Journal of Pediatric Cardiology and Cardiac Surgery 3(1): 8‒13 (2019)

Original Article

Early Surgical Closure of Patent Ductus Arteriosus
Improves Respiratory Outcome in
Symptomatic Preterm Neonates
Yoonjin Kang, MD, Jae Gun Kwak, MD, PhD, and Woong-Han Kim, MD, PhD
Seoul National University Childrenʼs Hospital, Department of Thoracic and Cardiovascular Surgery,
Seoul National University Hospital, Seoul, South Korea

Background: Surgical intervention to treat patent ductus arteriosus (PDA) is required when pharmacologicaltreatment is contra-indicated or fails; however, the optimal time to perform surgery remains unclear. We evaluated the clinical outcome of surgical closure of PDA on symptomatic preterm neonates according to the timingof the operation.
Methods: We retrospectively evaluated 117 symptomatic preterm neonates who underwent surgical correctionof PDA between April 2010 and December 2016.
Results: Morbidity and mortality rates were compared based on the timing of surgery. The early occlusion group
was associated with significantly lower incidences of bronchopulmonary dysplasia (BPD) (odds ratio [OR] 0.298,
p=0.011) and pneumonia (OR 0.874, p=0.023) than the late occlusion group. However, the former group had higher
rates of mortality and intraventricular hemorrhage (IVH). Early occlusion was performed principally on neonateswith primary occlusions. The morbidity rate of the secondary occlusion group did not vary by surgical timing.
Conclusions: Delayed PDA closure after medical treatment failure in neonates was associated with a higher
incidence of BPD. Early primary PDA closure may improve the respiratory outcomes of preterm neonates, withacceptable safety.

Keywords: patent ductus arteriosus, preterm, neonates, congenital heart disease

Introduction
In preterm neonates, patent ductus arteriosus (PDA)
is associated with heart failure, respiratory distress, necrotizing enterocolitis (NEC), and retinopathy. Surgicalintervention is usually performed when pharmacological treatment is contraindicated or fails. Although some
reports of postoperative morbidity have appeared, surgical occlusion is an eﬀective and safe method of PDA closure, reducing the risks of bronchopulmonary dysplasia(BPD) and mortality.1‒3) Two randomized controlled trials performed a few decades ago revealed improvements
in respiratory outcomes after surgical PDA closure.4, 5)
Vida et al. described the benefits of early closure of the

PDA after two cycles of medical treatment in prematureinfants.6) However, the optimal time to perform surgery
remains unclear. To the best of our knowledge, no studies have enrolled only symptomatic preterm neonates.
Surgical closure of clinically significant PDA may be
associated with less morbidity than prophylactic surgicalclosure in asymptomatic neonates. Thus, we analyzed
the surgical outcomes of symptomatic preterm neonates
who underwent PDA occlusion, and sought to identify
the optimal timing of closure.

Methods
Patients
We retrospectively evaluated 117 symptomatic

Received: May 1, 2018; Accepted: November 5, 2018
Corresponding author: Jae Gun Kwak, MD, PhD, Seoul National University Childrenʼs Hospital, 103 Daehakro, JongroGu, Seoul
110-744, South Korea
E-mail: switch.surgeon@yahoo.com
doi: 10.24509/jpccs.190102© 2019 Japanese Society of Pediatric Cardiology and Cardiac Surgery

