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\begin{document}

\title{Surgical ligation, not transcatheter closure, associated with a higher
severity of bronchopulmonary dysplasia in extremely preterm infant
intervened for patent ductus arteriosus}



\author[1]{Yu-Jen Wei}%
\author[1]{Ying-Tzu Ju}%
\author[1]{Min-Ling Hsieh}%
\author[1]{Chung-Dann Kan}%
\author[1]{Yung-Chieh Lin}%
\author[1]{Jieh Neng Wang}%
\affil[1]{National Cheng Kung University Hospital}%


\vspace{-1em}



  
  \date{June 05, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Objective}: Patent ductus arteriosus (PDA) is a common
complication among premature infants, and it may be responsible for
prematurity-related complications, such as bronchopulmonary dysplasia
(BPD). It is unclear whether different interventional methods contribute
to the severity of BPD. To date, surgical ligation and the transcatheter
approach have shown equal success in premature infants with
hemodynamically significant PDA after medical treatment failure.
Immediate improvement in the respiratory condition after transcatheter
closure has been reported. However, the short-term pulmonary outcome has
not been clarified yet. \textbf{Methods}: This retrospective study
investigated infants born with a body weight less than 1000 g and
underwent either surgical ligation or transcatheter closure of PDA in a
single tertiary institution. The infants were divided into groups
according to the type of procedure (surgical ligation or transcatheter
occlusion). The primary outcome was the severity of BPD at discharge or
at post-menstrual age of 36 weeks. The outcome was analyzed with
logistic regression. \textbf{Results}: Forty-four patients met the
inclusion criteria, and of these, 14 underwent transcatheter occlusion
and 30 underwent surgical ligation. The overall birth body weight and
gestational age ranges were not different. The univariate model revealed
an association between the procedure type and BPD severity. The
multivariate model confirmed associations of BPD severity with procedure
type and severe respiratory distress syndrome requiring surfactant after
adjusting for confounders. \textbf{Conclusion}: Compared with the
transcatheter approach, surgery for PDA in extremely preterm infants is
associated with severe BPD at discharge. Further large-scale studies are
needed to determine the exact mechanism.%
\end{abstract}%



\sloppy


\textbf{Title:}

\textbf{Surgical ligation, not transcatheter closure, associated with a
higher severity of bronchopulmonary dysplasia in extremely preterm
infant intervened for patent ductus arteriosus}

Yu-Jen Wei\textsuperscript{1}, Ying-Tzu Ju\textsuperscript{1}, Min-Ling
Hsieh\textsuperscript{1}, Chung-Dann Kan\textsuperscript{2}, Yung-Chieh
Lin\textsuperscript{1}, Jieh-Neng Wang\textsuperscript{1}

\textsuperscript{1}Department of Pediatrics, National Cheng Kung
University Hospital, College of Medicine, National Cheng Kung
University, Tainan, Taiwan

\textsuperscript{2}Department of Surgery, National Cheng Kung University
Hospital, College of Medicine, National Cheng Kung University, Tainan,
Taiwan

\textbf{Address reprint requests and corresponding to:}

Jieh-Neng Wang, M.D., Ph.D., Department of Pediatrics, National Cheng
Kung University Hospital, College of Medicine, National Cheng Kung
University, No. 138,

Sheng-Li Road, Tainan 70421, Taiwan.

Tel: +886-6-2353535 ext 4187

E-mail: jiehneng@mail.ncku.edu.tw

\textbf{Word count:} 1955 words excluding abstract, references, figures,
and table

\textbf{Key words:} patent ductus arteriosus, transcatheter closure,
bronchopulmonary dysplasia

\textbf{Contributorship:}

Dr. Yu-Jen Wei: acquisition of data and drafting of the manuscript;
Ying-Tzu Ju: acquisition and analysis of data; Dr. Yung-Chieh Lin:
research conception and design; Dr. Chung-Dann Kan: analysis and
interpretation of data; Dr. Min-Ling Hsieh: acquisition and analysis of
data; Dr. Jieh-Neng Wang: conception and design, analysis and
interpretation of data, and final approval of the published version.

\textbf{Ethics:} The study protocol was approved by the Institutional
Review Board (protocol code A-ER-109-137) in National Cheng Kung
University Hospital.

\textbf{Funding:} This research was supported by intramural grant
NCKUH-11105003 from National Cheng Kung University Hospital. The funds
aided in the fees required for the data analysis, English editing, and
publication process.

\textbf{Competing interests:} None of the authors have any competing
interests.



