Fetal blood (Table 15.1) is structurally and functionally different to adult blood; it contains larger and more numerous erythrocytes (red blood cells) with a higher haemoglobin content which maximizes their uptake of oxygen (Palis and Segel, 1998). Fetal haemoglobin with its two α-chains and two γ-chains has a higher affinity for oxygen in the slightly more acid fetal environment. Less-effective binding of 2,3-bisphosphoglycerate (or 2,3-diphosphoglycerate) to the γ-chains means that the oxygen–haemoglobin dissociation curve of the fetus and neonate is shifted to the left (Fig. 15.1). Shifts of pH in the placenta further increase both dissociation of oxygen from maternal haemoglobin and its uptake by fetal haemoglobin. This means that, although fetal haemoglobin has an increased oxygen uptake, it is less efficient at releasing oxygen to the tissues.

At term, the ratio of fetal haemoglobin to adult haemoglobin (HbF:HbA) is 80:20; by 6 months production of the β-chain replaces the γ-chain so the ratio is 1:99 (Fig. 15.2). Preterm infants tend to have an even higher HbF level and a decreased 2,3-bisphosphoglycerate concentration therefore oxygen unloading at the tissue level is even less efficient. The raised levels of HbF in the neonate mean that haemoglobinopathies caused by altered synthesis of β-chains (such as β-thalassaemia) or altered structure of β-chains (such as sickle-cell anaemia) are not evident immediately at birth but become evident when the infant is at least 2 months old. It is possible to detect fetal blood cells in the maternal circulation, an observation that is utilized in the management of Rhesus incompatibility (see Chapter 10) (Lamvu and Kuller, 1997).

At birth, fetal blood has an increased population of nucleated erythrocytes (even more so if the baby has been subjected to increased stress, is immature or has Down’s syndrome). For the first 3 months of life, the erythrocytes are more fragile, have an increased metabolism and a shorter half-life and erythropoietin production is suppressed (Box 15.3). Once respiration in the neonate is established, the excess red blood cells compensating for the lower oxygen saturation within the uterine environment are no longer needed. These red blood cells are broken down and physiological jaundice may result, usually around day 3 of life as the neonatal liver is immature and initially cannot keep up with the rate of bilirubin production from red blood cell breakdown.

As the fetal oxygen source is the placenta rather than the lungs, blood in the fetal circulation flows in a circuit that perfuses the placenta and largely bypasses the lungs (Fig. 15.3). In order to do this, the fetal circulation has several additional structures: the umbilical vein, which carries blood rich in oxygen and nutrients to the underside of the liver, the ductus venosus (a venosus is a shunt that connects a vein to a vein), which bypasses the liver taking blood from the umbilical vein to the inferior umbilical vein en route to the right side of the heart. With increasing gestational age, more blood goes to the liver rather than bypassing it (Askin, 2009a). The hypogastric arteries, which branch off the internal iliac arteries, are contiguous with the umbilical arteries of the umbilical cord, returning blood to the placenta. The lungs are bypassed by two structures: the foramen ovale, which allows blood to move directly from the right atrium to the left atrium, and the ductus arteriosus, which connects the pulmonary arterial trunk to the descending aorta (an arteriosus is a vascular shunt that connects an artery to an artery).

The oxygenated and nutrient-enriched blood is taken from the placenta in the umbilical vein that goes through the abdominal wall to the underside of the liver. This is the only unmixed blood and is about 80% saturated with oxygen; the blood goes through the ductus venosus to the inferior vena cava where it mixes with oxygen-depleted blood returning to the heart from the lower body (Fig. 15.4 A). The inflows of blood from the inferior and superior venae cavae do not mix thoroughly because of their angle of entry and the shape of the right atrium. Because the entry of the inferior vena cava is aligned with the foramen ovale, most (about 60%) of the blood from the inferior vena cava travels from the right atrium through the foramen ovale into the left atrium and thence to the left ventricle and the ascending aorta. The foramen ovale is kept open because the high pulmonary vascular resistance (PVR) means that the pressure in the right atrium is also high.