9preterm neonates who underwent surgery to treat
PDA at Seoul National University Childrenʼs Hospital
between April 2010 and December 2016. Neonates withcongenital intracardiac anomalies were excluded.
In our hospital, preterm neonates (<35 weeks) areroutinely admitted to neonatal intensive care units.
Whenever clinical parameters imply symptomatic PDA,
echocardiography is performed. The clinical parameters
used to define symptomatic PDA include worsening
blood gas values, cardiomegaly or pulmonary congestion evident radiologically, and hypotension, in agreement with the suggestions made by Limrungsikul.7)
In cases with symptomatic or hemodynamically significant PDA, intravenous ibuprofen is started if notcontraindicated. Follow-up echocardiography is performed to assess any change in the PDA after the firstibuprofen cycle. A second ibuprofen cycle is given if follow-up imaging reveals persistent PDA. Then, depending on their response to medical treatment, cardiologists
refer the neonates to surgeons. All patients in the present
study underwent surgical intervention because medical
treatment was contraindicated (such as NEC or acutekidney injury, IVH, or other evidence of bleeding; primary group) or failed (secondary group).
To evaluate the eﬀect of surgical timing on outcomes,
we divided all patients into two groups by surgical timing. The early group consisted of patients who were <10days of age at the time of surgery and the late groupconsisted of all other patients. In other studies, the mean
age after completion of the second cycle of ibuprofen was
9 to 10 days.6, 8) In comparison, the median age of thesubjects in our cohort was 10 days. Therefore, we defined
10 days as the criterion for the timing of the surgery.
As the characteristics of the infants in the two groups
diﬀered, we divided each group into two subgroups byprescription of preoperative ibuprofen, to form primaryand secondary subgroups.
We recorded gestational age, birth weight, Apgar
scores at 1 and 5 min, any history of respiratory distresssyndrome, use of surfactants, maternal pre-eclampsia
status, and delivery mode (vaginal or cesarean). Preoperative data included age at operation; size of the PDA as
revealed by echocardiography; the use of preoperative
ibuprofen; co-morbidities such as congenital diaphragmatic hernia (CDH) or NEC (Bellʼs classification≥II)9);
any pulmonary hemorrhage; hypotension; and acutekidney injury (AKI), BPD, intraventricular hemorrhage(IVH), sepsis, pneumonia, and pulmonary hypertension status. Postoperative complications included vocal
cord palsy, re-operation because of coarctation of theaorta, chylothorax, pneumothorax, and bleeding. The
outcomes included mortality; necrotizing enterocolitis(Bellʼs classification≥II); AKI (serum creatinine concentration≥1.5 mg/dL or urine output <1 mL/kg/h
after the first 48 h); IVH (≥ grade III), BPD; and pneumonia.
Surgical Procedure
Under general anesthesia, the PDA was approached
via a thoracotomy (usually through the third or fourthintercostal space). In approximately half of the cases(n=55), both ends of the PDA were ligated and thendivided; double ligation of the duct was performed in theremaining cases. Most of the operations were performedat the bedside in the neonatal intensive care unit, especially when the baby weighed less than 2 kg.
Statistics
Perioperative data were compared between thegroups. Demographic characteristics were comparedusing the t-test, chi-square test, and Fisherʼs exact test,
as appropriate. The chi-square and Fisherʼs exact test
were used to compare morbidity and mortality rates.
Predictors of mortality were sought by univariate andmultivariate logistic regression. For subgroup analysis,
we divided each group into a primary occlusion subgroup who underwent surgery without prior medical
treatment and a secondary occlusion subgroup who
underwent surgery after medical failure. All statisticalanalyses were performed with the aid of SPSS software(ver. 20.0; SPSS, Chicago, IL, USA). A p-value <0.05 wasconsidered to reflect significance.
The study was approved by the institutional review
board of Seoul National University Hospital (IRB no.
1706-072-859).

Results
Demographic Data and Preoperative Characteristics
Demographic characteristics, and preoperative andpostoperative details, are described in Table 1. Twenty-eight patients had significant comorbidities, including congenital diaphragmatic hernias (n=2; one patientin the early group), a chromosomal abnormality (n=1;© 2019 Japanese Society of Pediatric Cardiology and Cardiac Surgery

10

vs. 23.3 days; p<0.001) (Table 1). In terms of preoperative conditions, the early group had a lower incidenceof sepsis (9 vs. 26; p=0.0002) and a higher incidenceof pulmonary hemorrhage. Compared with the earlygroup, the late group tended to have a higher incidenceof NEC.

