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      Association of Chorioamnionitis With Bronchopulmonary Dysplasia Among Preterm Infants : A Systematic Review, Meta-analysis, and Metaregression

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          Key Points

          Question

          Is chorioamnionitis a risk factor for developing bronchopulmonary dysplasia in preterm infants?

          Findings

          This systematic review, meta-analysis, and metaregression found that chorioamnionitis was associated with an increased risk of bronchopulmonary dysplasia in preterm infants but also found significant differences in baseline characteristics between infants with and infants without chorioamnionitis. A multivariate metaregression model combining the difference in gestational age and the odds of respiratory distress syndrome was associated with 64% of the variance in the association between chorioamnionitis and bronchopulmonary dysplasia.

          Meaning

          Exposure to chorioamnionitis is associated with a higher risk of developing bronchopulmonary dysplasia in preterm infants, but this association may be modulated by gestational age and risk of respiratory distress syndrome.

          Abstract

          Importance

          Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, remains one of the major and most common complications of very preterm birth. Insight into factors associated with the pathogenesis of BPD is key to improving its prevention and treatment.

          Objective

          To perform a systematic review, meta-analysis, and metaregression of clinical studies exploring the association between chorioamnionitis (CA) and BPD in preterm infants.

          Data Sources

          PubMed and Embase were searched without language restriction (last search, October 1, 2018). Key search terms included bronchopulmonary dysplasia, chorioamnionitis, and risk factors.

          Study Selection

          Included studies were peer-reviewed studies examining preterm (<37 weeks’ gestation) or very low-birth-weight (<1500 g) infants and reporting primary data that could be used to measure the association between exposure to CA and the development of BPD.

          Data Extraction and Synthesis

          The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. Data were independently extracted by 2 researchers. A random-effects model was used to calculate odds ratios (ORs) and 95% CIs. Heterogeneity in effect size across studies was studied using multivariate, random-effects metaregression analysis.

          Main Outcomes and Measures

          The primary outcome was BPD, defined as supplemental oxygen requirement on postnatal day 28 (BPD28) or at the postmenstrual age of 36 weeks (BPD36). Covariates considered as potential confounders included differences between CA-exposed and CA-unexposed infants in gestational age, rates of respiratory distress syndrome (RDS), exposure to antenatal corticosteroids, and rates of early- and late-onset sepsis.

          Results

          A total of 3170 potentially relevant studies were found, of which 158 met the inclusion criteria (244 096 preterm infants, 20 971 CA cases, and 24 335 BPD cases). Meta-analysis showed that CA exposure was significantly associated with BPD28 (65 studies; OR, 2.32; 95% CI, 1.88-2.86; P < .001; heterogeneity: I 2 = 84%; P < .001) and BPD36 (108 studies; OR, 1.29; 95% CI, 1.17-1.42; P < .001; heterogeneity: I 2 = 63%; P < .001). The association between CA and BPD remained significant for both clinical and histologic CA. In addition, significant differences were found between CA-exposed and CA-unexposed infants in gestational age, birth weight, odds of being small for gestational age, exposure to antenatal corticosteroids, and early- and late-onset sepsis. Chorioamnionitis was not significantly associated with RDS (48 studies; OR, 1.10; 95% CI, 0.92-1.34; P = .24; heterogeneity: I 2 = 90%; P < .001), but multivariate metaregression analysis with backward elimination revealed that a model combining the difference in gestational age and the odds of RDS was associated with 64% of the variance in the association between CA and BPD36 across studies.

          Conclusions and Relevance

          The results of this study confirm that among preterm infants, exposure to CA is associated with a higher risk of developing BPD, but this association may be modulated by gestational age and risk of RDS.

          Abstract

          This systematic review, meta-analysis, and metaregression of clinical studies explores the association between chorioamnionitis and bronchopulmonary dysplasia in preterm infants.

          Related collections

          Most cited references176

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          • Article: not found

          Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period.

          The follow-up records of 605 infants with birth weights of less than 1,500 g, with data available for 2 years after birth, were examined for evidence of abnormal pulmonary signs or symptoms. A total of 119 infants were identified and the neonatal oxygen requirements of these infants were compared with those of 486 infants who had normal pulmonary function. A requirement for oxygen at 28 days of life had a positive predictive value for abnormal pulmonary findings at the time of follow-up of only 38%, whereas 31% of those with normal pulmonary findings at the time of follow-up were still receiving oxygen at this age. The need for oxygen at 28 days was a good predictor of abnormal findings in infants of greater than or equal to 30 weeks' gestational age at birth but became increasingly less useful as gestational age decreased. It was found that, irrespective of gestational age at birth, the requirement for additional oxygen at 36 weeks' corrected postnatal gestational age was a better predictor of abnormal outcome, increasing the positive predictive value to 63%. The prediction of a normal outcome remained 90% for infants not receiving oxygen at this corrected gestational age.
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            Evaluation and Management of Women and Newborns With a Maternal Diagnosis of Chorioamnionitis: Summary of a Workshop.