Most blood entering the right atrium from the superior vena cava passes through the tricuspid valve into the right ventricle and to the pulmonary arterial trunk. The ductus arteriosus is inserted into the vessel at the bifurcation of the right and left pulmonary artery (taking blood to the right and left lung, respectively); it shunts blood from the pulmonary arterial route into the descending aorta. The pulmonary circulation is vasoconstricted and has a high PVR, because the pulmonary environment is relatively hypoxic. Systemic vascular resistance (SVR) is low. Only about 10% of the output of the right ventricle continues into the pulmonary circulation for the growth and metabolic needs of the lungs; the rest is diverted through the ductus arteriosus which has a low resistance; its patency is maintained by the low fetal PO₂ and by high levels of prostaglandins produced by the placenta. Towards the end of gestation, the proportion of blood perfusing the lungs tends to increase. From the descending aorta, the blood supplies the remaining organs and the lower body. The hypogastric arteries branch off the internal iliac arteries and return to the placenta via the umbilical arteries.

The upper body and head are fed from arteries which branch off from the aortic arch before the insertion of the ductus arteriosus and the subsequent mixing of slightly less-well-oxygenated blood. The early branching of the coronary and carotid arteries means the heart and brain receive slightly better oxygenated blood. The advantages conferred by the early branching of the subclavian arteries which supply the upper limbs can be illustrated by the enhanced development of arms compared to the legs.

One of the most important transitional stages in the adaptation to extrauterine life is the establishment of the neonatal circulation. In fetal life, the source of oxygen is the placenta so most of the blood flow bypasses the fetal lungs. At birth, blood fully perfuses the lungs and flow through the fetal vascular structures ceases. At birth, these changes that mark the transfer of the fetal into adult-type circulation (see Fig. 15.4B) are not rapid or immediate. They are initiated within 60 s of delivery but may not be fully completed for a few weeks. The two determining events that initiate the closure of the fetal shunts are the arrest of the umbilical circulation, and therefore placental perfusion, and lung inflation and expansion, which results in increased pulmonary blood flow. The first breath results in lung expansion and vasodilatation of the pulmonary vessels in response to increased partial pressure of oxygen so blood flow to the lungs increases. The tortuosity of the capillaries is reduced and the pulmonary circulation changes from a high-resistance to a low-resistance pathway so 90% of the blood flows through the pulmonary vascular bed. There is a brief reversal of flow through the ductus arteriosus, which vasoconstricts in response to the change in oxygen level, mediated by prostaglandins, especially decreased prostaglandin PGE₂ (Thorburn, 1992). The placenta no longer contributes to prostaglandin production and prostaglandin breakdown is increased because more blood flows to the lungs where significant prostaglandin metabolism and breakdown occur.

The smooth muscle of the umbilical artery walls is not innervated but is irritable. Vasoconstriction is stimulated by stretching and handling the cord, by cooling and in response to stress-related catecholamine release. The thicker walls of the umbilical arteries are able to generate high intraluminal pressure, which arrests the placental circulation, preventing flow from the infant to the placenta. This is augmented by the increased synthesis of prostaglandins and thromboxanes in response to the raised oxygen level due to breathing, which increases vessel irritability and vasoconstriction. The umbilical vein remains dilated; blood flow from the placenta to the infant can continue via gravity. Thus, initial neonatal blood volume is affected by the timing of clamping of the umbilical cord and by the relative positions of the infant and placenta at the time of clamping. The usual practice is to clamp the umbilical cord earlier if the baby is subject to fluid overload (hydropic), or if the baby is polycythaemic (e.g. infants of diabetic mothers or growth retarded), to limit the transfer of maternal analgesic agents or antibodies or to avoid possible baby-to-baby transfusions in the cases of multiple births (Kinmond et al., 1993).

The flap of the foramen ovale (Fig. 15.5) is pushed closed because the decreased umbilical flow results in a decreased venous return from the inferior vena cava so the pressure in the right atrium and PVR falls in response to changes in oxygenation. The increased pulmonary blood flow results in an increased return to the left atrium and consequent increase in pressure. Thus, the pressure gradient across the foramen ovale is reversed. So at birth, PVR falls and SVR increases. The relatively thick layer of smooth muscle in the pulmonary blood vessels begins to thin from birth.

