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The earliest stages of pregnancy are marked by countless changes in the maternal environment. A specific coordination of activity is required for a successful pregnancy, starting early in the menstrual cycle. Early establishment of maternal-fetal crosstalk is critical for the progression of pregnancy. Many factors, both maternal and fetal derived, play specific and important roles immediately following fertilization, through implantation and beyond. Here we present a review of some of the key factors involved with a focus on PreImplantation Factor (PIF), a small peptide secreted only by competent embryos, which carries an important role required for pregnancy progression.

Cytomegalovirus (CMV) is the most common infectious cause of brain defects and neurological dysfunction in developing human babies. Due to the teratogenicity and toxicity of available CMV antiviral agents, treatment options during early development are markedly limited. Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential. However, it is not known whether this can be translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes. Using multiple models of CMV infection in the developing mouse brain, we show that subcutaneous low-dose VCD suppresses CMV by reducing the level of virus available for entry into the brain and by acting directly within the brain to block virus replication and dispersal. VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice. CMV-mediated brain defects, including decreased brain size, cerebellar hypoplasia, and neuronal loss, were substantially attenuated by VCD. No adverse side effects on neurodevelopment of uninfected control mice receiving VCD were detected. Treatment of CMV-infected human fetal astrocytes with VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell, a mechanism that differs from available anti-CMV drugs. These data suggest that VCD during critical periods of neurodevelopment can effectively suppress CMV replication in the brain and safely improve both immediate and long-term neurological outcomes.SIGNIFICANCE STATEMENT Cytomegalovirus (CMV) can irreversibly damage the developing brain. No anti-CMV drugs are available for use during fetal development, and treatment during the neonatal period has substantial limitations. We studied the anti-CMV actions of valnoctamide (VCD), a psychiatric sedative that appears to lack teratogenicity and toxicity, in the newborn mouse brain, a developmental period that parallels that of an early second-trimester human fetus. In infected mice, subcutaneous VCD reaches the brain and suppresses viral replication within the CNS, rescuing the animals from CMV-induced brain defects and neurological problems. Treatment of uninfected control animals exerts no detectable adverse effects. VCD also blocks CMV replication in human fetal brain cells.

Neurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current studies suggest that it is likely caused by infection(s) triggering a systemic immune response resulting in antigen/non-antigen-related autoimmune response in central nervous system (CNS). New therapeutic approaches are needed. Secreted by viable embryos, PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role. Synthetic PIF (PIF) duplicates endogenous peptide's protective effect in pre-clinical autoimmune and transplantation models. PIF protects against brain hypoxia-ischemia by directly targeting microglia and neurons. In chronic experimental autoimmune encephalitis (EAE) model PIF reverses paralysis while promoting neural repair. Herein we report that PIF directly promotes brain re-myelination and reverses paralysis in relapsing remitting EAE MS model. PIF crosses the blood-brain barrier targeting microglia. Systemically, PIF decreases pro-inflammatory IL23/IL17 cytokines, while preserving CNS-specific T-cell repertoire. Global brain gene analysis revealed that PIF regulates critical Na+/K+/Ca++ ions, amino acid and glucose transport genes expression. Further, PIF modulates oxidative stress, DNA methylation, cell cycle regulation, and protein ubiquitination while regulating multiple genes. In cultured astrocytes, PIF promotes BDNF-myelin synthesis promoter and SLC2A1 (glucose transport) while reducing deleterious E2F5, and HSP90ab1 (oxidative stress) genes expression. In cultured microglia, PIF increases anti-inflammatory IL10 while reducing pro-inflammatory IFNγ expression. Collectively, PIF promotes brain re-myelination and neuroprotection in relapsing remitting EAE MS model. Coupled with ongoing, Fast-Track FDA approved clinical trial, NCT#02239562 (immune disorder), current data supports PIF's translation for neurodegenerative disorders therapy.

Problem Women with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH. Method of study A human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA. Results Vitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release. Conclusion LMWH in combination with vitamin D may be more beneficial than single-agent therapy by preventing aPL-induced trophoblast inflammation and reversing LMWH-induced sFlt-1 secretion.

International audience; Recombinant human antithrombin (rhAT; ATryn), isolated from the milk of transgenic goats, provides an alternative to human plasma-derived antithrombin (AT) concentrate for perioperative and peripartum prophylaxis of venous thromboembolism (VTE) in patients with hereditary AT deficiency. Optimized rhAT dosing algorithms and improved plasma AT monitoring protocol were used in an open-label, single-arm, multinational, pivotal safety and efficacy study that was conducted in patients with hereditary AT deficiency in perioperative and peripartum settings. Loading and maintenance doses were calculated on the basis of pretreatment AT activity levels. Specific dosing regimens were used for pregnant and surgical patients; rhAT was to be given for at least 3 days and for 14 days or less. The primary efficacy end point was the incidence of any thromboembolic event during rhAT therapy or within 7 days of rhAT discontinuation. Safety and AT activity levels were secondary end points. Six surgical and 12 pregnant patients were treated for a median of 3.2 days (range 0.9-14 days). With the optimized dosing regimens, a median of 1 dose adjustment (range 0-6 dose adjustments) was needed to maintain AT activity levels within 80-120% of normal. No confirmed VTEs occurred during treatment or in the subsequent 7 days. Overall, rhAT was well tolerated, but some bleeding complications occurred after rhAT discontinuation and anticoagulation reinstitution. No antibodies to rhAT or goat milk proteins were detected. Perioperative and peripartum prophylactic rhAT therapy in patients with hereditary AT deficiency is well tolerated and effective in preventing VTE.