\textbf{Abstract}

\textbf{Objective} : Patent ductus arteriosus (PDA) is a common
complication among premature infants, and it may be responsible for
prematurity-related complications, such as bronchopulmonary dysplasia
(BPD). It is unclear whether different interventional methods contribute
to the severity of BPD. To date, surgical ligation and the transcatheter
approach have shown equal success in premature infants with
hemodynamically significant PDA after medical treatment failure.
Immediate improvement in the respiratory condition after transcatheter
closure has been reported. However, the short-term pulmonary outcome has
not been clarified yet. \textbf{Methods} : This retrospective study
investigated infants born with a body weight less than 1000 g and
underwent either surgical ligation or transcatheter closure of PDA in a
single tertiary institution. The infants were divided into groups
according to the type of procedure (surgical ligation or transcatheter
occlusion). The primary outcome was the severity of BPD at discharge or
at post-menstrual age of 36 weeks. The outcome was analyzed with
logistic regression. \textbf{Results} : Forty-four patients met the
inclusion criteria, and of these, 14 underwent transcatheter occlusion
and 30 underwent surgical ligation. The overall birth body weight and
gestational age ranges were not different. The univariate model revealed
an association between the procedure type and BPD severity. The
multivariate model confirmed associations of BPD severity with procedure
type and severe respiratory distress syndrome requiring surfactant after
adjusting for confounders. \textbf{Conclusion} : Compared with the
transcatheter approach, surgery for PDA in extremely preterm infants is
associated with severe BPD at discharge. Further large-scale studies are
needed to determine the exact mechanism.

\textbf{Introduction}

Patent ductus arteriosus (PDA) is a common cardiovascular complication
among premature infants, and it may be responsible for
prematurity-related complications. The ductus arteriosus is a vessel
between the pulmonary circulation and systemic circulation in a
fetus.\textsuperscript{1} In most term infants, the ductus arteriosus
closes spontaneously. However, in premature infants, the ductus often
fails to close spontaneously. The spontaneous closure rate has been
shown to be inversely related to the birth gestational age, and it
ranges from 13\% to 98\%. \textsuperscript{2}

In premature infants, a hemodynamically significant PDA has been
reported to be associated with complications, such as pulmonary
hemorrhage, \textsuperscript{3; 4} bronchopulmonary dysplasia
(BPD),\textsuperscript{5; 6} intraventricular hemorrhage,
\textsuperscript{7; 8} renal dysfunction, necrotizing enterocolitis,
\textsuperscript{9}neurological impairments, \textsuperscript{10} and
mortality.\textsuperscript{11; 12} A hemodynamically significant PDA
will usually be treated with non-steroidal anti-inflammatory drugs, such
as ibuprofen and indomethacin. A PDA may fail to respond to medical
treatment and may require non-pharmaceutical interventions. Surgical
ligation is a well-established procedure for a PDA that has not
responded to medical treatment. However, surgical ligation has been
shown to be associated with the development of BPD. \textsuperscript{2;
13}

Recently, transcatheter interventions involving ductus arteriosus
closure have been used in premature infants. Wang et al. reported the
detailed process and experience of performing this technique in very low
birth weight infants. \textsuperscript{14} Numerous studies have
compared complications and success rates between transcatheter
techniques and surgical ligation, and no statistically significant
differences were noted. Furthermore, a comparison of the short-term
effects after transcatheter techniques and those after PDA ligation
revealed that transcatheter techniques improved the pulmonary score
earlier. The authors reported the immediate benefits of respiratory
trajectory following the transcatheter closure of
PDA.\textsuperscript{15} However, the short-term impacts on the severity
of BPD at discharge have not been reported, especially for extremely
premature infants. Therefore, this retrospective study was conducted in
a single institution to investigate the association between the
different procedure types of PDA interventions and the severity of BPD
among extremely premature infants requiring intervention for a
hemodynamically significant PDA.

\textbf{Material and Methods}

\emph{2.1 Study Design}

We performed a retrospective chart review of infants born with a body
weight less than 1000 g and admitted to National Cheng Kung University
Hospital from July 2014 to June 2020. We enrolled infants who received
PDA invasive management involving either surgical ligation or
transcatheter occlusion and were diagnosed with BPD at 36 weeks'
post-menstrual age. Infants with BPD severity already classified before
the procedure were excluded. According to the NICHD 2001 BPD diagnosis
criteria, BPD was considered as 28 cumulative days of supplemental
oxygen more than 21\%. The severity of BPD was defined according to a
previously published definition (Supplementary Table
1).\textsuperscript{16} Based on the type of intervention, patients were
divided into a surgical ligation group (Group A) or a transcatheter
occlusion group (Group B). The study protocol was approved by the
Institutional Review Board (protocol code A-ER-109-137) of this
institution.

\emph{2.2 Data Collection and Outcomes}

We collected data on birth body weight, gestational age, fraction of
oxygen (FiO\textsubscript{2}) used before the procedure, sex, procedural
body weight, procedural gestational age (PMA), invasive ventilation use,
respiratory distress syndrome (RDS) requiring surfactant, and antenatal
and post-natal steroid use. The research population recruitment
algorithm is shown in Figure 1.

