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Foetal adaptation at birth
ARTICLE IN PRESS Current Paediatrics (2006) 16, 373–378
Available at www.sciencedirect.com
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Foetal adaptation at birth Tina A. Leone, Neil N. Finer Department of Neonatology, University of California, 200 W. Arbor Dr. MC 8774, San Diego, CA 92103, USA
KEYWORDS Neonatal transition; Foetal adaptation; Foetal physiology; Neonatal physiology
Summary The immediate newborn period is a critical time for an individual as the transition is made from foetal to neonatal life. The separation of the neonate from the mother and the placenta requires many physiologic adjustments necessary for survival in a completely new environment. Among the processes necessary for a smooth transition to neonatal life are the initiation of continuous breathing and pulmonary gas exchange, alteration of the circulatory pattern, and regulation of temperature in a cold environment. All clinicians caring for newborns must understand the expected course of these adaptations and be able to recognise when the transition is not occurring appropriately. With the identification of difficulties occurring during transition the clinician may institute interventions in a timely manner. & 2006 Published by Elsevier Ltd.
Introduction Practice points
Transition from foetal to neonatal life is a complex multi-organ system process
The preterm infant may have more difficulty with some aspects of the transition than the term infant
Temperature regulation, breathing, pulmonary gas exchange, and altered circulatory patterns are essential components of the transition process and should be monitored in the immediate newborn period
Corresponding author. Tel.: +1 619 543 3759;
fax: +1 619 543 3812. E-mail address: [email protected] (T.A. Leone). 0957-5839/$ - see front matter & 2006 Published by Elsevier Ltd. doi:10.1016/j.cupe.2006.08.005
Foetal physiology is distinct from that of adults or infants in many ways, and enables the foetus to exist and thrive in the uterine environment. At birth a neonate must make several adjustments in order to survive in a completely new environment. The physiologic processes necessary to accomplish this transition smoothly are complex and involve various adjustments of multiple organ systems, which are often interrelated. When the transition does not occur smoothly the newborn infant can become seriously ill. Some of the adaptations made by a neonate in the first few minutes of life are visible to an astute observer. The practice of neonatal resuscitation establishes a routine of early evaluation of the transition process and allows for provision of interventions to assist the infant with elements of the transition as necessary. The placenta is the foundation of foetal existence providing for constant nutrient access and gas exchange allowing the foetus to develop in a protected, fluid-filled compartment. When the placenta is removed and the
ARTICLE IN PRESS 374 neonate is transferred to an extra-uterine environment many of the processes that made foetal life possible are irreversibly altered and the newborn must immediately adapt to extra-uterine existence. Some of the necessary adjustments include, but are not limited to, developing adequate thermoregulation, establishing continuous breathing and pulmonary gas exchange, altering the route of circulation, and existing without a constant nutrient supply. The ability to make these adjustments is less reliable in preterm infants and therefore more support is frequently required in more immature infants. Much of the information known about foetal transition to neonatal life has come from research using animal models to evaluate the contribution of different mechanisms. This review will examine the physiologic processes of transition from foetal to newborn life with emphasis on the dramatic changes that occur in the first few minutes of life.
Thermoregulation Thermoregulation involves a balance between heat production and heat loss. The foetus maintains a temperature approximately 0.5 1C above the maternal temperature.1 Foetal heat production results from normal metabolic processes occurring at a rate much higher than the adult metabolic rate. Heat loss from the foetus takes place mostly through the placenta and to some degree through the skin into the amniotic fluid.2 This heat loss in the foetus is less than that of a neonate because of the small temperature gradient from foetus to mother compared with the large temperature gradient from the neonate to the surrounding environment. The neonate’s wet skin produces extensive evaporative heat loss and the relative temperature of the air and equipment surrounding the infant cause heat loss through conduction and radiation. Movement of air in the delivery room increases heat loss through convection. The neonate therefore requires additional sources of heat production after birth. Humans and other homoeothermic animals regulate their individual body temperature within a small range over a large range of environmental temperatures. The centre for temperature regulation is the hypothalamus. Methods of regulating heat production include adjusting metabolic processes, shivering, and non-shivering thermogenesis. Heat loss may be modulated through vasoconstriction or vasodilation of cutaneous blood vessels and varying evaporative losses through sweating. Heat production in the neonate immediately after birth is largely reliant on the nonshivering thermogenesis, the heat production that occurs from lipolysis of brown adipose tissue.3 Although the foetus near term has the ability to produce heat through this mechanism, it is generally inhibited in utero.4,5 After delivery the exposure to cold air and oxygen stimulate the sympathetic nervous system to release norepinephrine which acts on the brown adipocytes to activate adenyl cyclase.6 An increase in cytoplasmic cyclic adenosine monophosphate (cAMP) causes phosphorylation of hormone sensitive lipase that initiates lipolysis and energy production.7 An intracellular uncoupling protein, thermogenin or UCP1, the production of which is also upregulated by the increase in cytoplasmic cAMP, is necessary for the release of
