Low complement levels are related to poor obstetric outcomes in women with obstetric antiphospholipid syndrome. The EUROAPS Registry Study Group.

INTRODUCTION: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease related to antiphospholipid antibodies (aPL) with primaryinflammatory injury followed by clot cascade activation and thrombus formation. Complement system activation and their participation in aPL-related thrombosis is unclosed. METHODS: We haveanalysed adverse pregnancy outcomes (APO) related to low complement (LC) levels in a cohort of 1048 women fulfilling classification criteria for OAPS. RESULTS: Overall, 223 (21.3%) women presented LC values, during pregnancy. The length of pregnancy was shorter in OAPS women with LC compared to those with normal complement (NC) (median: 33 weeks, interquartile range: [24-38] vs. 35 weeks [27-38]; p = 0.022). Life new-born incidence was higher in patients with NC levels than in those with LC levels (74.4% vs. 67.7%; p = 0.045). Foetal losses were more related to women with triple or double aPL positivity carrying LC than NC values (16.3% vs. 8.0% NC; p = 0.027). Finally, some placental vasculopathies were affected in OAPS patients with LC as late Foetal Growth Restriction (FGR >34 weeks) rise to 7.2% in women with LC vs. 3.2% with NC (p = 0.007). DISCUSSION: Data from our registry indicate that incidence of APO was higher in OAPS women with LC levels and some could be reverted by the correct treatment.

Bleeding and antithrombotic therapy during pregnancy in women with poor aPL-related obstetric outcomes: A survey of 1075 cases from EUROAPS registry∗.

BACKGROUND: The combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) until the end of gestation are the currently the accepted standard of care for the treatment of antiphospholipid-related obstetric disorders. In refractory cases, hydroxychloroquine (HCQ) can be added to this standard of care. OBJECTIVE: To evaluate the haemostatic safety of LDA and LMWH (medium to high prophylactic doses) during pregnancy and the puerperium in women with both full-blown obstetric antiphospholipid syndrome (OAPS) (Sydney criteria) and noncriteria - incomplete - OAPS. STUDY DESIGN: Retrospective/prospective multicentre observational study. Obstetric background, laboratory categories, delivery mode, antithrombotic regimens and bleeding complications were compared. SETTING: A total of 30 tertiary European hospitals. PATIENTS: Mainly, Caucasian/Arian pregnant women were included. Other ethnicities were minimally present. Women were controlled throughout pregnancy and puerperium. MAIN OUTCOME MEASURES: The primary end-point was to evaluate the number of major and minor haemorrhagic complications in this cohort of women. Neuraxial anaesthetic bleeding complications were particularly assessed. Secondly, we aimed to compare local/general bleeding events between groups. RESULTS: We studied 1650 women, of whom 1000 fulfilled the Sydney criteria of the OAPS and 650 did not (noncriteria OAPS). Data on antithrombotic-related complications were available in 1075 cases (65.15%). Overall, 53 (4.93%) women had bleeding complications, with 34 being considered minor (3.16%) and 19 major (1.76%). Neither obstetric complications nor laboratory categories were bleeding-related. Assisted vaginal delivery and caesarean section were related to local haemorrhage. Heparin doses and platelet count were not associated with major bleeding. CONCLUSIONS: LDA and medium to high prophylactic LMWH during pregnancy in women with full-blown OAPS/noncriteria OAPS are safe. A slight increase in bleeding risk was noted in instrumental deliveries. No women who underwent spinal or epidural anaesthesia suffered bleeding complications. No haemorrhage was observed in cases where HCQ was added to standard therapy.

Obstetrical outcome and treatments in seronegative primary APS: data from European retrospective study.