the late group), and an ileostomy or colostomy status
due to bowel perforation (n=25; 14 patients in theearly group). Mean age at operation was 14 days. The
early group contained 56 patients; the late group had 61
patients. Fifty-four neonates underwent primary closure
because of contra-indications to ibuprofen (primary closure) and sixty-three underwent occlusion after medical
failure (secondary closure).
Demographic characteristics and preoperative outcomes were compared between the groups. The earlyand late groups did not diﬀer significantly in terms ofbaseline characteristics except for age at operation (4.9

Postoperative Outcomes
No operative death was noted. One patient underwent re-operation to treat coarctation of the aorta thatdeveloped after PDA ligation. The patient is currently
doing well and no residual coarctations have been

Table 1 Demographic and clinical characteristics according to the timing of surgery and the preoperative Ibuprofen usage
Early (n=56)
Total
Age at operation (days)
14.5 (13.0)
Apgar score at 1 minute
3.1 (2.1)
Apgar score at 5 minutes
5.31 (2.2)
Gestational Age (weeks)
26.73 (2.91)
Maternal Preeclampsia
12 (10.3％)
Body weight (g)956.8 (565.7)
Caesarean section
66 (56.9％)
Respiratory distress Syndrome
95 (81.2％)
Use of Surfactants
93 (79.5％)〈Preoperative status〉
Bronchopulmonary dysplasia
9 (7.7％)
Acute kidney injury
50 (42.7％)
Necrotizing enterocolitis
18 (15.4％)
Intraventricular hemorrhage
3
Sepsis35 (29.9％)
Hypotension
65 (55.6％)
Pneumonia
4 (％)
Pulmonary hemorrhage
22 (18.8％)
Pulmonary hypertension
32 (28.3％)

Late (n=61)

Primary(n=40)

Total

4.9 (2.5)
4.22 (2.069)
2.8 (2.0)
2.2(1.7)
5.3 (2.1)
5.0 (2.3)
26.6 (2.9)
27.2 (3.1)
6
5
986.8 (677.3) 1051.3 (775.7)
33
26
45
34
44
33
2
26
5
0
9
35
0
16
12

1
19
5
3
6
26
0
13
12

p value(Early vs. late)

Total

Primary(n=14)

23.3 (12.4)
3.3 (2.2)
5.3 (2.3)
26.8 (2.9)
6929.2 (443.3)
33
50
49

23.1 (11.4)
3.36 (2.5)
5.50 (2.4)
26.5 (3.4)
0996.4 (644.3)
6
12
11

7
24
13
0
26
30
4
6
20

1
6
9
0
9
12
2
1
6

0.000
0.211
0.882
0.768
0.876
0.584
0.669
0.824
0.814
0.166
0.439
0.064
0.067
0.002
0.148
0.120
0.010
0.169

Values in parentheses: standard deviation.

Table 2 Postoperative clinical outcomes according to the timing of surgery and the preoperative Ibuprofen usage
Total
Bronchopulmonary dysplasia
Moderate to severe
Use of Steroid
Acute kidney injury
Necrotizing enterocolitis
Intraventricular hemorrhage
SepsisRetinopathy of prematurity
Hypotension
Pneumonia
Pulmonary hypertension
Mortality

96 (82.1％)
71 (60.7％)
19 (16.2％)
16 (13.7％)
31 (26.5％)
24 (20.5％)
37 (31.6％)
54 (46.2％)
26 (22.3％)
10 (8.5％)
34 (29.3％)
19 (16.2％)

Early (n=56)

Late (n=61)ORΧ2

p value(Early vs.
late)

41
29
3
9
11
15
21
22
16
2
19
13

55
42
16
7
3
9
16
32
10
8
15
6

3.354
2.058
6.281
0.677
0.212
0.473
0.593
1.705
0.490
4.075
0.618
0.361

5.696
3.564
9.351
0.522
6.010
2.592
1.715
2.039
2.505
3.402
1.383
3.842

0.017
0.059
0.002
0.470
0.014
0.107
0.190
0.153
0.113
0.065
0.240
0.050

Values in parentheses: standard deviation. OR: odd ratios

J Pediatr Cardiol Card Surg Vol. 3, No. 1 (2019)

