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. 2024 Jul 9;19(7):e0306769. doi: 10.1371/journal.pone.0306769

Patent ductus arteriosus (also non-hemodynamically significant) correlates with poor outcomes in very low birth weight infants. A multicenter cohort study

Elena Chesi 1,#, Katia Rossi 2,#, Gina Ancora 3, Cecilia Baraldi 2, Mara Corradi 4, Francesco Di Dio 1, Giorgia Di Fazzio 5, Silvia Galletti 6, Giovanna Mescoli 7, Irene Papa 3, Agostina Solinas 8, Luca Braglia 9, Antonella Di Caprio 10, Riccardo Cuoghi Costantini 11, Francesca Miselli 2,12,*, Alberto Berardi 2, Giancarlo Gargano 1
Editor: Hakan Aylanc13
PMCID: PMC11233010  PMID: 38980835

Abstract

Objectives

To standardize the diagnosis of patent ductus arteriosus (PDA) and report its association with adverse neonatal outcomes in very low birth weight infants (VLBW, birth weight < 1500 g).

Study design

A multicenter prospective observational study was conducted in Emilia Romagna from March 2018 to October 2019. The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age. A diagnosis of hemodynamically significant PDA (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow pattern, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present.

Results

218 VLBW infants were included. Among infants treated for PDA closure in the first postnatal week, up to 40% did not have hsPDA on ultrasound, but experienced clinical worsening. The risk of death was 15 times higher among neonates with non-hemodynamically significant PDA (non-hsPDA) compared to neonates with no PDA. In contrast, the risk of death was similar between neonates with hsPDA and neonates with no PDA. The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early treatment for PDA closure. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) increased by 8.7-fold and 18-fold, respectively, when both systemic hypoperfusion and pulmonary overcirculation were present in hsPDA.

Conclusions

The increased risk of mortality in neonates with non-hsPDA underscores the potential inadequacy of criteria for defining hsPDA within the first 3 postnatal days (as they may be adversely affected by other clinically severe factors, i.e. persistent pulmonary hypertension and mechanical ventilation). Parameters such as length, diameter, and morphology may serve as more suitable ultrasound indicators during this period, to be combined with clinical data for individualized management. Additionally, BPD, IVH (grade ≥ 3) and ROP (grade ≥ 3) are associated with hsPDA. The existence of an optimal timeframe for closing PDA to minimize these adverse neonatal outcomes remains uncertain.

Introduction

The incidence of patent ductus arteriosus (PDA) is inversely related to gestational age (GA). Approximately half of preterm infants born before 28 weeks’ (wks) gestation present with PDA, particularly if ultrasound (US) scans are performed within the first 3 postnatal days [1]. PDA can result in pulmonary overcirculation and systemic hypoperfusion, the clinical significance of which depends on the size of the left-to-right shunt. The increased risks of death, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP) have been historically associated with PDA [2–4]. Delayed PDA treatment may also be associated with a higher risk of pulmonary hemorrhage, and failure to conduct screening echocardiography in extremely preterm infants within the initial 3 postnatal days is associated with elevated in-hospital mortality [5, 6]. In the last decade, therapeutic strategies for PDA have undergone significant changes. In addition to “classical” pharmacological treatments such as indomethacin and ibuprofen, acetaminophen has also been suggested as an effective drug in closing PDA [7]. However, despite the widespread diffusion of PDA treatment, the comorbidities historically attributed to PDA persistence have not actually decreased. New data also show that PDA can close spontaneously, even in extremely low birth weight infants [8]. Moreover, pharmacological treatment may be associated with significant side effects [7]. As a result, divergent perspectives persist, with one faction asserting that PDA treatment plays a role in preventing adverse neonatal outcomes, while another contends that it does not offer such preventive benefits [9, 10]. A conservative approach to managing PDA, encompassing strategies such as fluid restriction, diuretics, and higher positive airway end-expiratory pressure, has gained increasing favor [11, 12].

Studies and data from national registries present disparate rates of PDA-associated outcomes. These differences may be attributed to variations in methods and timing employed for assessing PDA and its treatment [13]. A large number of investigators have analyzed PDA hemodynamic significance in two ways, either by evaluating echocardiographic indexes only [14–16] or using clinical and US composite scores [17–19]. The term “hemodynamically significant patent ductus arteriosus (hsPDA)” has been increasingly used, and several protocols have been developed in an attempt to define hsPDA by integrating both clinical and US scores [18, 20]. Recent studies were carried out to identify preterm neonates with signs of pulmonary overcirculation or systemic hypoperfusion in order to tailor PDA treatment [14]. Despite these efforts, a consensus on the precise criteria for identifying hsPDA has yet to be reached. Vermont Oxford Network Registry (VON) data from neonatal Intensive Care Units (NICUs) of a northern region of Italy (Emilia-Romagna) revealed significant variability in the rates of diagnosing and treating PDA. To overcome this variability, a protocol was set up by the Emilia-Romagna Study Group with the aim to achieve shared US criteria for hsPDA diagnosis, and to develop a comprehensive PDA scoring system integrating both US and clinical findings. We hypothesized that a consensus on the definition and grading of PDA could enhance management, thereby reducing adverse neonatal outcomes.

The study objectives were 1) to standardize the diagnosis of hsPDA across the seven NICUs in the Emilia-Romagna region, and 2) to investigate associations between PDA severity grading and adverse neonatal outcomes.

Methods

This was an observational multicenter prospective study, carried out in Emilia-Romagna (Italy) from March 1st, 2018, to October 31st, 2019. Newborns with a birth weight < 1500 g (very low birth weight, VLBW) and/or GA ≤ 29 wks were enrolled. Exclusion criteria were: congenital malformations or first functional echocardiography performed after 72 hours of life. For data collection purposes, a standardized form was utilized to gather relevant data for each enrolled patient (chorioamnionitis, maternal hypertension/eclampsia and gestational diabetes, antenatal steroid use, GA, birth weight, 5-minute Apgar score, mode of delivery and surfactant administration, echocardiograms, treatment for PDA closure, neonatal outcomes). Adverse neonatal outcomes were defined as follows: death, pulmonary hemorrhage, IVH (classified according to Papile) [21], ROP (classified according to the International Classification of Retinopathy of Prematurity) [22], stage ≥ 2 NEC (classified according to Bell’s criteria) [23], and BPD (defined as oxygen requirement at 36 weeks corrected age) [24]. Each form for data collection was accessed online through a password protected system. A written informed consent was obtained from the parents of the neonates enrolled in the study. The study was approved by the Ethics Committee of the participating centers (reference 2017/0015900).

