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 participants: 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.

Exposure: Surgical ligation vs medical management.

Main outcomes and measures: 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.

Results: 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).

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.

Figure 1.. Flow Diagram of Infants Included in the Study

GA indicates gestational age; NSA, nonsteroidal anti-inflammatory drug; and PDA, patent ductus arteriosus.

Figure 2.. Average Daily Mean Airway Pressure Over the First 40 Days of Life

Average daily mean airway pressure (cm H₂O) with 68% and 95% CIs over the first 40 days of life for medically-treated infants (black line) vs infants who underwent ligation (orange line) before ductal closure. Infants no longer contributed data after the date of ductal closure, leading to the widening of CIs over time as the number of infants with persistent hemodynamically significant patent ductus arteriosus diminished with time. The median date of ligation was day of life 29, with the interquartile range (day of life 22 to day of life 38) (solid gray box). The earliest date of ligation was on day of life 7.