Background Postpartum hemorrhage (PPH) remains one of the leading causes of maternal morbidity and mortality worldwide, although the lack of a precise definition precludes accurate data of the absolute prevalence of PPH. Study Design and Methods An international expert panel in obstetrics, gynecology, hematology, transfusion, and anesthesiology undertook a comprehensive review of the literature. At a meeting in November 2011, the panel agreed on a definition of severe PPH that would identify those women who were at a high risk of adverse clinical outcomes. Results The panel agreed on the following definition for severe persistent (ongoing) PPH: “Active bleeding >1000 mL within the 24 hours following birth that continues despite the use of initial measures including first-line uterotonic agents and uterine massage.” A treatment algorithm for severe persistent PPH was subsequently developed. Initial evaluations include measurement of blood loss and clinical assessments of PPH severity. Coagulation screens should be performed as soon as persistent (ongoing) PPH is diagnosed, to guide subsequent therapy. If initial measures fail to stop bleeding and uterine atony persists, second- and third-line (if required) interventions should be instated. These include mechanical or surgical maneuvers, i.e., intrauterine balloon tamponade or hemostatic brace sutures with hysterectomy as the final surgical option for uncontrollable PPH. Pharmacologic options include hemostatic agents (tranexamic acid), with timely transfusion of blood and plasma products playing an important role in persistent and severe PPH. Conclusion Early, aggressive, and coordinated intervention by health care professionals is critical in minimizing blood loss to ensure optimal clinical outcomes in management of women with severe, persistent PPH.

Thrombophilias represent an evolving story that continues to stir controversy for care providers and obstetrical patients. The predominant thrombophilic mutations include the factor V Leiden mutation, prothrombin gene mutation G20210A, methylene tetrahydrafolate reductase C667T, and deficiencies of the natural anticoagulants proteins C and S, and antithrombin. Prospective cohort studies have provided an accurate assessment of the risk of placenta-mediated complications posed by common inherited thrombophilic conditions. Acquired thrombophilic conditions consist of the antiphospholipid antibody syndrome (APAS) and hyperhomocysteinemia. Well-conducted, placebo-controlled, randomized trials have demonstrated no benefit of anticoagulation in women with recurrent pregnancy loss and inherited thrombophilia. The routine use of anticoagulation to prevent other placenta-mediated complications in the setting of inherited thrombophilia should be considered experimental until the results of adequate clinical trials are available. Heparin anticoagulation and antiplatelet therapies are the cornerstone of treatment of APAS in pregnancy.

Objective: To identify current treatment strategies for postpartum hemorrhage used by obstetricians (OB/GYNs) and hematologists (HEMs). Study Design: We conducted a survey of OB/GYNs (n = 220) and HEMs (n = 30) to describe the characteristics of current treatment strategies for postpartum hemorrhage. Surveys were administered via a structured questionnaire on a secure internet website from 5 - 12 October 2009. Results: The majority of OB/GYN and HEM respondents were practicing in a community hospital environment (77%). Of the OB/GYNs, the majority practiced at hospitals with over 2000 deliveries per year (77%). A majority (58%) of OB/GYNs were affiliated with hospitals that lacked a massive transfusion protocol to treat severe postpartum hemorrhage. Subsequent to uterine massage and additional oxytocin, the majority of OB/GYNs (73%), preferred the administration of Methergine? as the next level of intervention for postpartum hemorrhage. There was considerable variability in response to specific treatment strategies for several hypothetical case scenarios; however, the large majority of OB/GYNs favored obstetrical procedures over interventional radiology or administration of rFVIIa. A large majority (77%) of physicians who are familiar with rRVIIa as treatment for postpartum hemorrhage reported being very satisfied with the agent for this indication. Conclusions: An established, systematic treatment strategy among OB/GYNs emerged only in the case of mild postpartum hemorrhage.

Preeclampsia is a multisystem disorder affecting 2% to 8% of pregnancies and a leading cause of maternal and perinatal morbidity and mortality worldwide. Recent investigations have improved our understanding of the pathogenesis of this potentially life-threatening disease, especially in its early-onset form of manifestation. Despite these advances, therapeutic options are still limited and no effective pharmacologic interventions are currently available. Ongoing lines of research indicate some potential novel treatments targeting specific pathogenic steps. In this article we provide an updated overview of the multiple therapeutic approaches under preclinical and clinical assessment for the treatment of early-onset preeclampsia.

Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor.

Bone marrow transplantation (BMT), a well-established treatment for hematological diseases, is frequently hampered by graft-versus-host disease (GVHD) and/or by infections due to delay in immune restoration. Prelmplantation Factor (PIF) is an embryo-derived peptide whose physiological function is to regulate local and systemic immunity and promote transplant acceptance. Synthetic PIF’s effectiveness to regulate immune response following BMT was herein examined in murine model. PIF administration reduced GVHD following allogenic BMT, decreased skin, liver, and colon inflammation and down regulated GVHD-associated gene expression in the liver. iNOS gene expression was reduced both in liver and colon. In syngeneic BMT, PIF administration reduced proinflammatory genes expression and promoted mice weight recovery up to two months after transplantation. PIF immune-regulatory effects were mediated via interaction with monocytes, resulting in decreased iNOS expression and NO secretion in-vitro. Overall, we demonstrate that by regulating immune response after BMT, PIF reduces inflammation and oxidative stress, leading to transplant success.

