Sylvie Bouvier

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study

The incidence of pregnancy outcomes for women with the purely obstetric form of antiphospholipid syndrome (APS) treated with prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) has not been documented. We observed women without a history of thrombosis who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week. We compared the frequencies of complications during new pregnancies between treated women with APS (n = 513; LMWH + LDA) and women negative for antiphospholipid antibodies as controls (n = 791; no treatment). Among APS women, prior fetal loss was a risk factor for fetal loss, preeclampsia (PE), premature birth, and the occurrence of any placenta-mediated complication. Being positive for anticardiolipin immunoglobulin M antibodies was a risk factor for any placenta-mediated complication. Among women with a history of recurrent abortion, APS women were at a higher risk than other women of PE, placenta-mediated complications, and neonatal mortality. Among women with prior fetal loss, LMWH + LDA-treated APS women had lower pregnancy loss rates but higher PE rates than other women. Improved therapies, in particular better prophylaxis of late pregnancy complications, are urgently needed for obstetric APS and should be evaluated according to the type of pregnancy loss.

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study.

The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.

Neuropsychiatric presentations of antiphospholipid antibodies

Antiphospholipid syndrome (APS) is a systemic disease which can affect the central nervous system (CNS) through thrombotic mechanisms prone to induce vascular damage: stroke or transient ischemic attack (TIA) on the arterial side, cerebral venous thrombosis on the venous side. Beside these academic syndromic manifestations, some nonvascular neurological manifestations of antiphospholipid antibodies (aPLAbs) are progressively emerging, being associated with a wide range of polymorphic neurological, psychological and psychiatric manifestations. Animal models and in vitro experimental data support an immune-mediated pathogenesis, with direct binding and effect of aPLAbs on neurons and glial cells which are thought to occur after a disruption or a permeability alteration of the blood-brain barrier (BBB). The magnitude of the association and cellular and molecular mechanisms involved need to be further elucidated. No standard treatment is available for nonvascular neuropsychiatric manifestations associated with positive aPLAbs and specific developments are warranted.

Fibrin-related markers in patients with septic shock: Individual comparison of D-dimers and fibrin monomers impacts on prognosis

Fibrin-related markers in patients with septic shock: Individual comparison of D-dimers and fibrin monomers impacts on prognosis -

Antiphospholid antibodies and the risk of pregnancy complications

Antiphospholipid antibodies (APLAbs) are generally considered as risk factors for foetal death, for premature birth ≤34weeks due to severe pre-eclampsia or severe placental insufficiency and for recurrent consecutive spontaneous abortions <10weeks. Among these three obstetrical morbidities, only the first one is however not regularly questioned. The coexistence of an inflammatory disease and/or of thrombotic manifestations increases the obstetrical risks. Among the three criteria APLAbs, i.e. lupus anticoagulant (LA), anticardiolipin (aCL) Abs, anti-β2 glycoprotein-I (aβ2GP1)Abs, LA seems the more widely associated to clinical risks, the clinical impact of aβ2GP1Abs is progressively defined and the pejorative impact of triple positivity is still discussed. High quality prospective multicentric epidemiological studies are still awaited. The identification of predictors of pregnancy outcome is necessary to streamline the design and use of new treatments acting on pathophysiological molecular targets.

Soluble CD146, an innovative and non-invasive biomarker of embryo selection for in vitro fertilization

Although progress was made in in vitro fertilization (IVF) techniques, the majority of embryos transferred fail to implant. Morphology embryo scoring is the standard procedure for most of IVF centres for choosing the best embryo, but remains limited since even the embryos classified as “top quality” may not implant. As it has been shown that i) CD146 is involved in embryo implantation and ii) membrane form is shed to generate soluble CD146 (sCD146), we propose that sCD146 in embryo supernatants may constitute a new biomarker of embryo selection. Immunocytochemical staining showed expression of CD146 in early embryo stages and sCD146 was detected by ELISA and Western-blot in embryo supernatants from D2. We retrospectively studied 126 couples who underwent IVF attempt. The embryo culture medium from each transferred embryo (n = 222) was collected for measurement of sCD146 by ELISA. Significantly higher sCD146 concentrations were present in embryo supernatants that did not implant (n = 185) as compared to those that successfully implanted (n = 37) (1310 +/- 1152 pg.mL-1 vs. 845+/- 1173 pg.mL-1, p = 0.024). Sensitivity analysis performed on single embryo transfers (n = 71) confirmed this association (p = 0.0054). The computed ROC curve established that the optimal sCD146 concentration for embryo implantation is under 1164 pg.mL-1 (sensitivity: 76%, specificity: 48%, PPV: 25% and NPV: 92%). Over this sCD146 threshold, the implantation rate was significantly lower (9% with sCD146 levels >1164 pg.ml-1 vs. 22% with sCD146 levels ≤ 1164 pg.mL-1, p = 0.01). Among the embryos preselected by morphologic scoring, sCD146 determination could allow a better selection of the embryo(s), thus improving the success of elective single embryo transfer. This study establishes the proof of concept for the use of sCD146 as a biomarker for IVF by excluding the embryo with the highest sCD146 level. A multicentre prospective study will now be necessary to further establish its use in clinical practice.

Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study

Abstract Objectives: Case reports describe neuropsychiatric manifestations associated with antiphospholipid antibodies (aPlAbs). In patients sharing the same symptoms fulfilling the antiphospholipid syndrome (APS) clinical criteria, the prevalence of common mental disorders has, however, never been studied. Methods: We observed women with three consecutive abortions before the 10th week of gestation or one foetal loss at or beyond the 10th week. We compared the prevalence of common psychiatric disorders detected through screening using the Mini International Neuropsychiatric Interview, 10 years after inclusion, in women with APS (n = 506), women negative for aPlAbs but carrying the F5rs6025 or F2rs1799963 thrombogenic polymorphism (n = 269), and women with negative thrombophilia screening results as controls (n = 764). Results: Similar prevalence values were obtained for controls and women bearing one of the two thrombogenic polymorphisms. Women with APS more frequently had mood disorders (relative risk (RR) 1.57 (1.262–1.953), P = .0001) and anxiety (RR 1.645 (1.366–1.979), P < .0001). Within the APS group, lupus anticoagulant (LA) and anti-β2GP1 IgG, or triple positivity, were strong risk factors for mood disorders. Conclusions: Women with obstetric APS have a higher risk of positive screening for common mental disorders than women without APS.

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10−2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047)

Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study

An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D‐dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non‐surviving patients, area under the receiver‐operator characteristic curve (AUCROC): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non‐survivors using each of the three FGMs. A dose‐effect relationship was observed between ISTH DIC scores and non‐survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non‐survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUCROC values testing the ability of the ISTH DIC score to predict non‐survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially‐available automated assays, automated FM is the FGM best related with late prognosis.