We examined a cohort of Asian VLBWs with HsPDA. Studies from National Institute of Child Health and Human Development (NICHD) showed that Asian-American are at higher risk of having HsPDA . A comparison between Japan and Canadian neonatal units showed that there is a difference in the composite outcome of morbidity and mortality among VLBW infants, where the Japanese population (46%) had a lower composite outcome than Canadian population (55%) among infants with PDA (OR 0.70 95% CI 0.62–0.80, p < 0.01) . Our study is one of the first to examine the immediate and neonatal outcomes of following various treatment strategies of HsPDA in the Asian population.
We found that surgical treatment of HsPDA in VLBW is associated with several worse short-term outcomes. They had more CLD, a poorer growth at discharge and a longer hospitalization. However, those surgical treated infants were of lower GA and BW, sicker with more severe RDS and a larger proportion of them had higher CRIB II scores. Surgical complications like vocal cord palsy may also contributed to poorer feeding and subsequent growth failure leading to longer hospital stay. Despite this, death and or adverse neurodevelopmental outcomes were not increased in early childhood in surgically treated group. However, a type-II error cannot be excluded as the number of surgically treated infants was small.
In our study, infants requiring surgical treatment were of lower GA and BW which lends further support to earlier studies that found the relationship between the rate of ductal closure, GA and BW [2, 3, 26] to be inversely proportionate. Similarly, in another Asian cohort of VLBW infants, a positive correlation between decreasing GA and lower survival was found and the incidence of major neonatal morbidities such as CLD, sepsis, severe ROP and severe IVH were higher with decreasing gestation, although NEC did not show a similar trend .
The effects of medical or surgical treatment of PDA on neurodevelopmental outcomes has become a topic of increasing interest. Yet, there has been no well-established relationship between the two. Two studies determined surgical ligation as a higher risk factor for neurodevelopmental impairment as compared to medical treatment [28, 29]. In contrast, Chorne et al  found no relationship between surgical ligation and neurodevelopment outcomes. Whereas, a study reported recently by Janz-Robinson et al.  found treatment with medical or surgical treatment to be associated with neurodevelopmental impairment. Our findings are consistent with Chorne et al.  and we found no significant differences in neurodevelopmental outcomes in both the main group analysis and subgroup analysis. The discrepancy in results among different studies highlights the gap in the literature and emphasizes the urgent need for large randomized control trials (RCT) to further evaluate the neurodevelopmental outcomes in the treatment of HsPDA.
We found that the infants in group M + S, group M and group S were sicker compared with infants in group C with a higher incidence of CRIB II score > 12, predicting a greater risk of neonatal mortality among very low BW infants. Base excess, a constituent of the CRIB II score, is an independent predictor of medical PDA closure response [32, 33]. Consequently, it may be challenging to manage the infant with worse base excess conservatively, resulting in the infant receiving either COX inhibitors or surgical ligation. Infants in group M + S, as well as M and S, were more likely to have severe RDS, in which mechanical ventilation is commonly administered . Mechanical ventilation has been identified to be an independent risk factor for failed medical PDA closure , and it is possible that severe RDS is in fact part of the causal pathway of HsPDA requiring medical or surgical treatment.
Earlier studies have suggested that prolonged exposure to PDA is associated with multiple neonatal morbidities [30, 36, 37]. We found differing results and determined that the group C infants did not have worse intermediate neonatal outcomes than group M and S infants. Several studies have shown surgical ligation to be associated with CLD [29, 30, 38, 39] which is congruent with our findings. A part of the confounding effect may be these surgical infants had failed medical treatment and had longer ventilation prior to surgical ligation.
The association between medical treatment and CLD is not well defined. Our findings suggest that there is a higher incidence and OR of group M infants developing CLD than group C infants, assuming the worst case scenario, that infants who died prior to 36 weeks had developed CLD. Prolonged exposure to PDA has historically been associated with CLD [36, 40]. Our study supports others  who found that the adjusted odds of having CLD for extremely low birth weight (ELBW) infants with persistent HsPDA is > 3 times that of ELBW infants whose PDAs were successfully closed medically. This is in contrast to the recent PDA-Tolerate study  where the authors found no difference in CLD or death outcomes but up to 48% of those in the conservative arm required rescue treatment before discharge. Even with medical treatment, up to 32% of the infants in the early treatment had treatment failure and subsequently some had ligation prior to discharge. These infants may hence dilute the effects of treatment in the primary outcomes. This serves as a call for bigger prospective study like the BeneDuctus Trial  currently ongoing to validate the true association between HsPDA exposure, management of HsPDA and CLD.
Group S infants had a longer duration of stay and hence discharged at an older GA. This is likely attributed to two reasons. Firstly, group S infants were significantly more premature at birth, with a lower GA (difference of 1 week) and BW (lighter by 130 g). This warrants them a longer inpatient stay, where discharge readiness is often assessed by functional maturation, feeding ability and weight gain . Secondly, group S infants’ condition may be affected by the complications of surgery. At discharge, the group M + S infants were smaller in size at discharge compared to group C infants; where the z-score of length and head circumference were significantly lower. Subgroup analysis showed that the group S infants were significantly lighter, shorter and smaller head circumference than the group C infants at discharge; whereas, group M and C infants had comparable discharge anthropometric parameters.
Limitations and strengths
This study has several limitations due to the retrospective nature. Firstly, there are no definite criteria for the diagnosis of HsPDA as bedside measurement of the PDA can be subjective and the decision for treatment is not standardised due to a lack of universal guidelines. Secondly, there were variations of treatment practices over the years with increasing trend towards conservative treatment. It has only been in the recent years that the trend of PDA treatment has shifted towards a less aggressive approach . As such, majority of the infants with HsPDA in our database from 2007–2016 were treated either medically or surgically. In addition, it is known from the natural history of PDA that more premature and lower BW infants are less likely to have spontaneous closure [2, 3] and hence there is a lower threshold to treat these infants. It was challenging to find infants managed conservatively, particularly those who were 24 and 25 weeks GA. Thirdly, as surgical ligation was only considered when the PDA failed to close after medical or conservative treatment, it was often performed in potentially sicker infants which can result in more surgically-related side effects. Because it is a retrospective study, we can only establish correlations but not determine the causation between the treatment type and the outcomes. Lastly, this is a single centre study with small sample size, thus a type II error cannot be excluded. A strength of our study is the protocol-based treatment. This reduces the variability in the treatment regimen and improve the quality of our results. As it is a single centre, we have removed the variability between cardiac echocardiographic assessment of the HsPDA and the surgical competency of the surgeon.