Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.

On the front lines of patient safety: implementation and evaluation of team training in Iraq.

BACKGROUND: Team training has been identified as a key strategy for reducing medical errors and building a culture of safety in health care. Communication and coordination skills can serve as barriers to potential errors, as in the modern deployed U.S. Military Healthcare System (MHS), which emphasizes rapid movement of critically injured patients to facilities capable of providing definitive care. A team training intervention--TeamSTEPPS--was implemented on a large scale during one of the most intense phases of the conflict in Iraq. This evaluation of the program constituted the first undertaken in a combat theater of operations. IMPLEMENTING TEAMSTEPPS IN IRAQ: The Baghdad combat support hospital (CSH) conducted continuous operations from a fixed facility for a 13-month deployment--between November 2007 and December 2008. The TeamSTEPPS implementation in Iraq began at this facility and spread throughout the combat theater of operations. Teamwork training was implemented in two primary training sessions, followed up with reinforcement of team behaviors on the unit by hospital leadership. RESULTS: A total of 153 patient safety reports were submitted during the 13 months reviewed, 94 before TeamSTEPPS implementation and 59 afterwards. After training, there were significant decreases in the rates of communication-related errors, medication and transfusion errors, and needlestick incidents. There was a significant decrease in the rate of incidents coded communication as the primary teamwork skill that could have potentially prevented the event. CONCLUSIONS: Process improvement programs such as TeamSTEPPS implementation can be conducted under the extremely austere conditions of a CSH in a combat zone. Teamwork training decreased medical errors in the CSH while deployed in the combat theater in Iraq.

Identification of haptoglobin switch-on status in archived placental specimens indicates antenatal exposure to inflammation and potential participation of the fetus in triggering preterm birth.

OBJECTIVE: Haptoglobin (Hp) has key immunoregulatory roles that vary with phenotype (Hp1-1, Hp2-1, Hp2-2). Cord blood Hp expression is switched-off in the normal fetus. We hypothesized that in the setting of fetal inflammation placenta becomes inundated with Hp of fetal origin that in turn modulates the output of PGE2 and MMP-9 in a phenotype dependent manner. METHODS: Placentas from 40 pregnancies complicated by preterm birth (PTB) (<37 weeks), without (n = 15) or with (n = 25) intra-amniotic infection and histological chorioamnionitis (HCA) were scored for intensity of Hp immunostaining. Hp mRNA levels were evaluated by PCR. Cord blood Hp levels, switch-on status and phenotypes were determined by ELISA and Western blotting. Using a villous trophoblast explant system we investigated if Hp can modulate the release of PGE2 and MMP-9 in the presence or absence of lipopolysaccharide (LPS). RESULTS: All cases with HCA had positive Hp immunoreactivity within fetal vascular spaces. Hp staining intensity correlated with cord blood Hp levels and IL-6. Placentas with and without HCA had similar Hp mRNA levels suggesting Hp immunostaining in the fetal spaces is of fetal rather than placental origin. Both Hp1-1 and Hp2-2 up-regulated PGE2 release in the presence of LPS (2-fold over the LPS level, P < .05), without affecting MMP-9 concentrations. CONCLUSIONS: Fetal Hp switch-on status, a marker of antenatal exposure to intra-amniotic infection/inflammation, can be reliably established through evaluation of archived placental specimens. In the setting of infection/inflammation, Hp enhances placental PGE2 output thereby supporting the role of the fetus in triggering parturition.

Imbalance of Amniotic Fluid Activin-A and Follistatin in Intraamniotic Infection, Inflammation, and Preterm Birth.

CONTEXT: Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFß superfamily involved in connective tissue remodeling. The role of AF follistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined. OBJECTIVE: The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM). STUDY DESIGN: The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation. RESULTS: AF follistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge. CONCLUSION: Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.

Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia.

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

Advances in medical diagnosis of intra-amniotic infection.

INTRODUCTION: Intrauterine infection is a global problem and a significant contributor to morbidity and perinatal death. The host response to infection causes an inflammatory state that acts synergistically with microbial insult to induce preterm birth and fetal damage. Prompt and accurate diagnosis of intra-amniotic infection in the asymptomatic stage of the disease is critical for improved maternal and neonatal outcomes. AREAS COVERED: This article provides an overview of the most recent progress, challenges, and opportunities for discovery and clinical implementation of various maternal serum, cervicovaginal, and amniotic fluid biomarkers in pregnancies complicated by intra-amniotic infection. EXPERT OPINION: Clinically relevant biomarkers are critical to the accurate diagnostic of intrauterine infection. Front-end implementation of such biomarkers will also translate in lower incidence of early-onset neonatal sepsis (EONS) which is an important determinant of neonatal morbidity and mortality associated with prematurity. However, of the hundreds of differentially expressed proteins, only few may have clinical utility and thus function as biomarkers. The small number of validation studies along with barriers to implementation of technological innovations in the clinical setting are current limitations.