Pregnancy and autoimmune disorders (ADs) coexist in a delicate balance. Whereas women are disproportionately affected by ADs – frequently occurring during reproductive years – the disease often improves during pregnancy, unless severe. However, when ADs are at an advanced stage, both mother and fetus can be severely affected. Maternal AD amelioration reduces fetal morbidity/mortality. AD improvement occurs without compromising immune tolerance for the fetus; however, it is short-lived since postpartum, flare-up frequently occurs. Consequences of pregnancy-related maternal disease can have life-long impact. Pregnancy is not an immune-suppressed state, but rather a controlled inflammatory environment with distinct local and systemic coordination. Pregnancy requires a delicate immune balance; the embryo/allograft does not cause graft-versus-host disease while the mother/host immunity is modulated without suppression. We herein critically examine the synergetic reciprocal relationship between pregnancy and ADs. We review key ADs and their current prognosis and management. Finally, we describe PreImplantation Factor, a peptide secreted by viable embryos that, beyond its essential autotrophic and proimplantation properties, regulates systemic immune response and also proved effective in nonpregnant autoimmune and transplantation models. Hence, PreImplantation Factor may have a key role in improving ADs in pregnancy, and provide a novel drug for treatment of immune disorders in general.

The association between inherited thrombophilia and deep vein thrombosis is well established. Adverse pregnancy outcomes, sometimes called placenta-mediated complications, have been attributed to excessive thrombosis and inflammation at the uteroplacental interface. This linkage resulted in widespread screening for thrombophilia in women with adverse pregnancy outcome. Anticoagulant therapy was initially liberally administered for prevention of adverse pregnancy outcome. Well-designed randomized trials were initiated and the results of some of these randomized trials have provided critical evidence-based data to serve as a guide for clinicians faced with managing patients with one or more of the common obstetric complications.

Bone marrow transplantation (BMT) to treat severe hematologic malignancies often leads to potentially fatal acute graft-versus-host disease (GVHD), despite attempts at better donor–recipient matching and/or use of immunosuppressive agents. We report that embryo-derived PreImplantation Factor (PIF) plays a determining role in developing maternal/host tolerance toward the semiallogeneic or total allogeneic embryo and in regulating systemic immune response. Synthetic PIF treatment has proven effective in preventing immune attacks in nonpregnant models of autoimmunity. In this study, we tested the capability of PIF to prevent the development of acute GVHD in semiallogeneic or totally allogeneic murine BMT models. We examined the regulatory effect of PIF both in vivo and in vitro to control deleterious GVHD while maintaining its ability to preserve the beneficial graft-versus-leukemia (GVL) effect. Bone marrow and spleen cells from C57BL/6 donors were transplanted in semiallogeneic (C57BL/6xBALB/c) F1 or allogeneic (BALB/c) mice, which were then treated with PIF 1 mg/kg/day for 2 weeks. Short-term PIF administration reduced acute GVHD in both models and increased survival for up to 4 months after semiallogeneic or totally allogeneic BMT. This effect was coupled with decreased skin inflammation (semiallogeneic model) and decreased liver inflammation (both models), as well as reduced colon ulceration (allogeneic model). GVHD-associated cytokine and chemokine gene expression were decreased in the liver. PIF further lowered circulating IL-17 levels, but not IFN-γ levels. Both in vivo and in vitro, PIF treatment was demonstrated to lead to decreased inducible nitric oxide synthase expression and decreased lipopolysaccharide-activated macrophages to lower nitric oxide secretion. Significantly, PIF did not diminish the beneficial GVL effect in the B cell leukemia model. PIF acts primarily by inducing the regulatory phenotype on monocytes/antigen-presenting cells, which controls T cell proliferation. Overall, our data demonstrate that PIF protects against semiallogeneic and allogeneic GVHD long term by reducing both target organ and systemic inflammation and by decreasing oxidative stress, while preserving the beneficial GVL effect.

Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

The challenging nature of recurrent pregnancy loss (RPL) is multifactorial, but largely begins with determining who meets diagnostic criteria for RPL as definitions vary and frequently change. Many patients seek obstetrical intervention after losses, even if they do not meet the criteria for RPL, and even those strictly meeting criteria often present a conundrum as to the etiology of their condition. The contribution of hereditary thrombophilia to RPL, the impact of each disorder on the clotting cascade, available evidence regarding pregnancy outcomes, and current recommendations for evaluation and treatment is presented.

Objectives The purpose of this analysis was to evaluate the use of recombinant human antithrombin (rhAT) in preventing venous thromboembolism (VTE) in pregnant patients with hereditary AT deficiency (HATD). Study Design Data from two clinical trials were pooled. Dosing of rhAT was based on body weight and baseline AT activity, started up to 24 hours before scheduled induction or cesarean delivery, or at the onset of labor. Results A total of 21 pregnant HATD patients were enrolled. Mean rhAT therapy duration was 4.3 days and dose was 245.1 IU/kg/day. All patients achieved target mean AT activity (80–120% of normal) during rhAT therapy. There were no confirmed VTEs during rhAT treatment or within 7 ( ± 1) days after dosing. Two VTE events (one deep vein thrombosis and one pulmonary embolism) occurred 11 and 14 days after discontinuation of rhAT, in patients managed with prophylactic doses of heparin or low-molecular-weight heparin following delivery. Conclusion rhAT was safe and effective in pregnant HATD patients when administered during the peripartum period, the period of highest VTE risk and a time when anticoagulation therapy is normally withheld. Pregnant HATD patients may benefit from therapeutic, rather than prophylactic, doses of anticoagulation after delivery to protect against postpartum VTE.

