A20 Is Increased in Fetal Lung in a Sheep LPS Model of Chorioamnionitis.

Chorioamnionitis is associated with an increased risk of preterm birth and aggravates adverse outcomes such as BPD. Development of BPD is associated with chronic inflammatory reactions and oxidative stress in the airways which may be antenatally initiated by chorioamnionitis. A20 is an immunomodulatory protein involved in the negative feedback regulation of inflammatory reactions and is a possible regulator protein in oxidative stress reactions. The influence of chorioamnionitis on A20 gene regulation in the fetal lung is unknown. We characterized the influence of LPS and proinflammatory cytokines on A20 expression in human lung endothelial (HPMEC-ST1.6R) and epithelial (A549) cells in vitro by real-time PCR and/or western blotting and used a sheep model of LPS-induced chorioamnionitis for in vivo studies. To study the functional role of A20, endogenous A20 was overexpressed in HPMEC-ST1.6R and A549 cells. LPS induced proinflammatory cytokines in HPMEC-ST1.6R and A549 cells. Both LPS and/or proinflammatory cytokines elevated A20 at transcriptional and translational levels. Intra-amniotic LPS transiently increased IL-1ß, IL-6, IL-8, and TNF-α mRNA levels in fetal lamb lungs, associated with an increase in A20 mRNA and protein levels. Overexpression of A20 reduced proinflammatory cytokines in vitro. Repeated LPS exposure induced LPS tolerance for proinflammatory cytokines and A20 in vitro and in vivo. Antenatal inflammation induced a transient increase in proinflammatory cytokines in the preterm fetal lung. The expression of proinflammatory cytokines increased expression of A20. Elevated A20 may have a protective role by downregulating chorioamnionitis-triggered fetal lung inflammation. A20 may be a novel target for pharmacological interventions to prevent chorioamnionitis-induced airway inflammation and lung damage, which can result in BPD later in life.

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide.

BACKGROUND: Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS). METHODS: Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared. RESULTS: Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h. CONCLUSIONS: In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation. IMPACT: The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.

The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications.

The fetus can deploy a local or systemic inflammatory response when exposed to microorganisms or, alternatively, to non-infection-related stimuli (e.g., danger signals or alarmins). The term "Fetal Inflammatory Response Syndrome" (FIRS) was coined to describe a condition characterized by evidence of a systemic inflammatory response, frequently a result of the activation of the innate limb of the immune response. FIRS can be diagnosed by an increased concentration of umbilical cord plasma or serum acute phase reactants such as C-reactive protein or cytokines (e.g., interleukin-6). Pathologic evidence of a systemic fetal inflammatory response indicates the presence of funisitis or chorionic vasculitis. FIRS was first described in patients at risk for intraamniotic infection who presented preterm labor with intact membranes or preterm prelabor rupture of the membranes. However, FIRS can also be observed in patients with sterile intra-amniotic inflammation, alloimmunization (e.g., Rh disease), and active autoimmune disorders. Neonates born with FIRS have a higher rate of complications, such as early-onset neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and death, than those born without FIRS. Survivors are at risk for long-term sequelae that may include bronchopulmonary dysplasia, neurodevelopmental disorders, such as cerebral palsy, retinopathy of prematurity, and sensorineuronal hearing loss. Experimental FIRS can be induced by intra-amniotic administration of bacteria, microbial products (such as endotoxin), or inflammatory cytokines (such as interleukin-1), and animal models have provided important insights about the mechanisms responsible for multiple organ involvement and dysfunction. A systemic fetal inflammatory response is thought to be adaptive, but, on occasion, may become dysregulated whereby a fetal cytokine storm ensues and can lead to multiple organ dysfunction and even fetal death if delivery does not occur ("rescued by birth"). Thus, the onset of preterm labor in this context can be considered to have survival value. The evidence so far suggests that FIRS may compound the effects of immaturity and neonatal inflammation, thus increasing the risk of neonatal complications and long-term morbidity. Modulation of a dysregulated fetal inflammatory response by the administration of antimicrobial agents, anti-inflammatory agents, or cell-based therapy holds promise to reduce infant morbidity and mortality.

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

BACKGROUND: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent.

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 µg/kg) or low dose (1 µg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.

The prevalence of histologic acute chorioamnionitis among HIV infected pregnant women in Uganda and its association with adverse birth outcomes.