The closure of the fetal structures may not be immediate or permanent and may never be completed. The closure of the foramen ovale is reversible at first; interruption of ventilation or a drop in alveolar oxygenation results in constriction of the pulmonary capillaries and consequent reversal of pressure across the atria and reversion to fetal circulation. The incomplete closure can result in intermittent and reversible cyanotic episodes. After a few days of functional closure, the tissue associated with the foramen ovale fuses and closure becomes permanent. In many adults, a patent foramen ovale can be demonstrated (a probe can be passed through) although the pressure gradient maintains effective functional closure. Intermittent flow through the ductus arteriosus may initially occur during each cardiac cycle when aortic pressure is maximal following ventricular contraction. Bradykinin released from the newly inflated lungs mediates the constriction of the ductus arteriosus. Production of prostaglandins, which had maintained the open ductus arteriosus in the fetus, is decreased as oxygenation increases. Most neonates have some degree of patency of the ductus arteriosus in the first 8 h of life but it becomes functionally closed within the first or second day (Askin, 2009a). Fibrolysis and obliteration of the lumen of the ductus arteriosus are usually complete within 3 weeks; continued patency is very serious and can result in left ventricular failure. The ductus venosus constricts when umbilical flow is halted. The obliterated vessels remain as anatomical ligaments; the slow closure of the umbilical vein and its degeneration into ligamentum teres are utilized as a route for neonatal blood transfusions if required.

The nervous control of the cardiovascular system is well developed in the neonate with mature physiological control of blood pressure and cardiac output demonstrable. The systemic arterial blood pressure is relatively low in the first few weeks as vascular tone develops which increases vascular resistance. Pulmonary arterial blood pressure is initially high but falls to mature values as pulmonary resistance falls. The neonate’s heart rate is fast, as in the fetus. As in the fetus, control of cardiac output is largely achieved by changing heart rate because the heart is small and non-compliant and has a relatively thick wall. At birth, the wall of the right ventricle is thicker than the left, which hypertrophies in response to the changed postnatal circulation.

In fetal life, the lungs are filled by fluid secreted by the lung epithelium; the lung fluid is essential for growth and development of the lungs and this fluid exchanges with amniotic fluid. At birth, the neonate has to rapidly clear fluid from its air-spaces; 10–25 mL/kg fluid will be expelled or resorbed. Fetal breathing movements (FBM) are observed on ultrasound from the first trimester. Initially, they are intermittent, rapid and irregular. As gestation progresses, FBM increase in strength and frequency, occurring up to 80% of the time in an organized episodic pattern (Nijhuis, 2003). The lung fluid is ‘breathed’ out by the fetus into the amniotic fluid. Patterns of FBM dominate during the daytime and are correlated with fetal behavioural states. Fetal wakefulness and arousal are associated with sustained vigorous respiratory patterns. Quiet sleep is associated with an absence of FBM. Adrenergic and cholinergic compounds, prostaglandin synthesis inhibitors and raised maternal carbon dioxide levels stimulate FBM. They are inhibited by hypoglycaemia, cigarette smoking, alcohol consumption and accelerated labour. Despite the relatively low partial pressure of oxygen and high partial pressure of carbon dioxide, the fetus makes only shallow respiratory movements although severe hypoxia and acidosis may stimulate gasping. Mild hypoxia leads to quiet sleep and reduced energy expenditure and oxygen consumption, which may be protective. The movement of the diaphragm generates about 25 mmHg pressure for between 1 and 4 h per day in a pattern that coincides with rapid eye movement (REM) sleep but not during slow-wave sleep or fetal ‘wakefulness’. FBM are important in lung development (Harding and Hooper, 1996), promoting growth and allowing rehearsal of the respiratory actions. Lung development is retarded in conditions where FBM are limited such as congenital disorders of the diaphragm or nervous system. The fluid volume in the fetal airways correlates with the functional residual capacity in postnatal life (Strang, 1991).