Objective. Preeclampsia has been linked to subsequent vascular disease with many shared predisposing factors. We investigated the association between severe preeclampsia, and its subtypes, and specific vascular-related polymorphisms. Design. The study was a retrospective nested case-cohort design. Setting. Pregnant Danish women participating in the Danish National Birth Cohort. Population. 263 cases of severe preeclampsia and 1851 random controls were selected from the Danish National Birth Cohort. Methods. We validated all cases of severe preeclampsia and genotyped for 108 single nucleotide polymorphisms (SNPs) that were selected based on previous publications on the association with vascular disease. Logistic models were used for statistical analyses. Main outcome measures. Maternal polymorphisms in genomic models. Results. We found 17 of 108 SNPs associated with severe preeclampsia (p < 0.05). Women homozygous for the rs1799983 in NOS3 were 1.6-fold [95% confidence interval (CI) 1.0–2.4] more likely to develop severe preeclampsia. Women homozygous for the rs1010 SNP in VAMP8 were twofold (95%CI 1.1–3.5) more likely to deliver preterm when preeclampsia was present. Women homozygous for the rs10811661 SNP were 2.1-fold (95%CI 1.1–3.9) more likely to develop severe preeclampsia and 3.7-fold (95%CI 1.1–12.4) more likely to deliver a small-for-gestational age child when preeclampsia was present. All associations are available as Supporting Information. Conclusion. We found several vascular-associated SNPs linked to severe preeclampsia; however, most of these associations are probably by pure chance, which warrants replication and further translational research. To date, no specific SNP has yet proven valuable in a clinical setting in predicting preeclampsia.

Low birthweight of the offspring has been associated with increased risk of early death and ischemic heart disease in the mother. However, other measurements of fetal growth than the basic birthweight are more accurate. We investigated the relation between the standardized birthweight by gestational age and gender and the ponderal index and the mother's subsequent mortality and cardiovascular morbidity.Registry-based retrospective cohort study.Women with a first singleton delivery in Denmark from 1978 to 2007.782 287 women followed for 14.6 years yielding 11 600 945 person-years.Cox proportional hazard models.The primary exposures were variation in the standardized birthweight and ponderal index. The endpoints were subsequent maternal death, hypertension, ischemic heart disease, stroke, thrombosis, and diabetes mellitus.The risk-profile for the standardized birthweight and subsequent maternal death had a nadir between -0.5 and -1 SD (HR 0.91; 95%CI 0.83-1.00) and increased with decreasing fetal growth peaking at-3 SD (HR 2.75; 95%CI 2.37-3.19) compared to the median. The risk-profile for subsequent diabetes mellitus by standardized ponderal index had a nadir between +0.5 to +1 SD (HR 0.82; 95%CI 0.76-0.89) rising with increasing fetal growth and peaking at+3 SD (HR 17.8; 95%CI 15.0-21.0). The risk-profiles for standardized ponderal index paralleled those for birthweight, but with smaller risk estimates. Adjusting for other pregnancy complications diminished the estimates.The fetal growth is a marker of subsequent risk for premature death, cardiovascular disease, and diabetes mellitus in the mother.

Introduction Embryo-derived PIF modulates systemic maternal immunity without suppression. Synthetic analog (sPIF) prevents juvenile diabetes, preserves islet function, reducing oxidative stress/protein misfolding. We investigate sPIF effectiveness in controlling neuroinflammation/MS. Methods Examine sPIF-induced protection against harsh, clinical-relevant murine EAE-PLP acute and chronic models. Evaluate clinical indices: circulating cytokines, spinal cord histology, genome, canonical global proteome, cultured PLP-activated splenocytes cytokines, and immunophenotype. Results Short-term, low-dose sPIF prevented paralysis development and lowered mortality (P 50%, by day 82. Prevention model: 12 days post-therapy, sPIF reduced circulating IL12 ten-fold and inflammatory cells access to spinal cord. Regression model: sPIF blocked PLP-induced IL17 and IL6 secretions. Long-term chronic model: sPIF reduced spinal cord pro-inflammatory cytokines/chemokines, (ALCAM, CF1, CCL8), apoptosis-promoters, inflammatory cells access (JAM3, OPA1), solute channels (ATPases), aberrant coagulation factors (Serpins), and pro-antigenic MOG. Canonical proteomic analysis demonstrated reduced oxidative phosphorylation, vesicle traffic, cytoskeleton remodeling involved in neuro-cytoskeleton breakdown (tubulins), associated with axon re-assembly by (MTAPs)/improved synaptic transmission. Conclusion sPIF – through coordinated central and systemic multi-targeted action – reverses neuroinflammation/MS and imparts significant neuroprotective effects up to total paralysis resolution. Clinical testing is warranted and planned.

Reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these effects and their relationship to preeclampsia (PE) and intrauterine growth restriction (IUGR).

OBJECTIVE: Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody-induced modulation of trophoblast function. METHODS: The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of no medication, low-dose LMW heparin, low-dose ASA, or combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-α, vascular endothelial growth factor (VEGF), placental growth factor, soluble FMS-like tyrosine kinase-1, and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay. RESULTS: Low molecular weight heparin improved basal trophoblast migration and induced potent increases in growth-regulated oncogene-α and soluble FMS-like tyrosine kinase-1. Aspirin did not affect basal function. Combined therapy promoted migration but did not reverse the LMW heparin-induced soluble FMS-like tyrosine kinase-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, placental growth factor, and soluble endoglin secretion, while decreasing cell migration and IL-6 and soluble FMS-like tyrosine kinase-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β upregulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased soluble FMS-like tyrosine kinase-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration. CONCLUSION: In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.