BACKGROUND: Preterm birth (PTB) is a leading cause of neonatal mortality and longer-term morbidity. Acute chorioamnionitis (ACA) is a common cause of PTB, however, there are limited data on the prevalence of ACA and its association with PTB in resource limited settings. METHODS: Data and samples came from a clinical trial evaluating novel strategies for the prevention of malaria in HIV infected pregnant women in Uganda. Women were enrolled between 12-28 weeks of gestation and followed through delivery. For each placenta delivered, three placental tissue types (membrane roll, umbilical cord and chorionic plate/villous parenchyma) were collected. Slides were assessed for diagnosis of maternal and fetal ACA by microscopic evaluation of neutrophilic infiltration using a standardized grading scale. The primary outcomes were PTB (<37 weeks), low birth weight (LBW, <2500 grams), and small-for-gestational age (SGA, birth weight <10th percentile for age). Univariate and multivariate logistic regression were used to estimate associations between 1) maternal characteristics (age, education, wealth, gravidity, gestational age at enrollment, placental malaria, anti-malarial prophylaxis treatment regimen, HIV disease parameters) and ACA, and 2) associations between ACA and adverse birth outcomes. FINDINGS: A total of 193 placentas were included in the analysis. The prevalence of maternal and fetal ACA was 44.5% and 28.0%, respectively. HIV infected women between 28-43 years of age had a higher risk of maternal ACA compared to those between 17-21 years of age (50.9% vs. 19.1%; aOR = 4.00 (1.10-14.5), p = 0.04) and the diagnosis of severe maternal ACA was associated with a significantly higher risk of PTB (28.6% vs. 6.0%; aOR = 6.04 (1.87-19.5), p = 0.003), LBW (33.3% vs. 9.4%; aOR = 4.86 (1.65-14.3); p = 0.004), and SGA (28.6% vs. 10.1%; aOR = 3.70 (1.20-11.4), p = 0.02). No maternal characteristics were significantly associated with fetal ACA and the diagnosis of fetal ACA was not associated with adverse birth outcomes. CONCLUSIONS: Histological evidence of severe maternal ACA was associated with an increased risk of PTB, LBW, and SGA in HIV infected, pregnant Ugandan women.

Fetal Portal System Flowmetry and Intra-Amniotic Inflammation in Preterm Prelabor Rupture of Membranes.

OBJECTIVES: To determine the pulsatility index (PI) in the fetal splenic vein, the main portal vein, the left portal vein, and the ductus venosus with respect to the presence or absence of intra-amniotic inflammation (IAI) in preterm prelabor rupture of membranes (PPROM). METHOD: Women with singleton pregnancies and PPROM, ranging in gestational age from 22+0 to 36+6 weeks, were included. Amniotic fluid samples were obtained by transabdominal amniocentesis and the amniotic fluid level of interleukin-6 (IL-6) was assessed by a point-of-care test. Doppler examination of the selected veins was performed, and the PI was assessed. IAI was defined as amniotic fluid levels of IL-6 ≥745 pg/mL. RESULTS: In total, 42 women were included. Fetuses with IAI compared with those without IAI exhibited a higher PI in the splenic vein (p = 0.005) and the main portal vein (p = 0.05). No differences were observed in the left portal vein PI (p = 0.36) and the ductus venosus PI (p = 0.98). CONCLUSION: IAI was associated with increased fetal splenic vein PI and main portal vein PI in PPROM. The absence of changes in the left portal vein PI and ductus venosus PI supports the local cause of the finding.

Influence of perinatal inflammation on the neurodevelopmental outcome of premature infants.

OBJECTIVE: To evaluate the influence of perinatal inflammation on neurodevelopmental outcome of premature infants. STUDY DESIGN: From a retrospective cohort study of women with preterm labor with intact membranes or preterm prelabor rupture of membranes (PPROM) with an amniocentesis to rule out intra-amniotic inflammation (IAI) and microbial invasion of the amniotic cavity (MIAC), we evaluated neurodevelopmental outcome of their infants born between 24.0 and 34.0 weeks gestation. Women with clinical chorioamnionitis at admission were excluded. Neurodevelopmental outcome was screened with the Ages & Stages Questionnaire (ASQ)-3. We analyzed the relationship between an altered ASQ-3 and antenatal, intra-partum and post-partum factors related to perinatal inflammation. RESULT: Among 98 infants evaluated, 22% had an abnormal score. Amniotic fluid interleukin-6 levels and early-onset sepsis (EOS) were independent factors of an altered ASQ-3 with delivery <26.0 weeks being the strongest predictor. CONCLUSIONS: In premature infants, the presence of IAI, delivery <26.0 weeks and EOS were found to be independent factors of an altered ASQ-3.

Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis.

In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2+ neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI.

Serum cytokine concentrations, chorioamnionitis and the onset of bronchopulmonary dysplasia in premature infants.

OBJECTIVE: To investigate the relationships between serum cytokine concentrations and chorioamnionitis (CAM) and CAM-related bronchopulmonary dysplasia (BPD) in premature infants. METHODS: Serum was collected at 0 and 7 days after birth from 36 premature infants born at <32 weeks of gestation. We examined the relationships between 30 cytokine concentrations and CAM, BPD, and other perinatal factors. RESULTS: On day 0, GM-CSF, IL-15, IL-17, IL-2, IL-2R, VEGF, and MIG concentrations were significantly higher in the CAM group (n = 17) than in the non-CAM group (n = 19). These concentrations had decreased by day 7 and were similar in both groups. The IL-12p70 concentration on day 0 was significantly lower in the BPD group (n = 16) than in the non-BPD group (n = 15). BPD incidence was similar between the CAM and non-CAM groups. CONCLUSIONS: These data support the hypothesis that intrauterine inflammation is not a primary risk factor for BPD. The immunological environment at birth or soon after, rather than intrauterine fetal inflammation (e.g., CAM), is a primary risk factor for BPD onset in preterm infants. Decreased inflammatory responses are particularly relevant, as indicated by the relationship between BPD and low serum IL-12p70 concentrations on day 0.

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes.

BACKGROUND: High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. METHODS: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. RESULTS: AF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. CONCLUSIONS: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth.

Pulmonary Morbidity in Infancy after Exposure to Chorioamnionitis in Late Preterm Infants.

RATIONALE: Chorioamnionitis is an important cause of preterm birth, but its impact on postnatal outcomes is understudied. OBJECTIVES: To evaluate whether fetal exposure to inflammation is associated with adverse pulmonary outcomes at 6 to 12 months' chronological age in infants born moderate to late preterm. METHODS: Infants born between 32 and 36 weeks' gestational age were prospectively recruited (N = 184). Chorioamnionitis was diagnosed by placenta and umbilical cord histology. Select cytokines were measured in samples of cord blood. Validated pulmonary questionnaires were administered (n = 184), and infant pulmonary function testing was performed (n = 69) between 6 and 12 months' chronological age by the raised volume rapid thoracoabdominal compression technique. MEASUREMENTS AND MAIN RESULTS: A total of 25% of participants had chorioamnionitis. Although infant pulmonary function testing variables were lower in infants born preterm compared with historical normative data for term infants, there were no differences between infants with chorioamnionitis (n = 20) and those without (n = 49). Boys and black infants had lower infant pulmonary function testing measurements than girls and white infants, respectively. Chorioamnionitis exposure was associated independently with wheeze (odds ratio [OR], 2.08) and respiratory-related physician visits (OR, 3.18) in the first year of life. Infants exposed to severe chorioamnionitis had increased levels of cord blood IL-6 and greater pulmonary morbidity at age 6 to 12 months than those exposed to mild chorioamnionitis. Elevated IL-6 was associated with significantly more respiratory problems (OR, 3.23). CONCLUSIONS: In infants born moderate or late preterm, elevated cord blood IL-6 and exposure to histologically identified chorioamnionitis was associated with respiratory morbidity during infancy without significant changes in infant pulmonary function testing measurements. Black compared with white and boy compared with girl infants had lower infant pulmonary function testing measurements and worse pulmonary outcomes.

Chorioamnionitis and Patent Ductus Arteriosus: A Systematic Review and Meta-Analysis.