T.A. Leone, N.N. Finer energy as heat during lipolysis.8 These processes are inhibited by prostaglandin E2 and adenosine through downregulation of the adenyl cyclase and a decrease in cytoplasmic cAMP. Prostaglandin E2 and adenosine are produced in the placenta and their levels decrease significantly after the umbilical cord is clamped. These substances are therefore thought to be inhibitors of nonshivering thermogenesis in utero.9,10 Thyroid hormone is utilised during brown adipose tissue development and facilitates an individual’s response to cold through modulation of the catecholamine response and UCP production.11,12 Newborns maintain a similar core body temperature as adults but can only do so within a more limited range of environmental temperatures. An adult can generate adequate heat to prevent hypothermia in environmental temperatures as low as 5 1C whereas a neonate only generates adequate heat for survival in a minimum environmental temperature of 23 1C.13 Preterm infants have more difficulty with thermoregulation than term neonates for several reasons, including immature skin leading to increased evaporative heat loss, decreased brown adipose tissue stores, and decreased thermogenin production.14,15 Hypothermia in the very preterm infant has been associated with decreased survival.16 Therefore careful attention to temperature regulation in preterm infants with use of servocontrolled radiant warmers and incubators and the use of barriers to heat loss is essential to neonatal intensive care.17
Gas exchange The placenta rather than the lungs is the site of foetal oxygenation and carbon dioxide elimination. Maternal blood is delivered to the placenta via the uterine arteries and ultimately closely approximates the foetal blood separated by a placental barrier in the terminal villi. Oxygen and carbon dioxide are exchanged between the maternal and foetal circulations by diffusion across this barrier. The delivery of oxygen to the foetus is affected by numerous factors including blood flow to the uterus, placenta and foetus, concentrations of haemoglobin present, relative pressures of gases in the two circulations, and properties of the placental diffusion barrier.18,19 The foetus maintains arterial oxygen tension much lower than that of the neonate or adult at levels of approximately 20–35 mmHg.20 Several factors allow the foetus to exist in these conditions which at other times of life would be considered hypoxemic. The most important of these are the type and properties of haemoglobin and the relatively increased foetal cardiac output compared with adult cardiac output. Foetal haemoglobin has a greater affinity for oxygen binding than adult haemoglobin thereby enhancing uptake of oxygen to haemoglobin causing foetal blood to have a higher oxyhemoglobin saturation than adult blood at a given oxygen tension with foetal P50 (the PaO2 at which haemoglobin is 50% saturated) of 19 mmHg compared with 27 mmHg for adult haemoglobin.21 The average foetal oxyhemoglobin saturation as measured in foetal lambs is approximately 50%22 but ranges in different sites within the foetal circulation between values of 20% and 80%.23 During labour foetal oxygenation may be compromised for various reasons and foetal oxygen saturation via pulse oximetry (SpO2) has
ARTICLE IN PRESS Foetal adaptation at birth been used to evaluate foetal well-being in the intrapartum period. A foetal SpO2 of o30% during labour, the level that is associated with acidosis in foetal lambs, is considered concerning.24 After birth the neonatal lungs become inflated with air by processes described in the following section and the lungs become the site of gas exchange. During foetal existence, pulmonary blood flow is o12% of total cardiac output, but this amount increases dramatically after birth. Blood in the pulmonary capillaries is exposed to levels of oxygen present in the alveoli corresponding to the fraction of inspired oxygen of the air the infant is breathing. Oxygen travels across the alveolar-capillary membranes via diffusion and is transferred to blood in the pulmonary vessels increasing the oxygen saturation of blood in the pulmonary venous return. A greater proportion of the cardiac output is now delivered to the lungs (eventually the entire cardiac output) allowing more blood to become oxygenated and increasing the neonatal arterial oxygen tension. When pulse oximetry is used to evaluate neonatal oxygenation in the first few minutes of life, SpO2 is found to gradually increase over 5–15 min of life with average levels of approximately 60% at 1 min of life, 80–90% at 5 min of life.25–27 A pre- and postductal gradient of 5–10% is seen in the first 10–15 min of life. Carbon dioxide produced from metabolic processes travels dissolved in blood in both the foetus and neonate. It is then excreted from foetal blood by diffusion across the placenta down the small concentration gradient between foetal and maternal carbon dioxide tensions. Maternal hyperventilation causes increased carbon dioxide excretion from the foetus by this route and can lead to foetal hypocarbia. After birth a transient increase in carbon dioxide tension in foetal blood results as the neonate begins breathing air and utilising the newly inflated lungs for gas exchange.