The most urgent need after delivery is the initiation of ventilation; the neonate has to clear its lungs of fluid, establish regular breathing and increase pulmonary blood flow to match pulmonary perfusion to ventilation. Many factors interact to stimulate the first breath, including changes in temperature and state. The mild asphyxia (decreased oxygen concentration, raised carbon dioxide concentration) and acidosis (decreased pH) due to flow in the cord ceasing sensitize the fetal aortic, carotid and central (medullary) chemoreceptors that increase ventilatory drive. Tactile stimulation, such as that which occurs during delivery, also promotes respiration. In additional, it is thought that the placental prostaglandins may inhibit breathing (decreased oxygen concentration, raised carbon dioxide concentration). The surge of endogenous steroids and catecholamines associated with labour also contributes; infants who do not experience labour are more likely to retain residual fluid in their lungs and have less efficient respiratory performance.

The fluid-filled lung with collapsed alveoli and undispersed surfactant proffers a high resistance to inflation and the first breath requires considerable effort. The diaphragm contracts strongly and the complaint flexible ribs and sternum of the newborn baby are pulled concave in the effort of the first breath. Once the lungs are inflated, the lung fluid is forced into the alveoli where it aids dispersal of surfactant and is rapidly resorbed into the pulmonary lymphatic vessels. Subsequent breaths require fewer changes in pressure and less mechanical work. The thoracic compression of a vaginal delivery contributes to fluid loss from the upper respiratory tract; the compression of the chest (known as the ‘vaginal squeeze’) creates negative pressure which draws air into the lungs and they re-expand. Most of the fluid clearance is due to a change in the lung epithelium from being a predominantly chloride-secreting membrane at birth to being predominantly a sodium absorbing membrane after birth (Jain and Eaton, 2006).

Most babies gasp within 6 s and have patterns of normal breathing and gas exchange within 15 min. Initially the newborn infant has metabolic and respiratory acidosis due to decreased oxygen concentrations (resulting in increased lactic acid) and increased carbon dioxide levels, respectively; this acid–base imbalance is corrected as ventilation improves. The risk of transient tachypnoea of the newborn (TTN) is increased in babies who are delivered by caesarean section or those who experience perinatal hypoxia. It is thought that TTN is due to immaturity of the sodium transport mechanisms of the lung epithelium (Jain and Eaton, 2006).

The rate of ventilation of the newborn is high compared with an adult but is similar when relative size is taken into account. Ventilation is often irregular with the baby exhibiting periods of fetal-like shallow breathing. The reflexes associated with lung inflation also appear to be different. As well as the Hering–Breuer Reflex (where filling of the lungs increases expiratory centre activity), the newborn infant demonstrates Paradoxical Reflex of Head (where filling the lungs excites the inspiratory centre thus stimulating further inspiration) (Givan, 2003). For the first few weeks, babies breathe via the nose and suck via the mouth. Control of ventilation by chemoreceptors is functional but qualitatively different in that hypoxia tends to increase depth of respiration (rather than respiratory rate) and that the response is temperature-dependent and is abolished in cold temperatures. The chemoreceptors seem to be more sensitive to raised carbon dioxide levels.

Babies have a relatively large oxygen consumption, which reflects their heat generation and that their more metabolically active tissues (e.g. liver and brain) are proportionately larger. The high airway resistance means that the energy cost of respiration is higher. PVR drops 6–8 weeks after birth when the diameter of the small arterioles increases. The relatively high requirement for oxygen means that neonates are more susceptible to asphyxia than other age groups. Neonatal resuscitation aims to prevent mortality and morbidity. Hypothermic neonates are predisposed to hypoglycaemia and acidosis. Acidosis compromises respiration because it increases PVR and suppresses both respiratory drive and surfactant production. The aims of neonatal resuscitation are to promote and maintain adequate ventilation and oxygenation, to initiate and maintain adequate cardiac output and perfusion and to maintain body temperature and adequate blood glucose levels.