Ultrasound and clinical grading of PDA

Periodic meetings were held among centers to analyze the literature and to share US criteria for diagnosis and treatment of hsPDA. Neonatologists performed functional US studies using 4–12 Hz probes (Phillips S.p.A., Milano) according to international guidelines [25]. The US studies were performed by neonatologists who received specific training in pediatric echocardiography (at the master’s level). Two-dimensional, M-mode, pulse and color flow Doppler imaging were performed. The PDA diameter was assessed based on at least two measurements, with the average taken from the two measurements. Hemodynamic evaluation was performed if PDA diameter was ≥ 1.6 mm at the pulmonary end [14, 26], and its flow was growing or pulsatile pattern [15]. PDA was defined as hsPDA if at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present (Table 1) [27, 28]. Echocardiographic assessments were repeated during the hospital stay based on clinical judgment. All neonates underwent US before hospital discharge. Table 2 shows the clinical severity grading: clinical criteria were modified from the McNamara scoring system [17]. A composite staging system (ranging from G0 to G3) was developed by combining clinical severity and US grading (Fig 1).

Table 1. Echocardiographic grading of PDA.

The US grading of PDA involves assessing its severity using the following criteria: PDA diameter, flow characteristics, and indexes of pulmonary overcirculation and/or systemic hypoperfusion.

Ultrasound score PDA diameter and flow Indices of pulmonary overcirculation and/or systemic hypoperfusion
PDA
d <1.6 mm		 PDA
d ≥1.6 mm		 PDA Flow:
Growing or pulsatile		 LPAedv > 0.2 m/sec and/or
LA/Ao ≥1.5 and/or
DAo Flow: absence or reverse
E1 +/- +/- - None present
E2 - + + At least 1 index
E3 - + + At least 2 indexes
E4 - + + All present
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DAo, descending aorta; LPAedv, left pulmonary artery end-diastolic velocity; LA/Ao, left atrial to aortic root ratio; PDA, patent ductus arteriosus.

Table 2. Grading of the severity of clinical conditions.

NIV MV FiO2 > 0.28 pH<7.1 BE>-12 MBP<30 mmHg AKI X-ray Cardiomegaly NEC ≥Bell’ s stage 2 Bleeding Clinical severity
C1 - - - - - - - - - -
C2 + - - - - - - - - - Mild
C3 +/- +/- + - - +/- - - - - Moderate
C4 - + + + + +/- +/- +/- +/- +/- Severe
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AKI, acute kidney injuryº; BE, bases excess; FiO2, oxygen inspiratory fraction; HFNC, high-flow nasal cannula; MBP, mean blood pressure*; MV, invasive mechanical ventilation; nCPAP, nasal continuous positive airway pressure; NEC, neonatal necrotizing enterocolitis; NIV, non-invasive ventilation.

ºAKI defined as serum creatinine>1.5 mg/dl or diuresis <0.5 ml/kg/h. From: Jetton JG, Askenazi DJ. Update on acute kidney injury in the neonate. Curr Opin Pediatr. 2012;24(2):191–6.

*Hypotension defined as MBP<30 mmHg in the first 72 hours of life. From: Dempsey EM, Barrington KJ. Diagnostic criteria and therapeutic interventions for the hypotensive very low birth weight infant. J Perinatol. 2006;26(11):677–81.

Fig 1. Combined clinical and ultrasound grading (G) at 72 hours of life.

Fig 1

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G0 (white boxes): infants without PDA (E0) whatever the clinical grading. G1 (pink boxes): infants with PDA (E1) whatever the clinical grading or asymptomatic infants (C1) with PDA. G2 (gray boxes): symptomatic infants (C2-C4) with PDA (E2) or infants with hsPDA (E3-E4) and mild symptoms (C2). G3 (red boxes): infants with hsPDA (E3-E4) and moderate-to-severe clinical conditions (C3-C4).

Timing and mode of treatment

The decision to initiate treatment for PDA closure was left to the attending clinician’s discretion. The drugs administered for PDA closure included ibuprofen (loading dose 10 mg/kg, maintenance dose 5 mg/kg/day), acetaminophen (15 mg/kg every 6 hours), and indomethacin (loading dose 0.2 mg/kg, maintenance dose 0.1 mg/kg/day). PDA treatment was classified as early (postnatal age ≤ 7 days) or late (postnatal age > 7 days). Surgical PDA closure was performed when medical treatment failed or was contraindicated. All PDA ligations were performed on-site by a mobile cardiosurgical team.

Adverse neonatal outcomes

Patient records provided the following data related to adverse neonatal outcomes: death, pulmonary hemorrhage, IVH, ROP, stage ≥ 2 NEC, and BPD.

Data analysis

Statistical analysis was carried out using SPSS software 23.0. Continuous variables were expressed as medians and interquartile ranges (IQR). Categorical data were expressed as numbers and percentages. The Student’s t-test was used for unadjusted comparisons of continuous variables between groups; Pearson’s χ2 test and Fisher’s exact test (when one or more cells had expected frequency < 5) were used for unadjusted comparisons of categorical variables between groups. To assess a potential association between US PDA scoring and neonatal outcomes, we estimated bivariate logistic regression models correcting for GA. The normality of the residuals of each model was assessed by using the standardized residuals, Q-Q plot. The results were reported as odds ratios (ORs), with 95% confidence interval (CI) and p-values. For all analyses, p-values were considered significant when below the alpha level set at 0.05.

Results

Study population

Out of 267 VLBW infants, 49 were ruled out (Fig 2), leaving a total of 218 subjects included in the study. Demographic, maternal, and neonatal characteristics are presented in Table 3, stratified by gestational age (GA < 26 weeks’ versus ≥ 26 weeks’ gestation).

Fig 2. Flow diagram of the study.

Fig 2

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Table 3. Demographics and clinical findings of the study population according to gestational age: < 26 weeks’ gestation vs ≥ 26 weeks’ gestation.

GA< 26
(n = 42)		 Missing Data† GA≥ 26
(n = 176)		 Missing Data† p
APGAR 5°, median [IQR] 7
[5.8; 8]		 2 9
[8; 9]		 1 0.024
Complete antenatal steroids, n (%) 19
(56%)		 8 136
(85%)		 15 <0.001
Cesarean section, n (%) 22
(54%)		 1 140
(81%)		 2 <0.001
Vaginal delivery, n (%) 18
(44%)		 1 32
(18%)		 2 <0.001
Chorioamnionitis, n (%) 20
(49%)		 1 36
(21%)		 5 <0.001
Maternal hypertension/eclampsia n (%) 4
(10%)		 1 36
(21%)		 3 0.154
Gestational diabetes, n (%) 1
(3%)		 2 24
(14%)		 2 0.074
No surfactant administration, n (%) 4
(10%)		 2 96
(55%)		 2 <0.001
PDA at 72 hours of life, n (%) 31
(74%)		 - 96
(55%)		 - 0.035
Early PDA treatment, n (%) 23
(55%)		 - 38
(22%)		 - <0.001
Late PDA treatment, n (%) 5
(12%)		 - 4
(2%)		 - 0.017
PDA surgical ligation, n (%) 9
(21%)		 - 1
(1%)		 - <0.001
Persistent PDA at discharge, n (%) * 1
(3%)		 2 8
(5%)		 3 0.840
Death, n (%) 9
(21%)		 - 3
(2%)		 - <0.001
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GA, gestational age in weeks. PDA, patent ductus arteriosus.