Effective breathing and pulmonary inflation Breathing movements are made by the foetus from approximately midway through gestation. However, these movements are intermittent and not used for respiration as gas exchange occurs in the placenta. Foetal breathing takes place in periodic episodes for approximately 20 min of each hour though the amount of time varies with gestational age. Severe hypoxaemia and acidosis suppress breathing movements,28 and in fact appropriate foetal breathing is a sign of foetal well-being evaluated as part of the standard biophysical profile used in perinatology.29 The onset of continuous breathing after birth has been studied in foetal sheep in an attempt to determine the factors that influence the change from episodic breathing to continuous breathing. The contribution of several mechanisms to the promotion of continuous breathing have been evaluated including sensory stimulation and cooling of the skin, changes in the arterial oxygen and carbon dioxide levels, and the detachment of the placenta.30 Foetal sheep exposed to skin cooling have responded with increased respiratory muscle movement.31 After birth a transient increase in PCO2 has been observed in neonatal lambs.32 Peripheral and central chemoreceptors respond to an
375 increased PCO2 by increasing ventilation though the levels of carbon dioxide at which chemoreceptors respond may be different after birth.33 The role of inhibitors of respiration, such as prostaglandin E2 and adenosine, produced by the placenta has been evaluated.34 In sheep experiments in which the umbilical cord is clamped and all other parameters are held constant, foetal sheep initiate continuous breathing movements when the umbilical cord is temporarily occluded and cease continuous breathing when the occlusion is released.35 Kuipers and co-workers evaluated breathing activity in foetal lambs in relation to changes in temperature, carbon dioxide levels, and umbilical cord occlusion.36 These investigators found that breathing activity increased mostly in response to increased carbon dioxide and decreased temperature but not in response to umbilical cord occlusion. Effective respiration after birth requires not only the onset of continuous breathing but the replacement of foetal lung fluid with air in the neonatal lung. Foetal lung fluid is produced by the pulmonary epithelial cells and is high in chloride but low in bicarbonate and protein.37 This fluid in utero flows out from the lung via the trachea to be swallowed by the foetus or mixed with amniotic fluid. The presence of foetal lung fluid within the forming air spaces is associated with progressive lung development.38 Foetuses with tracheal obstruction have increased lung size compared with foetuses whose lung fluid is allowed to flow out of the lung unimpeded. In fact artificial tracheal occlusion has been attempted as a method of increasing pulmonary development in foetuses with congenital diaphragmatic hernia to alleviate the pulmonary hypoplasia associated with this disorder. However, this therapy has not been shown to significantly improve outcome for these infants.39 The clearance of foetal lung fluid is a multi-step process, which begins before birth with decreased lung fluid production and increased absorption, and continues after birth with absorption into the interstitial spaces followed by uptake into the bloodstream and lymphatics.40,41 The normal volume of foetal lung fluid present near term is approximately 20 ml/kg, and this volume decreases just before birth leaving approximately 6 ml/kg of lung fluid to be cleared after birth.42 Absorption of lung fluid seems to be mediated by an increase in interstitial protein and sodium concentrations relative to the lung fluid, which creates an osmotic gradient encouraging fluid absorption.43 Spontaneous labour has also been found to be an important factor in the facilitation of foetal lung fluid clearance.44 As the infant begins breathing after birth and the residual lung fluid is replaced with air, surfactant present in the lung allows a small amount of air to remain in the lungs upon exhalation. This air is known as the functional residual capacity (FRC) and is critical to the development of effective respiration. Without surfactant the alveoli will become completely deflated and will require increasing levels of pressure to re-open, which may lead to lung injury. A healthy newborn when taking the first breaths after birth exerts a negative intrathoracic pressure of approximately 50 cm H2O,45,46 and with adequate surfactant supply will develop an FRC of approximately 5–6 ml/kg. When assisted ventilation is required to initiate respiration, inspiratory pressures of 30 cm H2O are generally recommended. For the infant who is not making spontaneous respiratory effort or
ARTICLE IN PRESS 376 who has significantly diseased lungs substantially higher pressures may be required. Alternately maintaining an even inspiratory pressure over several seconds may be used in an effort to develop FRC without using higher inspiratory pressures.47 Ideally assisted ventilation breaths will stimulate Head’s paradoxical reflex to cause the infant to initiate spontaneous breathing. This reflex distension of large airway stretch receptors via the vagus nerve enhances respiration with increased lung inflation. The newborn develops a more consistent and regular breathing pattern over the first several hours of life. Lung fluid is generally cleared within the first several hours of life and FRC is well established within the first few minutes of life. If any of these events do not occur as expected the newborn will develop signs of respiratory distress and may require assistance with ventilation. The presence of acidemia inhibits breathing so that an infant who has suffered an insult leading to acidemia will present at birth with apnoea. The evaluation of breathing during neonatal resuscitation is essential to determining neonatal well-being, and the provision of assisted ventilation when necessary is a critical skill required for all providers of neonatal care.
Circulation The circulatory changes that occur with birth may be the most dramatic of all the physiologic transitions the foetus must accomplish. Because foetal gas exchange occurs in the placenta, foetal circulation must allow deoxygenated blood to travel to the placenta (via the aorta) and oxygenated blood must be returned to the heart (via the inferior vena cava (IVC)) for distribution to critical organs. Foetal circulation is characterised by a low systemic vascular resistance because of the presence of the large low resistance placental vascular bed. In contrast the foetal pulmonary vascular resistance is high allowing only approximately 6–12% of the foetal cardiac output to travel to the lungs.48–50 The high foetal pulmonary vascular resistance is likely maintained by local levels of vasoactive substances such as leukotrienes and endothelin 1.51,52 The route of blood as it returns to the foetus from the placenta via the umbilical vein is described below. The oxygenated, nourished, and detoxified blood from the placenta travels through the umbilical vein and is split with half-traveling to the liver via the portal vein and half-bypassing the liver via the ductus venosus and entering the IVC just as it is about to enter the right atrium. The IVC is also carrying deoxygenated blood that is returning to the heart from the lower body. The right atrium receives blood from the IVC and the superior vena cava (SVC), which carries deoxygenated blood from the upper body. Once in the right atrium the most oxygenated blood from the placenta and thus the IVC is directed with the help of the Eustachian valve towards the foramen ovale into the left atrium where it will then travel to the left ventricle and out the aorta. This most oxygenated blood then supplies the myocardium via the coronary arteries and the brain and upper body via the aortic arch and its branch arteries (including carotid arteries).53 The deoxygenated blood that enters the right atrium from the SVC and IVC is directed towards the right ventricle where it exits via the pulmonary trunk. A small