25
18
0
8
4
14
15
14
14
0
15
12

12
9
3
2
1
3
4
9
3
3
4
3

11

found. No other complications related to the operation
were observed. There were 19 in-hospital deaths after
PDA closure: 13 in the early group and 6 in the lategroup (Table 2). The late group experienced significantly
lower mortality (odds ratio [OR] 0.36, p=0.05; Table 2).
Twelve of thirteen deaths in the early group were in the
primary closure subgroup. The causes of death wereassociated with prematurity (sepsis, pulmonary hemorrhage, etc.).
The late group had a significantly higher incidence ofBPD (OR 3.354, p=0.017) and tended to have a greater
incidence of pneumonia (OR 4.075, p=0.065). Withineach group, we compared subgroups by preoperative
medical treatment (yes or no). On subgroup analysis,
early primary surgical closure was significantly associated with lower incidences of BPD (OR 1.600, p=0.004)
Table 3 Odds ratios for the risk of postoperative morbidity and mortality according to the preoperative ibuprofen usage in the early group
Primary vs. Secondary
in the Early groupORΧ2p value

Bronchopulmonary dysplasia
Moderate to Severe
Use of Steroid
Acute kidney injury
Necrotizing enterocolitis
Intraventricular hemorrhage
SepsisRetinopathy of prematurity
Hypotension
Pneumonia
Pulmonary hypertension
Mortality

1.600
2.689
1.231
0.267
7.000
0.124
1
1.857
0.265
1.143
0.533
0.156

8.195
2.582
7.925
1.602
8.247
4.817
0.000
1.078
2.845
5.185
0.909
3.616

0.004
0.108
0.020
0.206
0.004
0.028
1.000
0.299
0.092
0.023
0.340
0.082

OR: odd ratios

Table 4 Prognostic factors of survival accepted in theforward model and all other clinical parameters analyzed and not regarded as explanatory
Postoperative outcomesβPneumonia
3.1
Hypotension
1.9
Pulmonary hypertension
1.9
Bronchopulmonary dysplasia 3.4
Sepsis1.8
Variables not significant
̶Acute kidney injury
Mean age at operation (S.D.) ̶̶Gestational age
̶Body weight̶
Early surgical occlusion̶Primary occlusion
OR: odd ratiosORp value

22.4 (2.4‒206.8)
6.38 (1.4‒28.2)
6.5 (1.3‒33.1)
28.6 (5.3‒166.7)
6.0 (1.2‒30.3)

0.006
0.014
0.025
0.000
0.031

̶
̶
̶
̶
̶
̶

0.256
0.818
0.683
0.239
0.917
0.583

and pneumonia (OR 1.143, p=0.023; Table 3).
Factors Prognostic of Mortality
BPD and pneumonia were significantly associatedwith an increased risk of mortality. No other variable(including gestational age and body weight) was significant in this context. Although the early group experienced a higher level of mortality, the timing of surgery
was not a significant predictor of survival (Table 4).

Discussion
Our experience shows that PDA closure in preterm
neonates is eﬀective and safe; there was no perioperative mortality. The 5% in-hospital mortality and5‒10% morbidity are similar to those of previous studies showing that PDA ligation was relatively safe.10‒12)
Although previous studies discussed the optimal timingof surgical intervention in preterm neonates, the results
are controversial. The studies targeted preterm infants
regardless of their symptoms or extent of hemodynamic
compromise. We focused on the perioperative outcomesof symptomatic preterm neonates. Although some studies11, 13, 14)have found that PDA closure in infants withcardiorespiratory complications or neural impairment
is detrimental, Jaillard et al.15) showed that early surgicalclosure was associated with improved lung complianceand nutrition. We found that early closure was associated with reductions in respiratory complications, suchas BPD and pneumonia. Consistent with other studies,16‒18) we found that early surgery for symptomatic
preterm neonates improved respiratory status.
We are the first to subject both the timing of surgery and preoperative medical treatment to subgroup
analysis. We found that the timing of surgery per se
was associated with the extent of preoperative medical
treatment. This finding diﬀers from those of other studies, possibly because of heterogeneity among the earlysurgical groups. Thus, as neonates who underwent earlyocclusion tended to undergo primary occlusion, we
divided each group into two subgroups to evaluate theeﬀect of preoperative medication on perioperative outcomes. Although the early group was at an increased riskof mortality, age at operation was not per se a significant
predictor of mortality. The early and primary groups
included neonates with contraindications for medical
therapy and who tended to be hemodynamically unstable; these preoperative characteristics explain their sus-