BACKGROUND: Chorioamnionitis has recently been reported as a risk factor for various neonatal diseases, including cerebral palsy, bronchopulmonary dysplasia, and necrotizing enterocolitis, but its effect on patent ductus arteriosus (PDA) is unclear. We performed a systematic review and meta-analysis to evaluate the effect of chorioamnionitis on PDA. METHODS: We searched PubMed, EMBASE, Cochrane Library, and KoreaMed databases using the terms: "intrauterine infection" or "maternal infection" or "antenatal infection" or "chorioamnionitis" or "placenta inflammation" or "placenta pathology" or "neonatal outcome" or "neonatal morbidity" or "PDA or patent ductus arteriosus" or "ductus arteriosus," and "prematurity" or "very low birth weight infant." Studies were included if they were randomized controlled trials, case-control studies, or cohort studies that included information relating to chorioamnionitis and PDA. RESULTS: Among 1,571 studies, a total of 23 studies (17,708 cases) were included in the meta-analysis to analyze the relationship between chorioamnionitis and PDA, except one study that only included PDA requiring surgical ligation. The association between chorioamnionitis and PDA was statistically significant (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.19, 1.72; P < 0.0001). In subgroup analysis, clinical chorioamnionitis was not associated with PDA (OR 1.28; 95% CI 1.00, 1.64, 1.790; P = 0.05), whereas histologic chorioamnionitis (OR 1.54; 95% CI 1.10, 2.15; P = 0.01) and chorioamnionitis diagnosed from both clinical and histologic findings (OR 1.75; 95% CI 1.07, 2.86; P = 0.03) showed significant associations with PDA. Chorioamnionitis did not increase the risk of PDA requiring surgical ligation (OR 1.23; 95% CI 0.69, 2.17; P = 0.48), and antenatal steroid use reduced the risk of PDA (OR 0.62; 95% CI 0.42, 0.90; P = 0.01) after chorioamnionitis. CONCLUSIONS: The results from this meta-analysis support an association between maternal chorioamnionitis and PDA in offspring.

Factors implicated in the initiation of human parturition in term and preterm labor: a review.

After accommodating the pregnancy for an average of 40 weeks, the uterus expels the fetus, the placenta and the membranes through the birth canal in a process named parturition. The absolute sequence of events that trigger and sustain human parturition are not yet fully clarified. Evidence suggests that spontaneous preterm and term labor seem to share a common inflammatory pathway. However, there are several other factors being involved in the initiation of human parturition. Placental corticotropin releasing hormone production seems to serve as a placental clock that might be set to ring earlier or later determining the duration of pregnancy and timing of labor. Estrogens do not cause contractions but their properties seem to capacitate uterus to coordinate and enhance contractions. Cytokines, prostaglandins, nitric oxide and steroids seem also to induce ripening by mediating remodeling of the extracellular matrix and collagen. Infection and microbe invasion resulting in chorioamnionitis also represents a common cause of early preterm labour. This review provides an overview of all these factors considered to be implicated in the initiation of human parturition.

Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

Chorioamnionitis (inflammation of the fetal membranes) is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA) lipopolysaccharide (LPS) is orchestrated via interleukin 1 (IL-1). We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra) (Anakinra; 100 mg) or saline (Sal) 3 h prior to second IA injections of LPS (4 mg) or Sal at 119d gestational age (GA). Preterm lambs were killed after delivery at 121d GA (term = 150 d). Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group) was 25% lower than in control lambs (Sal/Sal group; p=0.025). LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1ß mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS) ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

Chorioamnionitis: implications for the neonate.

Chorioamnionitis (CA) is characterized by inflammation of the fetal membranes. The incidence increases with decreasing gestational age at birth. When suspected on clinical criteria, pathologic assessment of the placenta should be performed. Although the mechanisms are not entirely clear, CA predisposes to premature birth, neonatal sepsis, and intraventricular hemorrhage. Its role in respiratory distress syndrome, bronchopulmonary dysplasia, and neurodevelopmental impairment is mixed. Prevention and treatment are ill-defined; antibiotics for preterm premature rupture of membranes reduce the incidence and increase the length of time to delivery. Antibiotics are recommended for infants exposed to CA while laboratory studies are being performed.

Related factors and adverse neonatal outcomes in women with preterm premature rupture of membranes complicated by histologic chorioamnionitis.