T.A. Leone, N.N. Finer amount of this blood from the pulmonary trunk travels to the lungs while most of this blood is shunted through the ductus arteriosus into the descending aorta and to the placenta for reoxygenation, detoxification and nutrition acquisition. Some of the blood from the aorta also supplies the lower body. With birth the systemic vascular resistance increases with the removal of the placenta and the pulmonary vascular resistance decreases via several mechanisms. Among the mechanisms involved in decreasing pulmonary vascular resistance are changes in the local levels and action of vasoactive substances from a predominantly vasoconstricted state to a predominantly vasodilated state. Endogenous nitric oxide is one of the most important vasodilators acting to reduce pulmonary vascular resistance. Mechanical forces from lung inflation and increased arterial oxygen tension also decrease pulmonary vascular resistance and consequently increase pulmonary blood flow. The right ventricular output becomes directed entirely to the lung. Once systemic vascular resistance increases to greater than pulmonary vascular resistance any blood flow through the ductus arteriosus will travel from the systemic towards the pulmonary side (‘left to right’). As the pulmonary blood flow increases, the pulmonary venous return to the left atrium increases causing increased pressure in the left atrium and decreased blood flow across the foramen ovale. This increased blood flow into the left atrium also causes increased preloading of the left ventricle increasing left ventricular output. Because of the presence of the ductus arteriosus and the foramen ovale, the blood from the systemic and pulmonary circulations is mixed throughout prenatal life. When evaluating cardiac output in the presence of these shunts it is necessary to consider the output of both ventricles. Therefore, the evaluation of cardiac output in utero is known as the combined ventricular output. Following delivery, blood flow through the ductus arteriosus decreases over hours and is usually absent by 3 days of life.54,55 However, anatomic closure of the ductus arteriosus occurs over approximately 2 weeks after birth. The foramen ovale may remain patent for years, although blood flow across this structure is usually minimal within the first few days of life. It is necessary to remember that these shunts may be present in the first few days of life and therefore the evaluation of cardiac output postnatally may be confounded by the presence of these shunts. The preterm infant is much more likely to maintain a patent ductus arteriosus postnatally causing variations in blood flow patterns with potential adverse consequences for the infant. Although the greatest decrease in pulmonary vascular resistance occurs within the first few minutes of life, a remodelling of the pulmonary vasculature further decreases the pulmonary vascular resistance over the next few days to weeks of life. When the pulmonary vascular resistance does not decrease as expected in early postnatal life the infant will not have the normal increase in postnatal pulmonary blood flow, and may continue to have some degree of right to left shunting across the foramen ovale or ductus arteriosus leading to systemic hypoxaemia and serious illness. This entity, currently known as persistent pulmonary hypertension of the newborn, can occur as a primary disorder but most frequently occurs in the presence of
ARTICLE IN PRESS Foetal adaptation at birth another pulmonary insult such as meconium aspiration syndrome, pneumonia, or pulmonary hypoplasia. The knowledge of the expected normal cardiovascular changes in the first days of life can help the clinician recognise a sick infant. By closely clinically evaluating normal infants in the immediate prenatal and first postnatal day of life, Desmond et al.56 found that the foetal heart rate decreased briefly just prior to delivery and was then irregular immediately after delivery. By 2–3 min of life the heart rate became regular at a slightly elevated level (approximately 180 beats/min) and then began decreasing to 140 beats/min or less by 30 min of life. These investigators also noted that the heart rate was somewhat unresponsive to activity in the first 2–3 h of life but then developed typical variability with activity.
Conclusions It is clear that the multiple physiologic adaptations that occur around the time of birth are complex and critical for survival. It is remarkable that most neonates pass through this transition without any significant problem. However, for those infants who have difficulty during this complex transition, prompt recognition and appropriate action will save lives and decrease morbidity.
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ARTICLE IN PRESS 378 34. Adamson SL, Kuipers IM, Olson DM. Umbilical cord occlusion stimulates breathing independent of blood gases and pH. J Appl Physiol 1991;70:1796–809. 35. Adamson SL, Richardson BS, Homan J. Initiation of pulmonary gas exchange by fetal sheep in utero. J Appl Physiol 1987;62:989–98. 36. Kuipers IM, Maertzdorf WJ, de Jong DS, Hanson MA, Blanco CE. Initiation of maintenance of continuous breathing at birth. Pediatr Res 1997;42:163–8. 37. Adamson TM, Boyd RDH, Platt HS, Strang LB. Composition of alveolar liquid in the foetal lamb. J Physiol 1969; 204:159–68. 38. Alcorn D, Adamson TM, Lambert TF, Maloney JE, Ritchie BC, Robinson PM. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat 1977;123:649–60. 39. Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916–24. 40. Kitterman JA, Ballard PL, Clements JA, Mescher EJ, Tooley WH. Tracheal fluid in fetal lambs: spontaneous decrease prior to birth. J Appl Physiol 1979;47:985–9. 41. Bland RD. Lung liquid clearance before and after birth. Semin Perinatol 1988;12:124–33. 42. Dickson KA, Maloney JE, Berger PJ. Decline in lung liquid volume before labor in fetal lambs. J Appl Physiol 1986;61:2266–72. 43. Pitkanen O. Lung epithelial ion transport in neonatal lung disease. Biol Neonate 2001;80(Suppl 1):14–7. 44. Bland RD, Bressack MA, McMillan DD. Labor decreases the lung water content of newborn rabbits. Am J Obstet Gynecol 1979;135:364–7.
