Protective Effects of Bronchopulmonary Sequestration (BPS) on the Prognosis of Neonates with Congenital Diaphragmatic Hernia (CDH)

Protective Effects of Bronchopulmonary Sequestration (BPS) on the Prognosis of Neonates with Congenital Diaphragmatic Hernia (CDH) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Protective Effects of Bronchopulmonary Sequestration (BPS) on the Prognosis of Neonates with Congenital Diaphragmatic Hernia (CDH) Sujin Gang, Yong Jae Kwon, Hyunhee Kwon, Suhyun Ha, Jueun Park, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5802831/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 May, 2025 Read the published version in BMC Pediatrics → Version 1 posted 8 You are reading this latest preprint version Abstract Background Congenital diaphragmatic hernia (CDH) and bronchopulmonary sequestration (BPS) are rare congenital anomalies that can coexist, with studies suggesting that 25–40% of CDH cases are accompanied by BPS. The association between CDH and BPS is thought to arise from embryological disruptions during early gestation, with BPS potentially serving as an anatomical barrier. This study aimed to evaluate the incidence, clinical characteristics, and outcomes of patients with concurrent CDH and BPS at a single institution to improve therapeutic approaches. Methods This study retrospectively analyzed the medical records of neonates diagnosed and treated for BPS concurrent with CDH at Asan Medical Center from 1990 to 2021, identifying 15 cases (3.0%) among 493 CDH patients. Comprehensive data on demographics, treatments, outcomes, diagnostic imaging, and pathological findings were collected and analyzed to explore disease characteristics and evaluate clinical outcomes. Results This study analyzed 15 neonates with concurrent BPS and CDH, with a male predominance (10:5) and an average gestational age of 37.8 weeks, of whom 80% were diagnosed prenatally. CDH repair was performed at a median of 8 days, with no acute repair-related complications observed. In some cases, additional procedures such as hiatal hernia or re-do CDH repair was required, and BPS resection was performed either simultaneous or delayed. Follow-up revealed that most patients grew within the 50th percentile range, with thoracoscopic approaches feasible in over half of the cases, and recurrence-free outcomes achieved in those treated for hiatal hernia or BPS. Discussions No statistical difference in CDH severity was observed between the CDH and CDH + BPS groups, and the clinical outcome of CDH + BPS was better, although the high prevalence of sac-associated CDH types may have confounded the results. Our findings provide additional evidence supporting the protective effect of BPS. However, they also highlight the need for further studies in larger populations to clarify the causal relationship. Congenital diaphragmatic hernia bronchopulmonary sequestration diagnosis surgery outcome Figures Figure 1 Figure 2 Figure 3 1 Introduction Congenital diaphragmatic hernia (CDH) is a rare condition identified in approximately 1 in 2,500 live births, and associated with high morbidity and mortality rates [ 1 ]. Bronchopulmonary sequestration (BPS), another rare congenital abnormality, is defined by the development of non-functional pulmonary mass disconnected from the normal tracheobronchial tree [ 2 ]. Studies based on prenatal ultrasonography and postmortem analysis have identified BPS in 0.15–1.8% of neonatal populations. Numerous case reports have indicated a strong association between CDH and BPS, with studies variable reporting that extralobar coexisting BPS could be identified in 30–40% of CDH cases, and that 25% of CDH cases (16/64) were accompanied by BPS [ 3 ]. One embryological theory explaining this association proposes that BPS, which arises during the fourth to fifth weeks of gestation, disrupts diaphragm formation by the 10th week, leading to incomplete closure of the pleuroperitoneal canal [ 2 ]. Sequestration may act as an anatomical barrier during diaphragmatic development, exacerbating hernia formation. The prognoses of these dual anomalies can vary. Although BPS exerts minimal impact on survival, CDH remains a major determinant of mortality [ 1 ]. Two contrasting outcomes are commonly observed: in some cases, sequestration serves as an anatomical barrier, preventing the herniation of abdominal contents and promoting lung growth [ 4 , 5 ], while in others, it contributes to a ‘liver-up condition’ that decreases the lung-to-head ratio (LHR), consequently worsening mortality [ 6 ]. Given the low prevalence of these anomalies, the factors influencing patient survival have not been extensively studied. Thus far, reduced LHR has been identified as the only negative prognostic factor [ 3 ]. Understanding the clinical course and prognostic factors in these patients is crucial for improving therapeutic approaches. Therefore, the study aimed to evaluate the incidence, clinical characteristics, and outcomes of patients diagnosed with CDH or BPS at a single institution. 2 Methods 2.1 Study Participants and Variables of Interest This study comprised a retrospective review of the medical records of a single institution, enrolling neonates diagnosed with and treated for CDH (with or without BPS) at Asan Medical Center, Seoul, between January 1990 and December 2021. The exclusion criteria included cases lost to follow-up at our institution or those confirmed as other disease, such as eventration after surgery. Among the 493 neonates diagnosed with CDH during the study period, 15 (3.0%) had concurrent BPS. Data related to demographics, treatments, and outcomes of CDH were collected through a comprehensive review of the medical records. Additionally, diagnostic imaging and pathological findings of BPS were analyzed to better understand the relationship between CDH and BPS. Follow-up data and clinical results were documented to evaluate the clinical outcomes. To compare the CDH concurrent with BPS to control group, data from the CDH group were extracted from our institution's CDH database. The control group consisted of data collected between 2008 and 2020, excluding patients with incomplete data (n = 235). Among them, 221 CDH patients (94.4%), whose CDH type was clearly documented in the surgical records, were included in the group comparison. 2.2 Statistical Analyses All statistical analyses were performed using R software (version 4.2.3; R Core Team, Vienna, Austria). The mean was calculated after testing data normality using the Shaprio-Wilks test, and an appropriate mean or median value was derived based on the results. Chi-square tests were used to compare difference between the CDH and CDH + BPS groups. Statistical significance was set at p < 0.05. 2.3 Ethics The study protocol was approved by the Institutional Review Board of Asan Medical Center (IRB No.: 2022 − 0445). The requirement for informed consent was waived after the information was deidentified. This study was conducted in accordance with the principles of the Declaration of Helsinki. 