OBJECTIVE: To compare characteristics, pregnancies and treatments during pregnancies of seronegative and seropositive antiphospholipid syndrome (APS), to analyse factors associated with obstetrical outcome. PATIENTS AND METHODS: Inclusion criteria were: (1) thrombotic and/or obstetrical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies (APL); (3) at least one persistent non-conventional APL among IgA anticardiolipin antibodies, IgA anti-B2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-phosphatidylethanolamine G/M and anti-phosphatidylserine/prothrombin G/M antibodies. The exclusion criteria were: (1) systemic lupus erythematosus ( SLE) or SLE-like disease; and (2) other connective tissue disease. RESULTS: A total of 187 women (mean 33±5 years) with seronegative APS were included from 14 centres in Austria, Spain, Italy, Slovenia and France and compared with 285 patients with seropositive APS. Seronegative APS has more obstetrical rather than thrombotic phenotypes, with only 6% of venous thrombosis in comparison to seropositive APS. Cumulative incidence of adverse obstetrical events was similar in seronegative and seropositive APS patients, although higher rates of intrauterine deaths (15% vs 5%; p=0.03), of preeclampsia (7% vs 16%, p=0.048) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) were noted in seropositive APS. The cumulative incidence of adverse obstetrical events was significantly improved in treated versus untreated seronegative APS (log rank<0.05), whereas there was no difference between patients who received aspirin or aspirin-low-molecular weighted heparin combination. CONCLUSION: Several non-criteria APL can be detected in patients with clinical APS features without any conventional APL, with various rates. The detection of non-criteria APL and thus the diagnosis of seronegative APS could discuss the therapeutic management similar to seropositive APS, but well-designed controlled studies are necessary.

Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry.

OBJECTIVES: To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS). METHODS: This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome. RESULTS: A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C). CONCLUSION: Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients.

The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 1000 consecutive cases.

AIM: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). METHODS: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. RESULTS: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in IIa, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). CONCLUSION: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.

[Annexins and recurrent pregnancy loss]. / Anexinas y pérdidas recurrentes de embarazo.

Recurrent Pregnancy Loss (RPL) affects public health and directly compromises the quality of life of hundreds of women, with a detrimental effect on their physical and mental health. Approximately 50% of RPL are not associated to any of the currently known etiology and will be considered idiopathic. Recently, it has been demonstrated that the expression of annexin 5 (ANXA5), a protein found on the trophoblastic surface, plays a fundamental role in the development of pregnancy due to its immunomodulator and anticoagulant function at the placentary level. Some genetic haplotypes of ANXA5 are associated to alterations in the expression of this gene, such as haplotype M2 which is associated to a decrease in the expression of ANXA5. The presence of this haplotype is related to the following conditions occurring during pregnancy: RPL, foetal intrauterine growth restriction, low child weight at birth, preeclampsia and maternal pulmonary thromboembolism. This review describes the structure, function and genetic expression of ANXA5, as well as its possible implication in RPL.

Anexinas y pérdidas recurrentes de embarazo / Annexins and recurrent pregnancy loss

Las pérdidas de embarazo recurrentes (PER), afectan a la salud pública y comprometen en forma directa la calidad de vida de cientos de mujeres, con detrimento de su salud física y psíquica. Aproximadamente un 50% de las PER no se asocian a alguna de las etiologías conocidas, y por lo tanto se consideran idiopáticas. Recientemente se ha demostrado que la expresión de la anexina 5 (ANXA5), una proteína ubicada en la superficie trofoblástica, juega un papel fundamental en el mantenimiento del embarazo ya que cumple un rol como inmunomodulador y anticoagulante a nivel de la placenta. Algunos haplotipos genéticos de la ANXA5 se asocian a alteraciones en la expresión de este gen, como el haplotipo M2 que se vincula a una reducción en la expresión de la ANXA5. La presencia de dicho haplotipo se relaciona con los siguientes eventos del embarazo: PER, restricción del crecimiento fetal intrauterino, bajo peso al nacer, preclampsia y tromboembolismo pulmonar materno. Esta revisión describe la estructura, función y expresión genética de la ANXA5, así como también su posible implicancia en la PER.

Recurrent Pregnancy Loss (RPL) affects public health and directly compromises the quality of life of hundreds of women, with a detrimental effect on their physical and mental health. Approximately 50% of RPL are not associated to any of the currently known etiology and will be considered idiopathic. Recently, it has been demonstrated that the expression of annexin 5 (ANXA5), a protein found on the trophoblastic surface, plays a fundamental role in the development of pregnancy due to its immunomodulator and anticoagulant function at the placentary level. Some genetic haplotypes of ANXA5 are associated to alterations in the expression of this gene, such as haplotype M2 which is associated to a decrease in the expression of ANXA5. The presence of this haplotype is related to the following conditions occurring during pregnancy: RPL, foetal intrauterine growth restriction, low child weight at birth, preeclampsia and maternal pulmonary thromboembolism. This review describes the structure, function and genetic expression of ANXA5, as well as its possible implication in RPL.