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Title	[기획과제] PDA management strategies in last years: a comparison of the Canadian and South Korean experience
Author	James Joonsik Park, Kyong-Soon Lee, Prakeshkumar Shah and Yoong-A Suh
작성자	서융아
Background	Patent ductus arteriosus and adverse outcomes among preterm infants Patent ductus arteriosus (PDA) is the most common congenital heart defect among preterm neonates and may be a significant cause of mortality and morbidity. 1 PDA occurs in approximately 39% of preterm neonates born under gestational age (GA) of 33 weeks, affecting 1251 neonates across Canada annually. 2 PDA in preterm infants is associated with severe necrotizing enterocolitis (NEC), chronic lung disease, intraventricular hemorrhage (IVH), and mortality. 3 Diverse treatment options in PDA management Several management strategies for PDA are currently practiced, ranging from conservative management, including fluid restriction, medical treatment using cyclooxygenase inhibitors such as indomethacin and ibuprofen, and, in some instances, surgical ligation. Presently, there has yet to be a consensus on PDA management strategies. 3,4 Association between surgical PDA ligation and adverse outcomes Previous retrospective studies have associated surgical PDA ligation with increased neonatal and neurodevelopmental morbidity. 5 However, there is a secular trend toward a reduction in surgical ligation. 6 The concern regarding these reports has been that there is a high risk of residual bias against infants who underwent ligation because of confounding by indication and increased pre-ligation illness severity. 5 Additionally, surgical ligation as a rescue treatment after failure of medical therapy showed worse outcomes compared with surgical ligation without medical therapy. 4 Variation in PDA treatment approaches. The impact of surgical ligation on neonatal morbidities is challenging to determine due to the presence of multiple confounders and cointerventions, and there have been attempts to assess their association with statistical adjustments such as the propensity scoring method. 3,7 Among preterm infants with gestational age (GA) <28 weeks and PDA, the surgical ligation rates for PDA have been reported at 12.3 % in the Korean Neonatal Network (KNN) 8-10 compared with 5% in the Canadian Neonatal Network (CNN) in 2021.2 While studies have compared national cohorts in Japan and Canada, these were for practices from 2006 to 2008. 11 Comparison of more recent approaches from two national cohorts from the KNN and CNN will provide insight into the variation in patterns, treatment trends, and whether these variations may be associated with outcomes.
Aim / Hypothesis	This study aims to compare the differences in PDA treatment strategies and trends in two national neonatal cohorts and analyze the association of PDA management with NICU outcomes. In two cohorts with different therapeutic approaches of PDA, differences exist in the treatment outcomes of preterm infants
Inclusion Criteria	1) All neonates between 24 weeks 0 days and 28 6/7 weeks GA diagnosed with patent ductus arteriosus and were enrolled in the CNN or KNN cohort. CNN cohort The CNN collects patient data on tertiary NICU admissions from 33 participating sites. The neonates must have had a length of stay at one of the CNN participating sites for greater than or equal to 24 hours, or died or were transferred to another level 2 or 3 facility within 24 hours. Delivery room deaths, moribund neonates, and readmissions are excluded. Data are entered by trained abstractors at each site for benchmarking and research (reference) with high internal consistency and reliability. 2) All neonates between 24 weeks 0 days and 28 6/7 weeks GA diagnosed with patent ductus arteriosus and were enrolled in the KNN cohort. KNN cohort The KNN collects patient data on tertiary NICU admissions with gestational age less than 32 weeks or birth weight less than 1,500 grams. The infant must have been born at a KNN participating hospital or admitted to a KNN after birth within 28 days of birth. Delivery room deaths are excluded. 3) PDA definitions : CNN Categorised as: 1. Having PDA: if infant had clinical or echocardiographic suspicion of PDA or received treatment for PDA 2. No PDA: if infant had no clinical suspicion of PDA KNN: Categorised as: 1. Having PDA: a) Clinical suspicion of PDA defined as: when two or more of the following five criteria exist Systolic murmur or continuous murmur. i. Bounding pulse or hyperactive precordium ii. Difficulty in maintaining blood pressure (e.g., hypotension unresponsive to fluid therapy or dopamine, with hypotension defined as the lower limit of normal arterial blood pressure for corrected gestational age) iii. Worsening respiratory status iv. Evidence on chest X-ray of pulmonary congestion, increased pulmonary blood flow with associated cardiomegaly (cardiothoracic ratio > 60%, etc.) or b) large left-to-right ductal flow through PDA is confirmed by Color-flow Doppler cardiac ultrasound 2. No PDA: if infant had no clinical suspicion of PDA
Exclusion Criteria	Exclusion Criteria: 1) Congenital cardiac anomalies except patent ductus arteriosus, patent foramen ovale, atrial septal defect or ventricular septal defect. 2) Known major congenital anomaly
Study Design Statistical methods	Statistical analysis Descriptive and inferential statistics will be calculated for each network (KNN and CNN) separately. The subjects' baseline characteristics will be assessed using chi-square and one-way ANOVA F-tests for categorical and continuous covariates, respectively. The Cochrane-Armitage trend test will be used to determine yearly patterns with PDA management assuming the following low-to-high intensity ordering of PDA treatment groups: conservative treatment, medical treatment only, surgical treatment only, and medical and surgical treatments. Linear and logistic regression models combined with Linear Mixed Model (LMM) and Generalized Estimating Equation (GEE) will be used to determine the association of risk factors or interventions with each outcome and reported with adjusted and unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) using data from KNN and CNN separately. Sample Size The number of patients diagnosed with PDA yearly is approximately 1000 in the CNN database and 500 in the KNN database. Over the 10-year study period, an estimated total of 15,000 patients will be included from both national cohorts.
Primary Outcomes	Moderate to severe bronchopulmonary dysplasia (BPD): defined as oxygen or positive pressure support at 36 weeks corrected GA or at the time of transfer to level two hospitals
Secondary Outcomes and Definitions	1. Moderate to severe necrotizing enterocolitis (NEC) is defined as Bell’s stage ≥ 2a 2. Length of ventilator days 3. Length of oxygen supplementation 4. Periventricular leukomalacia 5. Mortality
Protocols	Baseline data before the PDA management approach Gestational age at birth, birth weight, small for gestational age, male sex, cesarean birth, outborn, Apgar score at 5 minutes, maternal age, any antenatal steroid, maternal diabetes, maternal hypertension chorioamnionitis, severe intraventricular hemorrhage (IVH) defined as IVH with dilatation or periventricular venous hemorrhagic infarction and severe post-hemorrhagic ventricular dilatation.
Funding	none

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