Seminars in Fetal & Neonatal Medicine (2006) 11, 166e173

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s i n y

Fetal-to-neonatal maladaptation
Sunil K. Sinha a,*, Steven M. Donn b
a

The James Cook University Hospital, University of Durham, Marton Road, Middlesborough TS4 3BW, UK Division of Neonatal-Perinatal Medicine, C.S. Mott Childrens Hospital, University of Michigan Health System, Ann Arbor, MI, USA

KEYWORDS
Fetal adaptations and maladaptations; Neonatal adaptations and maladaptations; Newborns

Summary Although the majority of newly born babies will establish normal respiratory and circulatory function without help, 1e2% might run into difculties because of a disturbance in the normal adaptive processes required for a smooth transition from intrauterine to extrauterine life. An understanding of the normal and abnormal perinatal physiology is important to appreciate the practical differences in the approach to caring for such babies, and also for avoiding actions that might be detrimental in the longer term. 2006 Elsevier Ltd. All rights reserved.

Introduction
Adaptation to extrauterine life, also referred to as transition, involves functional modications in virtually every organ and system of the body. The most crucial events are: (1) the conversion of the uid-lled lungs into a hollow organ distended with air and capable of gaseous exchange sufcient to support life, and the establishment of adulttype circulation; (2) the separation of the fetus from the stable thermal environment of the uterus; and (3) metabolic adaptation to extrauterine life. In fact, the event of birth tests the integrity of cardiorespiratory, thermal and metabolic homeostasis, and failure to adequately make these conversions (maladaptation) can lead, directly or indirectly, to death or severe disability. Therefore, any supportive care provided in the immediate newborn period must be based on an understanding of the pathophysiology of these homeostatic mechanisms.

Respiratory adaptation
Human lung development goes through pseudoglandular (5e17 weeks), canalicular (16e26 weeks), saccular (24e38 weeks) and nally alveolar (36 weekse2 years) stages. During intrauterine development, the fetal lungs are lled with liquid secreted by the pulmonary epithelium. The volume and rate at which the liquid is secreted into the fetal lungs are calibrated to maintain lung volume at about functional residual capacity, and are the major determinants of normal lung growth.1 In the hours preceding labour, lung uid secretion falls and the onset of labour normally stimulates the production of adrenaline by the fetus and thyrotrophin-releasing hormone by the mother, causing fetal pulmonary epithelial cells to begin reabsorption of uid from the alveolar spaces. Both maternal thyroxine and glucocorticoids augment adrenaline in effecting this change. After birth, there is an acceleration of active pulmonary uid absorption, and most is cleared from the full-term newborn lung within 2 h of commencing spontaneous breathing. This is achieved by the initiation of complex series of mechanical and ion transport events.2 With the

* Corresponding author. Tel./fax: C44 1642 854874. E-mail address: sunil.sinha@stees.nhs.uk (S.K. Sinha).

1744-165X/$ - see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2006.01.008

Fetal-to-neonatal maladaptation introduction of air into the lungs, an air/liquid interface, facilitated by surfactant, forms the alveolar lining. The physical properties of the surfactant lining are such that the surface tension effect at the air/liquid interface is minimised, facilitating alveolar expansion and preventing the collapse of small alveoli. Because the absorptive mechanism of the fetal lung develops during the latter part of gestation, infants who are born prematurely may have a limited ability to clear uid from their lungs and to maintain a normal functional residual capacity because of the lack of endogenous surfactant. Another important event necessary to maintain life is the transition from fetal respiratory activity to normal ventilation (establishment of spontaneous breathing) soon after birth, which is triggered by a series of tactile and thermal stimuli. In addition, central chemosensory mechanisms also play an important part both during fetal and neonatal life. The rst breaths are important in aerating the uid-lled lungs and a healthy term baby can generate a negative pressure between 0 and 100 cmH2O (3.9 and 9.8 kPa) to aerate the lungs for the rst time as air, like liquid, moves from a region of higher pressure to one of lower pressure. This pressure is 10e15 times greater than that needed for subsequent breathing, but is necessary to overcome the viscosity of uid lling the airways, the surface tension of the uid-lled lungs, and the elastic recoil and resistance of the chest wall, lungs and airways. Once the alveoli are aerated, breathing needs less effort, requiring minimal negative intrathoracic pressure to maintain a normal tidal volume (LaPlaces law). In the term infant, alveolar surface tension is stabilised by the surfactant released by distension and ventilation of the lungs. During spontaneous breathing, the driving pressure required to overcome elastic, air-ow resistive and inertial properties of the respiratory system is the result of intrapleural pressure (PIP) changes generated by the respiratory muscles. Factors that inuence the respiratory muscles and respiratory mechanics have an effect on how air ows into and out of the lungs. The process of spontaneous breathing generally occurs at about a third of total lung capacity, so that about twothirds of the total capacity is available as reserve. The capacity of the lungs can be represented in four different ways: total lung capacity, vital capacity, inspiratory capacity, and functional residual capacity (FRC). FRC is the volume of gas in the lung when the respiratory system is at rest at the end of a normal expiration and is in continuity with the airways. A normal FRC avails optimal lung mechanics and alveolar surface area for efcient ventilation and gas exchange. On transition, gas exchange takes place through an air/liquid interface of alveolar epithelium, with alveolar gas in one compartment (air) and blood in the other compartment (vascular). The physiological processes that facilitate the onset of postnatal pulmonary gas exchange include: (1) the effect of ventilation on reducing pulmonary vascular resistance; (2) the effect of a more alkaline pH on reducing pulmonary vascular resistance to facilitate pulmonary blood ow; (3) the effect of driving pressure and successful establishment of respiration during the rst few breaths to achieve an optimal FRC; and (4) the effect of driving pressure to maintain optimal tidal volume and achieve the lowest work of breathing.