Problem Women with antiphospholipid antibodies (aPL) are at risk of miscarriage and pre-eclampsia, obstetrical disorders associated with reduced trophoblast invasion and spiral artery transformation. aPL target the placenta by binding beta2-glycoprotein I (β2GPI) on the trophoblast. In this study, we determined whether aPL alter the trophoblast secretion of angiogenic factors and evaluated the effect of low molecular weight heparin (LMWH) on this response. Method of study First-trimester trophoblast was treated with anti-β2GPI antibodies with or without LMWH. Angiogenic factor secretion was measured by enzyme-linked immunosorbent assay. Results Trophoblast cells produced more vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and soluble endoglin following exposure to anti-β2GPI Abs, and this occurred in both a MyD88-dependent and MyD88-independent manner. LMWH was unable to reverse the effects of the anti-β2GPI Abs on trophoblast VEGF secretion, but enhanced PlGF. Strikingly, LMWH upregulated soluble fms-like tyrosine kinase receptor-1 (sFlt-1) secretion independently of aPL. Conclusion This study demonstrates that aPL perturb the secretion of trophoblast angiogenic factors. LMWH does not reverse this effect but exacerbates sFlt-1 secretion, a potent anti-angiogenic factor. These findings may help to explain why women with antiphospholipid syndrome, who are treated with heparin to prevent early pregnancy loss, remain at increased risk of developing late obstetrical complications, such as pre-eclampsia.

Microangiopathic disorders present with thrombocytopenia, hemolytic anemia, and multiorgan damage. In pregnancy, these disorders present a challenge both diagnostically and therapeutically, with widely overlapping clinical scenarios and disparate treatments. Although rare, a clear understanding of these diseases is important because devastating maternal and fetal outcomes may ensue if there is misdiagnosis and improper treatment. Microangiopathic disorders presenting in pregnancy are thus best assessed and treated by both obstetric and hematology teams. As a better understanding of the pathophysiology underlying each of the disease processes is gained, new diagnostic testing and therapies will be available, which will lead to improved outcomes.

The combined effects of preterm delivery, small-for-gestational-age offspring, hypertensive disorders of pregnancy, placental abruption and stillbirth on early maternal death from cardiovascular causes have not previously been described in a large cohort. We investigated the effects of pregnancy complications on early maternal death in a registry-based retrospective cohort study of 782 287 women with a first singleton delivery in Denmark 1978-2007, followed for a median of 14.8 years (range 0.25-30.2) accruing 11.6 million person-years. We employed Cox proportional hazard models of early death from cardiovascular and non-cardiovascular causes following preterm delivery, small-for-gestational-age offspring and hypertensive disorders of pregnancy. We found that preterm delivery and small-for-gestational-age were both associated with subsequent death of mothers from cardiovascular and non-cardiovascular causes. Severe pre-eclampsia was associated with death from cardiovascular causes only. There was a less than additive effect on cardiovascular mortality hazard ratios with increasing number of pregnancy complications: preterm delivery 1.90 [95% confidence intervals 1.49, 2.43]; preterm delivery and small-for-gestational-age offspring 3.30 [2.25, 4.84]; preterm delivery, small-for-gestational-age offspring and pre-eclampsia 3.85 [2.07, 7.19]. Thus, we conclude that, separately and combined, preterm delivery and small-for-gestational-age are strong markers of early maternal death from both cardiovascular and non-cardiovascular causes, while hypertensive disorders of pregnancy are markers of early death of mothers from cardiovascular causes.

A multidisciplinary panel consisting of experts chosen by the 2 chairs of the group representing experts in anesthesiology, blood banking, hematology, critical care medicine, and various surgical disciplines (trauma, cardiac, pediatric, neurologic, obstetrics, and vascular) convened in January 2008 to discuss hemostasis and management of the bleeding patient across different clinical settings, with a focus on perioperative considerations. Although there are many ways to define hemostasis, one clinical definition would be control of bleeding without the occurrence of pathologic thrombotic events (i.e., when balance among procoagulant, anticoagulant, fibrinolytic, and antifibrinolytic activities is achieved). There are common hemostatic challenges that include lack of scientific evidence and standardized guidelines for the use of therapeutic drugs, need for reliable and rapid laboratory tools for measuring hemostasis, and individual variability. Clinically meaningful and accurate real-time laboratory data reflecting a patient's hemostatic status are needed to guide treatment decisions. Current available routine laboratory tests of hemostasis (e.g., platelet count, prothrombin time/international normalized ratio, and activated partial thromboplastin time) do not reflect the complexity of in vivo hemostasis and can mislead the clinician. Although point-of-care coagulation monitoring tests including measures of thromboelastography/elastometry provide insight into overall hemostatic status, they are time-consuming to perform, complex to interpret, and require trained personnel. There is a particular need to develop laboratory tests that can measure the effects of anticoagulant and antiplatelet agents for individual patients, predict bleeding complications, and guide therapy when and if treatment with blood products or pharmacologic drugs is required. Formation of an organization comprised of specialists who treat bleeding patients will foster multidisciplinary collaborations and promote discussions of the current state of hemostasis treatment and future priorities for hemostasis research. Controlled trials with clinically meaningful end points and suitable study populations, as well as observational studies, investigator-initiated studies, and large registry and database studies are essential to answer questions in hemostasis. Because of the complexities of maintaining hemostatic balance, advances in hemostasis research and continuing communication across specialties are required to improve patient care and outcomes.