T.A. Leone, N.N. Finer 45. Milner AD. Resuscitation at birth. Eur J Pediatr 1998;157:524–7. 46. Vyas H, Field D, Milner AD, Hopkin IE. Determinants of the first inspiratory volume and functional residual capacity at birth. Pediatr Pulmonol 1986;2:189–93. 47. Vyas H, Milner AD, Hopkin IE, Boon AW. Physiologic responses to prolonged and slow rise inflation. J Pediatr 1981;99:635–9. 48. Anderson DF, Bissonnette JM, Faber JJ, Thornburg KL. Central shunt flows and pressures in the mature fetal lamb. Am J Physiol 1981;241:H60–6. 49. Iwamoto HS, Teitel D, Rudoph AM. Effects of birth-related events on blood flow distribution. Pediatr Res 1987;22:634–40. 50. Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001;103:1662–8. 51. Ivy DD, LeCras TD, Parker TA, Zenge JP, Jakkula M, Markham NE, et al. Developmental changes in endothelin expression and activity in the ovine fetal lung. Am J Physiol Lung Cell Mol Physiol 2000;278:L785–93. 52. Soifer SJ, Loitz RD, Roman C, Heymann MA. Leukotriene end organ antagonists increase pulmonary blood flow in fetal lambs. Am J Physiol 1985;249:H570–6. 53. Edelstone DI, Rudolph AM. Preferential streaming of the ductus venosus blood to the brain and heart in fetal lambs. Am J Physiol 1979;237:H724–9. 54. Clyman RI. Mechanisms regulating closure of the ductus arteriosus. In: Polin RA, Fox WW, Abman SH, editors. Fetal and neonatal physiology. 3rd ed. Philadelphia, PA: Saunders; 2004. p. 743–8. 55. Evans NJ, Archer LN. Postnatal circulatory adaptation in healthy term and preterm neonates. Arch Dis Child 1990;65:24–6. 56. Desmond MM, Franklin RR, Vallbona C, et al. The clinical behavior of the newly born. J Pediatr 1963;62:307–25.
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/cupe
Foetal adaptation at birth Tina A. Leone, Neil N. Finer Department of Neonatology, University of California, 200 W. Arbor Dr. MC 8774, San Diego, CA 92103, USA
KEYWORDS Neonatal transition; Foetal adaptation; Foetal physiology; Neonatal physiology
Summary The immediate newborn period is a critical time for an individual as the transition is made from foetal to neonatal life. The separation of the neonate from the mother and the placenta requires many physiologic adjustments necessary for survival in a completely new environment. Among the processes necessary for a smooth transition to neonatal life are the initiation of continuous breathing and pulmonary gas exchange, alteration of the circulatory pattern, and regulation of temperature in a cold environment. All clinicians caring for newborns must understand the expected course of these adaptations and be able to recognise when the transition is not occurring appropriately. With the identification of difficulties occurring during transition the clinician may institute interventions in a timely manner. & 2006 Published by Elsevier Ltd.
Introduction Practice points
Transition from foetal to neonatal life is a complex multi-organ system process
The preterm infant may have more difficulty with some aspects of the transition than the term infant
Temperature regulation, breathing, pulmonary gas exchange, and altered circulatory patterns are essential components of the transition process and should be monitored in the immediate newborn period
Corresponding author. Tel.: +1 619 543 3759;
fax: +1 619 543 3812. E-mail address: [email protected] (T.A. Leone). 0957-5839/$ - see front matter & 2006 Published by Elsevier Ltd. doi:10.1016/j.cupe.2006.08.005
Foetal physiology is distinct from that of adults or infants in many ways, and enables the foetus to exist and thrive in the uterine environment. At birth a neonate must make several adjustments in order to survive in a completely new environment. The physiologic processes necessary to accomplish this transition smoothly are complex and involve various adjustments of multiple organ systems, which are often interrelated. When the transition does not occur smoothly the newborn infant can become seriously ill. Some of the adaptations made by a neonate in the first few minutes of life are visible to an astute observer. The practice of neonatal resuscitation establishes a routine of early evaluation of the transition process and allows for provision of interventions to assist the infant with elements of the transition as necessary. The placenta is the foundation of foetal existence providing for constant nutrient access and gas exchange allowing the foetus to develop in a protected, fluid-filled compartment. When the placenta is removed and the
ARTICLE IN PRESS 374 neonate is transferred to an extra-uterine environment many of the processes that made foetal life possible are irreversibly altered and the newborn must immediately adapt to extra-uterine existence. Some of the necessary adjustments include, but are not limited to, developing adequate thermoregulation, establishing continuous breathing and pulmonary gas exchange, altering the route of circulation, and existing without a constant nutrient supply. The ability to make these adjustments is less reliable in preterm infants and therefore more support is frequently required in more immature infants. Much of the information known about foetal transition to neonatal life has come from research using animal models to evaluate the contribution of different mechanisms. This review will examine the physiologic processes of transition from foetal to newborn life with emphasis on the dramatic changes that occur in the first few minutes of life.