© 2019 Japanese Society of Pediatric Cardiology and Cardiac Surgery

12

ceptibility. As mentioned in previous studies,19) neonates
who require early surgery tend to be at higher risk ofmorbidity and mortality. The early group in our cohort
tended to include those with significant comorbidities,
such as a congenital diaphragmatic hernia or previous
ileostomy or jejunostomy due to bowel perforation.
Moreover, outborn neonates contributed significantly tothe higher mortality in the early group. These findings
may explain why babies who had contraindications for
medical treatment had higher mortality.
On subgroup analysis, early primary surgical closure
was associated with a lower incidence of NEC. One
explanation for this result is that prolonged ibuprofen
usage by preterm neonates with medically retractable
symptomatic PDA may be associated with a higher
incidence of NEC, even in the early surgery group.
However, this result should be interpreted with caution.
Our surgical outcomes included new-onset NEC. As theearly primary surgery group included patients alreadysuﬀering from NEC, subgroup analysis may make it
appear that the secondary closure group exhibited ahigher incidence of NEC. Thus, further randomized
controlled studies on the association between NEC andPDA closure are required.
The late group was at higher risk of sepsis and NEC,
implying that delayed PDA closure may be associatedwith more morbidity. Some studies found that prolonged medical therapy may increase the risk of morbidity.6, 20)Delayed PDA closure is associated with pulmonary complications such as chronic lung disease and theneed for prolonged ventilator support.15, 21) Some authors
have suggested that early closure can prevent long-term
cardiorespiratory compromise.11) However, the details of
the association between PDA and respiratory complications remain unknown. Multivariate analysis revealed
that BPD and pneumonia were significantly prognosticof mortality. Little et al.21) found that early PDA closure
was beneficial and acceptably safe for preterm neonates.
Moreover, in line with our results, Tschuppert et al.22)
found that early closure seemed to be associated withimproved pulmonary function. However, some previous
studies23, 24) found that early PDA closure was no more
beneficial than late closure; the cited studies enrolled all
preterm neonates including those without symptoms.
Our study was limited by its retrospective nature; thiswas not a randomized controlled trial exploring theeﬀect of timing of PDA closure on the long-term outJ Pediatr Cardiol Card Surg Vol. 3, No. 1 (2019)comes of symptomatic preterm neonates. In addition,
as Limrungsikul et al.7) pointed out, the diagnoses ofsymptomatic or hemodynamically significant PDA vary.
Our institution uses in-house criteria to identify PDAs
requiring intervention. As preterm neonates usually
have comorbidities related to prematurity per se, decisions on PDA treatment will vary among neonatologists.

Conclusion
PDA closure is safe in preterm neonates, and earlysurgery seems to reduce respiratory complications. To
reduce morbidity, symptomatic preterm neonates with
PDA should be considered for prompt PDA closure assoon as medical therapy fails or contraindications to
medical therapy are identified. A future randomized
controlled trial is required to confirm the optimal timingof PDA closure in symptomatic neonates.
Acknowledgment
This paper was presented at the 13th Japan-China-Korea
Pediatric Heart Forum in Japan (July, 2017).
Conﬂicts of Interest
The authors have no conflicts of interest to declare.

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