3 Results The data of the 15 neonates with concurrent BPS and CDH are summarized in Supplement Table 1. The male-to-female ratio was 10:5, indicating a male predominance. The average gestational age (GA) was 37.8 weeks and 2.7 days, with most neonates being full-term, with appropriate birth weights for their gestational age. A prenatal diagnosis of BPS and CDH was made in 12 patients (80.0%). The mean 1-minute Apgar score (AS) was 7, with improvement at 5 min. The ratio of vaginal delivery to cesarean section (C-section) was 8:7, indicating a near even split. In our study, we used patients with CDH treated in our center between 2008 and 2020 as a control group, due to incomplete construction of the database for the entire CDH cohort. Compared to the CDHSG outcomes, our CDH + BPS cohort showed a male-dominant trend (male-to-female ratio: 2 vs. 1.2) and a similar prenatal diagnosis rate (80.0% vs. 86.1%) [6]. Cardiac anomalies were present in 13.3% of our cohort compared with 11.1% in the CDHSG group. Except for the sex ratio, the basic characteristics of the study patients were similar between the two study cohorts. In our isolated CDH cohort, the distribution of CDH types was as follows: A (5.1%), B (70.2%), C (13.2%), and D (5.5%). Among the 15 patients with CDH and concurrent BPS or CPAM, the distribution of types—A (6.7%), B (60.0%), C (26.7%), and D (6.7%)—showed no statistically significant difference compared to the overall cohort (χ² test, p = 0.577; Table 1). Hernial sacs were observed in 60.6% of patients with CDH + BPS, which was higher than the 32.4% reported in the CDHSG group. Mortality associated with CDH + BPS was not observed, as deaths were directly attributed to irreversible cardiac failure following cardiac anomaly correction. The reduced mortality rate observed in our cohort compared to the CDHSG database may reflect the advanced expertise of our center, which manages more than half of CDH patients in South Korea. The mean abdomen-to-chest circumference (A/C) ratio was 0.9 ± 0.1, suggesting a scaphoid abdomen, in which the abdominal circumference was smaller than the chest circumference. Cardiac anomalies that did not inotropic support were identified in two neonates. Among the three neonates requiring inotropic support (patients 7, 9, and 13), all were diagnosed with CDH type B or C, characterized by relatively larger defects or severe organ herniation (Supplement Table 2). Ventilation support was not associated with sac type, size, or presence. The median age at CDH repair was 8.0 days (IQR: 4.0–27.0 days, Supplement Table 3). Patch repair was performed in three neonates; in one case, the abdominal wall could not be closed, necessitating a second-stage operation for abdominal wall closure (Supplement Table 3). Feeding was initiated on postoperative day 3.0 (IQR: 2.5–8.0 days), and patients were discharged on postoperative day 14.0 (IQR: 9.0–10.0 days). No acute CDH repair-related complications were observed. Hiatal hernia was diagnosed in two cases postoperatively, on days 587 (patient 7) and 154 (patient 10), requiring hiatal hernia repair (Figure 1). Both patients were Type B with a sac, and underwent thoracoscopic repair without patch placement; medial-sided hiatal laxity of the esophagus was noted in both cases. Fundoplication was performed in Patient 7, whereas Patient 10 underwent only hiatal hernia repair. Both patients remained recurrence-free postoperatively. BPS was identified on the same side as that of the CDH, with varying sizes (Table 2). The two CPAM cases in our cohort were confirmed through resection and histopathological analyses. In one case, despite patient growth, the lesion size remained stable, requiring resection. The patient recovered well after surgery. These two neonates were still under follow-up with imaging studies at the time of writing, showing good growth without the need for urgent surgery (Figure 2). Among the 12 neonates who underwent BPS resection, eight underwent simultaneous resection during CDH repair, while four underwent delayed resection. One patient (patient 12) showed asymptomatic focal recurrence on follow-up CT, resulting in re-operation and re-resection. Thoracoscopic approaches were feasible in seven cases. Pathological examination revealed congenital pulmonary airway malformation (CPAM) in two patients, a hybrid lesion of CPAM and BPS in one patient, and BPS in the remaining cases. In two patients, fetal sonography follow-up reports clearly documented that initially undetectable CDH was ultimately diagnosed as the size of the sequestration decreased. The follow-up period had a median duration of 740.0 days (IQR: 204.0–2952.0 days, Table 3). One neonate (Patient 6) died during postoperative care following cardiac surgery. The Z-score for weight was 0.1 (IQR: -1.0–0.3), indicating that most patients ultimately grew within the 50th percentile range of the growth curve. 4 Discussion BPS is a form of bronchopulmonary malformation in which non-functional lung tissue, disconnected from the normal bronchial system, receives blood from the systemic circulation [ 6 , 7 ]. BPS is classified into intralobar and extralobar types, with the majority of cases occurring in the lower left lobe [ 7 ]. BPS is believed to develop at approximately 4–5 weeks of gestation, contributing to the progression of CDH by interfering with diaphragm fusion and pleuroperitoneal canal closure at around 10 weeks of gestation. Consequently, the extralobar type is more commonly associated with CDH. Our results show a trend similar to that of previous findings. CPAM is a hamartomatous lesion of the lung classified based on the size of the cyst and the mucosal lining [ 8 ]. These two conditions may coexist, and have also been reported to be associated with CDH [ 6 , 9 – 12 ]. The incidence of simultaneous CDH and BPS remains poorly understood owing to limited reports [ 2 , 4 , 7 , 13 – 16 ]. In one large-scale retrospective study based on the CDH Study Group (CDHSG) database, Coughlin et al. estimated the likelihood of co-occurrence as approximately 3.4% (72/2118) [ 6 ]. This aligns more closely with real-world data compared to previously reported prevalences of 1.2–30% in smaller series and case reports. In our retrospective cohort study, the incidence was similar, at 3.0% (15/493). There have also been a few reports of cases in which CPAM and CDH coexist. For example, in 2012, Herman & Siegel reported a case in which prenatal diagnosis was followed by surgical treatment [ 8 ]. When CDH and BPS occur simultaneously (CDH + BPS), the clinical course of CDH becomes more complex. However, the prognosis of patients with CDH has been reported to improve when BPS is present [ 5 ]. Hypotheses to explain this have alternately postulated that additional lung tissue from BPS may compensate for the hypoplasia caused by CDH, changes in blood flow due to BPS may positively affect pulmonary circulation, and that the interaction between CDH and BPS may mitigate the severity of each condition. However, other reports have suggested that BPS itself does not significantly affect the clinical course of CDH [ 17 ], while a 2008 study by Grethel et al. reached a skeptical conclusion regarding the anatomical protective effects of BPS [ 3 ]. Among the 14 patients with CDH + BPS (out of 110) in this latter, 13 had liver herniation, of whom eight had a lung-to-head ratio (LHR) < 1.0, predictive of poor prognosis. Only six patients survived, suggesting the limitations of the protective hypothesis. In contrast, Coughlin et al. provided more robust demographic data through a large-scale comparative analysis [ 