Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways.

A major mechanism of hypercoagulability in the antiphospholipid syndrome (APS) is antiphospholipid Ab-mediated upregulation of tissue factor (TF) on monocytes via activation of TLRs, p38 MAPK, and NF-kappaB pathways. We examined whether monocyte signaling pathways are differentially activated by IgG from patients with vascular thrombosis (VT) alone compared with IgG from patients with pregnancy morbidity (PM) alone. We purified IgG from 49 subjects. A human monocyte cell line and ex vivo healthy monocytes were treated with 100 microg/ml IgG for 6 h, and cell extracts were examined by immunoblot using Abs to p38 MAPK and NF-kappaB. To further investigate intracellular signaling pathways induced by these IgGs, specific inhibitors of p38 MAPK, NF-kappaB, TLR4, and TLR2 were used to determine their effect on TF activity. Only IgG from patients with VT but no PM (VT+/PM-) caused phosphorylation of NF-kappaBand p38 MAPK and upregulation of TF activity in monocytes. These effects were not seen with IgG from patients with PM alone (VT-/PM+), anti-phospholipid Ab-positive patients without APS, or healthy controls. TF upregulation caused by the VT+/PM- samples was reduced by inhibitors of p38 MAPK, NF-kappaB, and TLR4. The effects of VT+/PM- IgG on signaling and TF upregulation were concentrated in the fraction that bound beta-2-glycoprotein I. Our findings demonstrate that IgGs from patients with diverse clinical manifestations of APS have differential effects upon phosphorylation of NF-kappaB and p38 MAPK and TF activity that may be mediated by differential activation of TLR4.

Antiphospholipid syndrome.

The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency. Other clinical manifestations are cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, haemolytic anaemia, and cognitive impairment. Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. Of the different antiphospholipid antibodies, lupus anticoagulant is the strongest predictor of features related to antiphospholipid syndrome. Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thromboprophylaxis is recommended in patients with systemic lupus erythematosus and probably in purely obstetric antiphospholipid syndrome. Obstetric care is based on combined medical-obstetric high-risk management and treatment with aspirin and heparin. Hydroxychloroquine is a potential additional treatment for this syndrome. Possible future therapies for non-pregnant patients with antiphospholipid syndrome are statins, rituximab, and new anticoagulant drugs.

The maternal body mass index: a strong association with delivery route.

OBJECTIVE: We sought to assess body mass index (BMI) effect on cesarean risk during labor. STUDY DESIGN: The Consortium on Safe Labor collected electronic data from 228,668 deliveries. Women with singletons > or = 37 weeks and known BMI at labor admission were analyzed in this cohort study. Regression analysis generated relative risks for cesarean stratifying for parity and prior cesarean while controlling for covariates. RESULTS: Of the 124,389 women, 14.0% had cesareans. Cesareans increased with increasing BMI for nulliparas and multiparas with and without a prior cesarean. Repeat cesareans were performed in > 50% of laboring women with a BMI > 40 kg/m(2). The risk for cesarean increased as BMI increased for all subgroups, P < .001. The risk for cesarean increased by 5%, 2%, and 5% for nulliparas and multiparas with and without a prior cesarean, respectively, for each 1-kg/m(2) increase in BMI. CONCLUSION: Admission BMI is significantly associated with delivery route in term laboring women. Parity and prior cesarean are other important predictors.

In which groups of pregnant women can the caesarean delivery rate likely be reduced safely in the USA? A multicentre cross-sectional study.

OBJECTIVES: To identify obstetrical subgroups in which (1) the caesarean delivery (CD) rate may be reduced without compromising safety and (2) CD may be associated with better perinatal outcomes. DESIGN: A multicentre cross-sectional study. SETTING: 19 hospitals in the USA that participated in the Consortium on Safe Labor. PARTICIPANTS: 228 562 pregnant women in 2002-2008. MAIN OUTCOME MEASURES: Maternal and neonatal safety was measured using the individual Weighted Adverse Outcome Score. METHODS: Women were divided into 10 subgroups according to a modified Robson classification system. Generalised estimated equation model was used to examine the relationships between mode of delivery and Weighted Adverse Outcome Score in each subgroup. RESULTS: The overall caesarean rate was 31.2%. Repeat CD contributed 29.5% of all CD, followed by nulliparas with labour induction (15.3%) and non-cephalic presentation (14.3%). The caesarean rates in induced nulliparas with a term singleton cephalic pregnancy and women with previous CD were 31.6% and 82.0%, respectively. CD had no clinically meaningful association with perinatal outcomes in most subgroups. However, in singleton preterm breech presentation and preterm twin gestation with the first twin in non-cephalic presentation, CD was associated with substantially improved maternal and perinatal outcomes. CONCLUSIONS: Women with repeat CD, term non-cephalic presentation, term twins or other multiple gestation and preterm births may be the potential targets for safely reducing prelabour CD rate, while nulliparas or multiparas with spontaneous or induced labour, women with repeat CD, term non-cephalic presentation, term twins or other multiple gestation and preterm births are potential targets for reducing intrapartum CD rate without compromising maternal and neonatal safety in the USA. On the other hand, CD may still be associated with better perinatal outcomes in women with singleton preterm breech presentation or preterm twins with the first twin in non-cephalic presentation.

