarditis or pericardial effusion, the cause of which cannot be explained.
• Renal disorder: Proteinuria of 0.5 g/d or the presence of cellular casts, without another cause, is a criterion for APS.
• Neurologic disorder: Criteria include seizures in the absence of other causes or psychosis in the absence of other causes.
• Hematologic disorder: Features, without an otherwise explainable cause, include (1) hemolytic anemia with reticulocytosis, (2) leukopenia of less than 4000 cells/mm³ on at least 2 occasions, (3) lymphopenia of less than 1500 cells/mm³, or (4) thrombocytopenia of less than 100,000 cells/mm³.
• Immunologic disorder: Again, the cause remains unexplained.

The clinical manifestations of SLE include the following:  

• Skin lesions - 84-71%
• Arthritis - 63-95%
• Nephritis - 46-77%
• Raynaud phenomenon - 10-58%
• Neuropsychiatric features - 0-59%
• Lymphadenopathy - 0-58%
• Pleurisy - 37-56%
• Mucous membrane ulceration - 7-54%
• Pericarditis - 29-45%
• Splenomegaly - 9-18%
• Aseptic necrosis - 0-10%
• Clinical evidence of glomerulonephritis is found in more than 50% of cases. However, if biopsies are performed on all patients, the incidence of some nephritis may be as high as 90%. SLE is associated with encephalopathy and seizures, to a lesser degree with ischemic stroke, and, rarely, with subarachnoid hemorrhage.

Causes

Like other autoimmune disorders, APS does not have a known etiology.

Passive transfer of maternal antibodies mediate autoimmune disorders in the fetus and newborn. The mechanism of excess autoantibody production and immune complex formation is not well understood, although current investigation is focused on abnormal regulator functions and the possibility of a slow virus infection. In addition, certain genetic factors may be important, as indicated by a number of family and twin studies for systemic lupus erythematosus (SLE) and the demonstration of an increased frequency of HLA-DR2, HLA-DR3, and HLA-DR4 null alleles in patients with SLE.

Significant controversy still exists regarding the role of oral contraceptives in inducing SLE. Antinuclear antibodies (ANAs) associated with LP were reverted to negative when the drug was discontinued. Some patients using the intrauterine device complain of dysmenorrhea and recurrent infections, especially those taking prednisone and cytotoxic drugs. Although the incidence of SLE in families was initially believed to be no greater than in the general population, this is no longer thought to be true.

PL molecules are ubiquitous in nature and are present in the inner surface of the cell (ie, on the inner or outer surface of the cell membrane or intracellular organelles) and in microorganisms. Therefore, during infectious disease processes, including viral (eg, HIV, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenoviruses), bacterial (eg, bacterial endocarditis, tuberculosis, Mycoplasma pneumonia), spirochetal (eg, syphilis, leptospirosis, Lyme disease), and parasitic (eg, malaria infection), the disruption of cellular membranes may occur during cell damage. PLs release and stimulate aPL antibodies.

The SWISS PROT protein database revealed high homology between the hexapeptides that bind to ILA-1, ILA-3, and H-3 mAbs and the membrane particles of different bacteria and viruses. The sequence LKTPRV showed homology to 8 different bacteria (eg, Pseudomonas aeruginosa) and homologies to 5 types of viruses (ie, polyoma virus, human CMV, adenovirus). The sequence TL-RVYK shows homology to 8 different bacteria, including Haemophilus influenzae, Neisseria gonorrhoeae, and Shigella dysenteriae, and to viruses such as EBV and HIV. Therefore, data might support the theory predicting that epitope mimicry is involved in the propagation of the autoimmune status.

• Autoantibodies include the following:  
  • Antiphospholipid
  • Anticardiolipin
  • Antiphosphatidylinositol
  • Antiphosphatidylserine
  • Antiphosphatidylcholine
  • Anti–beta-2 glycoprotein I
  • Antinuclear antibody
  • Anti-DNA (double- or single-stranded)
  • Anti-Sjögren syndrome A antibody (Ro)
  • Anti-Sjögren syndrome B antibody (Ia)
• Antibodies against microorganism(s) associated with infection or vaccination include the following:  
  • Antibacterial PL
  • Antibacterial protein
  • Antiviral glycoprotein
  • Anti-Sjögren syndrome A antibody (Ro) and anti-Sjögren syndrome B antibody (Ia): These are associated with neonatal lupus erythematosus, including congenital complete heart block. These antibodies are usually present in patients with Sjögren syndrome.

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