Women with recurrent spontaneous abortions in the setting of antiphospholipid syndrome have a 15-fold greater risk of thrombotic events over the long term, compared with women who have had multiple miscarriages but who don’t have the syndrome.

If the finding is confirmed, "further studies would be warranted to assess the efficacy and risks of long-term thromboprophylaxis with aspirin and/or heparin in patients with [recurrent spontaneous abortion] associated with antiphospholipid syndrome," according to the investigators writing in the January issue of Annals of the Rheumatic Diseases.

Dr. Maria Angeles Martinez-Zamora of the University of Barcelona and colleagues looked at 57 women seen at a single tertiary-care center who had antiphospholipid syndrome (APS) and associated recurrent spontaneous abortion (Ann. Rheum. Dis. 2012;71:61-6).

APS was defined according to the 2006 international consensus statement (J. Thromb. Haemost. 2006;4:295-306).

Briefly, the criteria stipulate that the diagnosis can be made only when the patient has had at least one thrombotic event, plus pregnancy morbidity, plus all of the following: positive lupus anticoagulant; anticardiolipin antibody of IgG and/or IgM isotype present in medium or high titer; and anti-beta₂ glycoprotein-I antibody of IgG and/or IgM isotype in titers greater than the 99th percentile.

This group was then compared to three separate control groups. The first (n = 86) included patients with recurrent spontaneous abortions of unknown etiology who were negative for APS.

The second (n = 42) also had recurrent spontaneous abortions, but with known thrombophilic genetic defects.

"Thrombophilia in this group was defined as factor V Leiden (heterozygote) mutation (n = 17), prothrombin G20210A gene (heterozygote) mutation (n = 12), protein C deficiency (n = 9), or protein S deficiency (n = 4)," wrote the authors.

However, "No woman in this group had combined thrombophilia (two or more findings)."

Finally, the third group (n = 30) were antiphospholipid (APL)-positive on laboratory tests but had no history of thrombotic or obstetric morbidity.

Overall, 100% of women in all groups were white, and their mean ages were between 32 and 34 years at the time of their first miscarriage (or study inclusion, in the case of the APL group). Patients were followed for up to 12 years, with a mean follow-up ranging from 6 years among those with recurrent spontaneous abortions of unknown origin to 8.2 years among the patients who were antiphospholipid positive without thrombotic events of obstetric morbidity.

The researchers found that 11 patients (19.3%) with APS with recurrent spontaneous abortion had thrombotic events over the study period, including four cerebral arterial infarctions, one cerebellar arterial infarction, and two deep vein thromboses, pulmonary embolisms, and ischemic myocardial infarctions each.

In contrast, deep vein thromboses occurred in two of the women with recurrent spontaneous abortion with known thrombophilic genetic defects but in none of the patients with recurrent spontaneous abortions of unknown origin or antiphospholipid positive without thrombotic events or obstetric morbidity.

That correlated to a greatly increased risk for thrombosis among the women with APS and recurrent spontaneous abortions, with an odds ratio of 15.06, compared with the women with either recurrent spontaneous abortions of unknown origin who were negative for APL or antiphospholipid positivity without thrombotic events or obstetric morbidity (95% confidence interval, 3.2-70.5; P less than .0001).

"This was still true when only patients with thrombophilic disorders other than APL [recurrent spontaneous abortion with known thrombophilic genetic defects] were considered (OR, 4.8; 95% CI, 1-22.8; P less than .05)," wrote the authors.

The OR was even higher when the women with APS and recurrent spontaneous abortions were compared with the women with recurrent spontaneous abortions of unknown origin who were negative for APL (OR, 42.8; 95% CI, 2.5-742; P less than .0001), they added.

Nor did the use of aspirin therapy alter the outcome, as "the occurrence of thrombotic events among women with recurrent spontaneous abortion [all groups] treated with aspirin (16% or 2 of 12 patients) did not differ from patients who did not receive this treatment (6% or 11 of 173 women) (OR, 2.9; 95% CI, 0.5-15.1)," wrote the investigators.

Dr. Martinez-Zamora concluded that the findings of the current study support the "two-hit hypothesis," used to explain why thrombotic events occur only occasionally, despite the persistent presence of APL.

According to the hypothesis, antiphospholipid syndrome – the "first hit" – increases patients’ thrombophilic risk, and clotting takes place in the presence of another thrombophilic condition, that is, recurrent spontaneous abortion, the "second-hit."

"This would explain previous epidemiological studies suggesting that a woman’s reproductive history may indicate future cardiovascular risk," added the authors.

On the other hand, they pointed out that 80% of patients with recurrent spontaneous abortion associated with APL in their study did not develop a thrombotic event.

"Therefore, whether an individual will develop a thrombotic event depends on the concomitant presence of additional factors that may increase the whole thrombotic risk," they wrote.

The authors declared no funding for this study and stated that they had no competing interests to disclose.

Antiphospholipid Syndrome Plus Miscarriage Ups Clot Risk