†Percentages and significance are calculated based on the patients who were tested (i.e. after excluding missing cases).

* Percentages are calculated among 33 infants with GA < 26 weeks’ gestation and 173 infants with GA ≥ 26 weeks’ gestation who survived to discharge, excluding missing data.

US data and composite staging

Among 218 VLBW neonates included in the study, 139 (64%) underwent the first US assessment within 48 hours of life. PDA was more likely to be diagnosed within 48 hours of life (107/139, 77%) than at 49–72 hours of life (38/79, 48%; p<0.001) (Fig 2). During the initial 72 hours of life, a total of 155 out of 218 newborns (71%) underwent one US study, while 63 newborns (29%) underwent two US studies. At 72 hours of life, PDA was present in 127 neonates (58%). Based on the combined clinical and US grading of PDA within 72 hours of life (Fig 1), a total of 91 neonates were classified as G0, 71 neonates were classified as G1, 30 neonates were classified as G2, and 26 neonates were classified as G3.

PDA treatment

Overall, 70 of 218 neonates (32%) received at least one course of treatment. Treatment for PDA closure was more frequent in neonates with lower GA (28 out of 42 neonates < 26 wks’ gestation, 67% vs 42 out of 176 neonates ≥ 26 wks’ gestation, 24%, p<0.001).

Early treatment

Among 127 neonates with PDA diagnosed within the first 72 hours of life, 61 (48%) underwent early treatment for PDA closure (i.e. within the first 7 postnatal days; medical treatment, n = 60, surgical treatment, n = 1). Fig 3 shows the number of infants who received early treatment according to the US and clinical composite staging subgroup (ranging from G1 to G3). Among the 61 early treated infants, 38 had an hsPDA (E3 n = 28; E4 n = 10), while 23 had a PDA that was not diagnosed as hemodynamically significant (E1 n = 12; E2 n = 11). All the infants with E1 PDA (no signs of pulmonary overcirculation or systemic hypoperfusion) received early treatment for PDA closure due to moderate-to-severe clinical worsening.

Fig 3. Combined clinical and US severity score (ranging from G1 to G3) among 61 early-treated infants.

Fig 3

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The PDA US severity score is also reported for each group. VLBW, very low birth weight.

PDA was more likely to be treated early in infants with lower GA (<26 wks’ gestation, 23/31, 74% vs ≥ 26 wks’ gestation, 38/96, 40%, p = 0.024). Early medical treatment for PDA closure included ibuprofen (n = 46), paracetamol (n = 13) and indomethacin (n = 1). Among infants treated with ibuprofen, two developed oliguria, and one experienced gastric bleeding. The median age at the initiation of early treatment was 2 days, with a median duration of medical treatment lasting 3 days. Among the early medically treated neonates, the PDA closed in 42 out of 60 (70%) cases. Thirteen neonates (13/60, 22%) underwent a second treatment, with surgical intervention in 5 neonates and medical intervention in 8 neonates (2 of whom subsequently underwent surgical treatment) (Fig 4).

Fig 4. Flow diagram of patients treated for PDA closure.

Fig 4

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A flow diagram illustrating infants treated for PDA closure, including both early and/or late medical and/or surgical interventions, is presented. Early PDA treatment: any treatment in the first seven postnatal days. Late PDA treatment: any treatment after the first seven postnatal days.

Late treatment

Nine neonates (GA < 26 wks n = 5; GA ≥ 26 wks n = 4) received late treatment for PDA closure (i.e. after the first 7 postnatal days). Of these, 8 newborns received medical treatment (ibuprofen n = 1, paracetamol n = 5 and indomethacin n = 2) and one infant underwent surgical ligation. Among 8 late medically treated infants, the PDA closed in 4 (50%). The median age at initiation of treatment was 13 days, with median duration of medical treatment lasting 3.5 days. None of the infants who were medically treated after the first 7 postnatal days experienced adverse effects.

Surgical treatment

Overall, ten infants (10/218, 5%) underwent surgical ligation (median age at treatment 23.6 days of life). Six of ten surgically treated newborns (60%) developed complications (post ligation syndrome n = 4, vocal cord paralysis n = 2); none of them died.

Outcomes

Among 206 surviving infants, 9 (4%) had persistent PDA at the time of hospital discharge. Twelve infants died (median age 9.5 days), and none within the first 72 hours of life. Mortality was higher in those with GA < 26 wks (p<0.001, Table 3).

Table 4 presents the analysis of adverse neonatal outcomes based on US PDA grading after correction for GA. NEC and pulmonary hemorrhage were excluded from the analysis due to the small number of events. After adjusting for GA, the risk of mortality was higher among infants with E2 PDA. Conversely, the risk of BPD was higher among infants with hsPDA (E3 and E4). Among those who received early treatment, the incidence of BPD was lower among infants who responded to treatment with PDA closure (19 out of 38, 50%) compared to those who failed to respond (12 out of 16, 75%), but this difference did not reach statistical significance (p = 0.133). There was also a trend towards the development of any grade ROP in patients with E2 PDA. Finally, we identified an increased risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) in infants with E4 PDA.

Table 4. Correlation of adverse neonatal outcomes and ultrasound PDA grading (E0 to E4) after correction for gestational age.

OUTCOMES Ultrasound PDA grading OR 95% CI p N
Death E0 Ref 218
Death E1 7.63 (0.70–83.32) 0.096
Death E2 14.11 1.25 158.58 0.032
Death E3 2.62 0.21 32.69 0.455
Death E4 11.86 0.55 256.28 0.115
Death GA 0.49 0.33 0.73 0.001
BPD E0 Ref 207*
BPD E1 1.98 0.70 5.62 0.197
BPD E2 1.47 0.33 6.54 0.615
BPD E3 6.75 1.88 24.26 0.003
BPD E4 6.46 1.36 30.73 0.019
BPD GA 0.49 0.39 0.61 0.000
IVH ≥ 3 E0 Ref 216**
IVH ≥ 3 E1 1.24 0.24 6.50 0.795
IVH ≥ 3 E2 2.11 0.31 14.25 0.443
IVH ≥ 3 E3 2.34 0.46 12.01 0.308
IVH ≥ 3 E4 8.74 1.47 52.07 0.017
IVH ≥ 3 GA 0.75 0.58 0.97 0.026
ROP E0 Ref 208***
ROP E1 1.47 0.43 5.05 0.538
ROP E2 4.83 1.00 23.29 0.050
ROP E3 0.52 0.13 2.08 0.355
ROP E4 6.76 1.23 37.12 0.028
ROP GA 0.42 0.31 0.55 0.000
ROP ≥ 3 E0 Ref 208***
ROP ≥ 3 E1 1.07 0.19 5.93 0.940
ROP ≥ 3 E2 3.21 0.51 20.42 0.216
ROP ≥ 3 E3 1.62 0.34 7.70 0.547
ROP ≥ 3 E4 17.97 2.34 137.93 0.005
ROP ≥ 3 GA 0.49 0.35 0.69 0.000
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BPD, bronchopulmonary dysplasia; GA, gestational age; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus: ROP, retinopathy of prematurity; US, ultrasound.

