A total of 233 preterm neonates weighing less than 1,500 g with HSPDA were ultimately enrolled in our study (Fig. 1). Of these neonates, 134 (57.5%) underwent surgical ligation and were subdivided into the EL group (n = 49, 36.6%) and the LL group (n = 85, 63.4%). The conditions of 99 neonates improved with medical treatment alone according to the protocol described at Table 1. Nine preterm neonates with congenital anomalies were excluded, including two neonates with congenital tracheoesophageal fistula, one with congenital chylothorax, two with ileal atresia, two with Edwards syndrome, and two with dry lung syndrome.
The baseline characteristics of the patients in the PDA ligation and Non-ligation groups are summarized in Table 2. Regarding maternal characteristics, histologic chorioamnionitis was significantly higher in the PDA ligation group than in the Non-ligation group (p = 0.027), while pregnancy-induced hypertension (PIH) was significantly lower in the PDA ligation group than in the Non-ligation group (p = 0.031). Regarding neonate characteristics, gestational age (GA), birth weight, length, head circumference, and Apgar scores at 1 minute and 5 minutes were significantly lower in the PDA ligation group than in the Non-ligation group. In contrast, time on a mechanical ventilator or on oxygen therapy, total parenteral nutrition and hospitalization, and age at PDA closure were significantly higher in the PDA ligation group than in the Non-ligation group. Additionally, PDA size (2.13 ± 0.84 mm vs 1.68 ± 0.92 mm, p < 0.001) and the proportion of preterm neonates with PDA ductal diameters larger than 2.0 mm (52.2 vs 22.2%, p < 0.001) were significantly different between the PDA ligation and Non-ligation groups.
Table 2 Characteristics of preterm neonates of the PDA ligation and Non-ligation groups.
Variables
|
PDA ligation
(n = 134)
|
Non-ligation
(n = 99)
|
p value
|
Maternal characteristics
|
|
|
|
Maternal age, years
|
32.58 ± 4.30
|
33.29 ± 4.10
|
0.205
|
Mother’s education level
|
|
|
0.946
|
High, n (%)
|
9 (6.7)
|
6 (6.1)
|
|
Intermediate, n (%)
|
88 (65.7)
|
67 (67.7)
|
|
Low, n (%)
|
37 (27.6)
|
26 (26.3)
|
|
GDM
|
10 (7.5)
|
10 (10.1)
|
0.488
|
PIH
|
9 (6.7)
|
16 (16.2)
|
0.031
|
PPROM
|
56 (41.8)
|
42 (42.4)
|
> 0.999
|
Histologic chorioamnionitis
|
104 (77.6)
|
63 (63.6)
|
0.027
|
Neonate characteristics
|
|
|
|
Gestational age, weeks
|
26.27 ± 2.28
|
27.37 ± 1.90
|
< 0.001
|
Birth weight, grams
|
882.05 ± 226.61
|
1053.23 ± 244.76
|
< 0.001
|
Length
|
33.69 ± 4.59
|
35.96 ± 3.36
|
< 0.001
|
Head circumference
|
24.60 ± 3.10
|
25.58 ± 2.37
|
0.010
|
Cesarean section
|
98 (73.1)
|
81 (81.8)
|
0.157
|
Male sex
|
69 (51.5)
|
41 (41.8)
|
0.183
|
Apgar score at 1 minute
|
2.10 ± 1.30
|
2.73 ± 1.33
|
< 0.001
|
Apgar score at 5 minutes
|
4.58 ± 1.67
|
5.40 ± 1.55
|
< 0.001
|
Antenatal corticosteroids
|
92 (68.7)
|
73 (73.7)
|
0.467
|
Postnatal corticosteroids
|
57 (42.5)
|
31 (31.3)
|
0.101
|
Age at PDA closure, days
|
15.57 ± 8.94
|
8.10 ± 2.71
|
< 0.001
|
Body weight at surgical ligation
|
911.87 ± 270.16
|
-
|
-
|
IVH
|
50 (37.3)
|
43 (43.4)
|
0.417
|
IVH grade II
|
8 (6)
|
3 (3)
|
0.241
|
IVH grade ≥ III
|
21 (15.7)
|
17 (17.2)
|
0.858
|
PVL
|
10 (7.5)
|
9 (9.1)
|
0.809
|
