Association of Patent Ductus Arteriosus Ligation With Death or Neurodevelopmental Impairment Among Extremely Preterm Infants

Abstract

IMPORTANCE 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.OBJECTIVE Evaluate the association between PDA ligation vs medical management and neonatal and neurodevelopmental outcomes. DESIGN, SETTING, AND PARTICIPANTSThis 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.EXPOSURE Surgical ligation vs medical management. MAIN OUTCOMES AND MEASURESThe 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. RESULTSOf 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).CONCLUSIONS AND RELEVANCE 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.

Early surgery and neurodevelopmental outcomes of children born extremely preterm

“…However, Weisz et al  reported results of another retrospective cohort study in which postnatal confounders of various neonatal morbidities were adjusted for, motivated by awareness that previous retrospective studies failed to make such statistical adjustments. By minimising survival bias in the ligated group, they found no difference in outcomes of death, disability or neurodevelopmental impairment between those EP infants treated medically or surgically for PDA 23. When a similar analytic model was applied in our study, surgical management of PDA was no longer associated with poor neurodevelopment.…”

Effects of practice change on outcomes of extremely preterm infants with patent ductus arteriosus

“…Weisz et al , in a meta‐analysis of studies examining PDA ligation, found increased risk of neurodevelopmental impairment, BPD, and ROP in those that underwent ligation, although there may have been a concomitant reduction in mortality. A more recent observational study from the same group found no difference in the composite outcome of death or NDI between infants with a PDA undergoing ligation and those with a PDA not undergoing ligation. Additional reports found that infants who had treatments or surgery for closure of the PDA were at higher risk of developing BPD than were preterm infants that received no treatment for the PDA.…”

European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update

“…Permissive tolerance of PDA is a strategy which is being studied in clinical trials [182]. Surgical ligation of PDA should only be considered if medical therapy has failed and the PDA is causing significant clinical problems [183]. …”