新生兒出生後呼吸窘迫是晚期早產與足月兒入住新生兒加護病房的最常見原因，主要由肺部羊水未完全吸收引起的新生兒暫時性呼吸急促所致，通常在數小時內可自行改善，無需抗生素治療。然而，臨床上仍常使用預防性抗生素以降低新生兒敗血症的風險。先前研究已確認羊水和胃液中的發炎物質對早產兒子宮內感染和敗血症風險具有預測能力，但對足月和晚期早產兒的相關研究仍不足。此外，過去研究多集中於母親絨毛膜羊膜炎的病理現象，但對該族群的臨床預後缺乏闡明。本研究假設新生兒出生後胃液中的成分與產前子宮內感染或發炎以及之後的臨床預後具有相關性。本研究使用流式微球分析技術(Cytometric Bead Array; CBA assay)，在單一檢體內同時分析多種細胞激素，減少實驗誤差並確保測量的一致性。我們發現新生兒出生後胃液中的介白素-8 (IL-8)可作為晚期早產與足月兒在出生後有呼吸窘迫的後預測C反應蛋白（CRP）升高的潛在生物標誌，且最佳的臨界值為>1600 pg/mL。然而，其他細胞激素（如 IL-1β、IFN-α、IFN-γ、TNF-α、MCP-1、IL-6、IL-10、IL-12、IL-17A、IL-18、IL-23 和 IL-33）並未顯示相似的預測價值。此外，我們的結果未發現所有測得的細胞激素與臨床預後(如呼吸器使用時間或NICU住院天數)具有顯著相關性。雖然這些細胞激素與呼吸窘迫預後無顯著相關性，但我們首次確認新生兒胃液中可以測量到多種促發炎細胞激素，為未來相關研究提供基礎。根據本研究結果，快速測試新生兒出生後胃液中IL-8濃度可能成為預測新生兒之後CRP升高的有效檢測方法，從而減少不必要的抗生素使用，降低侵入性抽血檢查的需求，並改善臨床管理。

Respiratory distress in newborns is the most common reason for Neonatal Intensive Care Unit (NICU) admissions among late preterm and full-term infants. It is primarily caused by transient tachypnea of the newborn (TTNB), resulting from incomplete clearance of fetal lung fluid. This condition is typically self-limiting, resolving within hours without requiring antibiotic treatment. However, prophylactic antibiotics are often administered to reduce the risk of neonatal sepsis. Previous studies have demonstrated the predictive value of inflammatory cytokines in amniotic and gastric fluid for intrauterine infection and sepsis risk in preterm infants, but similar research in term and late preterm infants remains limited. Furthermore, earlier investigations primarily focused on the pathological aspects of maternal chorioamnionitis without adequately addressing the associated clinical outcomes. We hypothesize the inflammatory mediators in gastric fluid of newborns correlate with prenatal intrauterine infections or inflammation and their subsequent clinical outcomes. In this study, we used a Cytometric Bead Array (CBA) assay to simultaneously detect multiple cytokines in a single sample, minimizing experimental error and ensuring consistency across measurements. Among the cytokines analyzed, we identified interleukin-8 (IL-8) in gastric fluid as a potential predictive biomarker for elevated C-reactive protein (CRP) in late preterm and term infants with respiratory distress, with an optimal cut-off value of >1600 pg/mL. However, other cytokines, including IL-1β, IFN-α, IFN-γ, TNF-α, MCP-1, IL-6, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-33, did not exhibit similar predictive value. Additionally, no significant associations were observed between these cytokines and clinical outcomes such as ventilator duration or NICU length of stay. While these cytokines did not correlate with respiratory distress outcomes, our study is the first to confirm that multiple pro-inflammatory cytokines can be measured in neonatal gastric fluid, providing a foundation for future research. Based on our findings, a rapid test for IL-8 levels in gastric fluid collected immediately after birth could serve as an effective method to predict CRP elevation in newborns, potentially reducing unnecessary antibiotic use, minimizing invasive blood tests, and improving clinical management.

