Treatment of Patent Ductus Arteriosus and Neonatal Mortality/Morbidities: Adjustment for Treatment Selection Bias

doi:10.1016/j.jpeds.2012.05.007

The Journal of Pediatrics

Volume 161, Issue 4, October 2012, Pages 689-694.e1

https://doi.org/10.1016/j.jpeds.2012.05.007 Get rights and content

Objective

To examine the association between treatment for patent ductus arteriosus (PDA) and neonatal outcomes in preterm infants, after adjustment for treatment selection bias.

Study design

Secondary analyses were conducted using data collected by the Canadian Neonatal Network for neonates born at a gestational age ≤32 weeks and admitted to neonatal intensive care units in Canada between 2004 and 2008. Infants who had PDA and survived beyond 72 hours were included in multivariable logistic regression analyses that compared mortality or any severe neonatal morbidity (intraventricular hemorrhage grades ≥3, retinopathy of prematurity stages ≥3, bronchopulmonary dysplasia, or necrotizing enterocolitis stages ≥2) between treatment groups (conservative management, indomethacin only, surgical ligation only, or both indomethacin and ligation). Propensity scores (PS) were estimated for each pair of treatment comparisons, and used in PS-adjusted and PS-matched analyses.

Results

Among 3556 eligible infants with a diagnosis of PDA, 577 (16%) were conservatively managed, 2026 (57%) received indomethacin only, 327 (9%) underwent ligation only, and 626 (18%) were treated with both indomethacin and ligation. All multivariable and PS-based analyses detected significantly higher mortality/morbidities for surgically ligated infants, irrespective of prior indomethacin treatment (OR ranged from 1.25-2.35) compared with infants managed conservatively or those who received only indomethacin. No significant differences were detected between infants treated with only indomethacin and those managed conservatively.

Conclusions

Surgical ligation of PDA in preterm neonates was associated with increased neonatal mortality/morbidity in all analyses adjusted for measured confounders that attempt to account for treatment selection bias.

Section snippets

Methods

These secondary analyses examined data from preterm infants born between 2004 and 2008 at GA ≤32 weeks and diagnosed with PDA from 22 neonatal intensive care units (NICUs) that contributed data to the Canadian Neonatal Network (CNN). All NICUs are regional tertiary level referral centers and the CNN database comprises >90% of admissions to level 3 NICUs in Canada. The NICUs ranged in size from 9-70 beds and included between 74 and 1122 admissions annually. Data were collected by trained

Results

A total of 14 418 infants born at ≤32 weeks GA were admitted to NICUs participating in the CNN during the study period, of whom 3673 (25%) were diagnosed with PDA. After exclusion of 35 infants with PDA who died within 72 hours after birth and 82 infants with congenital heart defects, we examined data from 3556 infants admitted to 22 sites. Significant differences between PDA treatment groups were detected for the following potential confounders: year of birth, CNN site, GA, inborn/outborn

Discussion

Although ligation of PDA is considered the definitive treatment option, the evidence regarding the impact of this procedure on mortality and/or severe neonatal morbidities is conflicting. A randomized controlled trial of prophylactic ligation¹³ showed decreased rates of NEC in infants with early compared with late ligation; an observational study¹⁹ reported decreased mortality for ligation compared with only indomethacin treatment; and in a study of preterm baboons, Loeliger et al³⁴

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Cited by (118)