Thermoregulation Thermoregulation involves a balance between heat production and heat loss. The foetus maintains a temperature approximately 0.5 1C above the maternal temperature.1 Foetal heat production results from normal metabolic processes occurring at a rate much higher than the adult metabolic rate. Heat loss from the foetus takes place mostly through the placenta and to some degree through the skin into the amniotic fluid.2 This heat loss in the foetus is less than that of a neonate because of the small temperature gradient from foetus to mother compared with the large temperature gradient from the neonate to the surrounding environment. The neonate’s wet skin produces extensive evaporative heat loss and the relative temperature of the air and equipment surrounding the infant cause heat loss through conduction and radiation. Movement of air in the delivery room increases heat loss through convection. The neonate therefore requires additional sources of heat production after birth. Humans and other homoeothermic animals regulate their individual body temperature within a small range over a large range of environmental temperatures. The centre for temperature regulation is the hypothalamus. Methods of regulating heat production include adjusting metabolic processes, shivering, and non-shivering thermogenesis. Heat loss may be modulated through vasoconstriction or vasodilation of cutaneous blood vessels and varying evaporative losses through sweating. Heat production in the neonate immediately after birth is largely reliant on the nonshivering thermogenesis, the heat production that occurs from lipolysis of brown adipose tissue.3 Although the foetus near term has the ability to produce heat through this mechanism, it is generally inhibited in utero.4,5 After delivery the exposure to cold air and oxygen stimulate the sympathetic nervous system to release norepinephrine which acts on the brown adipocytes to activate adenyl cyclase.6 An increase in cytoplasmic cyclic adenosine monophosphate (cAMP) causes phosphorylation of hormone sensitive lipase that initiates lipolysis and energy production.7 An intracellular uncoupling protein, thermogenin or UCP1, the production of which is also upregulated by the increase in cytoplasmic cAMP, is necessary for the release of
T.A. Leone, N.N. Finer energy as heat during lipolysis.8 These processes are inhibited by prostaglandin E2 and adenosine through downregulation of the adenyl cyclase and a decrease in cytoplasmic cAMP. Prostaglandin E2 and adenosine are produced in the placenta and their levels decrease significantly after the umbilical cord is clamped. These substances are therefore thought to be inhibitors of nonshivering thermogenesis in utero.9,10 Thyroid hormone is utilised during brown adipose tissue development and facilitates an individual’s response to cold through modulation of the catecholamine response and UCP production.11,12 Newborns maintain a similar core body temperature as adults but can only do so within a more limited range of environmental temperatures. An adult can generate adequate heat to prevent hypothermia in environmental temperatures as low as 5 1C whereas a neonate only generates adequate heat for survival in a minimum environmental temperature of 23 1C.13 Preterm infants have more difficulty with thermoregulation than term neonates for several reasons, including immature skin leading to increased evaporative heat loss, decreased brown adipose tissue stores, and decreased thermogenin production.14,15 Hypothermia in the very preterm infant has been associated with decreased survival.16 Therefore careful attention to temperature regulation in preterm infants with use of servocontrolled radiant warmers and incubators and the use of barriers to heat loss is essential to neonatal intensive care.17
Gas exchange The placenta rather than the lungs is the site of foetal oxygenation and carbon dioxide elimination. Maternal blood is delivered to the placenta via the uterine arteries and ultimately closely approximates the foetal blood separated by a placental barrier in the terminal villi. Oxygen and carbon dioxide are exchanged between the maternal and foetal circulations by diffusion across this barrier. The delivery of oxygen to the foetus is affected by numerous factors including blood flow to the uterus, placenta and foetus, concentrations of haemoglobin present, relative pressures of gases in the two circulations, and properties of the placental diffusion barrier.18,19 The foetus maintains arterial oxygen tension much lower than that of the neonate or adult at levels of approximately 20–35 mmHg.20 Several factors allow the foetus to exist in these conditions which at other times of life would be considered hypoxemic. The most important of these are the type and properties of haemoglobin and the relatively increased foetal cardiac output compared with adult cardiac output. Foetal haemoglobin has a greater affinity for oxygen binding than adult haemoglobin thereby enhancing uptake of oxygen to haemoglobin causing foetal blood to have a higher oxyhemoglobin saturation than adult blood at a given oxygen tension with foetal P50 (the PaO2 at which haemoglobin is 50% saturated) of 19 mmHg compared with 27 mmHg for adult haemoglobin.21 The average foetal oxyhemoglobin saturation as measured in foetal lambs is approximately 50%22 but ranges in different sites within the foetal circulation between values of 20% and 80%.23 During labour foetal oxygenation may be compromised for various reasons and foetal oxygen saturation via pulse oximetry (SpO2) has
ARTICLE IN PRESS Foetal adaptation at birth been used to evaluate foetal well-being in the intrapartum period. A foetal SpO2 of o30% during labour, the level that is associated with acidosis in foetal lambs, is considered concerning.24 After birth the neonatal lungs become inflated with air by processes described in the following section and the lungs become the site of gas exchange. During foetal existence, pulmonary blood flow is o12% of total cardiac output, but this amount increases dramatically after birth. Blood in the pulmonary capillaries is exposed to levels of oxygen present in the alveoli corresponding to the fraction of inspired oxygen of the air the infant is breathing. Oxygen travels across the alveolar-capillary membranes via diffusion and is transferred to blood in the pulmonary vessels increasing the oxygen saturation of blood in the pulmonary venous return. A greater proportion of the cardiac output is now delivered to the lungs (eventually the entire cardiac output) allowing more blood to become oxygenated and increasing the neonatal arterial oxygen tension. When pulse oximetry is used to evaluate neonatal oxygenation in the first few minutes of life, SpO2 is found to gradually increase over 5–15 min of life with average levels of approximately 60% at 1 min of life, 80–90% at 5 min of life.25–27 A pre- and postductal gradient of 5–10% is seen in the first 10–15 min of life. Carbon dioxide produced from metabolic processes travels dissolved in blood in both the foetus and neonate. It is then excreted from foetal blood by diffusion across the placenta down the small concentration gradient between foetal and maternal carbon dioxide tensions. Maternal hyperventilation causes increased carbon dioxide excretion from the foetus by this route and can lead to foetal hypocarbia. After birth a transient increase in carbon dioxide tension in foetal blood results as the neonate begins breathing air and utilising the newly inflated lungs for gas exchange.