1. Harrison W, Goodman D. Epidemiologic Trends in Neonatal Intensive Care, 2007-2012. JAMA pediatrics 2015;169:855-62.
2. Edwards MO, Kotecha SJ, Kotecha S. Respiratory distress of the term newborn infant. Paediatric respiratory reviews 2013;14:29-36; quiz -7.
3. Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatrics in review 2014;35:417-28; quiz 29.
4. McGillick EV, Te Pas AB, van den Akker T, Keus JMH, Thio M, Hooper SB. Evaluating Clinical Outcomes and Physiological Perspectives in Studies Investigating Respiratory Support for Babies Born at Term With or at Risk of Transient Tachypnea: A Narrative Review. Front Pediatr 2022;10:878536.
5. Bruschettini M, Hassan KO, Romantsik O, Banzi R, Calevo MG, Moresco L. Interventions for the management of transient tachypnoea of the newborn - an overview of systematic reviews. The Cochrane database of systematic reviews 2022;2:Cd013563.
6. Brown MJ, Olver RE, Ramsden CA, Strang LB, Walters DV. Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb. The Journal of physiology 1983;344:137-52.
7. Jain L. Alveolar fluid clearance in developing lungs and its role in neonatal transition. Clinics in perinatology 1999;26:585-99.
8. Dehdashtian M, Aletayeb M, Malakian A, Aramesh MR, Malvandi H. Clinical course in infants diagnosed with transient tachypnea of newborn: A clinical trial assessing the role of conservative versus conventional management. Journal of the Chinese Medical Association : JCMA 2018;81:183-6.
9. Costa S, Rocha G, Leitão A, Guimarães H. Transient tachypnea of the newborn and congenital pneumonia: a comparative study. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2012;25:992-4.
10. Hagman C, Björklund LJ, Hellgren G, Tufvesson E, Hansen-Pupp I. Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants. Pediatric pulmonology 2018;53:1399-406.
11. Moresco L, Calevo MG, Bruschettini M. Antibiotics for the management of [suspected] transient tachypnea of the newborn. Cochrane Database of Systematic Reviews 2018.
12. Brown JVE, Meader N, Wright K, Cleminson J, McGuire W. Assessment of C-Reactive Protein Diagnostic Test Accuracy for Late-Onset Infection in Newborn Infants: A Systematic Review and Meta-analysis. JAMA pediatrics 2020;174:260-8.
13. Hengst JM. The role of C-reactive protein in the evaluation and management of infants with suspected sepsis. Advances in neonatal care : official journal of the National Association of Neonatal Nurses 2003;3:3-13.
14. McCartney SA, Kapur R, Liggitt HD, et al. Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model. American journal of obstetrics and gynecology 2021;225:89.e1-.e16.
15. Stranik J, Kacerovsky M, Andrys C, et al. Intra-amniotic infection and sterile intra-amniotic inflammation are associated with elevated concentrations of cervical fluid interleukin-6 in women with spontaneous preterm labor with intact membranes. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2022;35:4861-9.
16. Vorontsov O, Levitt L, Lilleri D, et al. Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection. The Journal of clinical investigation 2022;132.
17. Cobo T, Aldecoa V, Holeckova M, et al. A Rapid Amniotic Fluid Interleukin-6 Assessment for the Identification of Intra-Amniotic Inflammation in Women with Preterm Labor and Intact Membranes. Fetal diagnosis and therapy 2021;48:327-32.
18. Oshima Y, Tanaka S, Tsumura K, et al. Amniotic fluid Gram stain and interleukin-6 can predict early-onset neonatal sepsis. The journal of obstetrics and gynaecology research 2020.
19. Hong S, Jung YM, Lee YE, Park Y, Kim YM, Park KH. Complement and other immune-related factors in cervicovaginal fluid associated with intra-amniotic infection/inflammation and spontaneous preterm delivery in women with preterm labor. Archives of gynecology and obstetrics 2020;301:1431-9.
20. Matsuguma C, Takahashi K, Okada S, et al. Clinical utility of gastric fluid cytokine levels in preterm infants for predicting histological chorioamnionitis. Cytokine 2024;180:156642.