* Among 207 surviving infants at 36 weeks’ gestation (eleven patients were excluded because they died before 36 weeks’ gestation).

** Among 216 patients, 2 missing data.

*** Among 208 surviving infants at 32 weeks’ gestation (ten patients were excluded because they died before 32 weeks’ gestation).

Discussion

Our study shows that approximately 26% of neonates <26 wks’ gestation experience a spontaneous PDA closure, consistent with findings in the previous literature [8, 29]. About half of the enrolled infants with evidence of PDA on US received medical treatment: consistently with findings from previous studies, the success rate was about 70% [11, 12, 30–32]. By monitoring neonates during their entire hospitalization, we observed that about 4% had persistent PDA at the time of discharge. This proportion is lower than the rate reported by Clymann and Borràs-Novell, which was approximately 25% [29, 32]. In our cohort, no newborn underwent surgical ligation of PDA after hospital discharge. This is in line with previous studies, suggesting that a high percentage of persistent PDA at discharge in VLBW infants may subsequently close spontaneously (up to 86%) [33].

Consistent with the findings of a national survey [34], ibuprofen was administered as first-line drug for early treatment in 75% of cases. The rates of surgical ligation (14%) and its related complications were similar to those previously described in the literature [11, 12, 29, 35–37]. However, we observed a higher incidence of post-ligation syndrome (up to 60%), nearly double that reported by Moin et al [38]. This discrepancy may be due to our definition of post-ligation syndrome, which we did not define as the need for vasopressors within 72 hours post-procedure, but rather as a reduction in cardiac output on US within 6 hours of the procedure, possibly encompassing mild cases. In fact, no patient died from post-ligation syndrome in our cohort. Notably, percutaneous closure has demonstrated efficacy in PDA closure with several potential benefits over surgical ligation, as it eliminates the need for incisions and mitigates issues related to manipulating the lung for PDA access, along with reducing the risk of complications such as laryngeal recurrent nerve damage. These benefits contribute to the appeal of percutaneous closure as a favorable alternative, and this will be the focus of the PIVOTAL study [39].

Although it is commonly recommended to treat only patients with hsPDA based on both US and clinical deterioration, our data reveal the predominant influence of clinical conditions over US findings in the decision to treat neonates for PDA closure. In fact, up to approximately 40% of early treated infants had experienced moderate-to-severe clinical worsening even in the absence of evidence of hsPDA on US. This “overtreatment” could be related to clinicians’ inclination to consider the presence of the PDA in unstable infants as an aggravating factor. It is difficult to distinguish the role of the PDA itself versus other factors (preterm birth, perinatal transition, maternal chorioamnionitis, and hypertension) in determining the patient’s hemodynamic instability [40]. In our study, the risk of death was nearly 15-fold higher among neonates with E2 PDA (non-hsPDA), as compared to those without PDA (E0), independently from the GA. We highlight this higher risk of death observed in newborns with PDA who do not exhibit US findings of hsPDA, which merits further consideration. Several factors may explain this increased risk of death. First, the standard recognized US criteria for defining an hsPDA may be inadequate for this temporal window (within 72 hours of birth). In fact, persistent pulmonary hypertension of the newborn and/or high pulmonary pressures due to mechanical ventilation may affect the left-to-right shunt through the PDA, temporarily minimizing the pulmonary overcirculation. Also, the typical vasoconstriction of the fetus and an “inappropriate” fluid intake may contribute to a more prolonged equilibrium between systemic and pulmonary pressures. Finally, the use of inotropes and vasopressors in critically ill newborns may reduce the clinical and US findings of systemic hypoperfusion. Thus, from a clinical perspective, it appears that the most appropriate criteria for defining an hsPDA in the early hours of life may be the length, diameter and morphology of the PDA. Indeed, these factors are assumed to be the main determinants for subsequent pulmonary overcirculation and systemic hypoperfusion [41]. Given that PDA diameter in isolation is known to be poorly predictive, it may be beneficial to combine it with clinical data for a more comprehensive grading [42].

Surprisingly, the risk of death adjusted for GA in neonates with hsPDA (E3-E4) was similar to that of neonates without PDA (E0) in our population. One possible explanation is that almost all infants with hsPDA (E3-E4) receive early treatment to close the PDA; this is not the case for infants with non-hsPDA (E2), for whom clinicians are more prone to “watchful waiting”. Consequently, the proportion of treatment in E2 patients is lower, and the PDA may remain open, potentially leading to higher mortality. It is important to acknowledge that a significant limitation of the association between non-hsPDA and death in our cohort is the small number of deceased infants. The small sample size of deceased individuals limits the statistical power and generalizability of our findings.

In our study, we observed a 6-fold higher occurrence of BPD in hsPDA infants (E3-4) compared to newborns without PDA (E0), independent of GA. Indeed, previous epidemiological studies highlighted a strong association between PDA and BPD [43], although a causal relationship has not been proven. It is possible that the pulmonary overcirculation, common in infants with hsPDA, plays a role in promoting BPD development. In our cohort, almost all the newborns with hsPDA received treatment for PDA closure, whether medical or surgical. However, PDA closure after early treatment did not appear to significantly reduce the risk of developing BPD. This finding contrasts with previous studies that demonstrated a reduced BPD incidence following more aggressive treatment approaches in the first days of life [43], before the PDA caused clinical symptoms related to its hemodynamics [44]. This discrepancy could be related to our small sample size of neonates with BPD, which may have limited the statistical power to detect the protective role of early PDA closure.

In our study, the risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) was 8.7-fold and 18-fold higher, respectively, when hsPDA was most significant (E4) as compared to newborns without PDA (E0), independently from GA. Notably, systemic hypoperfusion (always present as a defining criterion for E4 staging) may be a risk factor for both IVH and ROP, and may favor their occurrence. Interestingly, we observed a trend towards higher risk of ROP (all stages included) among infants with non-hsPDA (E2) who survived to 32 wks’ gestation.

Conclusions

Despite standardization of US criteria for PDA diagnosis, clinical conditions still inform up to 50% of the decision to early treat PDA. Surprisingly, after adjusting for GA, the risk of death is similar among infants with hsPDA and infants without PDA. In contrast, the risk of death is nearly 15-fold higher among neonates with non hsPDA. We highlight the increased risk of death in newborns with PDA who do not exhibit US findings of hsPDA, suggesting that the standard recognized US criteria for defining hsPDA may be inadequate within the first 3 postnatal days. Instead, length, diameter and morphology of the PDA may be more appropriate parameters, to be integrated with clinical data for combined grading and an individualized approach. Interestingly, among infants with non-hsPDA, the risk of developing ROP (all stages included) is also higher.

