Chorioamnionitis or intrauterine inflammation is a frequent cause of preterm birth. Chorioamnionitis can affect almost every organ of the developing fetus. Multiple microbes have been implicated to ...cause chorioamnionitis, but "sterile" inflammation appears to be more common. Eradication of microorganisms has not been shown to prevent the morbidity and mortality associated with chorioamnionitis as inflammatory mediators account for continued fetal and maternal injury. Mounting evidence now supports the concept that the ensuing neonatal immune dysfunction reflects the effects of inflammation on immune programming during critical developmental windows, leading to chronic inflammatory disorders as well as vulnerability to infection after birth. A better understanding of microbiome alterations and inflammatory dysregulation may help develop better treatment strategies for infants born to mothers with chorioamnionitis.
The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of ...azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section.
In this trial conducted at 14 centers in the United States, we studied 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. We randomly assigned 1019 to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks.
The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval CI, 0.38 to 0.68; P<0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P=0.02), wound infection (2.4% vs. 6.6%, P<0.001), and serious maternal adverse events (1.5% vs. 2.9%, P=0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P=0.63).
Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; C/SOAP ClinicalTrials.gov number, NCT01235546 .).
Pulmonary hypertension is associated with bronchopulmonary dysplasia in extremely low birth weight (ELBW) infants and contributes to morbidity and mortality. The objective was to determine the ...prevalence of pulmonary hypertension among ELBW infants by screening echocardiography and evaluate subsequent outcomes.
All ELBW infants admitted to a regional perinatal center were evaluated for pulmonary hypertension with echocardiography at 4 weeks of age and subsequently if clinical signs suggestive of right-sided heart failure or severe lung disease were evident. Management was at discretion of the clinician, and infants were evaluated until discharge from the hospital or pre-discharge death occurred.
One hundred forty-five ELBW infants (birth weight: 755 ± 144 g; median gestational age: 26 weeks interquartile range: 24-27) were screened from December 2008 to February 2011. Overall, 26 (17.9%) were diagnosed with pulmonary hypertension at any time during hospitalization (birth weight: 665 ± 140 g; median gestational age: 26 weeks interquartile range: 24-27): 9 (6.2%) by initial screening (early pulmonary hypertension) and 17 (11.7%) who were identified later (late pulmonary hypertension). Infants with pulmonary hypertension were more likely to receive oxygen treatment on day 28 compared with those without pulmonary hypertension (96% vs 75%, P < .05). Of the 26 infants, 3 died (all in the late group because of cor pulmonale) before being discharged from the hospital.
Pulmonary hypertension is relatively common, affecting at least 1 in 6 ELBW infants, and persists to discharge in most survivors. Routine screening of ELBW infants with echocardiography at 4 weeks of age identifies only one-third of the infants diagnosed with pulmonary hypertension. Further research is required to determine optimal detection and intervention strategies.
The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and the clinical phenotype of BPD is extremely variable. Several clinical and laboratory biomarkers have been proposed for the ...early identification of infants at higher risk of BPD and for determination of prognosis of infants with a diagnosis of BPD. The authors review available literature on prediction tools and biomarkers of BPD, using clinical variables and biomarkers based on imaging, lung function measures, and measurements of various analytes in different body fluids that have been determined to be associated with BPD either in a targeted manner or by unbiased omic profiling.
Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is ...available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.
The Airway Microbiome at Birth Lal, Charitharth Vivek; Travers, Colm; Aghai, Zubair H ...
Scientific reports,
08/2016, Volume:
6, Issue:
1
Journal Article
Peer reviewed
Open access
Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is ...associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease.
Infant mortality rates (IMR) and neonatal mortality rates (NMR) in the United States have not decreased recently. The purpose of this study was to determine the contributions of birth weight and ...gestational age subgroups to the IMR and NMR in the United States.
We used the most recent (1983-2005) US linked birth and infant death data and simple regression analysis to determine the contributions of specific birth weight and gestational age subgroups to trends in IMR and NMR.
IMR and NMR decreased between 1983 and 2005 for all birth weight and gestational age subgroups. There was an increase in births of very low birth weight infants from 1.2% to 1.5% (P < .001) over this period. The proportion of very low birth weight-infant deaths increased from 42.9% to 54.8%, resulting in recent nonsignificant declines in IMR and NMR. The proportion of live-birth infants <500 g increased from 0.12% to 0.18% (P < .001). The adjusted IMR and NMR over time (excluding infants <500 g) have steeper declining trends than the ones including infants <500 g. The changes in overall IMR and NMR in recent years (2000-2005) are not statistically significant. However, the adjusted IMR and NMR trends during this time are highly significant.
The increased proportions of infants <500 g and other low birth weight infants contribute greatly to the lack of a decrease in IMR and NMR from 2000 to 2005, although birth weight- and gestational age-specific IMR and NMR continue to decrease.
DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations ...contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).
To determine the DNA methylation changes in IPF and their effects on gene expression.
Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.
DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.
Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance ...imaging at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly.
This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging–determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis.
This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks’ gestational age with acute moderate to severe histologic chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic chorioamnionitis and brain abnormality score using mediation analysis.
Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (β=2.84; 1.51–4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities after the significant indirect effects of preterm birth were accounted for.
Acute histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.
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