| | Foetal to neonatal transition — how does it take place?Abstract The rapid adaptation of the newborn baby to respiratory, cardiovascular, metabolic and neurological independence is only successful because of a series of evolved critical mechanisms and practised manoeuvres. This article reviews the physiology of these adaptations. It is particularly useful for clinicians to understand the underlying physiology as the treatments for maladaptation are based not only on treating the underlying disease which may be contributing, but also aimed at reversing the abnormal physiological processes. At the bedside, such understanding proves to be invaluable. The foetus is referred to in the male gender for convenience; no bias is intended. Introduction  Being born is arguably the most potentially dangerous event that most of us ever encounter. The foetus develops in an airless, dark, hypoxaemic environment where full nutrition and waste needs are met. However his survival depends on a series of rapid and profound physiological adaptations which must take place at or soon after delivery. Coupled with an understanding of normal processes, doctors need to be able to promptly recognize infants where transition is delayed or abnormal as resuscitation will invariably be more effective the earlier it is instituted. The accompanying article will describe the potentially life-threatening consequences of failure to adapt. How do the environments differ? In utero is a constant and reliable environment in which there are minimal fluctuations in temperature, darkness, glucose supply and nutritional needs, gas exchange and excretion. The upper airways, lungs and gut are fluid filled. The placenta fulfils the role of ‘life support machine’ by providing nutrition, regulating oxygen supply and carbon dioxide removal. The foetal circulation passes through the placenta continuously, there is relative hypoxia (PO2 3–4 kPa) and there is little perfusion to the lungs (Figure 1). The temperature is maintained at about 1°C above maternal core temperature. The foetus passes urine into the amniotic fluid. By contrast the ex utero environment is variable and inconsistent – temperature variations, periods of fasting and feeding, requirement for respiratory, cardiovascular, metabolic and nutritional ‘independence’ although still dependent on a carer to help meet these needs. So the normally developed, term newborn baby faces sudden and dramatic change necessary for survival. From blue to pink in under a minute Clearly breathing is fundamental to survival in air, and the newborn baby has to undergo substantial changes in the lungs and upper airways to support this. •Foetal fluid is driven from the lungs and any fluid remaining in the mouth is usually swallowed. •There are large increases in lung volume and intrathoracic pressure, forcing widespread alveolar expansion. This is facilitated by the release of pulmonary surfactant to reduce the surface tension at the alveolar air–fluid interface. •Establishment of functional residual capacity and a large surface area for gas exchange. As the baby begins to breathe air, the PO2 increases, and as a result there is a rapid fall in the pulmonary vascular resistance. This in turn greatly increases the pulmonary blood flow, facilitating better gas exchange in a positive feedback loop as the baby effectively resuscitates himself, and turns pink. These adaptations are normally so effective that over 90% of babies have established regular air breathing within a minute of birth. So how does this all work so well? Notwithstanding a few hundred thousand years of evolution, the foetus spends a considerable amount of time preparing for this moment. The following are key to a successful transition from foetal to neonatal existence. Developing sustained breathing The foetus practises breathing from an early age – 11 weeks, and keeps breathing until delivery. The breathing movements are shallow and rapid initially, but by 20 weeks they slow to a rate of about 50 per minute and become deeper and more regular. They occur only about 40% of the time, mostly while the foetus is in rapid eye movement (REM) sleep. If the PCO2 increases, then the rate increases, but if the PO2 is lowered they decrease and they become continuous if the PO2 is increased. Foetal breathing is not just helpful practice for the ‘blue to pink’ transition, it promotes the correct development of the lungs. At birth however the newborn needs to breathe continuously. The traditional view has been that the ‘stress’ of labour and delivery leads to a transient foetal asphyxia, leading to increased PCO2 and acidosis. It was thought that this gave a stimulus to peripheral chemoreceptors to induce the first breath, and then breathing was sustained through other stimuli such as touch, cold and sensory stimuli. However more recent evidence has dispelled this view. In animal experiments, denervation of the carotid and aortic chemoreceptors does not inhibit the initiation of respiration, and continual breathing is actually dependant on the rise in PO2 (as in the foetus) and is independent of rises in PCO2. This is a classic example of where adult physiology principles were wrongly applied to newborns. Furthermore, it has been shown that the placenta produces specific peptides which inhibit more sustained foetal breathing until the cord is clamped. Foetal lung fluid reabsorption Foetal lung fluid is derived from both interstitial fluid within the lung and vascular fluid in the lung circulation. All it takes to draw the fluid from the interstitium into the potential air space is a −5 mV potential generated by chloride pumps in the pulmonary epithelium. Animal models have shown that it is produced at a rate of about 2 ml/kg/hour at mid-gestation rising to 5 ml/kg/hour at term (so a 3.5 kg term baby is producing about 420 ml a day!). About 50% of foetal lung fluid is swallowed, and the rest mixes with amniotic fluid. Production is unaffected by pulmonary mechanics, but is affected by the presence of hormones – for example adrenaline and prostaglandin E2 (PGE2) decrease production of lung fluid. Experiments have shown that adequate lung expansion by foetal lung fluid is essential for the growth and development of normal lung structure. It is thus remarkable how quickly fluid-filled lungs become air-filled. Previously it was thought that the main process of removal was a mechanical one as the foetal chest was compressed as it passed through the vaginal canal. Whilst there is some expulsion of foetal fluid from the mouth at birth, we now know that the hormonal process of labour itself is a key factor. An interesting class of membrane-integrated water channels called aquaporins (AQPs), with several isoforms found in the human lung epithelium and in vascular endothelium, appears to be important. Movement of water via AQPs is efficient, osmotically driven by a sodium gradient actively generated by Na+, K+-ATPase (adenosine triphosphatase) in the epithelium. Furthermore, AQP production and activity appears to be dynamic and responsive to hormones, pH and other factors. Production of foetal lung fluid begins to diminish two to three days prior to delivery. It is known that cortisol increases the level of AQP1 in lung endothelium, as does maternal treatment with corticosteroids. During labour there is a 50% decrease in secretion and reabsorption of lung fluid commences. The precise mechanisms and relative contributions to this remain to be elucidated, but adrenaline, prostaglandin E2 (PGE2), nitric oxide and lung surfactant are involved and the AQPs appear to play a key role. Postnatally the reabsorption of foetal lung fluid is very fast as the lung epithelium switches chloride ion secretion to sodium absorption into the pulmonary interstitium. There is increased expression not only of the epithelial sodium channels and sodium pumps, but also of AQP4 which may be particularly important in removal of foetal lung fluid at this critical time. Surfactant production Human surfactant comprises 90% of lipid and 10% of protein and is secreted by type II alveolar cells in the lung. It first appears in the lung at about 22–24 weeks' gestation and its main role is to lower the surface tension on the liquid surface of the alveolus to facilitate alveolar expansion during inspiration (Figure 2). It is useful to think about the pressure required to maintain a gas bubble (even though alveoli are not spherical gas bubbles) which is related to the surface tension and the size, as described by the Laplace equation: where Δ P = difference in pressure inside and outside the bubble (Pa), γ = surface tension (N/m) and r = radius (m). In normal lung extracts, the surface tension is approximately 6 mN/m, thus for an alveolar radius of 50 μm, the ΔP is 2.4 cm H2O (where 1 cm H2O = 98.1 Pa). This is about the end expiratory pressure in the normal lung, sufficient to prevent lung collapse. In extracts of lung deficient in surfactant, the surface tension is about four times higher, so for the same size of alveolus (50 μm) the ΔP is 9.3 cm H2O. As the foetus approaches term, there is a surge in surfactant production around 33–35 weeks' gestation, with further stimulus around the time of delivery. The lipid component of surfactant is 80% composed of phosphatidylcholine, of which 60% is 2,3-dipalmitoyl phosphatidylcholine (DPPC). DPPC is the main surface tension-lowering lipid. The hydrophobic surfactant proteins (SP) B and C are also important in lowering surface tension; SP-A and SP-D are hydrophilic and have a role in immune defence. Surfactant is recycled by alveolar macrophages and by endocytosis back into the type II cells. Endogenous and exogenous steroids increase surfactant production, hence the importance of giving maternal steroids in threatened preterm labour. During expiration, the surfactant molecules coalesce temporarily, reducing the surface tension and thus the pressure required to maintain alveolar opening is reduced. This enables the baby to maintain a functional residual capacity in expiration, and to ensure that the pressures required to re-inflate the alveoli during inspiration are not so great that exhaustion and respiratory failure would ensue. Conversion from foetal to neonatal circulation The foetal circulation in Figure 1 is a sophisticated mechanism that ensures continuous, predictable supply of oxygen and nutrient and removal of the products of cellular metabolism. Well-oxygenated blood is directed primarily towards the developing brain, myocardium and the left ventricle, with less well oxygenated, low nutrient blood directed towards the right ventricle. This streaming of blood is vital to ensure optimal growth and development of the foetus (Figure 3). The inferior vena cava (IVC) is angled to direct different blood streams from the lower body (desaturated blood) which is directed into the right ventricle, and from the ductus venosus (saturated blood) which crosses the foramen ovale into the left atrium and the left ventricle. The superior vena cava (SVC) carries mainly desaturated blood from the upper body and is angled on the right atrium so that its flow passes to the right ventricle. The right ventricle pumps mainly desaturated blood into the pulmonary artery, most of which then crosses the ductus arteriosus into the descending aorta. Approximately 10–15% passes through the pulmonary circulation. Desaturated blood then mixes with saturated blood, 30% of it passes to the lower body and the rest returns to the placenta. By allowing blood to largely bypass the lungs, this prevents excessive strain being