The outcome measurement of BPD severity involved classification as none,
mild, moderate, or severe BPD or death before discharge, and severity
was further divided into lower severity (none or mild BPD) and higher
severity (moderate or severe BPD, or death).

\emph{Statistics and Analysis}

All analyses were performed using SPSS (Version 28, IBM Corp., Armonk,
NY, USA). A p-value \textless{}0.05 was considered significant. Basic
demographic data were compared with the Student's \emph{t} test for
continuous variables and the chi-square test or Fisher's exact test for
categorical variables as appropriate. The outcome analyses compared BPD
severity between surgical ligation and transcatheter occlusion using
logistic regression adjusted for selected risk factors. Two regression
models were used for multivariate logistic regression. Odds ratios (ORs)
with 95\% confidence intervals (CIs) were estimated.

\textbf{Results}

During the study period, a total of 66 patients received PDA
interventions involving either transcatheter occlusion or surgical
ligation, and 49 patients with a birth body weight less than 1000 g were
included. Among these patients, 5 were excluded owing to BPD severity
classified before the procedure. Thus, 44 patients met the inclusion
criteria and were included (14 patients underwent transcatheter
occlusion and 30 patients underwent surgical ligation). The overall
birth body weight ranged from 461 g to 979 g (transcatheter occlusion vs
surgical ligation: 694.0 \selectlanguage{ngerman}± 117.9 g vs 655.9 ± 153.5 g, p = 0.371) and
gestational age ranged from 22.43 weeks to 28.14 weeks (24.7 ± 1.4 weeks
vs 24.3 ± 1.5 weeks, p = 0.307). The number of days from birth to
treatment ranged from 3 to 92 days. The PMA at the procedure were not
statistically different between the groups. Moreover, the
FiO\textsubscript{2} values before the procedure were not different
between the groups (transcatheter occlusion vs surgical ligation: 33.9 ±
10.3 vs 42.0 ± 25.7, p = 0.274). Infants with RDS requiring surfactant
instillation accounted for 79.5\% of the total population, and the
proportion was similar between the two groups. Detailed clinical
variables are shown in Table 1.

Mild BPD was noted in 12 patients (5 in Group A and 7 in Group B),
moderate BPD was noted in 24 patients (19 in Group A and 5 in Group B),
and severe BPD was noted in 4 patients (all in Group A). Three patients
died before the diagnosis of BPD was established or the severity was
classified (1 in Group A and 2 in Group B). The BPD severity was further
divided into lower severity (none or mild BPD) and higher severity
(moderate or severe BPD, or death). The two-grade BPD severity was
analyzed with logistic regression. The univariate model revealed an
association between procedure type and BPD severity (Group A vs Group B,
OR: 4.000, 95\% CI: 1.009--15.862) (Table 2). After analyzing birth
gestational age, sex, invasive ventilation use,
FiO\textsubscript{2}used, RDS requiring surfactant, post-natal steroid
treatment, and post-menstrual age, the multivariate model revealed
associations of procedure type and RDS requiring surfactant with
two-grade BPD severity in different logistic regression models adjusting
for potential confounding variables (Table 3, Supplementary Table 2).

\textbf{Discussion}

The factors associated with BPD severity are heterogeneous. We
hypothesized that chest wall damage and lung manipulation can affect the
post-natal growth of the immature lung and hence can affect the severity
of BPD at the timing of assessment. In this study, the basic
characteristics of birth body weight, birth gestational age, surfactant
use, antenatal and post-natal steroid use, post-menstrual weight, and
age were similar between the groups. The multivariate logistic
regression analysis showed associations of BPD severity with procedure
type for PDA and RDS requiring surfactant. However, we failed to
demonstrate differences related to birth gestational age or invasive
ventilation before the procedure.

The use of antenatal steroids to prevent RDS and a conservative
ventilation strategy have reduced the old form of BPD. However, a new
form of BPD has been recognized as a developmental
disorder.\textsuperscript{17} Lung growth enters the saccular stage at
around 23 weeks of gestation, and the alveolar stage continues until
adolescence.\textsuperscript{18} In this study, the majority of patients
received antenatal steroids. Kulasekaran et al. and Chen et al. reported
no difference in BPD incidence between males and
females.\textsuperscript{19; 20} However, two previous studies reported
a higher incidence in males. \textsuperscript{21; 22} In this study,
male sex was not related to a poorer outcome.

