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Am J Perinatol 2018; 35(10): 972-978
DOI: 10.1055/s-0038-1632390
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Association of Antibiotic Utilization and Neurodevelopmental Outcomes among Extremely Low Gestational Age Neonates without Proven Sepsis or Necrotizing Enterocolitis

Joseph Y. Ting
1   Department of Pediatrics, University of British Columbia, Vancouver, Canada
,
Anne Synnes
1   Department of Pediatrics, University of British Columbia, Vancouver, Canada
,
Ashley Roberts
1   Department of Pediatrics, University of British Columbia, Vancouver, Canada
,
Akhil C. Deshpandey
2   Janeway Children's Health and Rehabilitation Centre, Saint John's, Newfoundland, Canada
,
Kimberly Dow
3   Department of Pediatrics, Kingston General Hospital and Queen's University, Kingston, Ontario, Canada
,
Junmin Yang
4   Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
,
Kyong-Soon Lee
4   Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
5   Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
,
Shoo K. Lee
4   Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
5   Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
,
Prakesh S. Shah
4   Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
5   Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
,
on behalf of the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network › Author Affiliations Funding This work was supported by the Canadian Neonatal Network (CNN) Coordinating Centre, which is based at the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada. The CNN and MiCare are supported by team grant funding from the Canadian Institutes of Health Research (FRN87518 and PBN150642). Dr. Ting receives salary support from the Investigator Grant Award by the British Columbia Children's Hospital Research Institute. Dr. Shah holds an applied research chair in Reproductive and Child Health Services and Policy Research awarded by the Canadian Institutes of Health Research (APR-126340).
Further Information

Publication History

12 October 2017

12 January 2018

Publication Date:
23 February 2018 (online)

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Abstract

Objective The objective is to evaluate the association between antibiotic utilization and neurodevelopmental outcomes at 18 to 21 months' corrected age among extremely low gestational age neonates without culture-proven sepsis or necrotizing enterocolitis (NEC).

Study Design We conducted a retrospective cohort study of infants born between April 2009 and September 2011 at <29 weeks' gestation and admitted to the neonatal intensive care units contributing data to the Canadian Neonatal Network. Multivariable analysis was performed to examine the primary composite outcome of death or significant neurodevelopmental impairment (sNDI) in infants with various antibiotic utilization rates (AURs).

Result There were 1,373 infants who fulfilled our inclusion criteria. Compared with infants in the lowest AUR quartile (Q1), those in the highest quartile (Q4) had higher odds of death or sNDI (adjusted odds ratio [AOR] = 7.44; 95% confidence interval [CI]: 4.55, 12.2) and death (AOR = 39.3; 95% CI: 16.1, 95.9).

Conclusion Our results indicate an association between high AUR and a composite outcome of death or adverse neurodevelopmental outcomes at 18 to 21 months' corrected age.

Keywords

extremely low gestational age - neonate - antibiotic - neurodevelopmental outcomes

Authors' Contributions

The first draft of this manuscript was written by Joseph Y. Ting. All authors take responsibility for the reported findings and have participated in the concept and design, analysis and interpretation of data, drafting or revising, and approval of this manuscript as submitted. No honorarium, grant, or other form of payment was given to anyone to write the manuscript.