6 ]. They reported a higher prevalence of CDH type C in patients with CDH + BPS than in patients with isolated CDH. Additionally, a higher proportion of patients with CDH + BPS underwent patch repair, with significantly higher extracorporeal membrane oxygenation use and mortality, presenting conclusions that differ from standard assumptions. BPS is traditionally treated with surgical resection [ 18 , 19 ]. Extralobar BPS allows resection without damaging the normal lung tissue, whereas intralobar BPS typically requires lobectomy [ 20 ]. Recently, embolization has been reported as a successful alternative treatment modality in children, with interventions using coils also proving effective in adults [ 20 – 22 ]. Among neonates, umbilical artery embolization of the BPS vessels has also shown promising results [ 22 ]. Nevertheless, treatment may not be required if the BPS lesion decreases in size before birth and is not associated with complications, such as fetal hydrops or pleural effusion [ 20 , 23 ]. Prognosis is generally favorable, with > 75% of antenatally diagnosed BPS cases showing regression or size reduction. Among 177 antenatally-diagnosed BPS patients, 46 (25.9%) had extralobar BPS, while 24 (52.2%) were managed conservatively [ 24 ]. CT follow-up after an average of six months revealed significant regression in 17 patients (70.8%) and complete resolution in two cases (8.3%) [ 20 ]. Among the patients who underwent simultaneous CDH repair and BPS resection, five underwent surgery using a thoracoscopic approach, including three neonates within 10 days of birth. The relatively high proportion of patients eligible for the thoracoscopic approach indirectly indicates that the clinical outcomes of these patients were favorable relative to the defect size, suggesting that the feasibility of attempting a thoracoscopic approach may be higher in patients with fewer herniated organs and adequately developed abdominal cavities, where BPS may have acted as a plug providing a protective effect against herniation before birth. Additionally, from a technical perspective, Yamada et al. reported that simultaneous correction using a thoracoscopic approach is feasible in neonates [ 25 ]. Six patients underwent CDH repair without a concurrent BPS resection. Of these, three (patients 3, 6, and 24) required additional resection due to non-regressing BPS. In another case, BPS resection coincided with re-do CDH repair because of a focal recurrence. However, during the follow-up period after CDH repair and BPS resection, none of the patients exhibited any BPS-related symptoms. The two patients who did not undergo BPS resection remained asymptomatic with a stable lesion size and were followed-up with periodic imaging. CPAM is a distinct condition from BPS in terms of histogenesis and blood supply. However, considering the location, characteristics, and size of the lesions in the patients included in this study, as well as their association with CDH, we presumed that CPAM could have a similar impact on the clinical course of CDH patients. Therefore, it was included in the analysis. In addition, we have provided supplementary table results excluding CPAM and histologically undiagnosed BPS. Additionally, we conducted an analysis of the pathologically confirmed BPS (pBPS) group, and the results are presented in the last row of the table. When comparing only the pBPS infants with those with isolated CDH, there was no statistically significant difference in the distribution of lesion types (Table 1 (b)). The clinical characteristics, clinical course, and trends in the surgical treatment of CDH, as shown in Supplementary Tables 1–3, also did not differ significantly. Among the four excluded patients, three underwent repair via a thoracoscopic approach, suggesting that the CPAM patients and BPS patients who did not undergo surgical resection were clinically stable enough to undergo a one-stage thoracoscopic reduction, despite being classified as type B or C. The size of the BPS lesions and the associated clinical course also did not demonstrate notable differences in overall trends (Table 2 – 3 ). This study has several limitations which should be considered, largely stemming from its single-center, retrospective design. However, our center deals with 35.5–61.5% of CDH patients born in South Korea, reflecting the characteristics of the national CDH patient population [ 26 ]. The nature of referral centers may introduce bias, as prenatally undiagnosed cases referred after birth are likely to be more severe. Overall, included data from 235 patients with CDH treated at our center between 2008 and 2020 as a comparison group to overcome the limitations of this case series. The consistent annual number of patients with CDH (16–29 patients per year) managed at our center supported the homogeneity of the study population. Furthermore, a high proportion of patients with CDH + BPS in this cohort had a sac. Since the presence of a sac is considered a favorable prognostic factor for CDH [ 27 ], it could confound the evaluation of BPS's impact of BPS on prognosis. However, the small cohort size of 15 patients limited our ability to assess this association. The primary significance of our study lies in the provision of comprehensive evidence on the clinical course of patients with CDH + BPS. Overall, we demonstrated that there was no statistically significant difference in the size of the hernia defect (CDH type) between these patients and the overall cohort. Further, in contrast to the findings of two previous reports, we confirmed favorable clinical outcomes relative to disease severity. We also hypothesize that BPS may act as a plug, facilitating lung growth and maintaining the abdominal organs in place, thereby contributing to favorable clinical outcomes relative to the defect size. However, the high prevalence of the sac-associated CDH types in our cohort complicates the attribution of these findings to the protective effects of BPS. Further large-scale studies are required to explore this interaction, along with broader analyses across diverse populations in order to establish generalized conclusions. 5 Conclusion The present study is significant as it provides evidence supporting the traditional theory of the effect of BPS on CDH. As various research findings have been presented across diverse populations, we anticipate more studies to gain a more accurate understanding of the impact of BPS on CDH. Declarations Conflict of Interest The authors declare that they have no conflict of interest. Author Contributions SG designed and NK supervised the study. SG collected and collected all clinical information of the patients. JN and YK reviewed clinical information of the patients. SG wrote the original draft manuscript. All authors discussed the results and commented on the manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements None Ethics, Consent to Participate, and Consent to Publish declarations Not applicable Data Availability Statement The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors at reasonable request. References Alhamad M, Anand D. Congenital diaphragmatic hernia with associated broncho-pulmonary sequestration: A report of two cases and a literature review. J Neonatal Perinat Med. 2024;17:123–31. 