Randomized trial of azithromycin to eradicate Ureaplasma respiratory colonization in preterm infants: 2-year outcomes.
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
27
10
2020
accepted:
05
02
2021
revised:
01
02
2021
pubmed:
5
3
2021
medline:
29
3
2022
entrez:
4
3
2021
Statut:
ppublish
Résumé
To assess the potential impact of azithromycin treatment in the first week following birth on 2-year outcomes in preterm infants with and without Ureaplasma respiratory colonization who participated in a double-blind, placebo-controlled randomized controlled trial. Respiratory morbidity was assessed at NICU discharge and at 6, 12, and 22-26 months corrected age using pulmonary questionnaires. Comprehensive neurodevelopmental assessments were completed between 22 and 26 months corrected age. The primary and secondary composite outcomes were death or severe respiratory morbidity and death or moderate-severe neurodevelopmental impairment, respectively, at 22-26 months corrected age. One hundred and twenty-one randomized participants (azithromycin, N = 60; placebo, N = 61) were included in the intent-to-treat analysis. There were no significant differences in death or serious respiratory morbidity (34.8 vs 30.4%, p = 0.67) or death or moderate-severe neurodevelopmental impairment (47 vs 33%, p = 0.11) between the azithromycin and placebo groups. Among all trial participants, tracheal aspirate Ureaplasma-positive infants experienced a higher frequency of death or serious respiratory morbidity at 22-26 months corrected age (58%) than tracheal aspirate Ureaplasma-negative infants (34%) or non-intubated infants (21%) (p = 0.028). We did not observe strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes in preterm infants treated with azithromycin in the first week of life compared to placebo. No strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes was identified at 22-26 months corrected age in infants treated with azithromycin in the first week of life compared to placebo. The RCT is the first study of 2-year pulmonary and neurodevelopmental outcomes of azithromycin treatment in ELGANs. Provides evidence that ELGANs with lower respiratory tract Ureaplasma have the most frequent serious respiratory morbidity in the first 2 years of life, suggesting that a Phase III trial of azithromycin to prevent BPD targeting this population is warranted.
Sections du résumé
BACKGROUND
To assess the potential impact of azithromycin treatment in the first week following birth on 2-year outcomes in preterm infants with and without Ureaplasma respiratory colonization who participated in a double-blind, placebo-controlled randomized controlled trial.
METHODS
Respiratory morbidity was assessed at NICU discharge and at 6, 12, and 22-26 months corrected age using pulmonary questionnaires. Comprehensive neurodevelopmental assessments were completed between 22 and 26 months corrected age. The primary and secondary composite outcomes were death or severe respiratory morbidity and death or moderate-severe neurodevelopmental impairment, respectively, at 22-26 months corrected age.
RESULTS
One hundred and twenty-one randomized participants (azithromycin, N = 60; placebo, N = 61) were included in the intent-to-treat analysis. There were no significant differences in death or serious respiratory morbidity (34.8 vs 30.4%, p = 0.67) or death or moderate-severe neurodevelopmental impairment (47 vs 33%, p = 0.11) between the azithromycin and placebo groups. Among all trial participants, tracheal aspirate Ureaplasma-positive infants experienced a higher frequency of death or serious respiratory morbidity at 22-26 months corrected age (58%) than tracheal aspirate Ureaplasma-negative infants (34%) or non-intubated infants (21%) (p = 0.028).
CONCLUSIONS
We did not observe strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes in preterm infants treated with azithromycin in the first week of life compared to placebo.
IMPACT
No strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes was identified at 22-26 months corrected age in infants treated with azithromycin in the first week of life compared to placebo. The RCT is the first study of 2-year pulmonary and neurodevelopmental outcomes of azithromycin treatment in ELGANs. Provides evidence that ELGANs with lower respiratory tract Ureaplasma have the most frequent serious respiratory morbidity in the first 2 years of life, suggesting that a Phase III trial of azithromycin to prevent BPD targeting this population is warranted.