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes.

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.

Management of hereditary antithrombin deficiency in pregnancy.

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency.

Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-ß2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts.

Is Cesarean Delivery Preferable in Twin Pregnancies at >=36 Weeks Gestation?

BACKGROUND: The optimal mode of delivery in twin pregnancies remains controversial. A recent randomized trial did not find any benefit of planned cesarean vs. vaginal delivery at 32-38 weeks gestation, but the trial was not powered to detect a moderate effect. We aimed to evaluate the impact of cesarean delivery on perinatal mortality and severe neonatal morbidity in twin pregnancies at ≥32 weeks through a large database exploration approach with the power to detect moderate risk differences. METHODS: In a retrospective birth cohort study using the U.S. matched multiple births, 1995-2000 (the available largest multiple birth dataset), we compared perinatal outcomes in twins (n = 181,810 pregnancies) delivered at 32-41 weeks gestation without congenital anomalies. The primary outcome was a composite of perinatal death and severe neonatal morbidity. Cox regression was used to estimate the adjusted hazard ratio (aHR) controlling for the propensity to cesarean delivery, fetal characteristics (sex, birth weight, birth weight discordance, same-sex twin or not) and twin-cluster level dependence. Prospective risks were calculated using the fetuses-at-risk denominators. RESULTS: The overall rates of the primary outcome were slightly lower in intended cesarean (6.20%) vs. vaginal (6.45%) deliveries. The aHRs of the primary outcome were in favor of vaginal delivery at 32 (aHR = 1.06, p = 0.03) or 33 (aHR = 1.22, p<0.001) weeks, neutral at 34-35 weeks, but in favor of cesarean delivery at 36 (aHR = 0.94, p = 0.004), 37, 38 and 39+ weeks (aHR: 0.72 to 0.78, all p<0.001). The lower risk of the primary outcome for cesarean vs. vaginal deliveries at 36+ weeks of gestation remained when the analyses were restricted to different-sex (dichorionic) twins (aHR = 0.84, 95% CI 0.80-0.88). CONCLUSION: Cesarean delivery may be beneficial for perinatal outcomes overall in twin pregnancies at ≥36 weeks gestation.

Autoantibodies against phosphatidylserine, prothrombin and phosphatidylserine-prothrombin complex: identical or distinct diagnostic tools for antiphospholipid syndrome?

BACKGROUND: To clarify the association and diagnostic utility of measuring antiphosphatidyl serine (aPS), antiprothrombin (aPT) and the antiphosphatidyl serine/prothrombin complex (aPS/PT) antibodies in patients with antiphospholipid syndrome (APS) and recurrent pregnancy loss (RPL). METHOD: We measured IgG and IgM anti-aPS/PT (2 different kits) as well as the aPS and aPT autoantibodies by ELISA. All subjects were also tested for the presence of Lupus anticoagulant (LA), IgG and IgM anti-cardiolipin (aCL) and anti-beta-2 glycoprotein I (ass(2)GPI), and these served as the gold standard unless otherwise indicated. Two groups of patients were studied: (i) APS with RPL and/or thrombosis (n=62); (ii) RPL only (n=66) and a group of healthy women with successful pregnancies (WSP; n=30). RESULTS: The area under curve (AUC) analyses demonstrated significant differences between the aPS/PT (0.980) and aPT (0.850) assays (p=0.002) with no significant differences between the 2 aPS/PT kits or the aPS/PT and aPS assays. The overall agreement between the tested aPL antibodies and lupus anticoagulant (LA) for the APS cohort was very poor but associations between aPL assays were substantial (kappa>0.5) as determined by Cohen kappa analysis. CONCLUSIONS: Our data show a lack of association between aPS/PT antibodies and LA in APS patients with recurrent pregnancy loss. In the evaluation of these patients, there may be redundancy in testing all three markers as the aPT and aPS assays formed part of the aPS/PT antibody repertoire.

Anti-inflammatory and immunosuppressive drugs and reproduction.

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.