10.3233/NPM-230042 . Kawamura N, Bhandal S. Coexistent congenital diaphragmatic hernia with extrapulmonary sequestration. Can Respir J (2016) 2016:1460480. 10.1155/2016/1460480 Grethel EJ, Farrell J, Ball RH, Keller RL, Goldstein RB, Lee H, et al. Does congenital diaphragmatic hernia associated with bronchopulmonary sequestration portend a better prognosis? Fetal Diagn Ther. 2008;23:250–3. 10.1159/000123609 . Kim HM, Hwang JH, Kim MJ, Cha HH, Seong WJ. 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Antenatal diagnosis of bronchopulmonary sequestration: A case report and review of the literature. Radiol Case Rep. 2024;19:604–13. 10.1016/j.radcr.2023.10.061 . https://www.pediatrics.or.kr/pdffile/60/01-O-017.pdf . Yamada K, Muto M, Onishi S, Machigashira S, Nishida N, Nagano A, et al. Thoracoscopic repair of neonatal left diaphragmatic hernia with sac combined with both extralobar pulmonary sequestration and congenital pulmonary airway malformation. Asian J Endosc Surg. 2023;16:127–30. 10.1111/ases.13120 . Raitio A, Salim A, Losty PD. Congenital diaphragmatic hernia-does the presence of a hernia sac improve outcome? A systematic review of published studies. Eur J Pediatr. 2021;180:333–7. 10.1007/s00431-020-03779-1 . Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx SuppTables.docx Cite Share Download PDF Status: Published Journal Publication published 21 May, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 09 Apr, 2025 Reviews received at journal 06 Apr, 2025 Reviews received at journal 04 Apr, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviewers agreed at journal 27 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 20 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5802831","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":433525610,"identity":"47659744-adf8-488e-9781-ad38e6942a20","order_by":0,"name":"Sujin Gang","email":"","orcid":"","institution":"Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sujin","middleName":"","lastName":"Gang","suffix":""},{"id":433525611,"identity":"c69fe9d8-2434-4177-818c-65e6d988d75a","order_by":1,"name":"Yong Jae Kwon","email":"","orcid":"","institution":"Gangneung Asan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"Jae","lastName":"Kwon","suffix":""},{"id":433525612,"identity":"a4ab6445-c186-4646-9f55-1764681104a0","order_by":2,"name":"Hyunhee Kwon","email":"","orcid":"","institution":"Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hyunhee","middleName":"","lastName":"Kwon","suffix":""},{"id":433525613,"identity":"a00d2c74-92fb-4e16-9517-6c7c69209644","order_by":3,"name":"Suhyun Ha","email":"","orcid":"","institution":"Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Suhyun","middleName":"","lastName":"Ha","suffix":""},{"id":433525614,"identity":"3d3767f7-785a-43d0-a2d4-fc55c1a4c8ac","order_by":4,"name":"Jueun Park","email":"","orcid":"","institution":"Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jueun","middleName":"","lastName":"Park","suffix":""},{"id":433525615,"identity":"36eee872-c797-4b04-8513-5efa0b339b79","order_by":5,"name":"Byong Sop Lee","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Byong","middleName":"Sop","lastName":"Lee","suffix":""},{"id":433525616,"identity":"f57e0709-b0a4-4821-a8be-14afb22832e3","order_by":6,"name":"Euiseok Jung","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Euiseok","middleName":"","lastName":"Jung","suffix":""},{"id":433525617,"identity":"ac1b884e-a2b9-4ca5-bd95-26747e454548","order_by":7,"name":"Jiyoon Jeong","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiyoon","middleName":"","lastName":"Jeong","suffix":""},{"id":433525618,"identity":"b7e5a488-5185-4a11-8eb2-5d0ce0605d63","order_by":8,"name":"Soo Hyun Kim","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Soo","middleName":"Hyun","lastName":"Kim","suffix":""},{"id":433525619,"identity":"03459a46-30fa-4185-b845-1053a021df29","order_by":9,"name":"Jung-Man Namgoong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYDADfvaGhAMfSNIi2XPg4cMZJGkxuJH42JiHGJXm7KeTX3youGPXcCM5Tdp2h11iv/QBxg8fc3BrsezJ3WY548yz5MaeZ2nSuWeSE2f2JTBLztyGxz0HcrcZ87YdTmZmzwFqaWM2NjjDwMbMi0/L+bcQLWwM+d+kLdvqje0JarmRu/kxUIsdD0dCsjFj22E5Ax6CWt5uY5xx5nCCBM+BxIe9bcflJM4wNuP3y/nczR8+VBy2tz8OjMqfbdU8/D3MBz98xKMFCNgkgERiA0KAsQGHSjhgBiUTe0KqRsEoGAWjYAQDAEZlV8qLHBktAAAAAElFTkSuQmCC","orcid":"","institution":"Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jung-Man","middleName":"","lastName":"Namgoong","suffix":""}],"badges":[],"createdAt":"2025-01-10 10:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5802831/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5802831/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-05755-w","type":"published","date":"2025-05-21T15:58:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79322613,"identity":"6838bb5c-49d8-4092-8ca7-9f49bd432938","added_by":"auto","created_at":"2025-03-27 04:40:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":946788,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurgical images of two patients (Patients 7 and 10) with hiatal hernial progression following CDH repair\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a), (b):\u003c/strong\u003e Patient 7 underwent thoracoscopic repair for Type B CDH with sac. Hiatal hernia was diagnosed 587 days postoperatively, accompanied by severe reflux symptoms; laparoscopic hiatal hernia repair was planned accordingly. Due to the large hernial defect, open conversion was performed along with fundoplication. The patient has remained symptom-free since the surgery. \u003cstrong\u003e(a)\u003c/strong\u003e Shows an image taken immediately after CDH repair, and \u003cstrong\u003e(b)\u003c/strong\u003e demonstrates the hernial defect. \u003cstrong\u003e(c), (d)\u003c/strong\u003e: Patient 10 underwent thoracoscopic repair for Type B CDH with sac. \u003cstrong\u003e(c) \u003c/strong\u003eShows the CDH lesion with the sac before repair, and\u003cstrong\u003e (d) \u003c/strong\u003eillustrates the defect in the hiatus observed during laparoscopic hiatal hernia repair. In the present case, the defect was closed and fixed, leading to resolution of reflux symptoms without recurrence.\u003cbr\u003e\nCDH: congenital diaphragmatic hernia\u003c/p\u003e","description":"","filename":"CPAMfigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/4dcef6ea0b112efb596f6f43.png"},{"id":79322612,"identity":"40aab332-0650-4074-b465-77da0e29111d","added_by":"auto","created_at":"2025-03-27 04:40:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":479626,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging findings of two patients (Patients 4 and 13) who underwent imaging follow-up without resection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the most recent chest CT scan of patient 4 (a 13-year-old boy), the previously observed left juxtadiaphragmatic extralobar pulmonary sequestration was smaller than before \u003cstrong\u003e(a\u003c/strong\u003e, arrow). The feeding artery supplied by the celiac trunk showed no noticeable changes compared with the previous scan. \u003cstrong\u003e(b\u003c/strong\u003e, arrow) Follow-up CT scan of a 3-year-old boy showing a partially expanded sequestered lung in the left lower hemithorax \u003cstrong\u003e(c\u003c/strong\u003e, arrow). The hyperlucent expanded area indicates the presence of a CPAM and a hybrid lesion, revealing the characteristics of an interlobar-type pulmonary sequestration supplied by the celiac axis, and drained by the inferior pulmonary vein. The soft tissue in the infradiaphragmatic area previously observed on ultrasonography before surgery is now thought to represent sequestration near the heart in the supradiaphragmatic area \u003cstrong\u003e(d\u003c/strong\u003e, asterisk).