Infants with hsPDA show 6-fold higher risk of BPD compared to infants with no PDA, independently from GA. Finally, the risk of grade ≥ 3 IVH and grade ≥ 3 ROP is 8.7-fold and 18-fold higher, respectively, when hsPDA is most significant with all signs of systemic hypoperfusion, compared to newborns without PDA, independently from GA.

Further investigation is needed to better clarify whether an optimal window for PDA evaluation and closure exists, helping to reduce the incidence of death and preterm associated comorbidities, including BPD, IVH and ROP. To date, it is unclear which criteria of hsPDA are most accurate in different temporal windows, and whether there exists an optimal window for PDA evaluation and closure.

Supporting information

S1 Data

(XLSX)

pone.0306769.s001.xlsx (77.7KB, xlsx)

Acknowledgments

We would like to thank Daniela Masi (Azienda USL-IRCCS di Reggio Emilia) for English editing. Special thanks to Dr. Cristina Cicero and Dr. Maria Laura Malaigia.

Abbreviations

BPD

bronchopulmonary dysplasia

GA

gestational age

HsPDA

hemodynamically significant patent ductus arteriosus

IVH

intraventricular hemorrhage

NEC

necrotizing enterocolitis

NICU

neonatal intensive care unit

PDA

patent ductus arteriosus

ROP

retinopathy of prematurity

US

ultrasound

VLBW

very low birth weight, birth weight < 1500 g

wks

weeks

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Sung SI, Chang YS, Kim J, Choi JH, Ahn SY, Park WS. Natural evolution of ductus arteriosus with non-interventional conservative management in extremely preterm infants born at 23–28 weeks of gestation. PLoS One. 2019;14(2):e0212256. doi: 10.1371/journal.pone.0212256 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bourgoin L, Cipierre C, Hauet Q, Basset H, Gournay V, Rozé JC, et al. Neurodevelopmental Outcome at 2 Years of Age according to Patent Ductus Arteriosus Management in Very Preterm Infants. Neonatology. 2016;109(2):139–46. doi: 10.1159/000442278 [DOI] [PubMed] [Google Scholar]
  • 3.Jensen EA, Foglia EE, Schmidt B. Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies. Semin Perinatol. 2018. Jun;42(4):228–234. doi: 10.1053/j.semperi.2018.05.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chock VY, Goel VV, Palma JP, Luh TM, Wang NA, Gaskari S, et al. Changing Management of the Patent Ductus Arteriosus: Effect on Neonatal Outcomes and Resource Utilization. Am J Perinatol. 2017. Aug;34(10):990–995. doi: 10.1055/s-0037-1601442 [DOI] [PubMed] [Google Scholar]
  • 5.Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. ArchDis Child Fetal Neonatal Ed. 1996. Nov;75(3):F183–6. doi: 10.1136/fn.75.3.f183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Su BH, Lin HY, Huang FK, Tsai ML. Pulmonary hemorrhage in very-low-birth-weight infants. Pediatr Neonatol. 2014. Aug;55(4):326–7. doi: 10.1016/j.pedneo.2014.01.005 [DOI] [PubMed] [Google Scholar]
  • 7.Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev 2020. Jan 27;1(1):CD010061; doi: 10.1002/14651858.CD010061.pub4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics. 2006. Apr;117(4):1113–21. doi: 10.1542/peds.2005-1528 . [DOI] [PubMed] [Google Scholar]
  • 9.Rolland A, Shankar-Aguilera S, Diomandé D, Zupan-Simunek V, Boileau P. Natural evolution of patent ductus arteriosus in the extremely preterm infant. Arch Dis Child Fetal Neonatal Ed. 2015. Jan;100(1):F55–8 doi: 10.1136/archdischild-2014-306339 [DOI] [PubMed] [Google Scholar]
  • 10.Kaempf JW, Wu YX, Kaempf AJ, Kaempf AM, Wang L, Grunkemeier G. Whathappenswhen the patent ductus arteriosus is treated less aggressively in very low birth weight infants? J Perinatol. 2012. May;32(5):344–8. doi: 10.1038/jp.2011.102 [DOI] [PubMed] [Google Scholar]
  • 11.Lokku A, Mirea L, Lee SK, Shah PS. Trends and Outcomes of Patent Ductus Arteriosus Treatment in Very Preterm Infants in Canada. Am J Perinatol. 2017. Apr;34(5):441–450. doi: 10.1055/s-0036-1593351 [DOI] [PubMed] [Google Scholar]
  • 12.Shin J, Lee JA, Oh S, Lee EH, Choi BM. Conservative Treatment Without Any Intervention Compared With Other Therapeutic Strategies for Symptomatic Patent Ductus Arteriosus in Extremely Preterm Infants: A Nationwide Cohort Study in Korea. Front Pediatr. 2021. Oct 6;9:729329. doi: 10.3389/fped.2021.729329 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Hagadorn JI, Bennett MV, Brownell EA, Payton KSE, Benitz WE, Lee HC. Covariation of Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Management and In-Neonatal Intensive Care Unit Outcomes Following Preterm Birth. J Pediatr. 2018. Dec;203:225–233.e1. doi: 10.1016/j.jpeds.2018.07.025 [DOI] [PubMed] [Google Scholar]
  • 14.Kluckow M, Evans N. Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation. J Pediatr. 1995. Nov;127(5):774–9. doi: 10.1016/s0022-3476(95)70172-9 [DOI] [PubMed] [Google Scholar]
  • 15.Condò M, Evans N, Bellù R, Kluckow M. Echocardiographic assessment of ductal significance: retrospective comparison of two methods. Arch Dis Child Fetal Neonatal Ed. 2012. Jan;97(1):F35–8. doi: 10.1136/adc.2010.207233 [DOI] [PubMed] [Google Scholar]
  • 16.Sehgal A, McNamara PJ. Does Echocardiography facilitate determination of hemodynamic significance attributable to the ductus arteriosus. Eur J Pediatr. 2009. 168:906–914 [DOI] [PubMed] [Google Scholar]
  • 17.McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed. 2007. Nov;92(6):F424–7. doi: 10.1136/adc.2007.118117 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.El-Khuffash A, James AT, Corcoran JD, Dicker P, Franklin O, Elsayed YN, et al. A Patent Ductus Arteriosus Severity Score Predicts Chronic Lung Disease or Death before Discharge. J Pediatr. 2015. Dec;167(6):1354–1361.e2. doi: 10.1016/j.jpeds.2015.09.028 [DOI] [PubMed] [Google Scholar]
  • 19.Sehgal A, Paul E, Menahem S. Functional echocardiography in staging for ductal disease severity: role in predicting outcomes. Eur J Pediatr. 2013. Feb;172(2):179–84. doi: 10.1007/s00431-012-1851-0 [DOI] [PubMed] [Google Scholar]
  • 20.Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol. 2012. Apr;36(2):123–9. doi: 10.1053/j.semperi.2011.09.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978. Apr;92(4):529–34. doi: 10.1016/s0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]
  • 22.International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. ArchOphthalmol. 2005. Jul;123(7):991–9. doi: 10.1001/archopht.123.7.991 [DOI] [PubMed] [Google Scholar]
  • 23.Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978. Jan;187(1):1–7. doi: 10.1097/00000658-197801000-00001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82(4):527–532) [PubMed] [Google Scholar]
  • 25.Mertens L, Seri I, Marek J, Arlettaz R, Barker P, McNamara P, et al. Targeted Neonatal echocardiography in the neonatal intensive care unit: practice guidelines and recommendations for training writing group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC). J Am Soc Echocardiogr 2011;24:1057–78. [DOI] [PubMed] [Google Scholar]