Canadian Neonatal Network Site Investigators

Prakesh S. Shah, MD, MSc (Director, Canadian Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, Ontario; Adele Harrison, MD, MBChB, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, MDCM, MHSC, and Joseph Ting, MD, B.C. Women's Hospital and Health Centre, Vancouver, British Columbia; Zenon Cieslak, MD, Royal Columbian Hospital, New Westminster, British Columbia; Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, British Columbia; Wendy Yee, MD, Foothills Medical Centre, Calgary, Alberta; Khalid Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, Alberta; Carlos Fajardo, MD, Alberta Children's Hospital, Calgary, Alberta; Zarin Kalapesi, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, MBChB, Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, Manitoba; Amit Mukerji, MD, Hamilton Health Sciences Centre, Hamilton, Ontario; Orlando Da Silva, MD, MSc, London Health Sciences Centre, London, Ontario; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, Ontario; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, Ontario; Michael Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario; Brigitte Lemyre, MD, Children's Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; Kimberly Dow, MD, Kingston General Hospital, Kingston, Ontario; Victoria Bizgu, MD, Jewish General Hospital, Montréal, Québec; Keith Barrington, MBChB, Hôpital Sainte-Justine, Montréal, Québec; Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre Hospitalier Universitaire de Québec, Sainte Foy, Québec; Martine Claveau, MSc, LLM, NNP, and Marc Beltempo, MD, McGill University Health Centre, Montréal, Québec; Valerie Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick; Akhil C. Deshpandey, MBBS, MRCPI, Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland; Jehier Afifi, MB BCh, MSc, IWK Health Centre, Halifax, Nova Scotia; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, Nova Scotia; Shoo K Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.


Canadian Neonatal Follow-Up Network Investigators

Thevanisha Pillay, MD, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, MDCM, MHSC (Director, CNFUN), B.C. Women's Hospital and Health Centre, Vancouver, British Columbia; Reg Sauvé, MD, MPh, Leonora Hendson MBBCH, MSc, Alberta's Children's Hospital, Foothills Medical Centre, Calgary, Alberta; Amber Reichert, MD, Glenrose Rehabilitation Hospital, Edmonton, Alberta; Jaya Bodani, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, Royal University Hospital, Saskatoon, Saskatchewan; Diane Moddemann, MD, Winnipeg Health Sciences Centre, St. Boniface General Hospital, Winnipeg, Manitoba; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, Ontario; Thierry Daboval, MD, Children's Hospital of Eastern Ontario, Ottawa, Ontario; Kimberly Dow, Kingston General Hospital, Kingston, Ontario; David Lee, MD, Children's Hospital London Health Sciences Centre, London, Ontario; Linh Ly, MD, Hospital for Sick Children, Toronto, Ontario; Edmond Kelly, MD, Mount Sinai Hospital, Toronto, Ontario; Salhab el Helou, MD, Hamilton Health Sciences Centre, Hamilton, Ontario; Paige Church, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario; Ermelinda Pelausa, MD, Jewish General Hospital, Montréal, Québec; Patricia Riley, MD, Montréal Children's Hospital, Royal Victoria Hospital, Montréal, Québec; Francine Levebrve, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec; Charlotte Demers, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Sylvie Bélanger, MD, Centre Hospitalier Universitaire de Québec, Québec City, Québec; Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick; Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Michael Vincer, MD, IWK Health Centre, Halifax, Nova Scotia; Phil Murphy, Charles Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland.


 