\u003cbr\u003e\n*CT: computed tomography; CPAM: congenital pulmonary airway malformation.\u003c/p\u003e","description":"","filename":"CPAMfigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/58b45df805a8cc439fd7f283.png"},{"id":79321570,"identity":"91c6016f-6a29-41c6-9dbc-e800b7eeb322","added_by":"auto","created_at":"2025-03-27 04:32:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":617364,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative pictures of a patient with CPAM concurrent with CDH (Patient 14)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e On a CT scan performed at 293 days of age, the suspected CPAM lesion measured 42.2 × 34.7 mm; at this point, the patient was healthy and asymptomatic, without respiratory distress. \u003cstrong\u003e(b)\u003c/strong\u003eOn a CT scan performed at 639 days of age, the suspected CPAM lesion measured 50.0 × 38.5 mm, showing no significant size change. As the patient remained stable and asymptomatic, surgery was performed at 674 days of age. \u003cstrong\u003e(c)\u003c/strong\u003eGross pathology of the specimen. Pathologic findings were consistent with anomalous cystic lung, confirmed as congenital pulmonary airway malformation (CPAM), type 2. \u003cstrong\u003e(d)\u003c/strong\u003e The final follow-up chest X-ray showed no abnormalities. The patient has been doing well postoperatively, without any evidence of complications or pulmonary dysfunction.\u003cbr\u003e\n*CT: computed tomography; CPAM: congenital pulmonary airway malformation.\u003c/p\u003e","description":"","filename":"CPAMfigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/4867e2354e566ddcfb6ad9b8.png"},{"id":83460262,"identity":"6ca7e05b-79e2-4024-8446-5bfcaed60482","added_by":"auto","created_at":"2025-05-26 16:12:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2656243,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/ac4f38fd-c427-4216-8678-73c91ecdfd90.pdf"},{"id":79321567,"identity":"1dfbc8d4-caec-40a8-8c04-97747c7922c6","added_by":"auto","created_at":"2025-03-27 04:32:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":37080,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/f42fc7743b4f69316dac2630.docx"},{"id":79322903,"identity":"e3683eb6-3021-4d62-813e-e79e2df5f02f","added_by":"auto","created_at":"2025-03-27 04:48:54","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":41130,"visible":true,"origin":"","legend":"","description":"","filename":"SuppTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5802831/v1/9397ecfdac68f3f9a5016d14.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Protective Effects of Bronchopulmonary Sequestration (BPS) on the Prognosis of Neonates with Congenital Diaphragmatic Hernia (CDH)","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eCongenital diaphragmatic hernia (CDH) is a rare condition identified in approximately 1 in 2,500 live births, and associated with high morbidity and mortality rates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Bronchopulmonary sequestration (BPS), another rare congenital abnormality, is defined by the development of non-functional pulmonary mass disconnected from the normal tracheobronchial tree [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Studies based on prenatal ultrasonography and postmortem analysis have identified BPS in 0.15\u0026ndash;1.8% of neonatal populations. Numerous case reports have indicated a strong association between CDH and BPS, with studies variable reporting that extralobar coexisting BPS could be identified in 30\u0026ndash;40% of CDH cases, and that 25% of CDH cases (16/64) were accompanied by BPS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne embryological theory explaining this association proposes that BPS, which arises during the fourth to fifth weeks of gestation, disrupts diaphragm formation by the 10th week, leading to incomplete closure of the pleuroperitoneal canal [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Sequestration may act as an anatomical barrier during diaphragmatic development, exacerbating hernia formation. The prognoses of these dual anomalies can vary. Although BPS exerts minimal impact on survival, CDH remains a major determinant of mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Two contrasting outcomes are commonly observed: in some cases, sequestration serves as an anatomical barrier, preventing the herniation of abdominal contents and promoting lung growth [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while in others, it contributes to a \u0026lsquo;liver-up condition\u0026rsquo; that decreases the lung-to-head ratio (LHR), consequently worsening mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the low prevalence of these anomalies, the factors influencing patient survival have not been extensively studied. Thus far, reduced LHR has been identified as the only negative prognostic factor [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Understanding the clinical course and prognostic factors in these patients is crucial for improving therapeutic approaches. Therefore, the study aimed to evaluate the incidence, clinical characteristics, and outcomes of patients diagnosed with CDH or BPS at a single institution.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Participants and Variables of Interest\u003c/h2\u003e \u003cp\u003e This study comprised a retrospective review of the medical records of a single institution, enrolling neonates diagnosed with and treated for CDH (with or without BPS) at Asan Medical Center, Seoul, between January 1990 and December 2021. The exclusion criteria included cases lost to follow-up at our institution or those confirmed as other disease, such as eventration after surgery. Among the 493 neonates diagnosed with CDH during the study period, 15 (3.0%) had concurrent BPS. Data related to demographics, treatments, and outcomes of CDH were collected through a comprehensive review of the medical records. Additionally, diagnostic imaging and pathological findings of BPS were analyzed to better understand the relationship between CDH and BPS. Follow-up data and clinical results were documented to evaluate the clinical outcomes. To compare the CDH concurrent with BPS to control group, data from the CDH group were extracted from our institution's CDH database. The control group consisted of data collected between 2008 and 2020, excluding patients with incomplete data (n\u0026thinsp;=\u0026thinsp;235). Among them, 221 CDH patients (94.4%), whose CDH type was clearly documented in the surgical records, were included in the group comparison.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Statistical Analyses\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using R software (version 4.2.3; R Core Team, Vienna, Austria). The mean was calculated after testing data normality using the Shaprio-Wilks test, and an appropriate mean or median value was derived based on the results. Chi-square tests were used to compare difference between the CDH and CDH\u0026thinsp;+\u0026thinsp;BPS groups. