In this comparative effectiveness research study, the rate of PDA pharmacotherapy failure was high among extremely preterm infants, with no observed differences in effectiveness between commonly used pharmacotherapy regimens, and compared with conservative management, pharmacotherapy was associated with lower mortality and higher BPD and NEC odds.
Key Findings
Results
Among extremely preterm infants who received PDA pharmacotherapy, 42.3% experienced failure of their primary pharmacotherapy regimen.
464 of 1097 treated infants experienced failure of primary pharmacotherapy, defined as need for additional medical and/or procedural PDA treatment
456 of 1097 infants (41.6%) received a repeat pharmacotherapy course
The cohort included infants born before 29 weeks' gestation with echocardiography-confirmed, predominantly left-right shunting, moderate- to large-sized PDA (diameter ≥1.5 mm)
Mean gestational age was 25.4 (SD 1.6) weeks and mean birth weight was 828 (SD 228) g
Results
There were no statistically significant differences in failure of primary pharmacotherapy among standard-dose ibuprofen, adjustable-dose ibuprofen, indomethacin, and acetaminophen after adjustment for confounders.
Analysis accounted for clustering within each site and adjusted for confounders
Among participating NICUs, 7 selected standard-dose ibuprofen, 8 selected adjustable-dose ibuprofen, 1 selected indomethacin, and 3 selected acetaminophen as primary pharmacotherapy
There was 28.1% (308 of 1097) protocol deviation, 75.0% of which was attributable to use of acetaminophen by sites that did not intend to use acetaminophen
Data from 19 tertiary NICUs in Canada as part of the Canadian Neonatal Network, collected January 1, 2020 to July 31, 2023
Results
Compared with conservatively managed infants, those who received pharmacotherapy had significantly lower odds of predischarge mortality.
Adjusted odds ratio (AOR) for mortality with pharmacotherapy vs. no pharmacotherapy: 0.35 (95% CI, 0.21–0.58)
259 infants (19.1%) received no pharmacotherapy (conservative management) and 1097 (80.9%) received pharmacotherapy
The authors note that confounding by contraindication and survival bias cannot be ruled out
Total cohort included 1356 infants
Results
Compared with conservatively managed infants, those who received pharmacotherapy had significantly higher odds of moderate to severe bronchopulmonary dysplasia (BPD).
AOR for moderate to severe BPD with pharmacotherapy vs. no pharmacotherapy: 1.91 (95% CI, 1.12–3.25)
BPD was a predefined secondary outcome
The authors note that confounding by contraindication and survival bias cannot be ruled out as explanations for this association
Results
Compared with conservatively managed infants, those who received pharmacotherapy had significantly higher odds of stage 2 or higher necrotizing enterocolitis (NEC).
AOR for NEC (stage 2 or higher) with pharmacotherapy vs. no pharmacotherapy: 2.15 (95% CI, 1.55–2.99)
NEC was a predefined secondary outcome
The authors note that confounding by contraindication and survival bias cannot be ruled out as explanations for this association
Results
Wide variation in PDA treatment practices existed across the 19 participating Canadian NICUs, including substantial protocol deviation.
Wide variation in primary pharmacotherapy selection: 7 NICUs used standard-dose ibuprofen, 8 used adjustable-dose ibuprofen, 1 used indomethacin, and 3 used acetaminophen
Protocol deviation rate was 28.1% (308 of 1097 infants)
75.0% of protocol deviations were due to use of acetaminophen by sites that had not selected acetaminophen as their primary regimen
Infants who received PDA treatment based solely on clinical diagnosis without echocardiographic confirmation or who underwent primary procedural closure were excluded
Methods
The study population consisted of 1356 extremely preterm infants with echocardiography-confirmed moderate-to-large PDA across 19 Canadian tertiary NICUs.
Mean (SD) gestational age: 25.4 (1.6) weeks; mean (SD) birth weight: 828 (228) g
746 males (55.0%)
Inclusion criteria required echocardiography-confirmed, predominantly left-right shunting, moderate- to large-sized PDA with diameter ≥1.5 mm
Study conducted between January 1, 2020, and July 31, 2023; data analyses conducted from May 9, 2024, to February 23, 2026
What This Means
This research suggests that among very premature babies (born before 29 weeks of pregnancy) with a heart condition called patent ductus arteriosus (PDA)—where a blood vessel that normally closes after birth remains open—none of the four commonly used medications (standard-dose ibuprofen, adjustable-dose ibuprofen, indomethacin, and acetaminophen) worked significantly better than the others. The study tracked 1,356 babies across 19 Canadian neonatal intensive care units and found that more than 4 in 10 babies who received drug treatment still needed additional treatment, indicating that treatment failure was common regardless of which medication was used.
The study also found important differences between babies who received drug treatment and those who were managed conservatively (without medications). Babies who received pharmacotherapy had lower odds of dying before hospital discharge, but they also had notably higher odds of developing two serious complications: bronchopulmonary dysplasia (a chronic lung condition) and necrotizing enterocolitis (a dangerous bowel condition). However, the researchers caution that these comparisons may be affected by the fact that sicker babies are more likely to receive treatment, and babies who survive longer are more likely to develop these complications—so the findings about conservative versus pharmacological management should be interpreted carefully.
This research suggests that no single drug stands out as superior for treating PDA in extremely preterm infants, and that treatment failure rates are high across all options. The findings highlight the need for further research to determine which babies benefit most from treatment versus a watchful waiting approach, since the choice of when and how to treat PDA in very premature infants remains a major unresolved question in neonatal care.
Mitra S, Jain A, Ting J, Ben Fadel N, Drolet C, Abou Mehrem A, et al.. (2026). Pharmacologic Therapies for Patent Ductus Arteriosus in Extremely Preterm Infants.. JAMA network open. https://doi.org/10.1001/jamanetworkopen.2026.17477