In a groundbreaking review published in Pediatric Research, scientists have unveiled the critical role of large animal research in revolutionizing perinatal care, with a particular focus on seminal advancements that have dramatically improved outcomes for preterm and at-risk newborns. This comprehensive analysis chronicles the scientific journey from early experimental insights to clinical protocols that have become standard practice, emphasizing how this translational research pipeline has transformed neonatal medicine and highlighting the present threats posed by declining large animal research initiatives.
The transformative discovery dating back to the 1960s owes much to the pioneering work of Sir Graham “Mont” Liggins, whose investigations into antenatal corticosteroids marked a pivotal moment in perinatal medicine. Liggins’ experiments with dexamethasone in pregnant sheep revealed that preterm lambs, when exposed to corticosteroids, could survive birth with lungs that were functionally mature and capable of effective gas exchange. This was a revelation, as the underlying mechanisms of surfactant production and lung maturation by glucocorticoids were not well understood at the time. The translation of this discovery into human clinical practice was rapid and profound, spearheaded by the collaborative efforts of Liggins and neonatologist Ross Howie.
Their landmark clinical trial introduced the synthetic glucocorticoid betamethasone to mothers in preterm labor, administered in two 12 mg doses spaced 24 hours apart. This regimen significantly reduced mortality and morbidity in preterm infants by accelerating lung development, offering the first effective intervention to combat respiratory distress syndrome. Despite initial slow uptake, subsequent trials and a 1994 NIH consensus firmly established antenatal corticosteroid therapy as a cornerstone of preterm labor management, now applied in approximately 90% of very preterm births worldwide. These steroids not only enhance lung function but have since been shown to impact other organ systems, including the developing brain, underscoring both their therapeutic potential and the imperative for judicious use.
The physiology of umbilical cord clamping, a seemingly routine obstetric practice, has also undergone profound re-evaluation through preclinical large animal studies. Historically, immediate cord clamping (ICC) was standard, primarily for the pragmatic goal of reducing postpartum hemorrhage. However, research dating back to the 1960s established that delayed cord clamping (DCC) increases neonatal blood volume and stabilizes cardiovascular transition post-birth. Preterm lamb models elucidated the physiological harm induced by rushing cord clamping: a dramatic reduction in cardiac output that leaves infants vulnerable to hypoxic injury and ischemia. These experimental insights gave rise to ‘physiological based cord clamping’ (PBCC), a refined clinical approach wherein lungs are aerated prior to clamping, thereby maintaining cardiac preload and oxygen delivery during the critical transition from womb to world.
Clinical trials have since corroborated the benefits of PBCC and DCC in both resource-rich and low-resource settings, demonstrating significant reductions in neonatal mortality and adverse outcomes. Notably, a major randomized controlled trial revealed that the benefits of PBCC vary by sex and gestational age, with very preterm male infants experiencing improved intact survival—a nuance underscoring the importance of tailoring interventions and ensuring meticulous clinical training to maximize benefit. The concept of ‘translational accuracy’ emerges powerfully here, illustrating that the successful clinical implementation of physiology-based interventions depends heavily on clinician expertise and procedural experience.
One of the most transformative advances in neonatal care addressed in this review is the development of therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), a condition caused by perinatal asphyxia leading to profound brain injury in term infants. Historical accounts trace the notion of hypothermia as a protective strategy back centuries, but it wasn’t until the 1980s that systematic preclinical research in animal models such as neonatal rats, sheep, and piglets firmly established its neuroprotective efficacy. These studies demonstrated that modest reductions in body temperature mitigated the cascade of metabolic disruption, neuronal death, and inflammation that follows oxygen deprivation.
Crucially, large animal models have facilitated detailed physiological, biochemical, and neurophysiological monitoring, thereby defining the optimal parameters for cooling therapy, such as the necessity for initiation within six hours of insult, the ideal duration of around 72 hours, and temperature targets in the mild hypothermic range (~33.5–34.5°C). These studies also highlighted that delayed initiation or excessively deep or prolonged cooling can negate benefits or cause harm. The piglet model has proven invaluable in correlating magnetic resonance spectroscopy (MRS) markers like the lactate to N-acetylaspartate (Lac/NAA) ratio with long-term neurological outcomes, serving as a surrogate endpoint for evaluating neuroprotection in both preclinical and clinical trials.
Further bolstering the translational pipeline, fetal sheep models have allowed longitudinal monitoring that captures real-time changes in systemic and cerebral parameters following hypoxic injury, elucidating the nuanced interplay between seizures, secondary energy failure, and optimal timing of intervention. These mechanistic insights directly informed human clinical trial design, culminating in landmark randomized trials in the early 2000s that demonstrated significant improvement in survival without disability for infants subjected to TH after moderate to severe HIE.
The widespread adoption of therapeutic hypothermia into standard neonatal care since 2005 exemplifies a remarkable bench-to-bedside success story, with evidence now demonstrating cost-effectiveness and substantial quality-of-life benefits extending well into childhood and beyond. Research continues to evolve with ongoing trials exploring TH’s efficacy in infants with mild HIE and investigating adjunct therapies aimed at augmenting neuroprotection. Large animal research remains integral to these developments, providing critical platforms for pharmacokinetic studies and safety profiling of novel therapeutics such as melatonin.
Despite these profound advancements, the article sounds an alarm, warning that reductions in funding and support for large animal research pose a serious threat to the perinatal translational research pipeline. Given the complex physiology and developmental timelines that large animal models uniquely recapitulate, especially those mimicking human birth and neonatal transitions, their diminishing use could halt progress in understanding and improving perinatal care. The authors stress the irreplaceable value of these models for bridging the gap between scientific discovery and clinical application, cautioning that without sustained investment, promising interventions may never cross the critical hurdle from lab bench to clinical practice.
The review vividly captures the intertwined history of scientific curiosity, methodological innovation, and clinical perseverance that has shaped modern neonatal care. It illustrates how the meticulous characterization of pathophysiology in animal models—ranging from surfactant biology to cardiovascular adaptation and cerebral injury—has translated into practical, lifesaving interventions. Critically, it urges the scientific and medical community to recognize and preserve the infrastructure supporting this essential research, emphasizing that future breakthroughs in infant health depend on maintaining robust translational pathways.
In summary, the trajectory of perinatal research from steroid administration through optimized cord clamping to therapeutic hypothermia reveals a paradigm of how carefully conducted large animal studies inform clinical breakthroughs. These contributions have not only enhanced neonatal survival but also improved lifelong neurological outcomes for countless infants worldwide. The current challenges of sustaining large animal research infrastructures represent a pivotal crossroads; their resolution is paramount to continue advancing the frontiers of perinatal medicine and safeguarding the health of the most vulnerable patients from the very beginning of life.
Subject of Research:
The pivotal role of large animal research in advancing perinatal therapeutics including antenatal corticosteroid use, umbilical cord clamping strategies, and therapeutic hypothermia for neonatal brain injury.
Article Title:
A reduction in large animal research threatens the perinatal translation research pipeline
Article References:
Allison, B.J., Hooper, S.B., Gunn, A.J. et al. A reduction in large animal research threatens the perinatal translation research pipeline. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04686-7
Image Credits: AI Generated
DOI:
18 December 2025
Keywords:
Perinatal research, antenatal corticosteroids, umbilical cord clamping, therapeutic hypothermia, hypoxic ischemic encephalopathy, large animal models, translational medicine, neonatal care, lung maturation, neuroprotection
