Guest Corner

Antiphospholipid Antibodies and Pregnancy, Peter Pryde, M.D.

Introduction.

The role of antiphospholipid antibody syndrome (APS) in pregnancy loss is a recent observation of increasingly recognized importance. Although APS principally causes systemic vaso-occlusive events (both venous and arterial), it can also present as isolated fetal complications. The most APS-specific of these is second trimester onset of fetal growth restriction followed by fetal distress or death. However, in some instances recurrent early spontaneous abortion will be the only clue to the presence of APS.

APS results in noninflammatory occlusion in blood vessels of all sizes, from the microcirculation to major veins and arteries. It is assumed the fetal growth restriction and intrauterine death secondary to APS arise because of cumulative vaso-occlusion in the placenta, but this is not yet proven. Likewise, precisely how clot formation and consequent vaso-occlusion arise is unresolved. In some manner binding of antiphospholipid antibodies to negatively charged phospholipids on the cell membranes of platelets and endothelial cells causes cellular procoagulant “activation.” In addition, antiphospholipid antibodies may inhibit several natural anticoagulants that are important in regulating hemostasis, such as protein S, protein C, thrombomodulin, and placental anticoagulant protein I (annexin V). Regardless of precise mechanism, APS is an important cause of pregnancy complications.

Definition of APS

APS is an autoimmune condition. It is characterized by the combination of a) one or more specific clinical phenomena accompanied by b) serologic evidence for the presence of relevant antiphospholipid antibodies [Table I].

Other clinical events sometimes described in these patients, but not required for diagnosis, include neurologic manifestations (transient ischemic attacks or amaurosis fugax), livedo reticularis of the skin, and, rarely, cardiac valve nodules.

APS is designated as “primary” when there is no other recognized autoimmune illness. APS in patients with underlying systemic lupus erythematosus (SLE) is classified as “secondary.”

Antiphospholipid antibodies are observed more commonly in women (70% of cases) than in men. There seems to be no racial predilection. Several reports describe familial APS but no specific pattern of inheritance is evident.

Reliable testing for antiphospholipid antibodies is particularly challenging. For that reason it is important to use an experienced and reliable specialty laboratory for testing. Among the antiphospholipid antibodies, anticardiolipin (aCL) antibodies are the only ones that are of clear clinical relevance; and for aCL antibodies, only IgG in medium to high titers is known to be significant. Detection of IgA or IgM aCL antibody isotopes is of uncertain clinical significance and neither is considered diagnostic for APS. Other antiphospholipid antibodies (antiphos-phatidylinositol, antiphosphatidylserine, antiphosphatidylcholine, antiphosphatidyl-ethanolamine, antiphosphatidylglycerol) for which testing is available in some laboratories are not standardized and also remain of unclear clinical diagnostic significance.

Prevalence and Ascertainment

Population studies show that 2-4% of all women are aCL positive at low titers. However, prospective studies indicate that low titer aCL does not identify women at increased risk for pregnancy loss.On the other hand, medium to high aCL titers (>40 IgG phos-pholipid units) are found in only 0.2% of the nor-mal population and are signi-ficantly associated with risk for fetal loss (28% fetal loss compared with 7% among controls).

What obstetrical history should lead one to suspect that APS is operative? First, sporadic miscarriages are rarely associated with antiphospholipid antibodies. In contrast, fetal death beyond 20 weeks gestation is highly associated with presence of antiphospholipid antibodies (with aCL antibodies found in 10-15% of instances). So, too, is recurrent fetal loss, in which antibodies are present in about 10% of cases.

Another at risk group is women with previously recognized SLE, among whom nearly 30% are found to have “secondary” anti-phospholipid antibodies. Differentiating those with SLE who do and do not have anti-phospholipid antibodies is important since those with the antibodies are thought to have up to three times the risk for fetal loss compared with those who do not.

Finally, an association between early onset severe preeclampsia and the presence of clinically relevant levels of antiphospholipid antibodies (10-17%) has been reported.

Therefore, while uniform screening for APS is not cost effective in normal, low risk women, it is indicated in women with histories of stillbirth, recurrent miscarriage, SLE or early onset severe preeclampsia. [Table 2].

Obstetrical Management

Women satisfying the diagnostic criteria for APS ideally should be evaluated and counseled preconceptionally. Medical history with emphasis on APS associated medical and obstetrical events should be obtained. Previous laboratory data should be reviewed and the presence of significant levels of relevant antiphospholipid antibodies should be confirmed. If the diagnostic criteria are satisfied, these women need to be informed about not only obstetrical risks (miscarriage, fetal growth restriction, stillbirth, early onset preeclampsia, iatrogenic preterm birth), but medical risks as well (thromboembolic disease, myocardial infarction, stroke). Baseline laboratory studies may include CBC with platelets, antinuclear antibody screen, and screening for unrecognized renal disease.