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Ethics\u003c/h2\u003e \u003cp\u003eThe study protocol was approved by the Institutional Review Board of Asan Medical Center (IRB No.: 2022\u0026thinsp;\u0026minus;\u0026thinsp;0445). The requirement for informed consent was waived after the information was deidentified. This study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003eThe data of the 15 neonates with concurrent BPS and CDH are summarized in Supplement Table 1. The male-to-female ratio was 10:5, indicating a male predominance. The average gestational age (GA) was 37.8 weeks and 2.7 days, with most neonates being full-term, with appropriate birth weights for their gestational age. A prenatal diagnosis of BPS and CDH was made in 12 patients (80.0%). The mean 1-minute Apgar score (AS) was 7, with improvement at 5 min. The ratio of vaginal delivery to cesarean section (C-section) was 8:7, indicating a near even split.\u003c/p\u003e\n\u003cp\u003eIn our study, we used patients with CDH treated in our center between 2008 and 2020 as a control group, due to incomplete construction of the database for the entire CDH cohort. Compared to the CDHSG outcomes, our CDH + BPS cohort showed a male-dominant trend (male-to-female ratio: 2 vs. 1.2) and a similar prenatal diagnosis rate (80.0% vs. 86.1%) [6]. Cardiac anomalies were present in 13.3% of our cohort compared with 11.1% in the CDHSG group. Except for the sex ratio, the basic characteristics of the study patients were similar between the two study cohorts. In our isolated CDH cohort, the distribution of CDH types was as follows: A (5.1%), B (70.2%), C (13.2%), and D (5.5%). Among the 15 patients with CDH and concurrent BPS or CPAM, the distribution of types\u0026mdash;A (6.7%), B (60.0%), C (26.7%), and D (6.7%)\u0026mdash;showed no statistically significant difference compared to the overall cohort (\u0026chi;\u0026sup2; test, p = 0.577; Table 1). Hernial sacs were observed in 60.6% of patients with CDH + BPS, which was higher than the 32.4% reported in the CDHSG group. Mortality associated with CDH + BPS was not observed, as deaths were directly attributed to irreversible cardiac failure following cardiac anomaly correction. The reduced mortality rate observed in our cohort compared to the CDHSG database may reflect the advanced expertise of our center, which manages more than half of CDH patients in South Korea.\u003c/p\u003e\n\u003cp\u003eThe mean abdomen-to-chest circumference (A/C) ratio was 0.9 \u0026plusmn; 0.1, suggesting a scaphoid abdomen, in which the abdominal circumference was smaller than the chest circumference. Cardiac anomalies that did not inotropic support were identified in two neonates. Among the three neonates requiring inotropic support (patients 7, 9, and 13), all were diagnosed with CDH type B or C, characterized by relatively larger defects or severe organ herniation (Supplement Table 2). Ventilation support was not associated with sac type, size, or presence. The median age at CDH repair was 8.0 days (IQR: 4.0\u0026ndash;27.0 days, Supplement Table 3). Patch repair was performed in three neonates; in one case, the abdominal wall could not be closed, necessitating a second-stage operation for abdominal wall closure (Supplement Table 3).\u003c/p\u003e\n\u003cp\u003eFeeding was initiated on postoperative day 3.0 (IQR: 2.5\u0026ndash;8.0 days), and patients were discharged on postoperative day 14.0 (IQR: 9.0\u0026ndash;10.0 days). No acute CDH repair-related complications were observed. Hiatal hernia was diagnosed in two cases postoperatively, on days 587 (patient 7) and 154 (patient 10), requiring hiatal hernia repair (Figure 1). Both patients were Type B with a sac, and underwent thoracoscopic repair without patch placement; medial-sided hiatal laxity of the esophagus was noted in both cases. Fundoplication was performed in Patient 7, whereas Patient 10 underwent only hiatal hernia repair. Both patients remained recurrence-free postoperatively.\u003c/p\u003e\n\u003cp\u003eBPS was identified on the same side as that of the CDH, with varying sizes (Table 2). The two CPAM cases in our cohort were confirmed through resection and histopathological analyses. In one case, despite patient growth, the lesion size remained stable, requiring resection. The patient recovered well after surgery. These two neonates were still under follow-up with imaging studies at the time of writing, showing good growth without the need for urgent surgery (Figure 2). Among the 12 neonates who underwent BPS resection, eight underwent simultaneous resection during CDH repair, while four underwent delayed resection. One patient (patient 12) showed asymptomatic focal recurrence on follow-up CT, resulting in re-operation and re-resection. Thoracoscopic approaches were feasible in seven cases. Pathological examination revealed congenital pulmonary airway malformation (CPAM) in two patients, a hybrid lesion of CPAM and BPS in one patient, and BPS in the remaining cases. In two patients, fetal sonography follow-up reports clearly documented that initially undetectable CDH was ultimately diagnosed as the size of the sequestration decreased.\u003c/p\u003e\n\u003cp\u003eThe follow-up period had a median duration of 740.0 days (IQR: 204.0\u0026ndash;2952.0 days, Table 3). One neonate (Patient 6) died during postoperative care following cardiac surgery. The Z-score for weight was 0.1 (IQR: -1.0\u0026ndash;0.3), indicating that most patients ultimately grew within the 50th percentile range of the growth curve.\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eBPS is a form of bronchopulmonary malformation in which non-functional lung tissue, disconnected from the normal bronchial system, receives blood from the systemic circulation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. BPS is classified into intralobar and extralobar types, with the majority of cases occurring in the lower left lobe [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. BPS is believed to develop at approximately 4\u0026ndash;5 weeks of gestation, contributing to the progression of CDH by interfering with diaphragm fusion and pleuroperitoneal canal closure at around 10 weeks of gestation. Consequently, the extralobar type is more commonly associated with CDH. Our results show a trend similar to that of previous findings.\u003c/p\u003e \u003cp\u003eCPAM is a hamartomatous lesion of the lung classified based on the size of the cyst and the mucosal lining [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These two conditions may coexist, and have also been reported to be associated with CDH [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The incidence of simultaneous CDH and BPS remains poorly understood owing to limited reports [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In one large-scale retrospective study based on the CDH Study Group (CDHSG) database, Coughlin et al. estimated the likelihood of co-occurrence as approximately 3.4% (72/2118) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This aligns more closely with real-world data compared to previously reported prevalences of 1.2\u0026ndash;30% in smaller series and case reports. In our retrospective cohort study, the incidence was similar, at 3.0% (15/493).