**9. Controversy and practice variation**

Controversy regarding if, when, and how to close the PDA abounds. Survey results of neonatologists and cardiologists in 2018 describe the practice variations in management of the PDA [31]. Some neonatologists responded that even a large, hemodynamically significant PDA in a premature baby never requires treatment including medical management as the majority are likely to close, while no cardiologists agree with this option. Nearly half the neonatologists believe that closing the PDA does not alter outcomes in children born <28 weeks' gestation, while most of the cardiologists disagree with this opinion. When institutions do believe that closure is needed after failed medical therapy, the majority of neonatologists and cardiologists currently still prefer surgical ligation to TCPC, while watchful waiting was still preferred by some neonatologists. There are immense variations in the practice of managing PDAs in ELBW infants in the United States. Neonatologists and cardiologists have differing opinions of the consequence of a hsPDA on the eventual outcomes. Certain landmark papers questioning the utility of PDA closure in premature infants may have influenced these opinions [16, 22].

In 2010, William Benitz performed a meta-analysis of 49 RCTs involving nearly 5000 preterm infants who underwent pharmacological or surgical treatment to close the PDA [16]. Evidence showed that while treatment was effective in achieving ductal closure, only a single study showed improvement in other outcomes such as pulmonary hemorrhage, BPD, NEC, or death. Correlations between PDA and IVH were and did not support the hypothesis that closure of the ductus improves neurological outcomes [16–22]. It was concluded that the association of comorbidities with PDA might arise from prematurity itself rather than through prolonged patency of the ductus. Benitz recommended prolonging treatment of the PDA in infants ≤1000 g until the second week after birth to increase the odds of spontaneous closure, and refraining from all treatment specifically intended to close the ductus in infants >1000 g. Fluid restriction, diuretics, supplemental oxygen, and other treatments were recommended in lieu of COX inhibitors and surgical ligation [16]. Certain patients at special risk for complications related to PDA would still require ductal closure and should be identified via a scoring system, such as the one proposed by McNamara and Sehgal [21]. Benitz's study provided impetus for the trend against early routine treatment of the PDA in premature infants and towards a more selective approach wherein only certain infants at increased risk received intervention to close the ductus.

In 2018, Ronald Clyman designed the PDA Tolerate Trial [13] to further examine early routine therapy versus conservative management by controlling for variables that had confounded many of the previous RCTs. Inclusion criteria was limited to

infants with a moderate-to-large PDA that did not close spontaneously within the first week. In so doing, the number of infants who spontaneously closed the ductus was reduced, though not eliminated. Early routine therapy (ERT) with pharmacological treatment was then compared to conservative management. As in previous trials, ERT did not always result in constriction of the ductus. Results indicated that ERT did not improve the incidence of NEC, IVH, BPD or death but instead delayed full feeding and may have increased the rate of sepsis and death in infants between 26 and 28 weeks gestation. Again, evidence did not support broad, routine ductal closure by pharmacotherapeutics in preterm infants.

With evidence mounting against the use of COX inhibitors and surgical ligation, the trend towards permissive conservative observation of this lesion has developed, reserving surgery for only the most severe cases [13–17, 32]. Unfortunately, recent data suggests that this approach is associated with an increased risk for the development of chronic lung disease and death, especially in infants born ≤26 weeks' gestation [8–17]. More recently in the United States, survival of infants born as early as 22 weeks' gestation is now possible [33], making the need for effective PDA therapy in this high risk, ELBW population more important than ever.
