Antiphospholipid Syndrome and Pregnancy

Updated: Jan 17, 2017
  • Author: Teresa G Berg, MD, FACOG; Chief Editor: Ronald M Ramus, MD  more...
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Overview

Background

Antiphospholipid syndrome (APS) is an autoimmune disorder that is associated with pregnancy complications, including preeclampsia, thrombosis, autoimmune thrombocytopenia, fetal growth restriction, and fetal loss. (See Prognosis and Presentation.)

APS is classified as primary or secondary, depending on its association with other autoimmune disorders. Primary APS is diagnosed in patients demonstrating the clinical and laboratory criteria for the disease without other recognized autoimmune disease. Secondary APS is diagnosed in patients with other autoimmune disorders, such as systemic lupus erythematosus (SLE). (See Presentation and Workup.)

Women with the clinical features of APS should be tested for 3 antiphospholipid antibodies that have proven association with the diagnosis of APS: lupus anticoagulant (LAC), anticardiolipin (aCL) antibody, and anti-beta-2glycoprotein I antibody. (See Pathophysiology, Etiology, and Workup.)

These antibodies predispose to clotting in vivo, predominantly by interfering with the antithrombotic role of PLs. 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. (See Pathophysiology, Etiology, Treatment, and Medication.)

Obstetric and nonobstetric clinical features

Obstetric features of APS are as follows:

  • Unexplained fetal death or stillbirth
  • Recurrent pregnancy loss - 3 or more spontaneous abortions with no more than 1 live birth
  • Unexplained second or third trimester fetal death
  • Severe preeclampsia at less than 34 weeks’ gestation
  • Unexplained severe fetal growth restriction
  • Chorea gravidarum

Nonobstetric features of APS are as follows:

  • Nontraumatic thrombosis or thromboembolism (venous or arterial)
  • Stroke, especially in individuals aged 24-50 years
  • Unexplained transient ischemic attack [1]
  • Unexplained amaurosis fugax
  • Autoimmune thrombocytopenia
  • Autoimmune hemolytic anemia
  • Unexplained prolongation of a clotting assay
  • Livedo reticularis
  • SLE or other connective tissue disorder
  • False-positive serologic test result for syphilis
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Pathophysiology

Biologic effects mediated by the human aPL antibodies include the following:

  • Reactivity with endothelial structures that disturbs the balance of prostaglandin E2/thromboxane production
  • Interaction with platelet PLs, with consequent upregulation of platelet aggregation
  • Dysregulation of complement activation
  • 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. (Human aCL antibodies cause placental necrosis in BALB/c mice.)

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, and 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.

The 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 the 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—from humans with APS or from autoimmune mice—either affinity-purified or as part of whole immunoglobulin fractions, has been shown to induce growth retardation and fetal loss.

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Etiology

Like other autoimmune disorders, APS does not have a known etiology, although it is known that the passive transfer of maternal antibodies mediates autoimmune disorders in the fetus and newborn. The mechanism of excess autoantibody production and immune complex formation is not well understood.

Certain genetic factors may be important, as indicated by a number of family and twin studies for SLE and the demonstration of an increased frequency of HLA-DR2, HLA-DR3, and HLA-DR4 null alleles in patients with SLE. As with other autoimmune disorders, women have a higher incidence than men and the diagnosis is more likely to be made in women of reproductive age.

Phospholipid release

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) infections, the disruption of cellular membranes may occur during cell damage. PLs are consequently released, stimulating aPL antibodies.

Epitope mimicry in autoimmune disease

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 also shows homology to 8 different bacteria, including Haemophilus influenzae, Neisseria gonorrhoeae, and Shigella dysenteriae, and to viruses such as EBV and HIV. Therefore, data may support the theory predicting that epitope mimicry is involved in the propagation of the autoimmune status.

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Epidemiology

Occurrence in the 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 all 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 have been found to occur 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.

Sex- and age-related demographics

Most cases of APS (80%) are in women. APS is predominantly diagnosed in reproductive-aged women (ie, 15-55 y). This is similar to other autoimmune states.

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Prognosis

APS is one of the major causes of thrombosis and its complications in women, with arterial thrombosis, coronary artery occlusions, and venous thrombosis being reported in patients with this syndrome. Previous thrombosis in the face of a diagnosis of APS has been documented to have a recurrence rate of 25% per year in untreated patients.

A 2015 retrospective analysis by the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS) found very good maternal-fetal outcomes in women whose obstetric APS [OAPS] was treated. [2]

Previous fetal loss appears to be a risk factor for fetal loss, preeclampsia, premature birth, and placenta-mediated complications in women with pure OAPS, according to a 2014 report from the Nîmes Obstetricians and Hematologists Antiphospholipid Syndrome (NOH-APS) study. [3] In addition, the incidence of such late-pregnancy complications were greater in the treated women with pure OAPS compared to nontreated women negative for antiphospholipid antibodies.

The investigators defined pure OAPS as pregnancy morbidity in women with no previous history of thrombosis (ie, repeated unexplained abortion < 10th gestational wk, unexplained fetal loss ≥ 10 gestational week, or premature birth < 34th gestational wk due to preeclampsia). [3] Treatment included low molecular weight heparin (LMWH) and low-dose aspirin (LDA).

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. Moreover, women with APS have an increased incidence of preeclampsia, which, when it occurs, frequently develops prior to 34 weeks’ gestation. The incidence of severe preeclampsia requiring premature delivery is also increased.

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

Landry-Guillain-Barré-Strohl syndrome

Landry-Guillain-Barré-Strohl syndrome (LGBSS) of acute inflammatory demyelinating polyradiculoneuropathy, although exceedingly rare in pregnancy, can occur in patients with APS and lupus.

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.

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.

Maternal mortality

Mortality rates during pregnancy are not well characterized. Multiorgan failure has been described during pregnancy by Asherson [4] and during postpartum by Kochenour. [5]

Perinatal morbidity

The 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 attributable to APS involvement. The rate of fetal loss may exceed 90% in untreated patients with APS. Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al. [6]

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