This retrospective analysis revealed associations of surgery and
surfactant use with BPD severity and mortality. As previously mentioned,
the saccular stage occurs from approximately 26 to 36 weeks, and insult
of the lung parenchyma may induce an inflammatory response and impair
further maturation. Verhaegh et al. reported that median sternotomy for
PDA ligation, in which the pleura was kept intact, was associated with a
lower mean airway pressure after surgery compared with posterolateral
thoracotomy. In addition, lower pneumothorax and atelectasis rate were
observed. \textsuperscript{23} Previous reports have suggested that
thoracic surgery performed in the neonatal period may result in reduced
post-natal lung growth \textsuperscript{24; 25} and a higher incidence
of either restrictive or obstructive ventilatory defects after the
surgery. \textsuperscript{26} An animal model also demonstrated
decreased lung compliance, decreased lung perfusion, and increased
pulmonary vascular resistance after thoracotomy.
\textsuperscript{27}These findings indicate an undesirable impact on
post-natal lung growth after thoracotomy. However, these studies focused
on post-natal lung growth in term infants, and studies discussing how
surgical thoracic manipulation affects preterm lung growth are limited.
A report discussing the impact of surgery in very low birth weight
infants showed an increased risk of death or neurodevelopmental
impairment.\textsuperscript{28} In contrast to term infants, premature
infants are born primarily in the saccular stage. Insult to the lungs
during this period may not only affect alveolarization but also impair
epithelium gas exchange and airway resistance.

Gestational age at birth was not associated with BPD severity in this
analysis; however, RDS requiring surfactant instillation was associated
with BPD severity. This association reflects the actual degree of lung
maturation and type II alveolar cell function. An immature alveolar
epithelium is more likely to have surfactant deficiency and is more
vulnerable to post-natal inflammatory insults. Owing to the widely
acknowledged use of antenatal steroids to prevent RDS, the birth
gestational age may not arbitrarily reflect maturation of the lungs.

Some potential mechanisms may explain our findings. In the physical
aspect, a traumatic injury to the thoracic wall may induce growth
impairments in the thoracic cavity, which can further inhibit lung
growth. Scoliosis has been recognized as a sequela of thoracic surgery
in the neonatal period. \textsuperscript{29; 30} Rib deformation after
PDA ligation has also been reported. \textsuperscript{31} In addition,
the pain after thoracic surgery may induce hypoventilation. It has been
indicated that a low tidal volume after birth in preterm infants induces
higher interleukin-8 and tumor necrosis factor-\selectlanguage{greek}α \selectlanguage{english}(TNF\selectlanguage{greek}α\selectlanguage{english}) levels compared
with a normal volume. Moreover, the mechanical ventilator dependent
period was longer in the low tidal volume group. \textsuperscript{32} In
the biomedical aspect, manipulation of the lung during surgery causes
some alveolar collapse, and there is rapid expansion after the surgery.
This mechanical change generates a shearing force in the lung and causes
mechanical injury, \textsuperscript{33; 34} which may induce
inflammatory cytokine production, a mechanism similar to ventilator
associated injury. In an animal model, TNF\selectlanguage{greek}α, \selectlanguage{english}transforming growth
factor-\selectlanguage{greek}β, \selectlanguage{english}interleukin-6, and interleukin-11 were shown to be able to
interfere with alveolarization. \textsuperscript{35} Interleukin-6, -8,
and -10 have been reported to be related to further BPD development and
severity. \textsuperscript{36; 37} However, whether these cytokines
contribute to or are induced by BPD is not well studied.

Several studies have reported an increased risk of BPD in preterm
infants who have undergone PDA ligation. \textsuperscript{13; 38; 39}The
safety and benefits of PDA ligation have been discussed recently, but
consensus is lacking. Watchful waiting is an alternative approach for
clinicians to deal with PDA after carefully weighing the benefits and
risks. \textsuperscript{40} Reports regarding conservative or surgical
treatment for PDA have questioned the selection bias of the surgery
group. In this study, we reported increased BPD severity and mortality
after PDA ligation compared with transcatheter occlusion. The findings
of this report contribute to the evidence that the drawback in PDA
ligation may be related to the impact of lung or thoracic manipulation
during surgery.

Some limitations of this study must be addressed. First, the study was
retrospective in nature, and the assignment of the treatment was not
randomized. Second, the number of participants in this study was small,
and this small population may have limited the power of our analysis.
Third, the clinical protocol of post-natal steroids varies among
physicians and can be modified or repeated under clinical conditions.
Fourth, although the statistical analysis showed no differences, infants
in the transcatheter group had a larger body weight and PMA. In addition
to the limitations of the study design, the transcatheter approach is a
new technique, and the safety issue is still under debate.

\textbf{Conclusion}

Compared with transcatheter closure, surgical ligation for PDA in
extremely preterm infants may be associated with increased severity of
BPD. However, the exact mechanism needs to be determined through further
large-scale studies and detailed biomedical investigations.

\textbf{Acknowledgements}

We are grateful to Dr. Sheng-Hsiang Lin and Ms. Wan-Ni Chen for
providing statistical consulting services from the Biostatistics
Consulting Center, Clinical Medicine Research Center, National Cheng
Kung University Hospital.

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