Identifiants
pubmed: 33658655
doi: 10.1038/s41390-021-01437-2
pii: 10.1038/s41390-021-01437-2
pmc: PMC8413397
mid: NIHMS1673094
doi:
Substances chimiques
Anti-Bacterial Agents
0
Placebos
0
Azithromycin
83905-01-5
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
178-187Subventions
Organisme : NICHD NIH HHS
ID : R01 HD067126
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Sillers, L., Alexiou, S. & Jensen, E. A. Lifelong pulmonary sequelae of bronchopulmonary dysplasia. Curr. Opin. Pediatr. 32, 252–260 (2020).
pubmed: 32084032
doi: 10.1097/MOP.0000000000000884
Yang, J. et al. Lung function of adults born at very low birth weight. Pediatrics 145, e20192359 (2020).
pubmed: 31900317
doi: 10.1542/peds.2019-2359
Gibbons, J. T. D., Wilson, A. C. & Simpson, S. J. Predicting lung health trajectories for survivors of preterm birth. Front. Pediatr. 8, 318 (2020).
pubmed: 32637389
pmcid: 7316963
doi: 10.3389/fped.2020.00318
Hibbs, A. M. et al. One-year respiratory outcomes of preterm infants enrolled in the nitric oxide (to prevent) chronic lung disease trial. J. Pediatr. 153, 525–529 (2008).
pubmed: 18534620
pmcid: 2745607
doi: 10.1016/j.jpeds.2008.04.033
Ambalavanan, N. et al. Identification of extremely premature infants at high risk of rehospitalization. Pediatrics 128, e1216–e1225 (2011).
pubmed: 22007016
pmcid: 3208965
doi: 10.1542/peds.2011-1142
Greenough, A. Long-term respiratory consequences of premature birth at less than 32 weeks of gestation. Early Hum. Dev. 89(Suppl 2), S25–S27 (2013).
pubmed: 23910576
doi: 10.1016/j.earlhumdev.2013.07.004
Zhang, H. et al. Prolonged respiratory support of any type impacts outcomes of extremely low birth weight infants. Pediatr. Pulmonol. 53, 1447–1455 (2018).
pubmed: 30062831
pmcid: 6599180
doi: 10.1002/ppul.24124
Cheong, J. L. Y. & Doyle, L. W. An update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia. Semin. Perinatol. 42, 478–484 (2018).
pubmed: 30401478
doi: 10.1053/j.semperi.2018.09.013
Murtha, A. P. & Edwards, J. M. The role of mycoplasma and ureaplasma in adverse pregnancy outcomes. Obstet. Gynecol. Clin. North Am. 41, 615–627 (2014).
pubmed: 25454994
doi: 10.1016/j.ogc.2014.08.010
Lowe, J. et al. Association between pulmonary ureaplasma colonization and bronchopulmonary dysplasia in preterm infants: updated systematic review and meta-analysis. Pediatr. Infect. Dis. J. 33, 697–702 (2014).
pubmed: 24445836
doi: 10.1097/INF.0000000000000239
Okogbule-Wonodi, A. C. et al. Necrotizing enterocolitis is associated with ureaplasma colonization in preterm infants. Pediatr. Res. 69, 442–447 (2011).
pubmed: 21258263
pmcid: 3968774
doi: 10.1203/PDR.0b013e3182111827
Viscardi, R. M. et al. Incidence of invasive ureaplasma in VLBW infants: relationship to severe intraventricular hemorrhage. J. Perinatol. 28, 759–765 (2008).
pubmed: 18596706
pmcid: 5334544
doi: 10.1038/jp.2008.98
Kasper, D. C. et al. In utero exposure to ureaplasma spp. Is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. J. Perinat. Med. 39, 331–336 (2011).
pubmed: 21526978
doi: 10.1515/jpm.2011.022
Huang, J. et al. Antenatal infection and intraventricular hemorrhage in preterm infants: a meta-analysis. Medicine 98, e16665 (2019).
pubmed: 31374040
pmcid: 6709165
doi: 10.1097/MD.0000000000016665
Ozdemir, R. et al. Clarithromycin in preventing bronchopulmonary dysplasia in Ureaplasma urealyticum-positive preterm infants. Pediatrics 128, e1496–e1501 (2011).
pubmed: 22123897
doi: 10.1542/peds.2011-1350
Nair, V., Loganathan, P. & Soraisham, A. S. Azithromycin and other macrolides for prevention of bronchopulmonary dysplasia: a systematic review and meta-analysis. Neonatology 106, 337–347 (2014).
pubmed: 25278176
doi: 10.1159/000363493
Smith, C. et al. Use and safety of azithromycin in neonates: a systematic review. BMJ Open 5, e008194 (2015).
pubmed: 26656010
pmcid: 4679913
doi: 10.1136/bmjopen-2015-008194
Hassan, H. E. et al. Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia. J. Clin. Pharmacol. 51, 1264–1275 (2011).
