title: Association of Patent Ductus Arteriosus Ligation With Death or Neurodevelopmental Impairment Among Extremely Preterm Infants.
abstract: Observational studies have associated patent ductus arteriosus (PDA) ligation among preterm infants with adverse neonatal outcomes and neurodevelopmental impairment in early childhood, with a resultant secular trend away from surgical treatment. However, to our knowledge, studies have inadequately addressed sources of residual bias, including survival bias and major neonatal morbidities arising before exposure to ligation.
  
  
  
  Evaluate the association between PDA ligation vs medical management and neonatal and neurodevelopmental outcomes.
  
  
  
  This retrospective cohort study of preterm infants younger than 28 weeks gestational age born between January 1, 2006, and December 31, 2012, with clinical and echocardiography diagnoses of hemodynamically significant PDA was conducted at 3 tertiary neonatal intensive care units and affiliated follow-up programs.
  
  
  
  Surgical ligation vs medical management.
  
  
  
  The primary outcome was a composite of death or neurodevelopmental impairment (NDI) at 18 to 24 months corrected age. Secondary outcomes included death before discharge, NDI, moderate-severe chronic lung disease, and severe retinopathy of prematurity. Multivariable logistic regression analysis was used to adjust for perinatal and postnatal confounders.
  
  
  
  Of 754 infants with hemodynamically significant PDA (mean [standard deviation] gestational age 25.7 [1.2] weeks and birth weight 813 [183] grams), 184 (24%) underwent ligation. Infants who underwent ligation had a higher frequency of morbidities before PDA closure, including sepsis, necrotizing enterocolitis, and a dependence on mechanical ventilation. After adjusting for perinatal characteristics and preligation morbidities, there was no difference in the odds of death or NDI (adjusted odds ratio (aOR), 0.83; 95% CI, 0.52-1.32), NDI (aOR, 1.27; 95% CI, 0.78-2.06), chronic lung disease (aOR, 1.36; 95% CI, 0.78-2.39) or severe retinopathy of prematurity (aOR, 1.61; 95% CI, 0.85-3.06). Ligation was associated with lower odds of mortality (aOR, 0.09; 95% CI, 0.04-0.21).
  
  
  
  Patent ductus arteriosus ligation among preterm neonates younger than 28 weeks gestational age was not associated with the composite outcome of death or NDI, and there were no differences in chronic lung disease, retinopathy of prematurity, or NDI among survivors. Mortality was lower among infants who underwent ligation, though residual survival bias could not be excluded. Previously reported associations of ligation with increased morbidity may be because of bias from confounding by indication.
authors.affiliation: Department of Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada2Department of Pediatrics, University of Toronto, Toronto, Canada.
authors.forename: Dany E
authors.initials: DE
authors.lastname: Weisz
authors.affiliation: Phoenix Children's Hospital, Phoenix, Arizona.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mirea
authors.affiliation: Department of Pediatrics, Hospital for Sick Children, Toronto, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Rosenberg
authors.affiliation: Department of Pediatrics, Mt. Sinai Hospital, Toronto, Canada.
authors.forename: Maximus
authors.initials: M
authors.lastname: Jang
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada4Department of Pediatrics, Hospital for Sick Children, Toronto, Canada.
authors.forename: Linh
authors.initials: L
authors.lastname: Ly
authors.affiliation: Department of Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada2Department of Pediatrics, University of Toronto, Toronto, Canada.
authors.forename: Paige T
authors.initials: PT
authors.lastname: Church
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada5Department of Pediatrics, Mt. Sinai Hospital, Toronto, Canada.
authors.forename: Edmond
authors.initials: E
authors.lastname: Kelly
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada5Department of Pediatrics, Mt. Sinai Hospital, Toronto, Canada.
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada4Department of Pediatrics, Hospital for Sick Children, Toronto, Canada7Department of Physiology, University of Toronto and Physiology and Experimental Medicine, SickKids Research Institute, Toronto, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada5Department of Pediatrics, Mt. Sinai Hospital, Toronto, Canada8Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
authors.forename: Prakesh S
authors.initials: PS
authors.lastname: Shah
mesh_terms: D002675:Child, Preschool; D015331:Cohort Studies; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy / Q000401:mortality / Q000601:surgery*; D005260:Female; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008026:Ligation / Q000009:adverse effects / Q000379:methods / Q000401:mortality*; D016015:Logistic Models; D008297:Male; D065886:Neurodevelopmental Disorders / Q000453:epidemiology / Q000209:etiology*; D012189:Retrospective Studies; D016896:Treatment Outcome