Pulmonary embolism (PE) is the leading cause of maternal mortality in the developed world. Mortality from PE in pregnancy might be related to challenges in targeting the right population for prevention, ensuring that diagnosis is suspected and adequately investigated, and initiating timely and best possible treatment of this disease. Pregnancy is an example of Virchow's triad: hypercoagulability, venous stasis, and vascular damage; together these factors lead to an increased incidence of venous thromboembolism. This disorder is often suspected in pregnant women because some of the physiological changes of pregnancy mimic its signs and symptoms. Despite concerns for fetal teratogenicity and oncogenicity associated with diagnostic testing, and potential adverse effects of pharmacological treatment, an accurate diagnosis of PE and a timely therapeutic intervention are crucial. Appropriate prophylaxis should be weighed against the risk of complications and offered according to risk stratification.

Please cite this paper as: Lykke J, Paidas M, Damm P, Triche E, Kuczynski E, Langhoff-Roos J. Preterm delivery and risk of subsequent cardiovascular morbidity and type-II diabetes in the mother. BJOG 2010;117:274–281. Objective Preterm delivery has been shown to be associated with subsequent maternal cardiovascular morbidity. However, the impact of the severity and recurrence of preterm delivery on the risk of specific cardiovascular events and the metabolic syndrome in the mother, have not been investigated. Design National registry-based retrospective cohort study. Setting Women delivering in Denmark from 1978 to 2007. Population Women with a first singleton delivery (n = 782 287), and with a first and second singleton delivery (n = 536 419). Methods Cox proportional hazard models, with the gestational age stratified into four groups as primary exposure. We made adjustments for maternal age, year of delivery, hypertensive pregnancy disorders, fetal growth deviation, placental abruption and stillbirth. Main outcome measures Subsequent maternal hypertension, ischaemic heart diseases, thromboembolism and type-II diabetes. Results After a first delivery at 32–36 completed weeks of gestation, the adjusted risk of subsequent type-II diabetes increased 1.89-fold (1.69–2.10) and the risk of thromboembolism increased 1.42-fold (1.24–1.62). Women having a preterm delivery in the first pregnancy and a term delivery in the second had a 1.58-fold (1.34–1.86) increased risk of type-II diabetes and a 1.18-fold (0.96–1.44) increased risk of thromboembolism. Women having two preterm deliveries had a 2.30-fold (1.71–3.10) increased risk of type-II diabetes and a 1.80-fold (1.29–2.50) increased risk of thromboembolism. Conclusions Preterm delivery is independent of other pregnancy complications associated with subsequent maternal overt type-II diabetes and thromboembolism. The recurrence of preterm delivery will augment these risks.

Problem Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2-glycoprotein I (β2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. Method of study First trimester trophoblast cells were treated with anti-β2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. Results We report that anti-β2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-α, and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-α, and IL-1β secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. Conclusion These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.

Minimal data exist concerning the relationship between hypertensive pregnancy disorders and various subsequent cardiovascular events and the effect of type 2 diabetes mellitus on these. In a registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton (n=782 287) and 2 first consecutive singleton deliveries (n=536 419). The exposures were gestational hypertension and mild and severe preeclampsia. We adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth and, in a second model, we also adjusted for the development of type 2 diabetes mellitus. The end points were subsequent hypertension, ischemic heart disease, congestive heart failure, thromboembolic event, stroke, and type 2 diabetes mellitus. The risk of subsequent hypertension was increased 5.31-fold (range: 4.90 to 5.75) after gestational hypertension, 3.61-fold (range: 3.43 to 3.80) after mild preeclampsia, and 6.07-fold (range: 5.45 to 6.77) after severe preeclampsia. The risk of subsequent type 2 diabetes mellitus was increased 3.12-fold (range: 2.63 to 3.70) after gestational hypertension and 3.68-fold (range: 3.04 to 4.46) after severe preeclampsia. Women having 2 pregnancies both complicated by preeclampsia had a 6.00-fold (range: 5.40 to 6.67) increased risk of subsequent hypertension compared with 2.70-fold (range: 2.51 to 2.90) for women having preeclampsia in their first pregnancy only and 4.34-fold (range: 3.98 to 4.74) for women having preeclampsia in their second pregnancy only. The risk of subsequent thromboembolism was 1.03-fold (range: 0.73 to 1.45), 1.53-fold (range: 1.32 to 1.77), and 1.91-fold (range: 1.35 to 2.70) increased after gestational hypertension and mild and severe preeclampsia, respectively. Thus, hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events.

To estimate the relationship between histologic chorioamnionitis and four amniotic fluid proteomic biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A).One hundred fifty-eight women with singleton pregnancies had a clinically indicated amniocentesis to rule out inflammation and infection in the context of preterm labor or preterm premature rupture of membranes. A proteomic fingerprint (Mass Restricted score) was generated from amniotic fluid using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The Mass Restricted score ranges from 0 to 4 (none to all four biomarkers present) in direct relationship with severity of intra-amniotic inflammation. Presence or absence of biomarkers was analyzed in relationship to placental pathology. Criteria for severity of histologic chorioamnionitis were 3 stages and 4 grades of inflammation of the amnion, choriodecidua and chorionic plate.The prevalence of histologic chorioamnionitis was 64% (stage I 12%, stage II 16%, and stage III 37%). The Mass Restricted score significantly correlated with stages of histologic chorioamnionitis (r=0.539, P.001), grades of choriodeciduitis (r=0.465, P.001), and amnionitis (r=0.536, P.001). African-American women were overrepresented in the group with severe inflammation (Mass Restricted score 3-4, P=.022). Of the four biomarkers of the Mass Restricted score, calgranulin C had the strongest relationship with presence of stage III chorioamnionitis, independent of race, amniocentesis-to-delivery interval, and gestational age.Proteomic analysis of amniotic fluid provides an opportunity for early recognition of histologic chorioamnionitis. This methodology may in the future identify candidates for antenatal therapeutic interventions.II.