  • 26.Evans N, Iyer P: Assessment of ductus arteriosus shunting in preterm infants supported by mechanical ventilation: Effect of inter-atrial shunting. J Pediatr 125:778–785, 1994. [DOI] [PubMed] [Google Scholar]
  • 27.Suzmura H, Nitta A, Tanaka O. Diastolic flow velocity of left pulmonary artery of patent ductus arteriosus in preterm infants. Pediatr Int 2001;43:146–51. [DOI] [PubMed] [Google Scholar]
  • 28.Iyer P, Evans N. Re-evaluation of the left atrial to aortic root ratio as a marker of patent ductus arteriosus. Arch Dis Child 1994;70:112–17 doi: 10.1136/fn.70.2.f112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, et al. and PDA-TOLERATEPDA-TOLERATE Trial. An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019. February; 205: 41–48.e6. doi: 10.1016/j.jpeds.2018.09.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2012;97:F279–F283. doi: 10.1136/archdischild-2011-300532 [DOI] [PubMed] [Google Scholar]
  • 31.Rozé J-C, Cambonie G, Marchand-Martin L, Gournay V, Durrmeyer, Durox M, et al. Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants. JAMA. 2015;313(24):2441–2448. doi: 10.1001/jama.2015.6734 [DOI] [PubMed] [Google Scholar]
  • 32.Borràs-Novell C, Riverola A, Aldecoa-Bilbao V, Izquierdo M, Domingo M, Iriondo M. Clinical outcomes after more conservative management of patent ductus arteriosus in preterm infants. J Pediatr (Rio J). 2020;96(2): 177–183 doi: 10.1016/j.jped.2018.10.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Herrman K, Bose C, Lewis K, Laughon M. Spontaneous closure of the patent ductus arteriosus in very low birth weight infants following discharge from the neonatal unit. Arch Dis Child Fetal Neonatal Ed. 2009. Jan;94(1):F48–50. Epub 2008 May 1. doi: 10.1136/adc.2007.129270 . [DOI] [PubMed] [Google Scholar]
  • 34.Ficial B, Corsini I, Fiocchi S, Schena S, Capolupo I, Cerbo RM et al. Survey of PDA management in very low birth weight infants across Italy. Italian J Pediatr 202046:22–29. doi: 10.1186/s13052-020-0773-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Park J, Yoon SJ, Han J, Song IG, Lim J, Shin JE, et al. Patent ductus arteriosus treatment trends and associated morbidities in neonates. Sci Rep. 2021. May 21;11(1):10689. doi: 10.1038/s41598-021-89868-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Ulrich TJB, Hansen TP, Reid KJ, Bingler MA, OLsen SL. Post-ligation cardiac syndrome is associated with increate morbidity in preterm infants. J Perinatol 2018. May; 38(5): 537–542 doi: 10.1038/s41372-0.18-0056-4 [DOI] [PubMed] [Google Scholar]
  • 37.Engeseth Merete Salveson, Olsen Nina Rydland, Maeland Silje, Halvorsen Thomas, Goode d Adam, Røksund Ola Drange. Left vocal cord paralysis after patent ductus arteriosus ligation: A systematic review” Paediatric Respiratory Reviews (2017), doi: 10.1016/j.prrv.2017.11.001 [DOI] [PubMed] [Google Scholar]
  • 38.Moin F, Kennedy KA, Moya FR. Risk factors predicting vasopressor use after patent ductus arteriosus ligation. Am J Perinatol. 2003. Aug;20(6):313–20. doi: 10.1055/s-2003-42693 [DOI] [PubMed] [Google Scholar]
  • 39.Available at PIVOTAL | (pivotalstudy.org)
  • 40.Polat TB, Celik IH, Erdeve O. Early predictive echocardiographic features of hemodynamically significant patent ductus arteriosus in preterm VLBW infants. Pediatr Int. 2016. Jul;58(7):589–94. doi: 10.1111/ped.12915 [DOI] [PubMed] [Google Scholar]
  • 41.Philip R, Waller BR, Chilakala S, Graham B, Stecchi N, Apalodimas L, et al. Hemodynamic and clinical consequences of early versus delayed closure of patent ductus arteriosus in extremely low birth weight infants. J Perinatol. 2021. Jan;41(1):100–108. doi: 10.1038/s41372-020-00772-2 [DOI] [PubMed] [Google Scholar]
  • 42.Smith A, Mullaly R, Franklin O, El-Khuffash A. Reproducibility of the El-Khuffash PDA severity score and PDA diameter measurements in extremely preterm infants. Early Hum Dev 2023. Sep;184:505832. doi: 10.1016/j.earlhumdev.2023.105832 [DOI] [PubMed] [Google Scholar]
  • 43.Clayman RI. Patent ductus arteriosus, its treatments, and the risks of pulmonary morbidity. Semin Perinatol 2018. June; 42(4): 235–242. doi: 10.1053/j.semperi.2018.05.006 [DOI] [PubMed] [Google Scholar]
  • 44.Liebowitz M, Clyman RI. Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: effects on neonatal outcomes. J Pediatr 2017. Aug; 187: 119–126.e1. doi: 10.1016/j.jpeds.2017.03.021 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Hakan Aylanc

22 Nov 2023

PONE-D-23-29459Patent ductus arteriosus: diagnosis, management and adverse neonatal outcomes in preterm Very Low Birth Weight Infants. Area-based prospective multicenter observational study.PLOS ONE

Dear Dr. Miselli,

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Dear Authors,

I evaluated the study named “Patent ductus arteriosus: diagnosis, management and adverse neonatal outcomes in preterm Very Low Birth Weight Infants. Area-based prospective multicenter observational study”, with great pleasure and interest. This is a relevant study. However, the manuscript may be suitable for publication after the correction is made. I listed my recommendations and comments below

Overall assessment

In this study, the authors found that when clinical and echocardiographic collaboration were used in the treatment of PDA, about 40 % of patients were treated as medical due to deterioration of the clinic in asymptomatic patients with PDA. Prevalence of death, intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia were higher in patients with PDA

Patent ductus arteriosus is one of the most common neonatal morbidity in neonatal intensive care but the relationship between the ductus arteriosus and neonatal morbidity remains unclear despite many research papers. Echocardiography is the gold standard for identifying significant PDA. However, every hs-PDA with echocardiographic findings may not cause significant clinical effects. Besides, there is still ongoing debate about the treatment approaches such as conservative? medical treatment? observation?. Therefore, the approaches vary among neonatal intensive care units. In this context, The study is much more important in terms of emphasizing the significance of the individualized approach in the current treatment of PDA

1. The title is not exactly reflective of the study or its content. could Authors please write a more appropriate and clear title to attract readers and encompass your study

The abstract conclusion should involve summarising the key points of the study and presenting the implications of its findings. The conclusion could be revised to get a clear understanding and should be far more specific to the study.