21. Bry KJ, Jacobsson B, Nilsson S, Bry K. Gastric fluid cytokines are associated with chorioamnionitis and white blood cell counts in preterm infants. Acta Paediatr 2015;104:575-80.
22. Choi SR, Kim T, Kim Y, Jung S, Choi SJ. The Relationship Between Matrix Metalloproteinase-8 in After Birth Oral Fluid and Acute Histologic Chorioamnionitis in Preterm Delivery. Reproductive sciences (Thousand Oaks, Calif) 2021;28:2023-8.
23. Okumura T, Horiba K, Tetsuka N, et al. Next-generation sequencing-based detection of Ureaplasma in the gastric fluid of neonates with respiratory distress and chorioamnionitis. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2023;36:2207113.
24. Kim YD, Kim SC, Choi KU, Jun ES. The relationship between amniotic and newborn gastric fluid inflammatory mediators. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2013;26:1069-75.
25. Stichel H, Bäckström E, Hafström O, Nilsson S, Lappalainen U, Bry K. Inflammatory cytokines in gastric fluid at birth and the development of bronchopulmonary dysplasia. Acta Paediatr 2011;100:1206-12.
26. Musilova I, Andrys C, Hornychova H, et al. Gastric fluid used to assess changes during the latency period in preterm prelabor rupture of membranes. Pediatric research 2018;84:240-7.
27. Oh KJ, Lee J, Romero R, Park HS, Hong JS, Yoon BH. A new rapid bedside test to diagnose and monitor intraamniotic inflammation in preterm PROM using transcervically collected fluid. American journal of obstetrics and gynecology 2020;223:423.e1-.e15.
28. Racusin DA, Chen HY, Bhalwal A, Wiley R, Chauhan SP. Chorioamnionitis and adverse outcomes in low-risk pregnancies: a population-based study. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2022;35:5555-63.
29. Perry AK, Rossi RM, DeFranco EA. Severe adverse maternal outcomes associated with chorioamnionitis. American journal of obstetrics & gynecology MFM 2019;1:100027.
30. Jain VG, Willis KA, Jobe A, Ambalavanan N. Chorioamnionitis and neonatal outcomes. Pediatric research 2022;91:289-96.
31. Tzialla C, Borghesi A, Serra G, Stronati M, Corsello G. Antimicrobial therapy in neonatal intensive care unit. Italian journal of pediatrics 2015;41:27.
32. Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. The Journal of antimicrobial chemotherapy 2017;72:1858-70.
33. Lebeaux RM, Karalis DB, Lee J, et al. The association between early life antibiotic exposure and the gut resistome of young children: a systematic review. Gut microbes 2022;14:2120743.
34. McDonnell L, Gilkes A, Ashworth M, et al. Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis. Gut microbes 2021;13:1-18.
35. Jung E, Romero R, Suksai M, et al. Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment. American journal of obstetrics and gynecology 2024;230:S807-s40.
36. Bickel M. The role of interleukin-8 in inflammation and mechanisms of regulation. Journal of periodontology 1993;64:456-60.
37. Yang L, Herrera J, Gilbertsen A, et al. IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity. American journal of physiology Lung cellular and molecular physiology 2018;314:L127-l36.
38. Romero R, Chaemsaithong P, Docheva N, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. Journal of perinatal medicine 2016;44:53-76.
39. Suff N, Webley E, Hall M, Tribe RM, Shennan AH. Amniotic fluid sludge is associated with earlier preterm delivery and raised cervicovaginal interleukin 8 concentrations. American journal of obstetrics & gynecology MFM 2023;5:101161.
40. Carter SWD, Neubronner S, Su LL, et al. Chorioamnionitis: An Update on Diagnostic Evaluation. Biomedicines 2023;11.
41. Kelly RW. Inflammatory mediators and cervical ripening. Journal of reproductive immunology 2002;57:217-24.
42. Chaemsaithong P, Romero R, Docheva N, et al. Comparison of rapid MMP-8 and interleukin-6 point-of-care tests to identify intra-amniotic inflammation/infection and impending preterm delivery in patients with preterm labor and intact membranes(). The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2018;31:228-44.