Culture-proven sepsis
|
83 (61.9)
|
55 (55.6)
|
0.347
|
NEC
|
12 (9.0)
|
10 (10.1)
|
0.823
|
NEC stage ≥ III
|
41 (30.8)
|
22 (22.2)
|
0.180
|
BPD
|
74 (55.6)
|
44 (44.9)
|
0.112
|
ROP
|
80 (60.2)
|
54 (55.1)
|
0.501
|
Days on mechanical ventilator
|
30.62 ± 18.63
|
16.20 ± 14.55
|
< 0.001
|
Days of oxygen therapy
|
68.70 ± 52.01
|
49.41 ± 28.20
|
0.001
|
TPN days
|
44.44 ± 25.64
|
36.59 ± 21.21
|
0.014
|
Hospital days
|
96.00 ± 40.44
|
79.89 ± 28.56
|
0.001
|
PDA size
|
2.13 ± 0.84
|
1.68 ± 0.92
|
0.001
|
PDA ductal diameter > 2.0 mm
|
70 (52.2)
|
22 (22.2)
|
< 0.001
|
Deaths
|
1 (0.7)
|
2 (2)
|
0.576
|
PDA, patent ductus arteriosus; GDM, gestational diabetes mellitus; PIH, pregnancy-induced hypertension; PPROM, preterm premature rupture of membranes; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; TPN, total parenteral nutrition.
Data are the mean ± SD or number (%).
The baseline characteristics of the patients in the EL and LL groups are summarized in Table 3. Age at PDA closure (8.18 ± 2.14 vs 19.44 ± 8.82 days, p < 0.001) and body weight at surgical ligation (847.96 ± 201.73 vs 948.71 ± 297.58 grams, p = 0.037) were significantly different between the EL and LL groups. The baseline maternal characteristics and preoperative status did not differ significantly between the EL and LL groups. Regarding neonate characteristics, cesarean section was significantly higher in the EL group than in the LL group (p = 0.044). In contrast, culture-proven sepsis (p = 0.026), NEC stage ≥ III (p = 0.030), and time on a mechanical ventilator (p = 0.048) were significantly lower in the EL group than in the LL group.
Table 3 Characteristics of preterm neonates of the early ligation and late ligation groups.
Variables
|
Early ligation
(n = 49)
|
Late ligation
(n = 85)
|
p value
|
Maternal characteristics
|
|
|
|
Maternal age, years
|
33.22 ± 5.16
|
32.21 ± 3.71
|
0.205
|
Mother’s education level
|
|
|
0.835
|
High, n (%)
|
3 (6.1)
|
6 (7.1)
|
|
Intermediate, n (%)
|
31 (63.3)
|
57 (67.1)
|
|
Low, n (%)
|
15 (30.6)
|
22 (25.9)
|
|
GDM
|
2 (4.1)
|
8 (9.4)
|
0.325
|
PIH
|
5 (10.2)
|
4 (4.7)
|
0.287
|
PPROM
|
15 (30.6)
|
41 (48.2)
|
0.068
|
Histologic chorioamnionitis
|
42 (85.7)
|
62 (72.9)
|
0.131
|
Neonate characteristics
|
|
|
|
Gestational age, weeks
|
26.67 ± 2.52
|
26.04 ± 2.11
|
0.123
|
Birth weight, grams
|
878.78 ± 216.77
|
883.94 ± 233.34
|
0.899
|
Length
|
33.10 ± 3.05
|
34.03 ± 5.27
|
0.259
|
Head circumference
|
24.48 ± 2.30
|
24.68 ± 3.49
|
0.719
|
Cesarean section
|
41 (83.7)
|
57 (67.1)
|
0.044
|
Male sex
|
24 (49)
|
41 (48.2)
|
> 0.999
|
Apgar score at 1 minute
|
2.08 ± 1.27
|
2.11 ± 1.33
|
0.918
|
Apgar score at 5 minutes
|
4.76 ± 1.58
|
4.48 ± 1.72
|
0.367
|
Antenatal corticosteroids
|
34 (69.4)
|
58 (68.2)
|
> 0.999
|
Postnatal corticosteroids
|
17 (34.7)
|
40 (47.1)
|
0.205
|
Age at PDA closure, days
|
8.18 ± 2.14
|
19.44 ± 8.82
|
< 0.001
|
Body weight at surgical ligation
|
847.96 ± 201.73
|
948.71 ± 297.58
|
0.037
|
IVH
|
18 (36.7)
|
32 (37.6)
|
> 0.999
|
IVH grade II
|
4 (8.2)
|
4 (4.7)
|
0.240
|
IVH grade ≥ III
|
4 (8.2)
|
17 (20.2)
|
0.086
|
PVL
|
3 (6.1)
|
7 (8.2)
|
0.746
|
Culture-proven sepsis
|
24 (49)
|
59 (69.4)
|
0.026
|
NEC
|
18 (36.7)
|
24 (28.2)
|
0.337
|
