Introduction: A feature of the management of extremely preterm infants in Japan is proactive circulatory management using early routine echocardiography performed by neonatologists. Methods: This study was a post hoc analysis of the Patent ductus arteriosus and Left Atrial Size Evaluation in preterm infants (PLASE) study, which is a prospective cohort study including preterm infants admitted to 34 tertiary neonatal intensive care units in Japan between October 2015 and December 2016. We described the details of the treatment strategy of patent ductus arteriosus (PDA) based on early routine echocardiography. Results: In total, 613 preterm infants were included into the analysis. Twenty percent of infants with prophylactic indomethacin were switched to therapeutic cyclooxygenase inhibitor (COX-I) before the completion of the full prophylactic indomethacin course. Therapeutic COX-I was mostly administered based on echocardiographic findings before PDA became symptomatic or hemodynamically significant. Therapeutic COX-I was frequently discontinued after one or two doses before the full course (three doses) was completed. The proportion of infants requiring additional treatment (additional therapeutic COX-I course or surgical PDA closure) after discontinued COX-I courses (<3 doses) compared to infants after completed 3 doses course was significantly lower (after the first therapeutic COX-I course 46% vs. 68%, p < 0.001) or without a significant difference (after the second or third course). Conclusions: The clinical management of PDA in Japan featured (1) COX-I administration based on echocardiographic findings before symptomatic or hemodynamically significant PDA appeared and (2) frequent discontinuation of therapeutic COX-I before completing the standard three doses course.

1.
Smith
LK
,
Morisaki
N
,
Morken
NH
,
Gissler
M
,
Deb-Rinker
P
,
Rouleau
J
, et al
.
An international comparison of death classification at 22 to 25 weeks’ gestational age
.
Pediatrics
.
2018
;
142
(
1
):
e20173324
.
2.
Shah
PS
,
Lui
K
,
Sjörs
G
,
Mirea
L
,
Reichman
B
,
Adams
M
, et al
.
Neonatal outcomes of very low birth weight and very preterm neonates: an international comparison
.
J Pediatr
.
2016
;
177
:
144
52.e6
.
3.
Isayama
T
,
Mirea
L
,
Mori
R
,
Kusuda
S
,
Fujimura
M
,
Lee
SK
, et al
.
Patent ductus arteriosus management and outcomes in Japan and Canada: comparison of proactive and selective approaches
.
Am J Perinatol
.
2015
;
32
(
11
):
1087
94
.
4.
Isayama
T
,
Kusuda
S
,
Adams
M
,
Berti
E
,
Battin
M
,
Helenius
K
, et al
.
International variation in the management of patent ductus arteriosus and its association with infant outcomes: a survey and linked cohort study
.
J Pediatr
.
2022
;
244
:
24
9.e7
.
5.
Toyoshima
K
,
Kawataki
M
,
Ohyama
M
,
Shibasaki
J
,
Yamaguchi
N
,
Hoshino
R
, et al
.
Tailor-made circulatory management based on the stress-velocity relationship in preterm infants
.
J Formos Med Assoc
.
2013
;
112
(
9
):
510
7
.
6.
Isayama
T
.
The clinical management and outcomes of extremely preterm infants in Japan: past, present, and future
.
Transl Pediatr
.
2019
;
8
(
3
):
199
211
.
7.
Kluckow
M
,
Jeffery
M
,
Gill
A
,
Evans
N
.
A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus
.
Arch Dis Child Fetal Neonatal Ed
.
2014
;
99
(
2
):
F99
104
.
8.
El-Khuffash
A
,
Bussmann
N
,
Breatnach
CR
,
Smith
A
,
Tully
E
,
Griffin
J
, et al
.
A pilot randomized controlled trial of early targeted patent ductus arteriosus treatment using a risk based severity score (the PDA RCT)
.
J Pediatr
.
2021
;
229
:
127
33
.
9.
de Waal
K
,
Phad
N
,
Stubbs
M
,
Chen
Y
,
Kluckow
M
.
A randomized placebo-controlled pilot trial of early targeted nonsteroidal anti-inflammatory drugs in preterm infants with a patent ductus arteriosus
.
J Pediatr
.
2021
;
228
:
82
6.e2
.
10.
Clyman
RI
,
Liebowitz
M
,
Kaempf
J
,
Erdeve
O
,
Bulbul
A
,
Håkansson
S
, et al
.
PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age
.
J Pediatr
.
2019
;
205
:
41
8.e6
.
11.
Liebowitz
M
,
Katheria
A
,
Sauberan
J
,
Singh
J
,
Nelson
K
,
Hassinger
DC
, et al
.
Lack of equipoise in the PDA-TOLERATE trial: a comparison of eligible infants enrolled in the trial and those treated outside the trial
.
J Pediatr
.
2019
;
213
:
222
6.e2
.
12.
Toyoshima
K
,
Isayama
T
,
Kobayashi
T
,
Su
C
,
Mikami
M
,
Yokoyama
T
, et al
.
