Ware Branch

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.

Treatment of pregnant patients with antiphospholipid syndrome

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on AntiphospholipidAntibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previousstroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.

Prophylaxis of the antiphospholipid syndrome: a consensus report

Hypothetical circumstances that may require prophylaxis for a potential antiphospholipid syndrome (primary prophylaxis), or in some instances when there already had been some manifestations of the syndrome (secondary prophylaxis), were presented to a panel of experts for their consideration on potential prophylactic intervention. These were subsequently presented to the participants in the First InternationalConsensuson Treatment of the AntiphospholipidSyndrome. In most instances there was consensus in adding low dose aspirin, an exception being aspirin allergy when other antiaggregants could be used in nonpregnant subjects. General measures to prevent thrombosis and other vaso-protective actions should also be provided. Higher risk of fetal loss or thrombosis called for anticoagulation with coumadin in nonpregnant subjects or subcutaneous low molecular weight heparin in pregnant ones. When indicated, prophylaxis of the antiphospholipid syndrome should be provided in systemic lupus erythematosus patients who are being treated for their disease. In no instanceshould corticosteroidsor immunosuppresantsbe given as prophylacticof an antiphospholipid syndrome.

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.

Midfollicular anticardiolipin and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome

OBJECTIVE To determine the prevalence of anticardiolipin and antiphophatidylserine antibodies in an IVF population and to correlate their presence and specific isotype with IVF cycle outcome. DESIGN Retrospective clinical study using stored midfollicular sera for determination of antibody status. SETTING University hospital infertility clinic. PATIENT(S) Women who underwent IVF treatment in 1991. INTERVENTION(S) Midfollicular sera were used to assess antibody status during the time of stimulation for IVF. MAIN OUTCOME MEASURE(S) Anticardiolipin and antiphosphatidylserine antibody titers and biochemical or sonographic documentation of IVF cycle outcome. RESULT(S) The overall prevalence of anticardiolipin and antiphosphatidylserine antibodies in IVF patients was 7.0% and 11.2%, respectively. There was no statistically significant difference in the prevalence of these antibodies in the groups of patients with a biochemical pregnancy (0 for anticardiolipin and 2.8% for antiphosphatidylserine), spontaneous miscarriage (11.4% for anticardiolipin and 20% for antiphosphatidylserine), ongoing pregnancy (7.3% for anticardiolipin and 11.6% for antiphosphatidylserine), and patients who failed to conceive (7.2% for anticardiolipin and 10.8% for antiphosphatidylserine). There was no correlation between outcome and the antibody isotype expressed. CONCLUSION(S) Anticardiolipin and antiphosphatidylserine antibodies are poorly predictive of the IVF cycle outcome. Routine testing of IVF patients for the presence of these antibodies is of limited clinical utility.

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-κB 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 μg/ml IgG for 6 h, and cell extracts were examined by immunoblot using Abs to p38 MAPK and NF-κB. To further investigate intracellular signaling pathways induced by these IgGs, specific inhibitors of p38 MAPK, NF-κB, 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-κBand 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-κB, and TLR4. The effects of VT+/PM− IgG on signaling and TF upregulation were concentrated in the fraction that bound β-2-glycoprotein I. Our findings demonstrate that IgGs from patients with diverse clinical manifestations of APS have differential effects upon phosphorylation of NF-κB and p38 MAPK and TF activity that may be mediated by differential activation of TLR4.

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.

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.

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.