Mind the gap: fetal physiology from bench to bedside

The beginning of the study of fetal physiology and medicine has long been ascribed to the initial findings of Sir Joseph Barcroft and the centenary of his research was recently celebrated at the University of Cambridge. Barcroft’s interest in fetal physiology did not begin until he was 60 when he had also been appointed to be The Professor of Physiology at Cambridge. Intertwining his interests in the hypoxia of high altitude and in fetal physiology, Barcroft equated the fetus to the acclimatised highland mountaineer. He coined the phrase ‘Everest in utero’, a term now used extensively to teach the conditions in which the fetus normally develops (1). In pregnant sheep preparations developed initially by Huggett in 1927 (2), in which sheep fetuses were acutely exteriorised into a warm water bath under the influence of anaesthesia, Barcroft begun to establish the very beginning of knowledge about placental function and the physiology of the fetus. These observations culminated in the 1946 publication of his final book, Researches on Pre-natal Life (3) the year before he died; the uncontested document that laid foundation for the study of Fetal Physiology and Medicine. Since then, the sheep has remained the animal model of choice for this field of research, primarily because in contrast to rodents, the temporal developmental milestones of several systems, like the heart and circulation, are similar between humans and sheep (see 4). In addition, the initial ovine acute preparation used by Huggett and Barcroft was much refined by investigators such as Barron, Meschia and Battaglia (5). Through their efforts, the chronic maternal and fetal sheep preparation was born, the only animal model that permits under general anaesthesia significant instrumentation of the fetus with vascular catheters and flow probes, thereby permitting in vivo study of fetal cardiovascular function in a robust physiological preparation, days or weeks after recovery from surgery. This preparation has since been exploited by several fetal physiologists to study many aspects of life before birth, giving rise to the Golden Age of Fetal Physiology and Medicine. However, advances in fetal physiology and their extrapolation to fetal medicine, as well as advances in fetal medicine and their physiological interpretation have fallen into a trap. There is a significant gap of translational understanding on both sides of the coin. For instance, since Dawes at Oxford (6) and Rudolph at the University of California San Francisco (7), generations of fetal physiologists have studied in sheep the fetal defence response to acute hypoxia. This has been achieved by lowering the maternal inspired fraction of oxygen in order to model the fetal circulatory response to impaired fetal oxygenation in complicated human pregnancy. Decades of work on the chronically instrumented fetal sheep preparation have since revealed that the fetal cardiovascular defence to moderate isocapnic hypoxia involves chemoreflex, endocrine and local redox components (4,8,9). However, episodes of reduced fetal oxygenation in human pregnancy rarely occur in isolation, being often accompanied by fetal acidaemia leading to fetal asphyxia (10,11). Despite its human clinical relevance, our understanding of the physiology mediating the fetal cardiovascular defence to episodes of fetal asphyxia is almost non-existent relative to the wealth of knowledge on the fetal physiological defence to acute hypoxia. A similar gap between fetal medicine and fetal physiology is exemplified by the clinical preoccupation on differential interpretation of fetal heart rate patterns during labor according to differences in the paper speed used by clinical centres in the United Kingdom, Australasia and much of Europe compared with North America. From a physiological perspective, we have known for over a decade that the pattern and magnitude of the fetal heart rate