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The clinical outlook of these infants is dependent on transition from intra-uterine life to postnatal life. Preterm infants are also commonly administered surfactant to manage respiratory distress syndrome. This physiology-based narrative describes optimal oxygen saturation, mechanical ventilation practices and circulatory imbalances that might happen after surfactant administration in preterm infants with congenital heart disease. Clinicians may consider higher oxygen requirement thresholds for surfactant therapy in this select cohort, in comparison to infants without congenital heart disease. The interplay between surfactant deficiency, surfactant replacement therapy, and the unique interaction with underlying congenital heart disease represents a knowledge gap. This perspectives article discusses the haemodynamic vulnerability of preterm infants and discusses the circulatory impact of surfactant in premature infants without and with structural heart disease. We provide physiology-based suggestions for duct-dependent lesions, parallel circulations and other structural heart disease.<\/jats:p>","DOI":"10.1038\/s41372-026-02654-5","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:22:42Z","timestamp":1776673362000},"page":"1350-1356","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Surfactant replacement therapy in preterm infants with congenital heart disease: Physiological concepts and therapeutic considerations"],"prefix":"10.1038","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-7529","authenticated-orcid":false,"given":"Arvind","family":"Sehgal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7648-8872","authenticated-orcid":false,"given":"Patrick J.","family":"McNamara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6915-2040","authenticated-orcid":false,"given":"Samuel","family":"Menahem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"2654_CR1","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/0002-9149(71)90053-1","volume":"28","author":"SC Mitchell","year":"1971","unstructured":"Mitchell SC, Sellmann AH, Westphal MC, Park J. 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