The infant is usually born into a wet and relatively cold environment. As environmental temperature is usually lower than maternal temperature, the baby will experience a temperature loss at birth. Heat transfer is affected by two gradients: the internal gradient involving transfer from the core to the surface of the baby and the external gradient involving heat transfer from the body surface to the environment. Cooling is usually rapid at a rate of 0.2–1.0°C per minute depending on the environmental factors and the gestational age of the infant (which affects body composition). Transfer of heat through the internal gradient depends on insulation and blood flow. Neonates are predisposed to heat loss; they have less subcutaneous fat than adults do (about 16% body fat compared with 30%), a higher surface area:mass ratio (about three times the relative surface area of an adult) and a lower ability to shiver. Should the baby be born small, it will not only have an even larger surface area:mass ratio but also the insulation provided by its subcutaneous fat will also be further compromised and skin permeability will be increased. Small-for-dates babies have proportionately bigger heads and higher metabolism and are disadvantaged in that their heat losses are higher. Changes in peripheral circulation affect heat loss via conduction.

Heat loss across the external gradient depends on the temperature difference between the body and the environment. Conduction, convection, evaporation and radiation transfer heat from the baby. Warming objects that will come into contact with the neonate, and increasing insulation by wrapping, limit heat loss by conduction. Evaporation offers the greatest route for heat loss immediately after delivery but drying the baby, especially the head, immediately after delivery is effective at reducing the loss. Skin keratinization is inadequate in immature infants so evaporative heat losses are higher. Evaporative insensible heat loss increases with respiratory problems, activity, the use of radiant heaters or phototherapy and low relative humidity. Convective losses are related to draughts and are affected by ambient temperature and humidity. Higher air temperatures, minimal air circulation, swaddling and baby hats reduce heat loss by convection. Radiation is the major form of heat loss from babies in incubators. It involves the transfer of radiant energy to surrounding objects not directly in contact with the baby. Consideration therefore has to be given to the temperature of objects in the local environment including the incubator, walls and windows. Skin-to-skin contact with the mother immediately following birth is a very efficient way of reducing heat loss from the neonate. The large skin area and the softness of the breasts enable a large amount of maternal skin to come into direct contact with the baby’s skin surface.

The mechanisms of heat conservation and generation mediated by the peripheral nervous system are insufficient in the neonate (Okken, 1991). Infants can produce heat from metabolic processes and by increasing activity. Postural changes are also important in conserving heat. Shivering is not so important in infants but heat generation by non-shivering thermogenesis (NST) is important. NST takes place in brown adipose tissue (BAT), a specialized type of adipose tissue that is well vascularized, particularly by sympathetic nerves, and has cells densely packed with mitochondria (Fig. 15.7). In humans, BAT is mostly replaced by white adipose tissue (WAT); adults have very few BAT cells which are interspersed with WAT (Wolf, 2009). However, BAT has a major role in heat production in the neonate. BAT is formed from about 30 weeks’ gestation until about 4 weeks’ postbirth. Fat mass is significantly altered by maternal nutrition and gestational length; stores of BAT (and white fat) are lower in preterm infants. BAT comprises about 2–7% of birth weight and is predominantly located around the core organs (Fig. 15.8). It generates heat by uncoupling electron transport from oxidative phosphorylation in the mitochondria so the energy released by electron transport will not be used to synthesize ATP but will be liberated as heat instead (Fig. 15.9). Fifty percentage of cellular respiration is uncoupled from ATP formation in BAT (Wolf, 2009). The unique uncoupling protein (UCP1) is a proton transporter located in the inner mitochondrial membrane. UCP1 causes protons to leak across the inner mitochondrial membrane so the electrochemical gradient, that usually drives ATP production, is lost and heat is produced. When UCP1 is maximally activated, it allows the production of at least 100 times as much heat from BAT compared to other tissue. UCP1 is synthesized during the maturation of fetal fat (Symonds et al., 2003). At birth, the activation of BAT is accompanied by mobilization of fat and a marked increase in lipolysis. Thermogenesis by BAT is inhibited in the fetus by PGE₂ and prostacyclin (PGI₂) produced by the placenta. The placenta also suppresses formation of active T₃ (tri-iodothyronine) from T₄ (thyroxine) (see below).