Active versus restrictive ligation strategy for patent ductus arteriosus – A retrospective two-center study of extremely preterm infants born between 22 + 0 and 25 + 6 weeks of gestational age
2024, Early Human Development
Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable.
To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA.
Retrospective, two-center, cohort study.
Infants born at 22⁺⁰–25⁺⁶ weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220).
Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP).
Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort.
Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.
Treatment of patent ductus arteriosus and short-term outcomes among extremely preterm infants: a multicentre cohort study
2024, eClinicalMedicine
The optimal treatment strategy for patent ductus arteriosus (PDA) in extremely preterm infants is currently highly controversial. This study aimed to evaluate the association between PDA treatment and short-term outcomes among extremely preterm infants.
This cohort study included all extremely preterm infants (≤27 and 6/7 weeks) who were admitted to hospitals participating in the Chinese Neonatal Network from January 2019 to December 2021, and were diagnosed to have PDA by echocardiogram. PDA treatment was defined as medical treatment and/or surgical ligation of PDA during hospitalization. Short-term outcomes included death, bronchopulmonary dysplasia (BPD), death/BPD, retinopathy of prematurity, necrotizing enterocolitis, and severe brain injury. Multivariate logistic regression was used to evaluate the association between PDA treatment and outcomes. Subgroup analysis were performed among infants with different respiratory support on 3 and 7 days of life.
A total of 2494 extremely preterm infants with the diagnosis of PDA were enrolled, of which 1299 (52.1%) received PDA treatment. PDA treatment was significantly associated with lower risk of death (adjusted odds ratio, 0.48; 95% confidence interval, 0.38–0.60). The decreased risk of death was accompanied by increased risk of BPD and death/BPD. In subgroup analysis according to respiratory support, PDA treatment was associated with lower risk of death among infants who required invasive ventilation. However, the beneficial effect on death was not significant among infants who did not require invasive ventilation.
PDA treatment was associated with reduced mortality in extremely preterm infants, but this beneficial effect was mainly present among infants who required invasive ventilation.
This study was funded by the Shanghai Science and Technology Commission's Scientific and Technological Innovation Action Plan (21Y21900800) and the Canadian Institutes of Health Research (CTP87518).
Trends in Procedural Closure of the Patent Ductus Arteriosus among Infants Born at 22 to 30 Weeks’ Gestation
2023, Journal of Pediatrics
To describe recent trend in procedural closure of the patent ductus arteriosus (PDA) among premature infants and compare the clinical characteristics of infants receiving surgical vs transcatheter closure.
We conducted a descriptive, retrospective cohort study of preterm infants born between 22^0/7 and 29^6/7 weeks’ gestation from 2014 through 2021. Infants were identified from the Pediatrix Clinical Data Warehouse. We excluded infants with any major congenital anomaly. We identified all preterm infants with a PDA and all those who underwent procedural closure (surgical ligation or transcatheter occlusion) and compared changes over time using ANOVA for continuous variables and the Cochran-Armitage trend test to evaluate time-related changes in proportions.
The study cohort included 64 580 infants, of whom 24 028 (37.2%) were diagnosed with a PDA. The number of infants receiving any procedural closure of the PDA decreased from 371 (4.4%) in 2014 to 144 (1.9%) in 2021. During the same period, number of surgical ligations decreased from 369 (4.36%) to 64 (0.84%), and the number of transcatheter occlusions increased from 2 (0.02%) to 80 (1.05% p for all < 0.001). The median age at time of surgical ligation increased from 25 days (10th and 90th percentile, 10, 61) to 31 days (10th and 90th percentile, 16, 66), and the median age of transcatheter occlusion decreased from 103 days (10th and 90th percentile, 32, 150) to 43 days (10th and 90th percentile, 22, 91).
There was a decrease in surgical closure and an increase in transcatheter occlusion of the PDA in infants born at 22-30 weeks' gestation from 2014 to 2021. Despite the decline in overall procedural closure, the rate of transcatheter occlusion surpassed surgical ligation by 2021. Narrowing differences in the median age and weight at closure suggest increasing overlap in the types of infants who received each type of procedural closure.
Clinical outcomes of different patent ductus arteriosus treatment in preterm infants born between 28 and 32 weeks in Taiwan
2023, Pediatrics and Neonatology
The patent ductus arteriosus (PDA) treatment in very preterm infants is controversial. This study focused on preterm infants born at 28–32 weeks of gestation and analyzed the association between various PDA treatments and clinical outcomes.
We conducted a retrospective cohort study of infants born at 28–32 weeks of gestation between 2016 and 2019 at 22 hospitals in the Taiwan Premature Infant Follow-up Network. We categorized the infants into four groups according to treatment strategies: medication, primary surgery, medication plus surgery, or conservative treatment.
A total of 1244 infants presented with PDA, and 761 (61.1%) were treated. Medication was the predominant treatment (50.0%), followed by conservative treatment (38.9%), medication plus surgery (7.6%), and primary surgery (3.5%). The risk of mortality was not reduced in the active treatment group compared to the conservative treatment group. There was a higher prevalence of severe intraventricular hemorrhage, necrotizing enterocolitis (NEC), and any degree of bronchopulmonary dysplasia (BPD) in both the primary surgery and medication plus surgery groups than in the conservative treatment group. After adjustment, both the primary surgery and medication plus surgery groups still had higher odds ratios for the occurrence of NEC and any degree of BPD.
Compared with active PDA treatment, conservative treatment for PDA did not increase the risk of mortality and morbidity in very preterm infants born at 28–32 weeks of gestation. The risks and benefits of surgery (PDA ligation) in these infants must be considered cautiously.
Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia
2022, Journal of Pediatrics
To test the hypothesis that elevated respiratory severity indices will identify patients with severe bronchopulmonary dysplasia (BPD) at the greatest risk for adverse in-hospital outcomes.
This was a retrospective cohort study. A modified respiratory severity score (mean airway pressure × fraction of inspired oxygen) and a modified pulmonary score (respiratory support score × fraction of inspired oxygen + sum of medication scores) were calculated in a consecutive cohort of patients ≥36 weeks of postmenstrual age with severe BPD admitted to a referral center between 2010 and 2018. The association between each score and the primary composite outcome of death/prolonged length of stay (>75th percentile for cohort) was assessed using area under the receiver operator characteristic curve (AUROC) analysis and logistic regression. Death and the composite outcome death/tracheostomy were analyzed as secondary outcomes.
In 303 patients, elevated scores were significantly associated with increased adjusted odds of death/prolonged length of stay: aOR 1.5 (95% CI 1.3-1.7) for the modified respiratory severity score and aOR 11.5 (95% CI 5.5-24.1) for the modified pulmonary score. The modified pulmonary score had slightly better discrimination of death/prolonged length of stay when compared with the modified respiratory severity score, AUROC 0.90 (95% CI 0.85-0.94) vs 0.88 (95% CI 0.84-0.93), P = .03. AUROCs for death and death/tracheostomy did not differ significantly when comparing the modified respiratory severity score with the modified pulmonary score.
In our referral center, the modified respiratory severity score or the modified pulmonary score identified patients with established severe BPD at the greatest risk for death/prolonged length of stay, death, and death/tracheostomy.
Management of the infant with bronchopulmonary dysplasia
2022, Goldsmith's Assisted Ventilation of the Neonate: An Evidence-Based Approach to Newborn Respiratory Care, Seventh Edition