Patent ductus arteriosus, Left Atrial Size Evaluation in preterm infants (PLASE) study group investigators. What echocardiographic indices are predictive of patent ductus arteriosus surgical closure in early preterm infants? A prospective multicenter cohort study
.
J Cardiol
.
2019
;
74
(
6
):
512
8
.
13.
Fowlie
PW
,
Davis
PG
.
Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis
.
Arch Dis Child Fetal Neonatal Ed
.
2003
;
88
(
6
):
F464
6
.
14.
Lago
P
,
Salvadori
S
,
Opocher
F
,
Ricato
S
,
Chiandetti
L
,
Frigo
AC
.
Continuous infusion of ibuprofen for treatment of patent ductus arteriosus in very low birth weight infants
.
Neonatology
.
2014
;
105
(
1
):
46
54
.
15.
Hiraishi
S
,
Horiguchi
Y
,
Misawa
H
,
Oguchi
K
,
Kadoi
N
,
Fujino
N
, et al
.
Noninvasive Doppler echocardiographic evaluation of shunt flow dynamics of the ductus arteriosus
.
Circulation
.
1987
;
75
(
6
):
1146
53
.
16.
Mitra
S
,
Scrivens
A
,
von Kursell
AM
,
Disher
T
.
Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants
.
Cochrane Database Syst Rev
.
2020
;
12
(
12
):
CD013278
.
17.
Davis
P
,
Turner-Gomes
S
,
Cunningham
K
,
Way
C
,
Roberts
R
,
Schmidt
B
.
Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus
.
Arch Pediatr Adolesc Med
.
1995
;
149
(
10
):
1136
41
.
18.
Evans
P
,
O'Reilly
D
,
Flyer
JN
,
Soll
R
,
Mitra
S
.
Indomethacin for symptomatic patent ductus arteriosus in preterm infants
.
Cochrane Database Syst Rev
.
2021
;
1
(
1
):
CD013133
.
19.
Mitra
S
,
Florez
ID
,
Tamayo
ME
,
Mbuagbaw
L
,
Vanniyasingam
T
,
Veroniki
AA
, et al
.
Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis
.
JAMA
.
2018
;
319
(
12
):
1221
38
.
20.
Jansen
EJS
,
Hundscheid
T
,
Onland
W
,
Kooi
EMW
,
Andriessen
P
,
de Boode
WP
.
Factors associated with benefit of treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis
.
Front Pediatr
.
2021
;
9
:
626262
.
21.
Bixler
GM
,
Powers
GC
,
Clark
RH
,
Walker
MW
,
Tolia
VN
.
Changes in the diagnosis and management of patent ductus arteriosus from 2006 to 2015 in United States neonatal intensive care units
.
J Pediatr
.
2017
;
189
:
105
12
.
22.
Hagadorn
JI
,
Brownell
EA
,
Trzaski
JM
,
Johnson
KR
,
Lainwala
S
,
Campbell
BT
, et al
.
Trends and variation in management and outcomes of very low-birth-weight infants with patent ductus arteriosus
.
Pediatr Res
.
2016
;
80
(
6
):
785
92
.
23.
Ngo
S
,
Profit
J
,
Gould
JB
,
Lee
HC
.
Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants
.
Pediatrics
.
2017
;
139
(
4
):
e20162390
.
24.
Zozaya
C
,
Shah
J
,
Pierro
A
,
Zani
A
,
Synnes
A
,
Lee
S
, et al
.
Neurodevelopmental and growth outcomes of extremely preterm infants with necrotizing enterocolitis or spontaneous intestinal perforation
.
J Pediatr Surg
.
2021
;
56
(
2
):
309
16
.
25.
Vaidya
R
,
Yi
JX
,
O'Shea
TM
,
Jensen
ET
,
Joseph
RM
,
Shenberger
J
, et al
.
Long-term outcome of necrotizing enterocolitis and spontaneous intestinal perforation
.
Pediatrics
.
2022
;
150
(
5
):
e2022056445
.
26.
Miyata
M
,
Toyoshima
K
,
Yoda
H
,
Murase
M
,
Kawato
H
,
Yamamoto
K
, et al
.
Extensive use of vasodilator agents and functional echocardiography to monitor extremely-low-birth-weight infants in Japan
.
J Neonatal Perinatal Med
.
2016
;
9
(
3
):
261
9
.
27.
Hundscheid
T
,
Onland
W
,
Kooi
EMW
,
Vijlbrief
DC
,
de Vries
WB
,
Dijkman
KP
, et al
.
Expectant management or early ibuprofen for patent ductus arteriosus
.
N Engl J Med
.
2023
;
388
(
11
):
980
90
.
28.
Gupta
S
,
Juszczak
E
,
Hardy
P
,
Subhedar
N
,
Wyllie
J
,
Kelsall
W
, et al
.
Study protocol: baby-OSCAR trial: outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial
.
BMC Pediatr
.
2021
;
21
(
1
):
100
.
You do not currently have access to this content.