Effective breathing and pulmonary inflation Breathing movements are made by the foetus from approximately midway through gestation. However, these movements are intermittent and not used for respiration as gas exchange occurs in the placenta. Foetal breathing takes place in periodic episodes for approximately 20 min of each hour though the amount of time varies with gestational age. Severe hypoxaemia and acidosis suppress breathing movements,28 and in fact appropriate foetal breathing is a sign of foetal well-being evaluated as part of the standard biophysical profile used in perinatology.29 The onset of continuous breathing after birth has been studied in foetal sheep in an attempt to determine the factors that influence the change from episodic breathing to continuous breathing. The contribution of several mechanisms to the promotion of continuous breathing have been evaluated including sensory stimulation and cooling of the skin, changes in the arterial oxygen and carbon dioxide levels, and the detachment of the placenta.30 Foetal sheep exposed to skin cooling have responded with increased respiratory muscle movement.31 After birth a transient increase in PCO2 has been observed in neonatal lambs.32 Peripheral and central chemoreceptors respond to an
375 increased PCO2 by increasing ventilation though the levels of carbon dioxide at which chemoreceptors respond may be different after birth.33 The role of inhibitors of respiration, such as prostaglandin E2 and adenosine, produced by the placenta has been evaluated.34 In sheep experiments in which the umbilical cord is clamped and all other parameters are held constant, foetal sheep initiate continuous breathing movements when the umbilical cord is temporarily occluded and cease continuous breathing when the occlusion is released.35 Kuipers and co-workers evaluated breathing activity in foetal lambs in relation to changes in temperature, carbon dioxide levels, and umbilical cord occlusion.36 These investigators found that breathing activity increased mostly in response to increased carbon dioxide and decreased temperature but not in response to umbilical cord occlusion. Effective respiration after birth requires not only the onset of continuous breathing but the replacement of foetal lung fluid with air in the neonatal lung. Foetal lung fluid is produced by the pulmonary epithelial cells and is high in chloride but low in bicarbonate and protein.37 This fluid in utero flows out from the lung via the trachea to be swallowed by the foetus or mixed with amniotic fluid. The presence of foetal lung fluid within the forming air spaces is associated with progressive lung development.38 Foetuses with tracheal obstruction have increased lung size compared with foetuses whose lung fluid is allowed to flow out of the lung unimpeded. In fact artificial tracheal occlusion has been attempted as a method of increasing pulmonary development in foetuses with congenital diaphragmatic hernia to alleviate the pulmonary hypoplasia associated with this disorder. However, this therapy has not been shown to significantly improve outcome for these infants.39 The clearance of foetal lung fluid is a multi-step process, which begins before birth with decreased lung fluid production and increased absorption, and continues after birth with absorption into the interstitial spaces followed by uptake into the bloodstream and lymphatics.40,41 The normal volume of foetal lung fluid present near term is approximately 20 ml/kg, and this volume decreases just before birth leaving approximately 6 ml/kg of lung fluid to be cleared after birth.42 Absorption of lung fluid seems to be mediated by an increase in interstitial protein and sodium concentrations relative to the lung fluid, which creates an osmotic gradient encouraging fluid absorption.43 Spontaneous labour has also been found to be an important factor in the facilitation of foetal lung fluid clearance.44 As the infant begins breathing after birth and the residual lung fluid is replaced with air, surfactant present in the lung allows a small amount of air to remain in the lungs upon exhalation. This air is known as the functional residual capacity (FRC) and is critical to the development of effective respiration. Without surfactant the alveoli will become completely deflated and will require increasing levels of pressure to re-open, which may lead to lung injury. A healthy newborn when taking the first breaths after birth exerts a negative intrathoracic pressure of approximately 50 cm H2O,45,46 and with adequate surfactant supply will develop an FRC of approximately 5–6 ml/kg. When assisted ventilation is required to initiate respiration, inspiratory pressures of 30 cm H2O are generally recommended. For the infant who is not making spontaneous respiratory effort or
ARTICLE IN PRESS 376 who has significantly diseased lungs substantially higher pressures may be required. Alternately maintaining an even inspiratory pressure over several seconds may be used in an effort to develop FRC without using higher inspiratory pressures.47 Ideally assisted ventilation breaths will stimulate Head’s paradoxical reflex to cause the infant to initiate spontaneous breathing. This reflex distension of large airway stretch receptors via the vagus nerve enhances respiration with increased lung inflation. The newborn develops a more consistent and regular breathing pattern over the first several hours of life. Lung fluid is generally cleared within the first several hours of life and FRC is well established within the first few minutes of life. If any of these events do not occur as expected the newborn will develop signs of respiratory distress and may require assistance with ventilation. The presence of acidemia inhibits breathing so that an infant who has suffered an insult leading to acidemia will present at birth with apnoea. The evaluation of breathing during neonatal resuscitation is essential to determining neonatal well-being, and the provision of assisted ventilation when necessary is a critical skill required for all providers of neonatal care.
