In this cohort, unit-level PDA management policy (conservative vs targeted-exposure) in extremely preterm infants was not associated with significant NDI or any NDI. Our results indicated overall higher motor scores averages in the interventional site, although this did not reach clinical significance based on cut-off thresholds of 85 and 70. Although the rate of mortality at Site 1 was higher, the composite outcome of death or NDI was similar between sites.
Controversies regarding optimal PDA management in the preterm population exist, and whether neonatal outcomes are influenced by accelerating ductal closure (31). The most commonly administered medications to accelerate ductal closure remain NSAIDs, although acetaminophen has been increasingly used in the past years (32). In our study, we could not explore the impact of acetaminophen exposure, as this medication had not been implemented during the years of the study. Exposure to NSAIDs has also been associated with side effects, such as oliguria, platelet dysfunction, cerebral vasoconstriction (5) and pulmonary anti-angiogenesis phenomenon (33, 34). Recently, a randomized controlled trial has shown that an expectant PDA management (defined as no intentional treatment to accelerate ductal closure with ibuprofen, within 72 hours of postnatal life in preterm infants with a left to right shunting PDA > 1.5 mm) was non-inferior to an early-ibuprofen strategy regarding the combined outcome of NEC, moderate-to-severe BPD or death (35). Authors postulated that early ibuprofen exposure may be harmful, as the incidence of moderate-to-severe BPD was significantly higher in their early-ibuprofen exposed group (7). With the motivation to find a better strategy to accelerate ductal constriction and mitigate its theoretical effects on systemic and pulmonary circulations, acetaminophen has been proposed but has shown variable efficacy regarding ductal constriction (36). PDA ligation has been associated with adverse neurodevelopmental outcomes, as well as surgical and post-surgical complications (37). Studies are currently ongoing regarding early shunt closure with a catheterized-based intervention (38).
A recent randomized multi-center controlled trial reported on the outcome of survival without CP at 24 months of cGA in < 28 weeks with a large PDA diagnosed between 6 to 12 hours of life and who were exposed to either ibuprofen or placebo (6). Early echocardiography-targeted ibuprofen did not impact the primary outcome. However, in the placebo group, 62% received open-label rescue therapy, raising doubts about the applicability of the results to a strict non-interventional approach. In another retrospective Japanese cohort study, preterm infants born at < 29 weeks and exposed to a conservative policy regarding the PDA were evaluated at 5 years cGA, using the Kaufman Assessment Battery for Children. No increased risk of neurodevelopmental disorders was found at 5 years of corrected age (39). Those with a closed ductus within the first 14 days of life were found to have similar neurodevelopmental scores when compared to those who achieved ductal closure after 14 days, indicating that early ductal patency duration did not significantly impact their outcomes. Furthermore, in a multicenter observational study of 1090 preterm low-birthweight infants, the presence of a PDA was found in 135 infants and was not associated with differences in cognitive or behavioral competences at age 3, 8, and 18 years (40). A report from Spain also evaluated the neurodevelopmental outcomes of premature infants < 29 weeks at birth after their adoption of a conservative PDA policy, in a pre-post study design (41). Although they found a significant drop in the exposure to PDA-related management strategies, infants within their conservative epoch were still exposed to medical (32%) or surgical (7%) related therapies. Neurodevelopmental outcomes at 2 years were similar between the two epochs. In their study, a longer PDA duration (> 28 days) was not associated with worst outcomes in terms of survival without neurodevelopmental impairment. Therefore, there is a growing body of evidence in the literature that supports our findings. Nonetheless, there is still a lack of comparisons between a conservative approach and the exposure to acetaminophen or to a catheter-based closure in terms of long-term follow-up and subsequent outcomes.
When comparing various strategies to accelerate ductal constriction, Oncel et al. did not describe any difference of Bayley II score at 18–24 months cGA of preterm infants born at < 30 weeks exposed to acetaminophen versus ibuprofen (42). Several studies have demonstrated increased rates of neurodevelopmental impairments in preterm infants who underwent PDA ligation (37). One study adjusting for perinatal characteristics and pre-ligation morbidities found no difference in mortality or neurodevelopmental impairment at 18–24 months cGA. This suggests some residual confounding by indication within the previous studies associating ligation to later adverse outcomes (43). Also, Robinson et al. reported, in a retrospective study, that medical and/or surgical PDA treatment in infants born at < 25 weeks GA was an independent risk factor for adverse neurodevelopment at 2 to 3 years of age (44). In addition, a Swedish study evaluating infants born at < 27 weeks described an increased risk of moderate to severe neurodevelopmental impairment and a lower full-scale intelligence quotient at 6.5 years of age in those exposed to a primary PDA surgery approach (45). Finally, a pre-post design retrospective study evaluated the impact of an “early ligation” versus a “selective ligation” approach in infants < 28 weeks exposed to prophylactic indomethacin (46). Infants in the selective ligation group had similar neurodevelopmental outcomes at 18–36 months compared to the historical more “aggressive” approach, outlining that introduction of a progressively increasing selection of patients undergoing ductal closure was not associated with a drastic change in their developmental outcomes.
Considering that studies on PDA treatment in the preterm population were not able to demonstrate meaningful short or long-term benefits of neonatal outcomes (35), many institutions have opted to progressively adopt a more conservative approach (9, 39, 47). However, most studies have underrepresented the most immature population of preterm infants, which are those born at < 26 weeks and even those born at < 24 weeks. Recently, Giesinger et al. described improved early outcomes in infants born at 22–23 weeks of GA after the introduction of a selective early PDA treatment (within 24 hours of postnatal life), using an initial approach with acetaminophen (48). Future studies within this vulnerable subgroup should evaluate whether these findings translate into improved neurodevelopmental outcomes within that high-risk population.
Our study is observational and with a high number of children lost to follow-up or who did not survive to follow-up (n = 91 infants; Supplemental Table). Differential mortality rates between sites (Site 1: 28% vs Site 2: 15%) may also have brought a survival bias in the analysis. Although we found no association between sites and the composite outcomes of death or any NDI, as well as death or significant NDI, these analyses are limited by the lack of information regarding the patients lost to follow-up. In addition, language scores for the Bayley-III assessment were not included, due to a substantial number of unilingual families whose primary language at home was neither French nor English. Moreover, socio-economic factors may significantly influence the neurodevelopment during infancy, which were not accounted for. Data regarding the duration of ductal patency and magnitude of the left to right shunt were not available. Our database lacked other important information, such as antenatal magnesium sulfate and delayed cord clamping, which have been associated with neuroprotective properties in the preterm population. Also, follow-up beyond 18–24 months may also be important to detect subtle, longer-term impacts on neurodevelopment. Despite these limitations, our study provides some real-context implementation of a conservative approach regarding the PDA management, with a progressive drop to 0% of treatment exposure in the conservative site, with reassuring evidence of the implementation of such policy pertaining to neurodevelopmental outcomes. The neurodevelopmental evaluation was performed by trained personnel, using validated neurodevelopmental tools. Our study was carried in two comparable sites in terms of clinical practices, socioeconomic status of targeted population (same city), organization of care and training/experiences of medical teams. Finally, all data were collected through the local CNN and CNFUN registries, which are both dataset with standardized definitions across sites (49).
In conclusion, progressive adoption of a conservative PDA policy was not associated with different neurodevelopmental motor and cognitive outcomes in infants born at < 29 weeks, compared with a targeted PDA treatment strategy using mainly NSAIDs. Although our findings are reassuring, they need to be corroborated in larger studies including infants born before < 26 weeks, as well as at later ages at follow-up.