Eva Cochery-Nouvellon

Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study: Factor V Leiden and prothrombin mutations and fetal loss

Summary.  Factor V Leiden (FVL) and prothrombin G20210A (FIIG20210A) mutations are associated with a higher risk of miscarriage: we sought to understand whether this association differs by clinical time of unexplained miscarriage, and by ethnic origin, among women with no previous thrombotic episode, during the first intended pregnancy. We performed a case–control study nested in a cohort of 32 683 women. We analyzed 3496 pairs of women matched for classical confounding factors. The FVL and FIIG20210A mutations were associated with an increased risk of miscarriage in Caucasian women [odds ratio (OR) 3.19, 95% confidence interval (CI) 2.37–4.30, P < 0.001 and OR 2.36, 95% CI, 1.72–3.24, P < 0.001, respectively]. Among non‐Caucasian women, the mutations were rare and the associations with risk of miscarriage less clear. FVL and FIIG20210A mutations were independent risk factors for miscarriages only for women with related clinical signs occurring from the 10th week of gestation on (OR 3.46, 95% CI 2.53–4.72, P < 0.001 and OR 2.60, 95% CI 1.86–3.64, P < 0.001, respectively). These results indicate that FVL and FIIG20210A mutations are associated with a significant risk of spontaneous abortion which clinical signs occur from the 10th week on of the first intended pregnancy.

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.

Some hemostasis variables at the end of the population distributions are risk factors for severe postpartum hemorrhages

Summary.  Background: Severe postpartum hemorrhages (PPH) represent a significant cause of maternal morbidity/mortality, but little is known about its hemostasis‐related risk factors. Among the 32 463 women enrolled in the NOHA First cohort, 317 developed severe PPH (S‐PPH group), 1269 non‐severe PPH (NS‐PPH group) and the remaining individuals were considered as control women (C group). Methods: We performed a case–control study, including 317 triplets of women allocated from the three groups that shared the same clinical characteristics as the S‐PPH group. Results: From values obtained 6–9 months after delivery, low (but not‐deficient) levels of fibrinogen, von Willebrand factor (VWF) antigen, factor (F) XI, platelet CD42b, TRAP‐induced increase of platelet CD41a and high values of serum residual prothrombin activity or closure aperture times using the collagen‐ADP cartridge on the PFA‐100® system, and blood group O, were independently associated with a significant risk of severe PPH. Being positive for at least two of these eight variables was found in 1.6%, 3.5% and 20.8% of the women from the C, the NS‐PPH and the S‐PPH groups, respectively, the odds ratio for S‐PPH in such a case being 16.4, 95%CI (6.5–41), P < 0.0001. Conclusions: Women with some hemostasis‐related variables at the low or high end of the population distributions are prone to the severe forms of PPH. Clinical trials will allow us to know if acting on these risk factors can lower the clinical severity of PPH.

Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies.

Summary.  Background: A clinical subtype of purely obstetrical antiphospholipid antibody (aPL‐Ab) syndrome (APS) requires three or more unexplained consecutive embryonic losses before the 10th week of gestation associated with persistently positive lupus anticoagulant (LAC), and/or anticardiolipin IgG or IgM, and/or anti‐β2‐glycoprotein I (aβ2GpI) IgG or IgM. Although this diagnostic classification of APS appeared to be the most sensitive, the APS‐associated serological criteria are still debated. Patients/methods: We prospectively observed the second pregnancy of 284 women with a previous embryonic loss, both with and without aPL‐Ab. Results: aPL‐Ab‐positive women were more prone to pregnancy loss, embryonic loss, pre‐eclampsia, placental abruption and intrauterine fetal growth restriction. Type IIa aPL‐Ab positivity (LAC present alone) was associated with the highest risk of recurrent embryonic loss and intrauterine growth restriction. Type I aPL‐Ab positivity (combinations of aPL‐Ab type positivity) was associated with the strongest risks of late complications, pre‐eclampsia and placental abruption. Finally, aβ2GpI‐M positivities were not clinically relevant in these women. Conclusion: Patients with a first unexplained pregnancy loss before the 10th week of gestation who are also positive for aPL‐Abs have a higher risk of various complications in their second pregnancy. In this study, measurement of aβ2GpI‐M had a questionable prognostic value.

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.

Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy

Summary.  Background:  A first thromboembolic event during pregnancy and puerperium is predisposed to by polymorphisms G1691A in the factor V gene (F5) (F5G1691A) and G20210A in the prothrombin gene (F2) (F2G20210A).

Interleukin 10 Gene Promoter Polymorphisms in Women with Pregnancy Loss: Preferential Association with Embryonic Wastage

Abstract Interleukin 10 (IL10) is associated with maternal immunotolerance. IL10 also down-regulates decidual cell tissue factor expression, the main molecule triggering coagulation activation: this antithrombotic effect may protect the umbilicoplacental vasculature from the 10th wk of gestation onward. IL10 down-regulation may thus dispose to early pregnancy loss (PL) due to maternal immunotolerance defect or late pregnancy failure due to placental vascular insufficiency. IL10 gene promoter polymorphisms associated with cytokine down-regulation may help to identify the actual and probable mechanisms of IL10 modulation in pregnancy outcomes. We investigated the following four IL10 promoter polymorphisms associated with IL10 down-regulation: two single-nucleotide polymorphisms rs1800871 and rs1800872 and two polymorphic CA repeat microsatellites IL10 X78437.2:g8134CA(14_29) and IL10 X78437.2:g.5325CA(11_15). Each microsatellite was analyzed as a biallelic polymorphism. Based on a review of the literature, we define a short allele and a long allele for each microsatellite. We compared their frequencies in early PL occurring before 10 wk of amenorrhea (n = 342) and in PL occurring later on (n = 123). The mutated alleles rs1800871T (odds ratio, 3.083; 95% confidence interval, 1.984–4.792) and rs1800872A (odds ratio, 3.013; 95% confidence interval, 1.924–4.719) were associated with early PL. The haplotype rs1800872A/rs1800871T/X78437.2:g.8134CA[14_25]/X78437.2:g.5325CA[11_13], which includes the two mutated alleles, was significantly associated with the risk of early PL in a dose-dependent manner. Positivity for one haplotype was significantly associated with a 5.6-fold increase in the risk of early pregnancy failure, and positivity for two haplotypes was associated with an 8-fold increase in risk. In women with PL, some polymorphisms of the IL10 gene promoter seem to be constitutional risk factors for early (embryonic) pregnancy failure.

Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort

Severe postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6-17) and 4.7 (1.5-15) respectively), independent of caesarean section delivery and low-molecular-weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively). Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis.

ISTH overt disseminated intravascular coagulation score in patients with septic shock: automated immunoturbidimetric soluble fibrin assay vs. D-dimer assay

J . -C . G R I S ,* J . L . FA I LL I E , § É . C OCHERY -NOUVELLON,* G. L I SSALDE-LAV IGNE * and J . -Y . LE FRAN T – *Haematology Laboratory, University Hospital, Nı̂mes, France The Haematology Laboratory, Faculty of Pharmacy and Biological Sciences; Research Unit 2992, University Montpellier 1; §Department of Medical Information, University Hospital, Nı̂mes; and –Central Intensive Care Unit, University Hospital, Nı̂mes, France