SNOWMASS, COLO. – Whether a woman with antiphospholipid antibodies meets diagnostic criteria for antiphospholipid syndrome makes a huge difference in her risk of pregnancy failure.
Having antiphospholipid antibodies alone confers only a modest increase in the risks of thrombosis and/or pregnancy mishap, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium, sponsored by the American College of Rheumatology.
"You don’t have to jump all over these patients and get them worked up into a tizzy that they’re going to have blood clots or major pregnancy problems if they’ve never had them before," said Dr. Clowse, director of the Duke University Autoimmunity in Pregnancy registry in Durham, N.C.
The published experience indicates that women with antiphospholipid antibodies (aPL) but not antiphospholipid syndrome (APS) have roughly a 15% rate of pregnancy loss in their first pregnancy, not much different than the 11% rate in the general population. In contrast, women with untreated APS have up to a 90% pregnancy loss rate. With aspirin at 81 mg/day, this rate drops to 50%, and with dual therapy of low-dose aspirin plus either low-molecular-weight (LMW) or unfractionated heparin, the risk falls further to 25%, still twice that of the general population.
Dr. Megan E.B. Clowse
Thus, the distinction between aPL and APS is key. In addition to its implications for pregnancy outcome, it also guides the duration of anticoagulation following thrombosis. Anticoagulation needs to continue indefinitely in patients with APS because of their high risk of another clotting event. Indeed, patients with APS, if left untreated after a thrombotic event, have a 25% chance of another event within the next year, the rheumatologist noted.
"The diagnosis of APS is actually straightforward, but in patients referred to our lupus clinic from outside I see the term being used pretty fast and loose, and I think it’s somewhat inappropriate to do so. There are many patients with antiphospholipid antibodies who don’t have APS," she continued.
The current diagnostic criteria for APS – the so-called Sydney criteria (J. Thromb. Haemost. 2006;4:295-306) – require both laboratory and clinical findings. The laboratory criteria require a finding of lupus anticoagulant, medium- or high-titer IgG or IgM anticardiolipin antibodies, and/or medium- or high-titer anti-beta2-glycoprotein-1 antibody. The test results need to be positive on two occasions 12 weeks apart, although treatment for presumptive APS can start after tentative diagnosis based upon the first positive test.
To meet the vascular criteria for APS, a patient simply has to have had an arterial, venous, or small vessel thrombosis in any tissue or organ. The pregnancy criteria are more elaborate. To qualify, a woman must have had spontaneous abortions at less than 10 weeks’ gestation in at least three or more consecutive pregnancies, or a second- or third-trimester pregnancy loss of a normal fetus, or premature birth of a morphologically normal fetus before week 34 due to preeclampsia or placental insufficiency.
In women with full-blown APS, antibody titers matter quite a bit in terms of pregnancy outcome. In a study of 51 women with APS who were treated with LMW heparin and aspirin throughout 55 pregnancies, the 20 women with antibody titers greater than four times the upper limit of normal had a 35% rate of delivering an appropriately grown baby after 32 weeks’ gestation. The 35 antibody-positive women with titers less than four times the upper limit of normal had a 77% rate of normal delivery (Acta Obstet. Gynecol. Scand. 2011;90:1428-33).
In women with aPL only, the risk of pregnancy loss may be so low that aspirin isn’t protective. In an intriguing Italian study of 139 pregnancies in 114 women with aPL but not APS, the pregnancy loss rate in 104 pregnancies treated throughout with low-dose aspirin was 7.7%, while in 35 untreated pregnancies the rate was 2.9% (J. Rheumatol. 2013;40:425-9).
"The conclusion here is you can go ahead and use aspirin, but we don’t know that it’s doing a whole lot. Maybe we’re really just treating ourselves," Dr. Clowse mused.
Evidence from the PROMISSE trial, the largest-ever U.S. study of pregnancy loss in lupus patients, points to lupus anticoagulant as the main driver of pregnancy morbidity in patients with aPL. Thirty-nine percent of lupus anticoagulant–positive patients had adverse pregnancy outcomes, compared with just 3% of those without lupus anticoagulant. Unfortunately, treatment with heparin, aspirin, prednisone, or hydroxychloroquine didn’t mitigate the risk (Arthritis Rheum. 2012;64:2311-8).
While pregnancy loss is the biggest concern among most women with APS, it’s important to watch for maternal complications, including early severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and thrombotic events.