2.2 Data Collection and Outcomes
We collected data on birth body weight, gestational age, fraction of
oxygen (FiO2) 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).
Statistics and Analysis
All analyses were performed using SPSS (Version 28, IBM Corp., Armonk,
NY, USA). A p-value <0.05 was considered significant. Basic
demographic data were compared with the Student’s 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.
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 ± 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
FiO2 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, FiO2used, 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).
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.17 Lung growth enters the saccular stage at around 23
weeks of gestation, and the alveolar stage continues until adolescence.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.19; 20 However, two previous studies reported a higher
incidence in males. 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. 23 Previous reports have suggested that
thoracic surgery performed in the neonatal period may result in reduced
post-natal lung growth 24; 25 and a higher incidence
of either restrictive or obstructive ventilatory defects after the
surgery. 26 An animal model also demonstrated
decreased lung compliance, decreased lung perfusion, and increased
pulmonary vascular resistance after thoracotomy. 27These 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.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. 29; 30 Rib deformation after
PDA ligation has also been reported. 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-α (TNFα) levels compared
with a normal volume. Moreover, the mechanical ventilator dependent
period was longer in the low tidal volume group. 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, 33; 34 which may induce
inflammatory cytokine production, a mechanism similar to ventilator
associated injury. In an animal model, TNFα, transforming growth
factor-β, interleukin-6, and interleukin-11 were shown to be able to
interfere with alveolarization. 35 Interleukin-6, -8,
and -10 have been reported to be related to further BPD development and
severity. 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. 13; 38; 39The 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. 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.
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.
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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