The transition from intrauterine life to extrauterine existence encompasses significant cardiorespiratory adaptations. These include rapid lung aeration and increase in pulmonary blood flow (PBF). Perinatal asphyxia and fetal growth restriction can severely hamper this transition. Hypoxia is the common denominator in these 2 disease states, with the former characterized by acute insult and the latter by utero-placental insufficiency and a chronic hypoxemic state. Both may manifest as hemodynamic instability. In this review, we emphasize the role of physiologic-based cord clamping in supplementing PBF during transition. The critical role of lung aeration in initiating pulmonary gas exchange and increasing PBF is discussed. Physiologic studies in animal models have enabled greater understanding of the mechanisms and effects of various therapies on transitional circulation. With data from sheep models, we elaborate instrumentation for monitoring of cardiovascular and pulmonary physiology and discuss the combined effect of chest compressions and adrenaline in improving transition at birth. Lastly, physiologic adaptation influencing management in human neonatal cohorts with respect to cardiac and vascular impairments in hypoxic-ischemic encephalopathy and growth restriction is discussed. Impairments in right ventricular function and vascular mechanics hold the key to prognostication and understanding of therapeutic rationale in these critically ill cohorts. The right ventricle and pulmonary circulation seem to be especially affected and may be explored as therapeutic targets. The role of comprehensive assessments using targeted neonatal echocardiography as a longitudinal, reliable, and easily accessible tool, enabling precision medicine facilitating physiologically appropriate treatment choices, is discussed.

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