Cigarette smoking during pregnancy continues to be a significant public health concern. Maternal smoking during pregnancy has been associated with low birth weight (

Autoimmune diseases are a group of heterogeneous disorders equally characterized by the same pathogenetic mechanism: an immunological reaction against self antigens promoted by antibodies, immuno-complex formation, and self-reactive T lymphocytes. Autoimmune diseases may be separated into organ-restricted diseases and systemic ones. The damage of single organs produced by antibodies focused against specific cellular antigens characterizes the first group of diseases, whereas the latter are produced by a systemic inflammatory process initiated by inappropriate and excess immune activation that leads to immuno-complex formation and deposition onto sensitive tissues. Since connective and vascular tissue are principally damaged in these disorders, systemic autoimmune diseases are more commonly known as "connective tissue diseases" (CTD) and include: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren syndrome, and others. Although they are considered as different from a pathogenetic point of view, they overlap in many aspects, such as general symptoms as fever and fatigue, chronical ongoing, steroid therapy. As patients suffering from CTD are predominantly young women between the ages of 20 and 40 years, which is the period of the highest childbearing potential, particular interest must be regarded to the impact that these diseases and their therapies have on pregnancy and, conversely, the effect of pregnancy on these disorders, which may have long-lasting implications for mothers and neonates. Adverse fetal outcomes, maternal disease flares, and drug potential teratogenic risk are the main reasons why women suffering from CTD and who are pregnant or intend to become pregnant are considered a high-risk population. These patients require integrated, interdisciplinary care, addressing every aspect of rheumatology, obstetrics, and neonatology to reduce maternal, fetal, and neonatal complications.

Adverse pregnancy outcome refers to placenta-mediated complications that may share a common etiopathogenesis in some cases. Unraveling associations between prothrombotic genetic predispositions and these pregnancy disorders, namely recurrent fetal loss, stillbirth, severe preeclampsia, intrauterine growth restriction, and placental abruption, requires rigorous epidemiological studies involving large cohorts of patients with sufficient numbers of the adverse pregnancy outcomes in question. Such is the case with the Denmark National Birth Cohort, which was initiated in 1996 and followed pregnant women giving birth from the years 1996 to 2002. In addition, national registers exist which can be linked together. Two studies have been initiated. One is a retrospective cohort study concerning primiparous women, with singleton pregnancy and with no identifiable congenital malformation. The purpose of this study is to determine the long-term cardiovascular risk of women whose pregnancies were complicated by adverse pregnancy outcome. Preliminary evidence suggests that the presence of an adverse pregnancy outcome augments the cardiovascular disease risk by an odds ratio of 1.21 (P < 0.001). The second study focuses on pro-thrombotic and cardiovascular genetic polymorphisms in a nested-case control study comparing pregnancies with and without an adverse pregnancy outcome in the index pregnancy. This study will be adequately powered to determine the relationship between adverse pregnancy outcome and pro-thrombotic and cardiovascular genetic polymorphisms. These studies are urgently needed to accurately assess the linkage between family history, presence of adverse pregnancy outcome, and long-term cardiovascular risk.

Andra H James,1 David L Cooper,2 Michael J Paidas31Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Duke University, Durham, NC, 2Novo Nordisk Inc., Princeton, NJ, 3Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Women and Children’s Center for Blood Disorders and Preeclampsia Advancement, Yale University, New Haven, CT, USAObjective: To assess potential diagnostic and practice barriers to successful management of massive postpartum hemorrhage (PPH), emphasizing recognition and management of contributing coagulation disorders.Study design: A quantitative survey was conducted to assess practice patterns of US obstetrician-gynecologists in managing massive PPH, including assessment of coagulation.Results: Nearly all (98%) of the 50 obstetrician-gynecologists participating in the survey reported having encountered at least one patient with “massive” PPH in the past 5 years. Approximately half (52%) reported having previously discovered an underlying bleeding disorder in a patient with PPH, with disseminated intravascular coagulation (88%, n=23/26) being identified more often than von Willebrand disease (73%, n=19/26). All reported having used methylergonovine and packed red blood cells in managing massive PPH, while 90% reported performing a hysterectomy. A drop in blood pressure and ongoing visible bleeding were the most commonly accepted indications for rechecking a “stat” complete blood count and coagulation studies, respectively, in patients with PPH; however, 4% of respondents reported that they would not routinely order coagulation studies. Forty-two percent reported having never consulted a hematologist for massive PPH.Conclusion: The survey findings highlight potential areas for improved practice in managing massive PPH, including earlier and more consistent assessment, monitoring of coagulation studies, and consultation with a hematologist.Keywords: acquired hemophilia, blood coagulation disorders, disseminated intravascular coagulation, von Willebrand disease

Embryonic-maternal interaction from the earliest stages of gestation has a key, sustained role in neurologic development, persisting into adulthood. Early adverse events may be detrimental in adulthood. Protective factors present during gestation could significantly impact post-natal therapy. The role of PreImplantation Factor (PIF) within this context is herein examined. Secreted by viable early embryos, PIF establishes effective embryonic-maternal communication and exerts essential trophic and protective roles by reducing oxidative stress and protein misfolding and by blunting the nocive let-7 microRNA related pathway. PIF's effects on systemic immunity lead to comprehensive immune modulation, not immune suppression. We examine PIF's role in protecting embryos from adverse maternal environment, which can lead to neurological disorders that may only manifest post-nataly: Synthetic PIF successfully translates endogenous PIF features in both pregnant and non-pregnant clinically relevant models. Specifically PIF has neuroprotective effects in neonatal prematurity. In adult relapsing-remitting neuroinflammation, PIF reverses advanced paralysis while promoting neurogenesis. PIF reversed Mycobacterium smegmatis induced brain infection. In graft-vs.-host disease, PIF reduced skin ulceration, liver inflammation and colon ulceration while maintaining beneficial anti-cancer, graft-vs.-leukemia effect. Clinical-grade PIF has high-safety profile even at supraphysiological doses. The FDA awarded Fast-Track designation, and university-sponsored clinical trials for autoimmune disorder are ongoing. Altogether, PIF properties point to its determining regulatory role in immunity, inflammation and transplant acceptance. Specific plans for using PIF for the treatment of complex neurological disorders (ie. traumatic brain injury, progressive paralysis), including neuroprotection from newborn to adult, are presented.