            In January 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited an expert panel to a workshop to address numerous knowledge gaps and to provide evidence-based guidelines for the diagnosis and management of pregnant women with what had been commonly called chorioamnionitis and the neonates born to these women. The panel noted that the term chorioamnionitis has been used to label a heterogeneous array of conditions characterized by infection and inflammation or both with a consequent great variation in clinical practice for mothers and their newborns. Therefore, the panel proposed to replace the term chorioamnionitis with a more general, descriptive term: "intrauterine inflammation or infection or both," abbreviated as "Triple I." The panel proposed a classification for Triple I and recommended approaches to evaluation and management of pregnant women and their newborns with a diagnosis of Triple I. It is particularly important to recognize that an isolated maternal fever is not synonymous with chorioamnionitis. A research agenda was proposed to further refine the definition and management of this complex group of conditions. This article provides a summary of the workshop presentations and discussions.
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              • Abstract: found
              • Article: not found

              Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia.

              Bronchopulmonary dysplasia (BPD) is the focus of many intervention trials, yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians. Thus, we wished to define BPD by a standardized oxygen saturation monitoring at 36 weeks corrected age, and compare this physiologic definition with the standard clinical definition of BPD based solely on oxygen administration. A total of 199 consecutive very low birthweight infants (VLBW, 501 to 1500 g birthweight) were assessed prospectively at 36+/-1 weeks corrected age. Neonates on positive pressure support or receiving >30% supplemental oxygen were assigned the outcome BPD. Those receiving or =88% for 60 minutes) or "BPD" (saturation < 88%). At the conclusion of the test, all infants were returned to their baseline oxygen. Safety (apnea, bradycardia, increased oxygen use), inter-rater reliability, test-retest reliability, and validity of the physiologic definition vs the clinical definition were assessed. A total of 199 VLBW were assessed, of whom 45 (36%) were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks corrected age. The physiologic definition identified 15 infants treated with oxygen who successfully passed the saturation monitoring test in room air. The physiologic definition diagnosed BPD in 30 (24%) of the cohort. All infants were safely studied. The test was highly reliable (inter-rater reliability, kappa=1.0; test-retest reliability, kappa=0.83) and highly correlated with discharge home in oxygen, length of hospital stay, and hospital readmissions in the first year of life. The physiologic definition of BPD is safe, feasible, reliable, and valid and improves the precision of the diagnosis of BPD. This may be of benefit in future multicenter clinical trials.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                6 November 2019
                November 2019
                6 November 2019
                : 2
                : 11
                : e1914611
                Affiliations
                [1 ]Department of Pediatrics, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
                [2 ]Pediatric Cardiology Department, Hospital Ramón y Cajal, Madrid, Spain
                Author notes
                Article Information
                Accepted for Publication: September 16, 2019.
                Published: November 6, 2019. doi:10.1001/jamanetworkopen.2019.14611
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Villamor-Martinez E et al. JAMA Network Open.
                Corresponding Authors: Eduardo Villamor-Martinez, MSc, MA, Department of Pediatrics, Maastricht University Medical Center, Postbus 5800, 6202 AZ Maastricht, the Netherlands ( e.villamormartinez@ 123456maastrichtuniversity.nl ); Eduardo Villamor, MD, PhD, Department of Pediatrics, Maastricht University Medical Center, Postbus 5800, 6202 AZ Maastricht, the Netherlands ( e.villamor@ 123456mumc.nl ).
                Author Contributions: Mr Villamor-Martinez and Dr Villamor had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Villamor.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Villamor-Martinez, Ghazi, Villamor.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Villamor-Martinez, Ghazi, Kramer, Villamor.
                Obtained funding: Zimmermann, Kramer, Villamor.
                Administrative, technical, or material support: Villamor-Martinez, Degraeuwe, Kramer, Villamor.
                Supervision: Villamor-Martinez, Zimmermann, Villamor.
                Conflict of Interest Disclosures: None reported.
                Additional Contributions: Mohammed A. Kilani, MD, Maastricht University Medical Center, Maastricht, the Netherlands, provided assistance in data collection and analysis as part of his medical training, and he was not compensated.
                Article
                zoi190562
                10.1001/jamanetworkopen.2019.14611
                6865274
                31693123
                653bec41-42e9-49d7-a15c-c149aef70aa2
                Copyright 2019 Villamor-Martinez E et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 5 June 2019
                : 16 September 2019
                Categories
                Research
                Original Investigation
                Online Only
                Pediatrics

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