Treatment of pregnancy loss in Hughes syndrome: a critical update

Abstract

Recurrent pregnancy loss is one of the main manifestations of antiphospholipid (Hughes) syndrome (APS). Fetal deaths (beyond the 10th week of gestation) are the most typical obstetric complication of APS. Data from controlled therapeutic trials are difficult to analyse, due to small samples and great heterogeneity in the obstetric history and antiphospholipid antibody profiles of women included. Corticosteroids are more harmful than beneficial. Heparin and aspirin are the drugs of choice for APS-related miscarriage, although it is not clear whether combination of both drugs is necessary for all women. The role of immunoglobulins is not well defined.

Introduction

Recurrent pregnancy loss is one of the most prominent, and often dramatic, features of antiphospholipid syndrome (APS or Hughes syndrome). The precise cause (or causes) of this manifestation is not known, but several have been proposed, including interference with prostacyclin/thromboxane balance at the endothelial level, inhibition of annexin V—a natural placental anticoagulant—inhibition of antithrombin, protein C and protein S and activation of platelets [1]. The pathologic findings in placentas of women with APS and the fact that other thrombophilias may produce miscarriage as well [2] reinforce the role of placental insufficiency—secondary to placental thrombosis and infarction—as the main mechanism of pregnancy loss in APS. However, other mechanisms may also be involved, especially in early miscarriages, including abnormalities in placentation [3].

It is useful to define the periods of pregnancy loss in order to establish the relationship between miscarriage and APS. Preembryonic and embryonic losses happen before the 10th week of gestation and are frequent events in the general population, most cases due to genetic abnormalities [4]. APS is not a cause of sporadic early pregnancy loss [4]. However, recurrent (three or more) early pregnancy losses are more rare, and among other causes (genetic, hormonal, uterine abnormalities), thrombophilias, including APS, play a role. Fetal death, that is after the 10th week of gestation, is an infrequent event in the general population. APS is an important cause of fetal death, which is considered more specific of Hughes syndrome than recurrent early miscarriage. An early work in 1988 showed that women with aCL tend to lose their babies a mean of 4 weeks later than controls [5]. More recently, a study including 366 women with two or more pregnancy losses showed that among women with aCL at medium to high titers and/or LA, 50% of losses were fetal deaths, in contrast to 10% in women who were aPL-negative [6].

Apart from the clinical history, isotype and levels of anticardiolipin antibodies (aCL) are important in taking clinical decisions. Low-titer aCL have a questionable association with features of APS, including recurrent miscarriage [7], for this reason they are not considered in the laboratory criteria for the classification of definite APS [8]. Women with persistent medium-high titers aCL, particularly of the IgG isotype, and/or lupus anticoagulant (LA) are at the other end of the spectrum. Specifically, those with a history of fetal death and high levels aCL IgG have a 80% risk of a new fetal death in the next pregnancy [9]. Another important point to consider is the previous obstetric history of the patients. In fact, previous miscarriage or fetal death is the strongest predictor of further complications in women with APS [10], [11], [12], [13]. On the other hand, the significance of aPL found in women without a history of obstetric complications or other features of APS is not well established, most women in this group having uneventful pregnancies even when untreated [14], [15].

Finding the best therapy for APS-related pregnancy loss has generated much data during the last decade, with 8 controlled trials published studying women with recurrent miscarriage and aPL (see Table 1). However, although these studies have clarified some points, the optimal treatment of pregnancy complications of Hughes syndrome is still far from clear. As Branch [16] has pointed out, the major limitation for solid conclusions is that studies have frequently combined populations with different conditions: patients with definite APS, with medium-high titers aCL and LA and history of fetal deaths, are mixed with women with recurrent early miscarriage and aCL at low levels. Indeed, a recent systematic review including 7 of these trials [17] has reached very limited conclusions.