Introduction

The hypothesis of the article is not clear. Authors should determine a more concise, testable, and specific statement of the research question. The hypothesis should directly support the main research question. This should establish a clear link between the hypoyhesis and the purpose of the study

Methodology

Line 113 (An observational prospective area-based study…) may be more appropriate if changed as a multicenter observational study

Authors don't have a control group, why did the authors consider having a control group that was evaluated with echocardiography performed by a cardiologist?

Line 114: authors should not write the aim of the study in the method section

Line 118 For data collection purposes, standardized form… what was the component standardized form used by the authors? The authors should elaborate on its content, providing more details and explanations

Ultrasound and clinical grading of PDA

The authors should provide some insight into the reliability of the neonatologist who conducted the functional echocardiography. For example, how or how many times was PDA measured (one or more), which can be influenced by straining, crying, and cold environment, Which measurement was confirmed PDA? single or the average of measurements?

Please authors should give definitions of AKI, hypotension, and other morbidities such as NEC, BPD, and ROP in the method section. Authors should add these definitions and references to the methods

Short-term clinical outcomes

Authors should state other morbidities related to PDA such as respiratory support (CPAP and mechanical ventilation), surfactant administration, surfactant doses, extubation failure, postnatal steroids…

Line 147: Data analysis Statistical analysis was carried out using SPSS software 23.0. … which test was used to assess the normality distribution of data. The appropriate statistical method should be written for each specific situation

Line 147: Continuous variables were expressed as the means ± standard deviations or medians and interquartile ranges. Authors presented all continuous data as median and interquartile so you don’t need to use means and standard deviation

Figure 1 is very interesting. Authors should add Figure 1 to the methods section, explaining how to make or comment because it will guide readers and enhance the overall understanding of the figure’s significance in the context of the research

Line 152: “Confidence Interval (CI) was 0.95; when p < 0.05, tests were considered

statistically significant” should be the final sentence for the data analysis section.

Line 154: ‘The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines were followed for this study’ The sentence seems unnecessary because authors must follow it in observational studies to structure their manuscript, making it easier to be understood

Line 178: Demographic and further maternal and neonatal characteristics according to gestational age (GA < 26 versus . 26 wks gestation) are shown in Table 3. This sentence might have been changed to “Demographic, maternal and neonatal characteristics are shown in Table 3.

The English language must be revised throughout the text. If the manuscript is checked by a Language Editing in terms of grammar and punctuation, it would be better

In Table 3, there is no need to give as a column in table 3 because the missing data is exclusion criteria

Line 236 ‘The Fisher exact test was used to calculate the p-value for each variable except the Apgar score for which the Kruskal-Wallis¥ test is applied’ should be placed in the statistical section

this sentence need not be repeated under Table 3

Line 242 Among 207 surviving infants at 36 weeks’ gestation. Eleven patients were excluded because they…. please

Please put a comma instead of a dot before eleven patients.

There is the same error in Line 245, which must be corrected.

Line 343 Figure 2 Flow diagram of the study: ultrasound studies and findings.

there is no need to write “Ultrasound studies and findings “

Figure 4:

Flow diagram of patients treated for PDA. Early and/or late medical and/or surgical

treatment are reported. of PDA. PDA: patent ductus arteriosus. Early PDA treatment: any treatment in the first week of life. Late PDA treatment: any treatment after the first week of life.

Please revise to get a clear understanding. You may change as “Flow diagram of patients treated with medical or surgical ligation”

Discussion

The authors should begin the discussion by summarising the main findings of their study concisely. For example, our study shows….

Authors should make much more comprehensive explanations about the clinical implications of their findings. How might these results impact the monitoring and treatment guidelines of PDA?

Please ensure that clear messages will be accessible to broad readers related to your study

Conclusion

Please focus on summarising key findings without unnecessary details

Reviewer #2: Thank you for the opportunity to review this work. I believe the authors efforts merit publication; however, I have added some areas of clarification which I think would strengthen the present manuscript.

Methods:

Chesi and colleagues performed a ~10year prospective, multicenter observational study with the objective of standardizing PDA diagnosis and report associated outcomes for (218) VLBW infants.

Of these, 40% were treated for PDA in the first postnatal week didn’t have HsPDA but exhibited “clinical worsening.”

After adjustment for gestational age, finding include:

Risk of death 15-fold higher among these infants (no US evidence of HsPDA, only clinical suspicion).

Risk of death similar between infants with HsPDA and those without PDA.

I assume that adjustment for GA was an attempt to control for problems of prematurity to address associations between PDA treatment (contributing to or diminishing these outcomes: death, ROP, IVH, BPD etc.). Given that most (>80%) of infants who undergo definitive PDA closure require mechanical ventilation (invasive or non-invasive) I would like to see more data (aside from FiO2) in regard to level and duration of respiratory support as these data are competing risks/influenced the observed differences for mortality (15-fold), BPD (6-fold higher) and ROP (18-fold) among infants with HsPDA, without an observed benefit of early closure.

Please include n (%) for invasive/noninvasive respiratory support and high-frequency ventilation utilization to the clinical finding/demographics table. Further, please provide duration of mechanical ventilation for comparison between groups (PDA closed vs. those without PDA).

Discussion line 283ish: Please add to discussion that while PDA diameter has historically been incorporated into these scores, it is a poor indicator of adverse outcomes in isolation. https://www.sciencedirect.com/science/article/abs/pii/S0378378223001287?via%3Dihub

290: Indeed, the large challenge for treatment of PDA is agreement on what constitutes a hemodynamically significant PDA and is it pathologic as noted for group E4-flow reversal in descending Ao. Conversely, the watch and wait E2 may be subject to protracted mechanical ventilation and related morbidity/mortality. As such, continued work is needed to elucidate when the “watch” ends and what it the optimal method of definitive closure (TCPC or ligation) based on infant criteria (weight, PDA size, morphology, length, presence of absence of infection etc.)

293: Authors appropriately acknowledge the statistical associations were likely impacted by small sample size and low number of deaths (events).

Please include within your discussion that percutaneous closure has demonstrated efficacy for closing HsPDA with several potential benefits over surgical ligation (mainly avoidance of incision and related problems related to manipulating the lung to access PDA or laryngeal recurrent nerve damage). Moreover, it’s worth noting that the PIVOTAL study may help answer some of these questions. https://www.pivotalstudy.org

Conclusion: I agree with the authors that there are knowledge gaps insofar as criteria, timing, and method of assessing for a HsPDA (including concensus definition) and type of definitive closure that minimize adverse outcomes in this population.

