Regular Article
The association between antiphospholipid antibodies and placenta mediated complications: A systematic review and meta-analysis

https://doi.org/10.1016/j.thromres.2011.02.006Get rights and content

Abstract

Background

The association between antiphospholipid antibodies (APLA) and placenta mediated pregnancy complications (pre-eclampsia, intrauterine growth restriction (IUGR), late fetal loss and placental abruption) remains controversial.

Methods

We performed a systematic review of published case-control, cohort and cross sectional studies (MEDLINE (1975 to 2009), EMBASE 16 (1980 to 2009) and all EBM Reviews (2009)) to evaluate the association between APLA and placenta mediated complications in untreated women without autoimmune diseases.

Results

Our search strategy identified 1207 potentially relevant studies. Twenty eight were included in the final analysis. LA was associated with pre-eclampsia (OR 2.34; 95%CI 1.18-4.64), IUGR (OR 4.65 95% CI 1.29-16.71) and late fetal loss (OR 4.73; 95%CI 1.08-20.81) amongst case-control studies and only with late fetal loss (OR 10.59 95% CI 1.87-59.88) amongst cohort studies. ACA were associated with pre-eclampsia (OR 1.52; 95%CI 1.05-2.20) and late fetal loss (OR 4.29; 95% CI 1.34-13.68) amongst case-control studies and only late fetal loss (OR 8.85 95% CI 1.84-42.50) amongst cohort studies. Finally, anti-B2 GP1 antibodies showed associations with pre-eclampsia (OR 19.14, 95% CI 6.34-57.77), IUGR (OR 20.03; 95%CI 4.59-87.43) and late fetal loss (OR 23.46, 95% CI 1.21-455.01) in two cohort studies.

Conclusion

APLAs appear to be associated with late fetal losses. However, the association between APLAs and other placenta mediated complications is inconsistent. LA is most strongly and consistently associated with placenta mediated complications. There are currently insufficient data to support a significant link between anti-B2 GP1 antibodies and pregnancy morbidity.

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.

Section snippets

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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