Circulation The circulatory changes that occur with birth may be the most dramatic of all the physiologic transitions the foetus must accomplish. Because foetal gas exchange occurs in the placenta, foetal circulation must allow deoxygenated blood to travel to the placenta (via the aorta) and oxygenated blood must be returned to the heart (via the inferior vena cava (IVC)) for distribution to critical organs. Foetal circulation is characterised by a low systemic vascular resistance because of the presence of the large low resistance placental vascular bed. In contrast the foetal pulmonary vascular resistance is high allowing only approximately 6–12% of the foetal cardiac output to travel to the lungs.48–50 The high foetal pulmonary vascular resistance is likely maintained by local levels of vasoactive substances such as leukotrienes and endothelin 1.51,52 The route of blood as it returns to the foetus from the placenta via the umbilical vein is described below. The oxygenated, nourished, and detoxified blood from the placenta travels through the umbilical vein and is split with half-traveling to the liver via the portal vein and half-bypassing the liver via the ductus venosus and entering the IVC just as it is about to enter the right atrium. The IVC is also carrying deoxygenated blood that is returning to the heart from the lower body. The right atrium receives blood from the IVC and the superior vena cava (SVC), which carries deoxygenated blood from the upper body. Once in the right atrium the most oxygenated blood from the placenta and thus the IVC is directed with the help of the Eustachian valve towards the foramen ovale into the left atrium where it will then travel to the left ventricle and out the aorta. This most oxygenated blood then supplies the myocardium via the coronary arteries and the brain and upper body via the aortic arch and its branch arteries (including carotid arteries).53 The deoxygenated blood that enters the right atrium from the SVC and IVC is directed towards the right ventricle where it exits via the pulmonary trunk. A small
T.A. Leone, N.N. Finer amount of this blood from the pulmonary trunk travels to the lungs while most of this blood is shunted through the ductus arteriosus into the descending aorta and to the placenta for reoxygenation, detoxification and nutrition acquisition. Some of the blood from the aorta also supplies the lower body. With birth the systemic vascular resistance increases with the removal of the placenta and the pulmonary vascular resistance decreases via several mechanisms. Among the mechanisms involved in decreasing pulmonary vascular resistance are changes in the local levels and action of vasoactive substances from a predominantly vasoconstricted state to a predominantly vasodilated state. Endogenous nitric oxide is one of the most important vasodilators acting to reduce pulmonary vascular resistance. Mechanical forces from lung inflation and increased arterial oxygen tension also decrease pulmonary vascular resistance and consequently increase pulmonary blood flow. The right ventricular output becomes directed entirely to the lung. Once systemic vascular resistance increases to greater than pulmonary vascular resistance any blood flow through the ductus arteriosus will travel from the systemic towards the pulmonary side (‘left to right’). As the pulmonary blood flow increases, the pulmonary venous return to the left atrium increases causing increased pressure in the left atrium and decreased blood flow across the foramen ovale. This increased blood flow into the left atrium also causes increased preloading of the left ventricle increasing left ventricular output. Because of the presence of the ductus arteriosus and the foramen ovale, the blood from the systemic and pulmonary circulations is mixed throughout prenatal life. When evaluating cardiac output in the presence of these shunts it is necessary to consider the output of both ventricles. Therefore, the evaluation of cardiac output in utero is known as the combined ventricular output. Following delivery, blood flow through the ductus arteriosus decreases over hours and is usually absent by 3 days of life.54,55 However, anatomic closure of the ductus arteriosus occurs over approximately 2 weeks after birth. The foramen ovale may remain patent for years, although blood flow across this structure is usually minimal within the first few days of life. It is necessary to remember that these shunts may be present in the first few days of life and therefore the evaluation of cardiac output postnatally may be confounded by the presence of these shunts. The preterm infant is much more likely to maintain a patent ductus arteriosus postnatally causing variations in blood flow patterns with potential adverse consequences for the infant. Although the greatest decrease in pulmonary vascular resistance occurs within the first few minutes of life, a remodelling of the pulmonary vasculature further decreases the pulmonary vascular resistance over the next few days to weeks of life. When the pulmonary vascular resistance does not decrease as expected in early postnatal life the infant will not have the normal increase in postnatal pulmonary blood flow, and may continue to have some degree of right to left shunting across the foramen ovale or ductus arteriosus leading to systemic hypoxaemia and serious illness. This entity, currently known as persistent pulmonary hypertension of the newborn, can occur as a primary disorder but most frequently occurs in the presence of
ARTICLE IN PRESS Foetal adaptation at birth another pulmonary insult such as meconium aspiration syndrome, pneumonia, or pulmonary hypoplasia. The knowledge of the expected normal cardiovascular changes in the first days of life can help the clinician recognise a sick infant. By closely clinically evaluating normal infants in the immediate prenatal and first postnatal day of life, Desmond et al.56 found that the foetal heart rate decreased briefly just prior to delivery and was then irregular immediately after delivery. By 2–3 min of life the heart rate became regular at a slightly elevated level (approximately 180 beats/min) and then began decreasing to 140 beats/min or less by 30 min of life. These investigators also noted that the heart rate was somewhat unresponsive to activity in the first 2–3 h of life but then developed typical variability with activity.
Conclusions It is clear that the multiple physiologic adaptations that occur around the time of birth are complex and critical for survival. It is remarkable that most neonates pass through this transition without any significant problem. However, for those infants who have difficulty during this complex transition, prompt recognition and appropriate action will save lives and decrease morbidity.
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