  • References

  • 1 Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 2006; 117 (06) 1979-1987
    CrossrefPubMedGoogle Scholar
  • 2 Osowicki J, Gwee A, Noronha J. , et al; ANZPID-ASAP group (Australian and New Zealand Paediatric Infectious Diseases-Australasian Stewardship of Antimicrobials in Paediatrics). Australia-wide point prevalence survey of antimicrobial prescribing in neonatal units: how much and how good?. Pediatr Infect Dis J 2015; 34 (08) e185-e190
    CrossrefPubMedGoogle Scholar
  • 3 Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011; 159 (05) 720-725
    CrossrefPubMedGoogle Scholar
  • 4 Cotten CM, Taylor S, Stoll B. , et al; NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009; 123 (01) 58-66
    CrossrefPubMedGoogle Scholar
  • 5 Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin Jr DK. ; National Institute for Child Health and Human Development Neonatal Research Network. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006; 118 (02) 717-722
    CrossrefPubMedGoogle Scholar
  • 6 Ting JY, Synnes A, Roberts A. , et al; Canadian Neonatal Network Investigators. Association between antibiotic use and neonatal mortality and morbidities in very low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis. JAMA Pediatr 2016; 170 (12) 1181-1187
    CrossrefPubMedGoogle Scholar
  • 7 Clausen TD, Bergholt T, Bouaziz O. , et al. Broad-spectrum antibiotic treatment and subsequent childhood type 1 diabetes: a nationwide Danish cohort study. PLoS One 2016; 11 (08) e0161654
    CrossrefPubMedGoogle Scholar
  • 8 Batool T, Reece PL, Schulze KM. , et al; FAMILY Study Investigators. Prenatal and early-life predictors of atopy and allergic disease in Canadian children: results of the Family Atherosclerosis Monitoring In earLY life (FAMILY) Study. J Dev Orig Health Dis 2016; 7 (06) 665-671
    CrossrefPubMedGoogle Scholar
  • 9 Mbakwa CA, Scheres L, Penders J, Mommers M, Thijs C, Arts IC. Early life antibiotic exposure and weight development in children. J Pediatr 2016; 176: 105-113
    CrossrefPubMedGoogle Scholar
  • 10 Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr 2013; 167 (04) 374-379
    CrossrefPubMedGoogle Scholar
  • 11 Neufeld KA, Kang N, Bienenstock J, Foster JA. Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol 2011; 4 (04) 492-494
    CrossrefPubMedGoogle Scholar
  • 12 Synnes A, Luu TM, Moddemann D. , et al; Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network. Determinants of developmental outcomes in a very preterm Canadian cohort. Arch Dis Child Fetal Neonatal Ed 2017; 102 (03) F235-F234
    CrossrefPubMedGoogle Scholar
  • 13 Bell MJ, Ternberg JL, Feigin RD. , et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 14 Mukhopadhyay S, Puopolo KM. Antibiotic use and mortality among premature infants without confirmed infection-perpetrator or innocent bystander?. JAMA Pediatr 2016; 170 (12) 1144-1146
    CrossrefPubMedGoogle Scholar
  • 15 Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe 2015; 17 (05) 553-564
    CrossrefPubMedGoogle Scholar
  • 16 Arboleya S, Sánchez B, Solís G. , et al. Impact of prematurity and perinatal antibiotics on the developing intestinal microbiota: a functional inference study. Int J Mol Sci 2016; 17 (05) 649
    CrossrefPubMedGoogle Scholar
  • 17 Schumann A, Nutten S, Donnicola D. , et al. Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome. Physiol Genomics 2005; 23 (02) 235-245
    CrossrefPubMedGoogle Scholar
  • 18 Neu J, Douglas-Escobar M, Lopez M. Microbes and the developing gastrointestinal tract. Nutr Clin Pract 2007; 22 (02) 174-182
    CrossrefPubMedGoogle Scholar
  • 19 Soliman N, Chaput K, Alshaikh B, Yusuf K. Preeclampsia and the risk of bronchopulmonary dysplasia in preterm infants less than 32 weeks' gestation. Am J Perinatol 2017; 34 (06) 585-592
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Lapcharoensap W, Gage SC, Kan P. , et al. Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA Pediatr 2015; 169 (02) e143676
    CrossrefPubMedGoogle Scholar
  • 21 Ward Platt M, Deshpande S. Metabolic adaptation at birth. Semin Fetal Neonatal Med 2005; 10 (04) 341-350
    CrossrefPubMedGoogle Scholar
  • 22 Robel-Tillig E, Knüpfer M, Vogtmann C. Cardiac adaptation in small for gestational age neonates after prenatal hemodynamic disturbances. Early Hum Dev 2003; 72 (02) 123-129
    CrossrefPubMedGoogle Scholar
  • 23 Cryan JF, O'Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 2011; 23 (03) 187-192
    CrossrefPubMedGoogle Scholar
  • 24 Diaz Heijtz R. Fetal, neonatal, and infant microbiome: perturbations and subsequent effects on brain development and behavior. Semin Fetal Neonatal Med 2016; 21 (06) 410-417
    CrossrefPubMedGoogle Scholar
  • 25 Hoban AE, Stilling RM, Ryan FJ. , et al. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry 2016; 6: e774
    CrossrefPubMedGoogle Scholar
  • 26 Diaz Heijtz R, Wang S, Anuar F. , et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 2011; 108 (07) 3047-3052
    CrossrefPubMedGoogle Scholar