\u003c/p\u003e \u003cp\u003eThere have also been a few reports of cases in which CPAM and CDH coexist. For example, in 2012, Herman \u0026amp; Siegel reported a case in which prenatal diagnosis was followed by surgical treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. When CDH and BPS occur simultaneously (CDH\u0026thinsp;+\u0026thinsp;BPS), the clinical course of CDH becomes more complex. However, the prognosis of patients with CDH has been reported to improve when BPS is present [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hypotheses to explain this have alternately postulated that additional lung tissue from BPS may compensate for the hypoplasia caused by CDH, changes in blood flow due to BPS may positively affect pulmonary circulation, and that the interaction between CDH and BPS may mitigate the severity of each condition. However, other reports have suggested that BPS itself does not significantly affect the clinical course of CDH [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], while a 2008 study by Grethel \u003cem\u003eet al.\u003c/em\u003e reached a skeptical conclusion regarding the anatomical protective effects of BPS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among the 14 patients with CDH\u0026thinsp;+\u0026thinsp;BPS (out of 110) in this latter, 13 had liver herniation, of whom eight had a lung-to-head ratio (LHR)\u0026thinsp;\u0026lt;\u0026thinsp;1.0, predictive of poor prognosis. Only six patients survived, suggesting the limitations of the protective hypothesis.\u003c/p\u003e \u003cp\u003eIn contrast, Coughlin et al. provided more robust demographic data through a large-scale comparative analysis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. They reported a higher prevalence of CDH type C in patients with CDH\u0026thinsp;+\u0026thinsp;BPS than in patients with isolated CDH. Additionally, a higher proportion of patients with CDH\u0026thinsp;+\u0026thinsp;BPS underwent patch repair, with significantly higher extracorporeal membrane oxygenation use and mortality, presenting conclusions that differ from standard assumptions.\u003c/p\u003e \u003cp\u003eBPS is traditionally treated with surgical resection [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Extralobar BPS allows resection without damaging the normal lung tissue, whereas intralobar BPS typically requires lobectomy [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Recently, embolization has been reported as a successful alternative treatment modality in children, with interventions using coils also proving effective in adults [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Among neonates, umbilical artery embolization of the BPS vessels has also shown promising results [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Nevertheless, treatment may not be required if the BPS lesion decreases in size before birth and is not associated with complications, such as fetal hydrops or pleural effusion [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Prognosis is generally favorable, with \u0026gt;\u0026thinsp;75% of antenatally diagnosed BPS cases showing regression or size reduction. Among 177 antenatally-diagnosed BPS patients, 46 (25.9%) had extralobar BPS, while 24 (52.2%) were managed conservatively [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CT follow-up after an average of six months revealed significant regression in 17 patients (70.8%) and complete resolution in two cases (8.3%) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong the patients who underwent simultaneous CDH repair and BPS resection, five underwent surgery using a thoracoscopic approach, including three neonates within 10 days of birth. The relatively high proportion of patients eligible for the thoracoscopic approach indirectly indicates that the clinical outcomes of these patients were favorable relative to the defect size, suggesting that the feasibility of attempting a thoracoscopic approach may be higher in patients with fewer herniated organs and adequately developed abdominal cavities, where BPS may have acted as a plug providing a protective effect against herniation before birth. Additionally, from a technical perspective, Yamada et al. reported that simultaneous correction using a thoracoscopic approach is feasible in neonates [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSix patients underwent CDH repair without a concurrent BPS resection. Of these, three (patients 3, 6, and 24) required additional resection due to non-regressing BPS. In another case, BPS resection coincided with re-do CDH repair because of a focal recurrence. However, during the follow-up period after CDH repair and BPS resection, none of the patients exhibited any BPS-related symptoms. The two patients who did not undergo BPS resection remained asymptomatic with a stable lesion size and were followed-up with periodic imaging.\u003c/p\u003e \u003cp\u003eCPAM is a distinct condition from BPS in terms of histogenesis and blood supply. However, considering the location, characteristics, and size of the lesions in the patients included in this study, as well as their association with CDH, we presumed that CPAM could have a similar impact on the clinical course of CDH patients. Therefore, it was included in the analysis. In addition, we have provided supplementary table results excluding CPAM and histologically undiagnosed BPS.\u003c/p\u003e \u003cp\u003eAdditionally, we conducted an analysis of the pathologically confirmed BPS (pBPS) group, and the results are presented in the last row of the table. When comparing only the pBPS infants with those with isolated CDH, there was no statistically significant difference in the distribution of lesion types (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(b)). The clinical characteristics, clinical course, and trends in the surgical treatment of CDH, as shown in Supplementary Tables\u0026nbsp;1\u0026ndash;3, also did not differ significantly. Among the four excluded patients, three underwent repair via a thoracoscopic approach, suggesting that the CPAM patients and BPS patients who did not undergo surgical resection were clinically stable enough to undergo a one-stage thoracoscopic reduction, despite being classified as type B or C. The size of the BPS lesions and the associated clinical course also did not demonstrate notable differences in overall trends (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations which should be considered, largely stemming from its single-center, retrospective design. However, our center deals with 35.5\u0026ndash;61.5% of CDH patients born in South Korea, reflecting the characteristics of the national CDH patient population [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The nature of referral centers may introduce bias, as prenatally undiagnosed cases referred after birth are likely to be more severe. Overall, included data from 235 patients with CDH treated at our center between 2008 and 2020 as a comparison group to overcome the limitations of this case series. The consistent annual number of patients with CDH (16\u0026ndash;29 patients per year) managed at our center supported the homogeneity of the study population. Furthermore, a high proportion of patients with CDH\u0026thinsp;+\u0026thinsp;BPS in this cohort had a sac. Since the presence of a sac is considered a favorable prognostic factor for CDH [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], it could confound the evaluation of BPS's impact of BPS on prognosis. However, the small cohort size of 15 patients limited our ability to assess this association.