Review
The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 247 consecutive cases

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Abstract

Aim

To analyse the clinical features, laboratory data, foetal–maternal outcomes, and follow-up in a cohort of 247 women with obstetric antiphospholipid syndrome (OAPS).

Methods

The European Registry on APS became a Registry within the framework of the European Forum on Antiphospholipid Antibody projects and placed on a website in June 2010. Cases with obstetric complaints related to aPL who tested positive for aPL prospectively and retrospectively were included. The three-year survey results are reported.

Results

338 women with 1253 pregnancy episodes were included; 915 were historical and 338 were latest episodes. All these women tested positive for aPL. 247 of the 338 fulfilled the Sydney criteria. According to the laboratory categories, 84/247 were in category I, 42 in IIa, 66 in IIb and 55 in IIc. Obstetric complications other than foetal losses, appeared in 129 cases (52.2%). 192 (77.7%) had a live birth and 55 (22.3%) did not. The latter group of only 38 cases (69%) received adequate treatment and 17 (31%) did not. 177/247 (72%) women were put on heparin plus LDA. Thrombosis appeared in two during pregnancy and in 14 during the puerperium. 7 (3%) women evolved to complete SLE.

Conclusions

OAPS shows differential characteristics than classical APS. All laboratory test categories are needed to avoid false-negative diagnoses. In some cases, complement levels could act as a serological marker. OAPS has very good foetal–maternal outcomes when treated. Thrombosis and progression to SLE in mothers with OAPS are scarce compared with “classical APS”, suggesting that they have different aPL-mediated pathogenic mechanisms.

Introduction

The antiphospholipid syndrome (APS) is characterised by an increased risk of vascular thrombosis and/or pregnancy complications, both related to antiphospholipid/anticofactor antibodies (aPL) [1]. This classical form is believed to be related to activation of the clot cascade with further thrombosis. Cases with poor obstetric outcomes, mainly recurrent first trimester miscarriage, foetal losses, stillbirth, early and severe pre-eclampsia or prematurity, but without a thrombotic history, are known to have obstetric antiphospholipid syndrome (OAPS) [2]. Classically, these outcomes have also been attributed to placental thrombosis and/or infarcts. However, in around 50% of cases decidual or placental thrombosis cannot be confirmed [3], [4]. Foetal loss can be explained by inflammatory histopathological signs, probably due to complement pathway activation [4], [5], [6], [7], tissue factor over-expression in neutrophils and monocytic cells [8], or through a negative imbalance of angiogenic factors [9], even in the absence of thrombosis. Although no complete agreement exists, there is evidence that laboratory markers, treatment response, maternal complications and long-term follow-up may differ from those observed in classical APS form [2], [10], [11], [12], [13], [14]. Similarly, after years of women being treated and papers published in this regard, no definitive data exist on the true relationship between early miscarriage and placental insufficiency and aPL, or on appropriate treatment [14]. Furthermore, in the last decade, a wide array of “non-criteria” obstetric morbidities and diverse non-classical aPL, or low titres of accepted aPL — aCL, and antiβ2-GPI antibodies — have been proposed by an increasing number of colleagues [15], [16], [17], [18], [19], [20], [21]. Thus, the recent 14th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric APS concluded that there is a paucity of data on several OAPS-related concerns, and that new information should be obtained, mainly through randomised clinical trials and large series of patients recruited from multicentre registries [14]. In an attempt to confirm the hypothesis that OAPS exist as a separate form of “classical” APS, we assessed the clinical features, laboratory data, treatment, foetal and maternal outcomes and long-term follow-up of 247 women with pure OAPS.

Section snippets

Patients

Given the scarcity of OAPS cases, it was considered useful to have access to a single, homogeneous database in a multicentre European Registry where physicians could send, consult or insert patient data to facilitate and further understanding of several existing gaps associated with aPL-related obstetric syndromes.

From June 2010, the ad-hoc website and database have been accessible and ongoing. Since then, patients have been included systematically, both retrospectively and prospectively, as

Statistical analysis

Values are expressed as the mean, standard deviation, median, 25th and 75th percentiles (Q1 and Q3, respectively), sum and extreme values (minimum and maximum) for continuous variables and number and percentages for qualitative variables. A Student's t-test was used to compare values following normal distribution, while a Mann–Whitney–Wilcoxon's test or Kruskal–Wallis test was used for data not following a normal distribution. A chi-squared (χ2) test and Fisher exact test was used to compare

Patient baseline clinical characteristics

The general and demographic characteristics of the analysed group are depicted in Table 1. Briefly, 338 women who had had 1253 obstetric episodes were included; and 915 episodes were historical. 247 of 338 women (73%) fulfilled the Sydney classification criteria. From then on, these 247 cases were studied. These women were largely Caucasian (89%) and, reproductively speaking, tended to be older (mean ± SD: 39.18 ± 6.0 years); 22.7% were smokers. On the other hand, five (2%) had type I diabetes and

Analysis of treatment

Treatment data are shown in Table 9. Briefly, 213 of 247 (86.2%) women were treated and 35 (14%) were not, or no data were available. Interestingly, only 177 (83%) of the treated women received the LDA plus heparin combination, and only 74 (34.7%) were put on LDA pre-conceptionally. Daily LDA doses used were 100 mg in 98.9% of cases, 120 mg in 0.4% and 150 mg in 0.7%. Only two cases were treated with non-fractionated heparin. LMWH was used in different schedules. Prophylactic doses of LMWH were

Discussion

Between 10 and 50% of unexplained recurrent pregnancy losses are related to positivity for aPL, with, i.e. the positivity average for LA being 8%, and rises to 30% in cases of foetal loss [23]. Thus, aPL/APS is a leading cause of pregnancy morbidity.

Although venous and arterial thromboses have classically been reported to be the most common and serious complications associated with aPL, and the majority of these patients will have thrombotic phenomena [24], complete agreement regarding these

Conclusion

Recurrent first trimester miscarriage followed by foetal loss was the most common obstetric morbidities in this cohort. Diverse obstetric complications appeared in half the cases; fortunately, many of them did not end in foetal death.

All laboratory categories and isotypes are represented in the registry, being necessary to avoid false-negative diagnoses. In the same way, strong correlations between categories I and/or IIa and practically all the obstetric complications were obtained. By

Take-home messages

  • Obstetric APS is a specific subset within the APS box. Maternal thrombosis and progression to SLE are scarce.

  • All obstetric complications are well represented in this series.

  • All laboratory test categories are needed to avoid false-negative diagnoses.

  • The stronger laboratory risk markers are: LA and triple positivity.

  • LMWH plus LDA achieve 80% of live births, with few maternal complications.

Conflict of interests

The authors declare that there is no conflict of interest.

Funding/financial support

The authors stated that ONAGRUP (01/2009/298) (Barcelona, Spain) is supporting the EUROAPS project.

IRB approval

This study (EUROAPS) was approved by the Ethics Committee of the Vall d'Hebron University Hospital (CEIC-HUVH) as well as by the University Departments of Medicine and Obstetrics, Gynaecology and Paediatrics of the Universitat Autònoma de Barcelona, Spain.

Acknowledgements

The authors thank Ms. Christine O'Hara for reviewing and correcting the English style and grammar of the manuscript.

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    This paper has not been previously published nor is currently being under consideration for publication elsewhere.

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    Jaume Alijotas-Reig and Raquel Ferrer-Oliveras have contributed equally in the realization of this manuscript.

    1

    Current worplace: Department of Pediatrics, Turku University Hospital, Turku, Finland.

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