Once the diagnosis of APS has been established, serial evaluation of antiphospholipid antibody titers does not appear to be of any clinical utility.

Pregnant women with APS require intensive clinical attention. They must be educated about symptoms of vaso-occlusive problems, preeclampsia and fetal distress (as heralded by decreased fetal movement). They also must be examined frequently for signs of these events and for assessment of fetal growth. Serial ultrasound for fetal growth assessment is indicated at intervals as frequently as 3 to 6 weeks, depending upon the clinical status of the patient. So long as the fetal growth profile and amniotic fluid volume remain normal, ultrasound intervals of 4 to 6 weeks can be maintained until around 30 to 32 weeks of gestation. At that time initiation of antepartum fetal surveillance, through, for example, twice weekly nonstress test and measurement of amniotic fluid index should be initiated. If there is suspicion of developing fetal growth restriction, more frequent ultrasounds and earlier initiation of fetal surveillance may be indicated.

Several treatment regimens have been suggested in efforts to improve obstetrical outcome. These include aspirin alone, aspirin plus pred-nisone, and aspirin plus heparin. Clinical data now suggest that com-bination therapies are superior to aspirin alone (and to no intervention), and that as-pirin plus he-parin has a safer side ef-fect profile than does aspirin plus prednisone. Currently, usual recommendations include 81 mg of aspirin daily in combination with thromboprophylactic doses of unfractionated heparin (15,000 to 20,000 units in 2-3 divided subcutaneously administered dosages). Such therapy has been reported to improve fetal survival from 40% in untreated to 80% in treated patients.

Variations of this protocol have been tried. Patients whose obstetrical history is of recurrent spontaneous abortion may benefit from heparin doses as low as 10,000 to 15,000 units per day. Trials using low molecular heparins (which carry with them less risk) are ongoing and it is likely that in the near future these will replace the current use of unfractionated heparin. Because of apparent risk of thromboembolic events in the puerperium, some experts advocate extension of thromboprophylaxis for 6 to 8 weeks postpartum as well.

Patients choosing to receive heparin therapy must be told of possible adverse effects. Long term treatment can result in bone mineral loss with osteoporosis related fractures occurring in 1-2% of women receiving heparin anti-coagulation throughout pregnancy. This risk can be minimized by weight bearing exercise (walking), daily calcium supplementation (1500 mg calcium carbonate daily) and adequate vitamin D intake. In addition, idiosyncratic heparin-induced thrombocytopenia arises in something less than 5% of patients treated with unfractionated heparins. It typically begins within 3 to 15 days of onset of therapy and, fortunately, most cases are mild. However, if undetected and if heparin is continued, a potentially catastrophic form of the reaction may develop (in 0.5% of patients) with severe thrombocytopenia accompanied by paradoxical arterial and venous thromboses (“white clot syndrome”). Therefore serial monitoring of platelet counts is recommended for all treated patients.

APS after Obstetrical Care

APS is not only an obstetrical disease. Women with this diagnosis, even if initially ascertained by fetal loss as the sole clinical criterion, are at markedly elevated risk for eventually developing nonobstetrical sequelae. In fact, an estimated 50% of such women will develop thrombosis, TIA, stroke, amaurosis fugax, immune thrombocytopenia or new onset SLE over a median follow-up of 5 years. These women, therefore, require lifelong, close medical attention by physicians with interest and expertise in the management of APS. Finally, because risks in women with APS are greater during pregnancy and with oral contraceptive use, unintended pregnancy should be avoided and non-hormonal methods of contraception encouraged.

Further Reading:

ACOG Educational Bulletin: Antiphospholipid Syndrome. 1998;244-1-15.

Branch DW. Antiphospholipid antibodies and reproductive outcome: the current state of affairs. J Reprod Immunol 1998;38:75-87.

Lockshin MD. Antiphospholipid antibodies: babies, blood clots, biology. JAMA 1997;277:1549-1551.

Rand JH. Antiphospholipid antibody syndrome: new insights on thrombogenic mechanisms. Am J Med Sci 1998; 316:142-151.

Welsch S, Branch DW. Antiphospholipid syndrome in pregnancy. Rheum Dis Clin North Am 1997;23:71-84.