\u003c/p\u003e \u003cp\u003eThe primary significance of our study lies in the provision of comprehensive evidence on the clinical course of patients with CDH\u0026thinsp;+\u0026thinsp;BPS. Overall, we demonstrated that there was no statistically significant difference in the size of the hernia defect (CDH type) between these patients and the overall cohort. Further, in contrast to the findings of two previous reports, we confirmed favorable clinical outcomes relative to disease severity. We also hypothesize that BPS may act as a plug, facilitating lung growth and maintaining the abdominal organs in place, thereby contributing to favorable clinical outcomes relative to the defect size. However, the high prevalence of the sac-associated CDH types in our cohort complicates the attribution of these findings to the protective effects of BPS. Further large-scale studies are required to explore this interaction, along with broader analyses across diverse populations in order to establish generalized conclusions.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThe present study is significant as it provides evidence supporting the traditional theory of the effect of BPS on CDH. As various research findings have been presented across diverse populations, we anticipate more studies to gain a more accurate understanding of the impact of BPS on CDH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSG designed and NK supervised the study. SG collected and collected all clinical information of the patients. JN and YK reviewed clinical information of the patients. SG wrote the original draft manuscript. All authors discussed the results and commented on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics, Consent to Participate, and Consent to Publish declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors at reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlhamad M, Anand D. 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Antenatal diagnosis of bronchopulmonary sequestration: A case report and review of the literature. Radiol Case Rep. 2024;19:604\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radcr.2023.10.061\u003c/span\u003e\u003cspan address=\"10.1016/j.radcr.2023.10.061\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cp\u003ehttps://www.pediatrics.or.kr/pdffile/60/01-O-017.pdf\u003c/em\u003e\u003c/a\u003e.\u003c/p\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamada K, Muto M, Onishi S, Machigashira S, Nishida N, Nagano A, et al. Thoracoscopic repair of neonatal left diaphragmatic hernia with sac combined with both extralobar pulmonary sequestration and congenital pulmonary airway malformation. 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Eur J Pediatr. 2021;180:333\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00431-020-03779-1\u003c/span\u003e\u003cspan address=\"10.1007/s00431-020-03779-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Congenital diaphragmatic hernia, bronchopulmonary sequestration, diagnosis, surgery, outcome","lastPublishedDoi":"10.21203/rs.3.rs-5802831/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5802831/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCongenital diaphragmatic hernia (CDH) and bronchopulmonary sequestration (BPS) are rare congenital anomalies that can coexist, with studies suggesting that 25\u0026ndash;40% of CDH cases are accompanied by BPS. The association between CDH and BPS is thought to arise from embryological disruptions during early gestation, with BPS potentially serving as an anatomical barrier. This study aimed to evaluate the incidence, clinical characteristics, and outcomes of patients with concurrent CDH and BPS at a single institution to improve therapeutic approaches.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study retrospectively analyzed the medical records of neonates diagnosed and treated for BPS concurrent with CDH at Asan Medical Center from 1990 to 2021, identifying 15 cases (3.0%) among 493 CDH patients. Comprehensive data on demographics, treatments, outcomes, diagnostic imaging, and pathological findings were collected and analyzed to explore disease characteristics and evaluate clinical outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study analyzed 15 neonates with concurrent BPS and CDH, with a male predominance (10:5) and an average gestational age of 37.8 weeks, of whom 80% were diagnosed prenatally. CDH repair was performed at a median of 8 days, with no acute repair-related complications observed. In some cases, additional procedures such as hiatal hernia or re-do CDH repair was required, and BPS resection was performed either simultaneous or delayed. Follow-up revealed that most patients grew within the 50th percentile range, with thoracoscopic approaches feasible in over half of the cases, and recurrence-free outcomes achieved in those treated for hiatal hernia or BPS.\u003c/p\u003e\u003ch2\u003eDiscussions\u003c/h2\u003e \u003cp\u003eNo statistical difference in CDH severity was observed between the CDH and CDH\u0026thinsp;+\u0026thinsp;BPS groups, and the clinical outcome of CDH\u0026thinsp;+\u0026thinsp;BPS was better, although the high prevalence of sac-associated CDH types may have confounded the results. Our findings provide additional evidence supporting the protective effect of BPS. However, they also highlight the need for further studies in larger populations to clarify the causal relationship.\u003c/p\u003e","manuscriptTitle":"Protective Effects of Bronchopulmonary Sequestration (BPS) on the Prognosis of Neonates with Congenital Diaphragmatic Hernia (CDH)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:32:49","doi":"10.21203/rs.3.rs-5802831/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-09T08:46:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-06T05:52:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-05T01:55:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294041984166883809608262341978462001680","date":"2025-03-28T08:22:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312277551054606475394809359182943580743","date":"2025-03-28T00:48:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T05:11:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T12:16:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-03-21T02:29:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"951968b9-3ed6-48e3-b8ee-cbd79f5535bc","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:07:37+00:00","versionOfRecord":{"articleIdentity":"rs-5802831","link":"https://doi.org/10.1186/s12887-025-05755-w","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-05-21 15:58:18","publishedOnDateReadable":"May 21st, 2025"},"versionCreatedAt":"2025-03-27 04:32:49","video":"","vorDoi":"10.1186/s12887-025-05755-w","vorDoiUrl":"https://doi.org/10.1186/s12887-025-05755-w","workflowStages":[]},"version":"v1","identity":"rs-5802831","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5802831","identity":"rs-5802831","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}