Transitional Fetal Circulation: A Comprehensive Review of Physiological Adaptation, Failure, and Neonatal Outcomes

The change from fetal to neonatal circulation is one of the most rapid and consequential physiological reorganizations in human life, and it is more accurately described as an integrated cardiopulmonary and placental sequence than as simple closure of fetal shunts.Before birth, the placenta is the organ of gas exchange, pulmonary vascular resistance (PVR) is high, and the ductus venosus, foramen ovale, and ductus arteriosus sustain a parallel circulation that preferentially directs relatively oxygenated umbilical venous blood to the myocardium and brain.At birth, lung aeration, clearance of fetal lung liquid, a rise in alveolar and arterial oxygen tension, and mechanical recruitment of the pulmonary microvasculature produce a steep fall in PVR and a several-fold increase in pulmonary blood flow.Pulmonary venous return then replaces umbilical venous return as the dominant source of left ventricular preload, while interruption of the lowresistance placental circuit raises systemic vascular resistance (SVR) and left ventricular afterload.These pressure and flow changes, rather than any intrinsic anatomical event, drive functional closure of the foramen ovale and progressive constriction of the ductus arteriosus.Failure or delay of this coordinated sequence produces a spectrum of hemodynamic disorders: persistent pulmonary hypertension of the newborn (PPHN), myocardial dysfunction, inadequate preload, hemodynamically significant patent ductus arteriosus (PDA) in the preterm infant, and decompensation of previously unrecognized duct-dependent congenital heart disease.The mechanisms include incomplete alveolar recruitment, hypoxemia, acidosis, inflammation, impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling, excess endothelin-1 and Rho-kinase activity, oxidative stress, ventricular maladaptation, and adverse ventriculo-ventricular interaction.Because hypoxemia, hypotension, acidosis, and poor perfusion are shared surface features of mechanistically distinct states, assessment based on blood pressure or oxygen saturation alone is inadequate.This review synthesizes fetal circulatory physiology, the molecular and mechanical basis of normal transition, the principal failed-transition phenotypes, and contemporary physiology-guided monitoring and management.It integrates recent evidence on deferred and physiology-based cord clamping, including the 2023 individual participant data meta-analysis of preterm cord management and the 2024 ABC3 randomized trial; the 2024 American Society of Echocardiography update on targeted neonatal echocardiography; the 2025 American Heart Association and American Academy of Pediatrics neonatal resuscitation guidelines; randomized and network meta-analytic evidence on PPHN pharmacotherapy; and the shift from routine early PDA closure to selective, phenotype-based management.A mechanistic understanding of transitional circulation allows earlier recognition of neonatal cardiovascular compromise and discourages the indiscriminate treatment of numerical hypoxemia or hypotension.