pubmed: 21098694
doi: 10.1177/0091270010382021
Viscardi, R. M. et al. Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose. Antimicrob. Agents Chemother. 57, 2127–2133 (2013).
pubmed: 23439637
pmcid: 3632913
doi: 10.1128/AAC.02183-12
Merchan, L. M. et al. Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for ureaplasma respiratory colonization. Antimicrob. Agents Chemother. 59, 570–578 (2015).
pubmed: 25385115
doi: 10.1128/AAC.03951-14
Viscardi, R. M. et al. Randomised trial of azithromycin to eradicate ureaplasma in preterm infants. Arch. Dis. Child. Fetal Neonatal Ed. https://doi.org/10.1136/fetalneonatal2019-318122 (2020).
Natarajan, G. et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum. Dev. 88, 509–515 (2012).
pubmed: 22236557
pmcid: 3686277
doi: 10.1016/j.earlhumdev.2011.12.013
Poindexter, B. B. et al. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann. Am. Thorac. Soc. 12, 1822–1830 (2015).
pubmed: 26397992
pmcid: 4722827
doi: 10.1513/AnnalsATS.201504-218OC
Jobe, A., Ikegami, M., Jacobs, H. & Jones, S. Surfactant and pulmonary blood flow distributions following treatment of premature lambs with natural surfactant. J. Clin. Investig. 73, 848–856 (1984).
pubmed: 6546766
pmcid: 425089
doi: 10.1172/JCI111280
Martinez, F. D. et al. Asthma and wheezing in the first six years of life. The group health medical associates. N. Engl. J. Med. 332, 133–138 (1995).
pubmed: 7800004
doi: 10.1056/NEJM199501193320301
Taussig, L. M. et al. Tucson children’s respiratory study: 1980 to present. J. Allergy Clin. Immunol. 111, 661–675 (2003).
pubmed: 12704342
doi: 10.1067/mai.2003.162
Stevens, T. P. et al. Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT). J. Pediatr. 165, 240.e4–249.e4 (2014).
doi: 10.1016/j.jpeds.2014.02.054
Amiel-Tison, C. & Gosselin, J. Neurological Development from Birth to Six Years: Guide for Examination and Evaluation (Johns Hopkins University Press, 2001).
Palisano, R. J. et al. Validation of a model of gross motor function for children with cerebral palsy. Phys. Ther. 80, 974–985 (2000).
pubmed: 11002433
doi: 10.1093/ptj/80.10.974
Adams-Chapman, I. et al. Neurodevelopmental impairment among extremely preterm infants in the neonatal research network. Pediatrics 141, e20173091 (2018).
Greene, M. M., Patra, K., Nelson, M. N. & Silvestri, J. M. Evaluating preterm infants with the bayley-III: patterns and correlates of development. Res. Dev. Disabil. 33, 1948–1956 (2012).
pubmed: 22738765
doi: 10.1016/j.ridd.2012.05.024
Kerstjens, J. M. et al. The ages and stages questionnaire and neurodevelopmental impairment in two-year-old preterm-born children. PLoS ONE 10, e0133087 (2015).
pubmed: 26193474
pmcid: 4508030
doi: 10.1371/journal.pone.0133087
Vaucher, Y. E. et al. Neurodevelopmental outcomes in the early cpap and pulse oximetry trial. N. Engl. J. Med. 367, 2495–2504 (2012).
pubmed: 23268664
pmcid: 4140695
doi: 10.1056/NEJMoa1208506
Jensen, E. A. et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am. J. Respir. Crit. Care Med. 200, 751–759 (2019).
pubmed: 30995069
pmcid: 6775872
doi: 10.1164/rccm.201812-2348OC
Zeger, S. L., Liang, K. Y. & Albert, P. S. Models for longitudinal data: a generalized estimating equation approach. Biometrics 44, 1049–1060 (1988).
pubmed: 3233245
doi: 10.2307/2531734
Follmann, D., Proschan, M. & Leifer, E. Multiple outputation: inference for complex clustered data by averaging analyses from independent data. Biometrics 59, 420–429 (2003).
pubmed: 12926727
doi: 10.1111/1541-0420.00049
Rubin, D. B. Multiple Imputation for Nonresponse in Surveys (Wiley, 1987).