BACKGROUND: The aim of this study was to identify factors predicting histologic chorioamnionitis (HCA) in women with preterm premature rupture of membranes (PPROM). MATERIAL AND METHODS: We retrospectively enrolled 371 women diagnosed with PPROM at less than 34 weeks of gestation at the Second Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2012. HCA was diagnosed by placental histopathology in 70% of participants. Binary logistic regression was used to identify factors associated with HCA and neonatal outcomes. RESULTS: Patient age, rate of parity, tocolysis, cesarean section, serum C reactive protein (CRP) level at admission, white blood cell count, and latency duration did not significantly differ between the 2 groups. Binary logistic regression revealed that oligohydramnios at admission, gestational age at PPROM, and serum CRP >8 mg/L before delivery were significantly associated with HCA. Gestational age at delivery and birth weight were significantly lower in HCA patients than control patients. The rate of 1-min Apgar score <7, abnormal neonatal intracranial ultrasound findings, neonatal pneumonia, bronchopulmonary dysplasia, early-onset neonatal sepsis, and mortality were higher in HCA patients, but no significant difference was observed in the incidence of neonatal respiratory distress syndrome, necrotizing enterocolitis, hyperbilirubinemia, or hypoglycemia. CONCLUSIONS: Younger gestational age at time of PPROM, higher CRP level before delivery, and oligohydramnios at admission in women with PPROM are associated with HCA, and HCA is associated with some adverse neonatal outcomes.

Lipopolysaccharide-induced chorioamnionitis causes acute inflammatory changes in the ovine central nervous system.

OBJECTIVE: To better understand the inflammatory response in the central nervous system (CNS) after lipopolysaccharide (LPS)-induced chorioamnionitis. STUDY DESIGN: Fetal sheep were exposed to intra-amniotic LPS 2 or 14 days before preterm delivery at 125 days of gestation. mRNA levels of cytokines, TLRs and anti-oxidants were determined in different CNS regions. RESULTS: Interleukin 1ß levels increased in hippocampus, cortex and cerebellum 2 days after LPS exposure, while Interleukin 8 levels increased in the periventricular white matter as well. Levels returned back to control levels after 14 days. Tumor necrosis factor-α levels increased in hippocampus and cortex after 2 days. Toll like receptor 4 levels was upregulated in all grey matter regions 2 and 14 days after exposure. Glutathione s-transferase mRNA levels were lower after 2 and 14 days in all grey matter regions. CONCLUSION: Intra-amniotic LPS exposure causes acute and region-specific changes in inflammatory markers in the fetal brain, with grey matter being more affected than white matter. CONDENSATION: Intra-amniotic LPS exposure causes acute and region-specific changes in cytokines, TLR and anti-oxidants levels, with grey matter being more affected than white matter.

Protective ventilation of preterm lambs exposed to acute chorioamnionitis does not reduce ventilation-induced lung or brain injury.

BACKGROUND: The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response. METHODS: Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury. RESULTS: LPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (p<0.02) and cell death (p<0.05) in the WM, which were equivalent in magnitude between groups. CONCLUSIONS: Ventilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.

Oligohydramnios in women with preterm prelabor rupture of membranes and adverse pregnancy and neonatal outcomes.

OBJECTIVE: To determine the association between the presence of oligohydramnios, determined as an amniotic fluid index ≤ 5 cm and the intra-amniotic inflammatory response, fetal inflammatory response and neonatal outcomes in actively managed preterm prelabor rupture of membranes (PPROM). METHODS: Women with singleton pregnancies complicated by PPROM at a gestational age of between 24+0 and 36+6 weeks were included in the study. Ultrasound assessments of the amniotic fluid index and evaluation of the amniotic fluid interleukin (IL)-6 levels were performed at admission. The umbilical cord blood IL-6 levels were evaluated after delivery. RESULTS: In total, 74 women were included. The women with oligohydramnios did not have different amniotic fluid IL-6 levels [with oligohydramnios: median 342 pg/mL, interquartile range (IQR) 110-1809 vs. without oligohydramnios: median 256 pg/mL, IQR 122-748; p = 0.71] or umbilical cord blood IL-6 levels (with oligohydramnios: median 8.2 pg/mL, IQR 3.8-146.9 vs. without oligohydramnios: median 5.9 pg/mL, IQR 2.1-27.9; p = 0.14) than those without oligohydramnios. No association between oligohydramnios and neonatal morbidity was found. A correlation between the amniotic fluid index and the interval from rupture of membranes to amniocentesis was observed (rho = -0.34; p = 0.003). CONCLUSION: The presence of oligohydramnios is not associated with an adverse outcome in actively managed PPROM in singleton pregnancies in the absence of other complications.