View all citing articles on Scopus

: The Canadian Institutes of Health Research team in Maternal-Infant Care (MiCare) provided organizational support to the Canadian Neonatal Network. The Maternal-Infant Care Research Center is supported by the Ministry of Health and Long-Term Care, Ontario, Canada. The authors declare no conflicts of interest.

^∗: List of members of the Canadian Neonatal Network is available at www.jpeds.com (Appendix).

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Original ArticleTreatment of Patent Ductus Arteriosus and Neonatal Mortality/Morbidities: Adjustment for Treatment Selection Bias

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

J Pediatr

J Pediatr

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Pediatr Clin North Am

J Pediatr

J Pediatr Surg

Patent ductus arteriosus, indomethacin, and necrotizing enterocolitis in very low birth weight infants: a population-based study

J Pediatr Gastroenterol Nutr

Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. North Carolina Neonatologists Association

Pediatrics

Intraventricular hemorrhage: a prospective evaluation of etiopathogenesis

Pediatrics

Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants

Arch Dis Child Fetal Neonatal Ed

Failure of ductus arteriosus closure is associated with increased mortality in preterm infants

Pediatrics

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

J Perinatol

Patent ductus arteriosus in the preterm infant: to treat or not to treat?

J Perinatol

Treatment strategies to prevent or close a patent ductus arteriosus in preterm infants and outcomes

J Perinatol

A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth

N Engl J Med

Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial

Pediatrics

Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants

N Engl J Med

Original Article
Treatment of Patent Ductus Arteriosus and Neonatal Mortality/Morbidities: Adjustment for Treatment Selection Bias