NEC stage ≥ III
|
2 (4.1)
|
15 (17.6)
|
0.030
|
BPD
|
25 (52.1)
|
49 (57.6)
|
0.588
|
ROP
|
32 (66.7)
|
48 (56.5)
|
0.273
|
Pneumothorax before ligation
|
2 (4.1)
|
2 (2.4)
|
0.623
|
Pulmonary hemorrhage before ligation
|
3 (6.1)
|
8 (9.4)
|
0.746
|
GI hemorrhage before ligation
|
1 (2.0)
|
7 (8.2)
|
0.257
|
Hypotension before ligation
|
11 (22.4)
|
21 (24.7)
|
0.836
|
Hypotension after ligation
|
2 (4.1)
|
3 (3.5)
|
> 0.999
|
Days on mechanical ventilator
|
26.38 ± 15.31
|
33.02 ± 19.95
|
0.048
|
Days of oxygen therapy
|
59.88 ± 33.88
|
74.51 ± 56.89
|
0.107
|
TPN days
|
40.73 ± 21.45
|
47.41 ± 28.36
|
0.156
|
Hospital days
|
94.53 ± 38.86
|
95.88 ± 41.52
|
0.853
|
PDA size
|
2.06 ± 0.67
|
2.16 ± 0.92
|
0.481
|
PDA ductal diameter > 2.0 mm
|
25 (51.0)
|
45 (52.9)
|
0.859
|
Deaths
|
0 (0)
|
1 (1.2)
|
> 0.999
|
GDM, gestational diabetes mellitus; PIH, pregnancy-induced hypertension; PPROM, preterm premature rupture of membranes; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; GI, gastrointestinal; TPN, total parenteral nutrition; PDA, patent ductus arteriosus.
Data are the mean ± SD or number (%).
No patients died during their operations. Two neonates required reoperation due to residual flow of PDA, as diagnosed by immediate postoperative transthoracic echocardiography. The residual flow was corrected with an additional metal clip. Three patients died during the postoperative hospital day. In the LL group, one neonate died 100 days after PDA ligation due to NEC. In the Non-ligation group, two neonates died 12 and 17 days after birth, and the cause of death was sepsis. There were no statistically significant differences in mortality rate between the PDA ligation and Non-ligation groups (p = 0.576), or between the EL and LL groups (p > 0.999).
The logistic regression analysis for factors associated with PDA surgical ligation is presented in Fig. 2. PDA ductal diameter > 2.0 mm (p < 0.001), low GA (p = 0.004), low Apgar score at 5 minutes (p = 0.033), and histologic chorioamnionitis (p = 0.037) remained significant after the analysis was controlled for GA, histologic chorioamnionitis, PIH, Apgar score at 5 minutes, and PDA ductal diameter > 2.0 mm.
The ROC curve for the ability to predict PDA surgical ligation showed that PDA ductal diameter > 2.0 mm predicted surgical treatment with an area under the curve (95% confidence interval (CI)) of 0.650 (0.579-0.721). Histologic chorioamnionitis showed an area under the curve (95% CI) of 0.570 (0.495-0.645), making it statistically significant in relation to the factors associated with PDA surgical ligation (Fig. 3).
The clinical factors that were shown to affect the postoperative clinical outcomes of the patients (EL versus LL) in the multivariate model are shown in Fig. 4. Clinical outcomes with associations with p < 0.1 in the univariate analyses were analyzed by multivariate logistic regression with adjustments for cesarean delivery, weight on PDA ligation and PDA diameter > 2.0 mm. After adjustments were made for confounders, EL was found to be significantly associated with a low incidence of IVH grade ≥ III (p = 0.035), culture-proven sepsis (p = 0.004), NEC stage ≥ III (p = 0.022) and time on a mechanical ventilator > 4 weeks (p = 0.007).