Regular ArticleThe association between antiphospholipid antibodies and placenta mediated complications: A systematic review and meta-analysis
Introduction
Antiphospholipid antibodies (APLA) are a group of auto-antibodies that have the ability to bind to cardiolipin alone, to cardiolipin complexed to a cofactor or to a cofactor alone. APLA are found in up to 5% of healthy subjects [1] in the general population and in 35% of patients with SLE [2], [3]. The prevalence of APLA in the low risk obstetrical population ranges from 1-9% [4], [5], [6], [7], [8]. The concept of antiphospholipid syndrome (APS) was first introduced when the association between APLA and hypercoagulability became evident [9], [10]. In addition to an increased risk of vascular thrombosis in women with APLA, some studies have suggested an association with pregnancy complications including recurrent pregnancy losses (RPL) and placenta mediated pregnancy complications such as late fetal losses, pre-eclampsia, placental abruption and intrauterine growth restriction (IUGR) [11].
The international preliminary classification criteria for APS (Sapporo criteria) were first introduced in 1998 [12] and were revised in 2005 [13]. The current definition requires at least one clinical and one laboratory criterion to make a diagnosis of APS. Clinical criteria include the presence of vascular thrombosis and/or pregnancy complications. As described by the revised Sapporo criteria, pregnancy morbidity includes ≥ 1 unexplained deaths of morphologically normal fetus at ≥ 10 weeks gestation; ≥ 1 premature birth of morphologically normal neonate before 34 weeks gestation because of preeclampsia, eclampsia or features of placental insufficiency (non-reassuring fetal surveillance test, abnormal Doppler flow velocimetry suggestive of fetal hypoxiemia, oligohydramnios, intrauterine growth restriction (IUGR)); ≥ 3 unexplained spontaneous abortions at < 10 weeks gestation not due to anatomic or hormonal abnormalities in the mother or chromosomal abnormalities on maternal or paternal side. Laboratory criteria require one of the following detected in patient's serum or plasma on two separate occasions ≥ 12 weeks apart: 1) lupus anticoagulant (LA), 2) anticardiolipin antibodies (ACA) of IgG and/or IgM isotype present in medium/high levels (> 40 GPL or MPL or > 99th percentile) by standardized ELISA or 3) anti-B2 glycoprotein 1 (anti-B2 GP1) IgG and/or IgM antibodies in levels > 99th percentile by standardized ELISA.
Most of the data supporting the association between APLA and pregnancy complications are derived from small case-control studies that have inherent limitations including retrospective outcome determination and ascertainment of exposure (i.e. APLA) often well after the outcome. The association between APLA and recurrent fetal losses in women without autoimmune diseases was thoroughly examined in a recent systematic review and meta-analysis of 25 studies. This association was strongest with LA and varied significantly according to the type and levels of the APLA studied. [14].
We performed a systematic review and meta-analysis to study the association between APLAs currently included in the Sapporo criteria for the diagnosis of the APS and late placenta mediated pregnancy complications (late fetal loss, pre-eclampsia, IUGR, placental abruption) in women without autoimmune diseases.
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Data sources and searches
A systematic literature search strategy was initially conducted to identify potentially eligible studies from MEDLINE (1950 to October week 2 2007), EMBASE (1980 to 2007 week 42) and all EBM Reviews (3rd quarter of 2007) using the OVID interface. The search was subsequently updated to May 2009 using the same databases. The systematic search strategy is outlined in Appendix Table 1 (on-line). The search was restricted to English and French language articles. References of included studies and
Results
Our search strategy identified 1794 citations (Fig. 1). Twenty-eight studies were included in the final analysis (Table 1) [6], [8], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]. Formal quality assessment using the NewCastle-Ottawa scale [17] was performed on the included studies; results are reported in Appendix Table 2 (on-line). Twenty studies were case-control studies and 8 were
Discussion
To our knowledge, this is the most comprehensive systematic review and meta-analysis analysis examining the association between APLA and placenta mediated complications. Our results indicate that most studies conducted to date have been considerably underpowered to detect significant associations between APLA and placenta mediated pregnancy complications. Despite pooling data from twenty-eight studies, lack of adequate power has remained a serious limiting factor in our ability to draw firm
Conflict of interest statement
All authors of this manuscript have no relevant conflict of interest to declare.
Acknowledgments of research support
K Abou-Nassar is the recipient of a Physicians Services Incorporated resident research grant.
M Rodger is the recipient of a Career Scientist Award from the Heart and Stroke Foundation of Ontario.
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