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Reviewer #1: Yes: Associate Professor Fatih BOLAT, MD

Reviewer #2: No

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Attachment

Submitted filename: PLOS One PDA review.docx

pone.0306769.s002.docx (14.3KB, docx)

Decision Letter 1

Hakan Aylanc

24 Jan 2024

PONE-D-23-29459R1Patent ductus arteriosus is associated with higher mortality and adverse neonatal outcomes in preterm Very Low Birth Weight Infants. Multicenter prospective area-based observational study.PLOS ONE

Dear Dr. Miselli,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 09 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Hakan Aylanc

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The title still does not exactly reflect the study content. Please write a more appropriate and clear title that is associated with your study

Abstract

Line 52: …Patent Ductus Arteriosus (patent ductus arteriosus (PDA) should be written as lowercase letter

Line 53:… in preterm Very Low Birth Weight Infants (VLBW, birth weight < 1500 g)

Int

it would be more appropriate if changed as `? in very low birth weight infants’

Line 57:The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age (GA)…. you could delete GA because you only use it once in the abstract

Line 62:…. in the first postnatal week, up to 40% did not have hsPDA at ultrasound (US), but… US" should not be abbreviated as it was not mentioned previously.

Line 72: ‘The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early PDA treatment. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) were 8-fold a…..’ Please consider providing exact percentages or numerical values when referring to increased risk

Line 67: In the result section of the abstract, there should be no comment. The authors may add the comments to the conclusion section of the abstract. The conclusion of the abstract should be written as a subheading apart from the result section.

Introduction

There are some typographical and grammatical errors like these:

Line 102: Many investigators analyzed the hemodynamic significance of PDA, either by evaluating only echocardiographic indexes [14-16], or by using both clinical and US composite scores [17-19].

Line 104: “The term “hemodynamically significant patent ductus arteriosus 104 (hsPDA)” has being been increasingly used:..”plesase delete "being"

The language is generally clear, but some sentences could be more concise. Please consider a thorough proofread for grammatical accuracy and clarity.

METHODS

Line 183:…(loading and maintenance dose 10 and 5 mg/kg/die….maintenance dose 0.2 and 0.1 mg/kg/die…. These sentences need to be changed to a clearer definition, die converting to day (to be more understandable for the reader)

RESULT

Complete antenatal steroides (correct it as ‘antenatal steroids’) and write

Table 3:

Those percentage values need to be corrected: For example, 19/42 is 45.2% but it is written as 56% in Table 3.

Cesarean section, Vaginal delivery, Chorioamnionitis, Maternal hypertension/eclampsia, Gestational diabetes…The numbers seem to have been calculated incorrectly.

Mistakes should be corrected throughout the text, tables, and figures.

You should standardize all the numbers throughout the paper and either round them down or round them up to one decimal place (some are rounded up, some are in decimals, some are whole numbers)

Line 228: Overall, 70 of 218 neonates (32.1%).. please standardize the numbers:. … not 32.1% but 32%. All of them need to be in the same numerical type.

Lin 237: no signs of 237 pulmonary over circulation nor systemic hypoperfusion—could you change it as ‘no sign of pulmonary over circulation or systemic hypoperfusion’ or use ‘neither pulmonary over circulation nor systemic hypoperfusion’

Line 245: The total number of patients treated is not 61 patients (when I sum up, it is 60 patients)

Please check all of the numbers and percentages thoroughly again

Again, the numbers in Figure 2 should be standardized as previously described.

Line 261:’ …with median duration of medical treatment lasting 3.5 days.’ How did the median duration of medical treatment last 3.5 days? Didn't you give a 3-day cure treatment?

Line 263: please write the number without decimals.

Discussion

Line 308: In the study, the authors found that post-ligation syndrome was twice as high

How do you explain this situation?

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Fatih Bolat, MD Associate Professor

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Decision Letter 2

Hakan Aylanc

2 May 2024

PONE-D-23-29459R2Patent Ductus Arteriosus (even non-Hemodynamically Significant) correlates with poor outcomes in Very Low Birth Weight Infants. Multicenter cohort study.PLOS ONE

Dear Dr. Miselli,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 16 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Hakan Aylanc

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear Author,

The English version of the article needs to be edited. Grammatical errors need to be eliminated. You are expected to correct numerical errors in the tables within the article and respond adequately to the revision request. I will be waiting for your revision. I wish conveniences.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Editor

I'd like to suggest the manuscript titled "Patent Ductus Arteriosus (even non-Hemodynamically Significant) correlates with poor outcomes in Very Low Birth Weight Infants. Multicenter cohort study" that was submitted to PLOS ONE for review. After reading through the manuscript carefully, I would like to thank the authors' efforts in addressing some of the previous feedback. However, there are still some significant issues that need to be resolved before the manuscript can be considered for publication.

Even after trying to revise the manuscript, there are still quite a few grammar errors throughout the text. These mistakes can make it difficult for readers to understand the content clearly,

SOME SUGGESTIONS:

1. Please condense the conclusion in the abstract, as it is currently too long to provide a concise conclusion

2. Line 55: please change as “Multicenter prospective observational study was conducted in Emilia Romagna from”

3. Line 58:.” A diagnosis of hemodynamically significant (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present” should be added to study design

3) LİNE 83: PDA can cause result in pulmonary overcirculation and systemic… Please correct

4. Line 103... PDA by evaluating either only…grammar error

4) please calculate the ratio accurately, especially in Table 3

The suggested corrections have not been made in Table 3 “Those percentage values need to be corrected: For example, 19/42 is 45.2% but it is written as 56% in Table 3. Cesarean section, Vaginal delivery, Chorioamnionitis, Maternal hypertension/eclampsia, Gestational diabetes…The numbers seem to have been calculated incorrectly.

4) The manuscript has grammatical errors that should be corrected. For example. Line 55

…. Multicenter prospective observational study was conducted in Emilia Romagna from 56 March 2018 to October 2019.

Please comprehensively check by a native speaker

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Fatih Bolat, Associate Professor

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Decision Letter 3

Hakan Aylanc

25 Jun 2024

Patent ductus arteriosus (also non-hemodynamically significant) correlates with poor outcomes in very low birth weight infants. A multicenter cohort study

PONE-D-23-29459R3

Dear Dr. Miselli,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hakan Aylanc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Hakan Aylanc

28 Jun 2024

PONE-D-23-29459R3

PLOS ONE

Dear Dr. Miselli,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hakan Aylanc

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Data

    (XLSX)

    pone.0306769.s001.xlsx (77.7KB, xlsx)
    Attachment

    Submitted filename: PLOS One PDA review.docx

    pone.0306769.s002.docx (14.3KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    pone.0306769.s003.docx (28.6KB, docx)
    Attachment

    Submitted filename: Response to Reviewer.docx

    pone.0306769.s004.docx (16.6KB, docx)
    Attachment

    Submitted filename: Response to Reviewer.docx

    pone.0306769.s005.docx (16.5KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting information files.

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