Poindexter, B. B. & Jobe, A. H. The diagnostic conundrum of bronchopulmonary dysplasia. J. Pediatr. 167, 517–518 (2015).
pubmed: 26138878
doi: 10.1016/j.jpeds.2015.06.029
Maitre, N. L. et al. Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. J. Perinatol. 35, 313–321 (2015).
pubmed: 25811285
pmcid: 4414744
doi: 10.1038/jp.2015.19
Steinhorn, R. et al. Chronic pulmonary insufficiency of prematurity: developing optimal endpoints for drug development. J. Pediatr. 191, 15–21 e11 (2017).
pubmed: 29173299
doi: 10.1016/j.jpeds.2017.08.006
Brady, J. M., Zhang, H., Kirpalani, H. & DeMauro, S. B. Living with severe bronchopulmonary dysplasia-parental views of their child’s quality of life. J. Pediatr. 207, 117–122 (2019).
pubmed: 30404737
doi: 10.1016/j.jpeds.2018.10.001
Morrow, L. A. et al. Antenatal determinants of bronchopulmonary dysplasia and late respiratory disease in preterm infants. Am. J. Respir. Crit. Care Med. 196, 364–374 (2017).
pubmed: 28249118
pmcid: 5549867
doi: 10.1164/rccm.201612-2414OC
Ryan, R. M. et al. Respiratory medications in infants <29 weeks during the first year postdischarge: the Prematurity and Respiratory Outcomes Program (prop) Consortium. J. Pediatr. 208, 148.e3–155.e3 (2019).
doi: 10.1016/j.jpeds.2018.12.009
Brick, T. et al. Parents know it best: prediction of asthma and lung function by parental perception of early wheezing episodes. Pediatr. Allergy Immunol. 30, 795–802 (2019).
pubmed: 31441979
doi: 10.1111/pai.13118
Vissing, N. H., Jensen, S. M. & Bisgaard, H. Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study. BMC Med. Res. Methodol. 12, 160 (2012).
pubmed: 23088330
pmcid: 3504537
doi: 10.1186/1471-2288-12-160
Pinna, G. S., Skevaki, C. L. & Kafetzis, D. A. The significance of Ureaplasma urealyticum as a pathogenic agent in the paediatric population. Curr. Opin. Infect. Dis. 19, 283–289 (2006).
pubmed: 16645491
doi: 10.1097/01.qco.0000224824.73223.e7
Barks, J. D. E., Liu, Y., Wang, L., Pai, M. P. & Silverstein, F. S. Repurposing azithromycin for neonatal neuroprotection. Pediatr. Res. 86, 444–451 (2019).
pubmed: 31100754
pmcid: 6764891
doi: 10.1038/s41390-019-0408-6
Brumbaugh, J. E., Colaizy, T. T., Patel, N. M. & Klein, J. M. The changing relationship between bronchopulmonary dysplasia and cognition in very preterm infants. Acta Paediatr. 107, 1339–1344 (2018).
pubmed: 29333635
doi: 10.1111/apa.14219
Ruuskanen, O. Safety and tolerability of azithromycin in pediatric infectious diseases: 2003 update. Pediatr. Infect. Dis. J. 23, S135–S139 (2004).
pubmed: 14770077
doi: 10.1097/01.inf.0000112528.75956.41
Eberly, M. D., Eide, M. B., Thompson, J. L. & Nylund, C. M. Azithromycin in early infancy and pyloric stenosis. Pediatrics 135, 483–488 (2015).
pubmed: 25687145
doi: 10.1542/peds.2014-2026
Stark, C. M., Rogers, P. L., Eberly, M. D. & Nylund, C. M. Association of prematurity with the development of infantile hypertrophic pyloric stenosis. Pediatr. Res. 78, 218–222 (2015).
pubmed: 25950452
doi: 10.1038/pr.2015.92
Ray, W. A., Murray, K. T., Hall, K., Arbogast, P. G. & Stein, C. M. Azithromycin and the risk of cardiovascular death. N. Engl. J. Med. 366, 1881–1890 (2012).
pubmed: 22591294
pmcid: 3374857
doi: 10.1056/NEJMoa1003833
Lowe, J. et al. Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants. BMJ Open 10, e041528 (2020).
pubmed: 33028566
pmcid: 7539578
doi: 10.1136/bmjopen-2020-041528
Guillen, U. et al. Relationship between attrition and neurodevelopmental impairment rates in extremely preterm infants at 18 to 24 months: a systematic review. Arch. Pediatr. Adolesc. Med. 166, 178–184 (2012).
pubmed: 22312176
doi: 10.1001/archpediatrics.2011.616