A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

Context: Decidual neutrophil infiltration complicates spontaneous abortions associated with inflammation and hemorrhage. Transendothelial neutrophil migration into inflamed tissues involves IL-8mediatedchemoattraction,thenneutrophilattachmenttoendothelial cell-expressed intercellular adhesion molecule-1 (ICAM-1). Objective: The aim of this study was to assess IL-8 and ICAM-1 regulation in decidual inflammation and hemorrhage; the effects of the proinflammatory cytokines, TNF, IL-1 and the hemostatic, proinflammatory cytokine thrombin were measured on IL-8 expression in first trimester decidual cells (DCs), and ICAM-1 immunostaining was compared in normal, inflamed, and hemorrhagic first trimester decidua. Design: Immunohistochemistry of human decidua and in vitro treatment of human decidual cells were performed Setting: The study was conducted at the Academic Medical Center. Intervention:. DCs were passaged until they were leukocyte-free (CD45 free by FACS), then were incubated with estradiol or medroxyprogesterone acetate alone or with TNF or IL-1 or thrombin. Normal, inflamed, and hemorrhagic decidua were immunostained for ICAM-1 and the neutrophil marker CD14. Main Outcome Measure: ICAM-1 immunostaining was performed in decidua. IL-8 levels in DC-conditioned media were assessed by ELISA and immunoblotting; IL-8 mRNA levels were measured by quantitative RT-PCR. Results: Endothelial cell ICAM-1 immunostaining was similar in normal and inflamed or hemorrhagic decidua. In cultured DCs, optimal concentrations of IL-1, TNF, and thrombin elevated secreted IL-8 levels by 1083 261-, 370 77-, and 45 15-fold, respectively (mean SEM; P 0.05; n 8). The effects were dose dependent and were unaffected by medroxyprogesterone acetate. Western blotting confirmed the ELISA results, and corresponding effects on IL-8 mRNA levels were observed. Conclusions: Cytokine/thrombin-enhanced DC IL-8 expression interacts with constitutively expressed ICAM-1 in decidual endothelium to modulate neutrophil trafficking into hemorrhagic and inflamed first trimester decidua. (J Clin Endocrinol Metab 90: 4710–4715, 2005)

Summary. Objective: We posit that low levels of protein S (PS) and protein Z (PZ) contribute to adverse pregnancy outcome (APO). Patients: We evaluated 103 women with subsequent normal pregnancy outcome (NPO), 106 women with APO, and 20 women with thrombophilia (TP). Methods: We compared first trimester (1st TRI) PZ levels in 103 women with NPO, 106 women with APO, and in 20 women with TP. We compared plasma levels of PZ and free PS antigen during the second (2nd TRI) and third trimesters (3rd TRI) of pregnancy in 51 women with APO and 51 matched women with NPO. Results: The mean 1st TRI PZ level was significantly lower among patients with APO, compared to pregnant controls (1.81 ± 0.7 vs. 2.21 ± 0.8 µg mL−1, respectively, P < 0.001). Of patients with known TP, those with APO had a tendency for lower mean PZ levels compared to those TP women with NPO (1.5 ± 0.6 vs. 2.3 ± 0.9 µg mL−1, respectively, P

SummaryWe investigated the association between inherited and acquired maternal thrombophilias and adverse pregnancy events. A cohort of 491 patients with a history of adverse pregnancy outcomes was evaluated for activated protein C resistance, factor V Leiden and prothrombin G20210A mutations, hyperhomocysteinemia, deficiencies of antithrombin, protein C and S and both anticardiolipin antibodies and lupus anticoagulants. The study had an 80% power to detect a 15% difference in the prevalence of thrombophilia for 1st trimester loss. In our high-risk cohort the presence of 1 maternal thrombophilia or more than one thrombophilia were found to be protective of recurrent losses at < 10 weeks (1 thrombophilia: OR: 0.55, 95% CI: 0.33–0.92; >1 thrombophilia: OR: 0.48, 95%CI:0.29–0.78). In contrast, the presence of maternal thrombophilia(s) was modestly associated with an increased risk of losses ≥ 10 weeks (1 thrombophilia: OR:1.76, 95%CI: 1.05–2.94, >1 thrombophilia: OR:1.66, 95%CI:1.03–2.68). Women who experienced only euploid losses were not more likely to have an identified thrombophilia than women who experienced only aneuploid losses (OR 1.03; 0.38–2.75). The presence of maternal thrombophilia was associated with an increased risk of fetal loss after 14 weeks, fetal growth restriction, abruption and preeclampsia. There was a significant “dose-dependent” increase in the risk of abruption (OR:3.60, 95%CI: 1.43–9.09) and preeclampsia (OR:3.21, 95%CI:1.20–8.58). In conclusion, these data indicate maternal thrombophilias are not associated with pregnancy wastage prior to 10 weeks of gestation.