placed on the right ventricle. The left ventricle contains mainly saturated blood, received from the IVC stream described above. Sixty per cent of this output is pumped to the brain and upper body, 10% goes to the myocardium and 30% to the lower body. The flow of blood is radically altered by a series of events, commencing with the clamping of the umbilical cord. This removes the low pressure placental circulation, resulting in an increase in the left-sided pressure and a drop in the right-sided pressure. This is accentuated by the taking of the first breath, which triggers a rapid fall in the pulmonary vascular resistance and a resulting massive increase in pulmonary blood flow. A major regulator of vascular tone is nitric oxide (NO), released via the oxidation of L-arginine by pulmonary vascular endothelium nitric oxide synthase (eNOS) in response to increased oxygenation. NO acts via guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) to cause vasodilation. The foramen ovale closes within minutes as a result of the increase in left-sided pressure and the fall in right-sided pressure, but permanent closure occurs more slowly over weeks to months. Simultaneously the flow in two foetal vessels falls dramatically – flow in the ductus arteriosus falls, with functional closure occurring usually within hours of birth. This closure is mediated by increased intraluminal oxygen tension and reduction in prostaglandin E2 causing constriction of ductal vascular smooth muscle. Closure is also dependent on muscular maturity, nutritional reserves, ATP stores and autonomic nervous system activity. Once closed, ATP depletion and cell death lead to permanent remodelling of the ductus wall. Flow in the ductus venosus is reduced by 95% as the cord is clamped, again resulting in closure within hours and permanent closure within 7–14 days. Again, increased oxygen tension is thought to play a role in the closure of this vessel. Thus it is pressure changes at birth which are mainly responsible for the change from foetal to neonatal circulation. Nutritional independence The nutritional demands of the foetus are met entirely by the placenta, and the foetus does not need to control its fluid intake or output. Glucose is the predominant substrate for the foetus, provided primarily via the placenta but also, towards the end of gestation, by gluconeogenesis in the foetal liver as preparation for neonatal existence. There is also a step-up in ketone body production at 34–36 weeks' gestation. The sudden transition from continuous maternal glucose to intermittent breast milk triggers mild hypoglycaemia leading to production of adrenalin, growth hormone and glucagon and a fall in insulin level. This leads to gluconeogenesis, lipolysis and glycogenolysis so the newborn is not only able to produce glucose at a rate of 4–6 mg/kg/minute in the postnatal period, but also to utilize other substrates such as ketone bodies (acetoacetate and 3β-hydroxybutyrate) and lactic acid during the postnatal phase and during fasting. Thus neonatal ketogenesis does not reflect starvation, but is a normal part of the adaptive response. Renal maturation Foetal urine, which comprises about 50% of the amniotic fluid composition, is extremely dilute. Immature glomeruli have high vascular resistance and nephrons continue to form until they reach adult numbers at about 34–35 weeks, so the foetal renal blood flow and glomerular filtration rate are low. The foetus is in positive sodium and water balance, which are essential for growth. After birth, the blood pressure rises as described above and continues to rise over the first few days. Renal vascular resistance falls with greater flow and rapid maturation of the glomeruli takes place. Increased expression of renal AQPs play an important role in the concentrating capacity of the kidney which does not fully mature until 18 months. Gastrointestinal maturation The foetus starts swallowing amniotic fluid from 11 weeks, and from 18 weeks' gestation more complex sucking movements can be seen. This is not just practice for postnatal life, it is also essential for the development of the gut in utero. Swallowing matures at about 37 weeks at the same time as gastric emptying cycles strengthen and become fewer and more prolonged in preparation for intermittent milk feeds and satiety. Ophthalmological adaptation Foetal eye movements are seen at 16–18 weeks and eyes develop despite no visual stimulus, suggesting that these movements are essential to enable the maturation and functional connections. Haematological adaptation During foetal life, haemoglobin F (HbF) accounts for over 90% of the total haemoglobin. HbF has a different dissociation curve to HbA, binding oxygen with greater avidity. Towards term, there is increasing production of HbA so that it accounts for 15–50% of the total at birth, and this continues postnatally so that by 2 years it accounts for about 98% of the total. Summary At birth a series of practised physiological events occur rapidly to ensure that the foetus can make the successful transition from the intrauterine fluid-filled environment to the ex utero one. The reader should now have an insight into these processes, which will help in further understanding the principles of resuscitation and disease processes which take place when the adaptive processes do not proceed adequately. The accompanying article considers the most common and/or clinically severe examples when babies fail to adapt to the postnatal environment. Peter Reynolds MBBS PhD FRCPCH is a Consultant Neonatologist at St Peter's Hospital, Chertsey, Surrey, UK. Conflicts of interest: none declared PII: S0263-9319(09)00252-X doi:10.1016/j.mpsur.2009.10.012 © 2010 Elsevier Ltd. All rights reserved. | |
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