167

Circulatory adaptation
The placenta is the organ of gas exchange in fetal life. The circulation is modied to accommodate placental perfusion and is designed so that fetal arterial blood with the greatest oxygen content supplies the heart and brain and less saturated blood passes to the lower part of the body and placenta. This is accomplished in utero by creating shunts, which favour the ow of blood in the direction of the placenta. Placental vascular resistance is very low, primarily as a result of the sinusoids. Conversely, pulmonary vascular resistance is appreciably elevated, owing to the collapsed state of the lungs and muscularisation of the pulmonary arterioles. Shunting of blood occurs through the fetal channels: the foramen ovale (a ap valve within the atrial septum) and the ductus arteriosus, which connects the pulmonary artery to the aorta. Oxygenated blood returning from the placenta through the umbilical vein enters the right atrium, from where, instead of being pumped to the lungs, some of it is directed across the foramen ovale, where it enters the left atrium and subsequently the aorta. The remainder enters the right ventricle, and is pumped through the pulmonary artery, where additional blood will cross the ductus arteriosus and enter the aorta distally (Fig. 1). Normally, there is a dramatic fall in pulmonary arteriolar resistance and an increase in pulmonary blood ow when the lungs are inated at birth. Thus, the fetal pulmonaryto-systemic pressure relationships are reversed and the systemic pressure becomes greater than the pulmonary pressure. With the decrease in pulmonary resistance associated with increased left atrial and decreased right atrial lling subsequent to clamping of the umbilical vein, the closure of the foramen ovale takes place. In the rst few days the pulmonary artery pressure falls with a concomitant increase in aortic pressure, which reverses the ow through the ductus arteriosus. This results in its closure. The shunt across the ductus venosus obliterates in the rst 3 weeks of life in term infants, although it might take longer in premature babies and in babies with pulmonary hypertension.3 This pulmonary-to-systemic pressure relationship is largely dependent on the reactivity of the pulmonary vascular bed. Hypoxia and acidosis, features of many different cardiac and respiratory diseases of the newborn, cause pulmonary arteriolar vasoconstriction, pulmonary hypertension, and reduced pulmonary blood ow. In these circumstances, pulmonary venous return to the left atrium is reduced, left atrial pressure falls, and right-to-left shunting of blood (instead of the normal left-to-right shunting) through the foramen ovale and patent ductus arteriosus is facilitated. The reactivity of the pulmonary vascular bed is an important phenomenon that inuences the magnitude and direction of shunts through fetal channels in the transitional period after birth.4,5 The above events related to cardiorespiratory adaptation highlight the series of biochemical and physiological processes that occur concurrently to successfully establish normal breathing and maintain the matching of ventilation to perfusion. It should be clear, therefore, that although much is made of the postnatal cardiovascular adaptation at

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S.K. Sinha, S.M. Donn

DV & IVC (69%) FORAMEN OVALE (48%)

PV (12%)

SVC (19%)

RIGHT VENTRICLE

LEFT VENTRICLE

PA 40%

AORTA

DA 28% BRAIN & SVC 19% DESCENDING AORTA 69%

LOWER LIMBS 23%

UMBILICAL ARTERIES 46%

Figure 1 Fetal circulation: schematic diagram showing right-to-left shunting. This facilitates movement of deoxygenated blood to the placenta, where gas exchange and removal of metabolic waste products occurs.

birth, it must always be viewed as a cardiorespiratory adaptation. In fact, the closure of the foramen ovale and ductus arteriosus are merely the logical outcome of changing from placental to pulmonary gas exchange. Aberrations in any of the above mechanisms may signicantly impair transition to adequate pulmonary gas exchange and can lead to either oxygenation or ventilation failure.

Metabolism
Glycogen stores in the fetal liver increase with gestation but there is a rapid rise from 36 weeks onwards; during this time, glycogen is also deposited in muscle and heart. Under normal circumstances, the fetus in utero is entirely dependent on its mother for glucose delivery. During delivery, plasma concentrations of adrenaline, noradrenaline and glucagon increase rapidly, whereas insulin concentration declines. The effect of this is to mobilise stored glycogen and fatty acids. After birth, the glucose concentration declines, reaching a nadir at about 1 h of age. Infants born before 36 weeks will therefore have fewer available energy resources.

and the newborn responds by increasing oxygen consumption, utilisation of energy sources (especially brown fat) and thus heat production. In response to cold, sympathetic activity increases, releasing noradrenaline in nerve endings in brown adipose tissue. Lipase activity increases the release of fatty acids, which are used by the adipocytes to produce heat. Triiodothyronine, which is important in this process, rises through gestation and increases sharply at term birth. In animal models, exposure to cold can increase oxygen consumption by 100%. Hypoxia attenuates thermogenesis.

Respiratory maladaptation in the newborn

In the newborn, the oxygen tension needed to maintain the arterial haemoglobin saturation above 90% varies between 40 and 60 torr (approximately 5e8 kPa), depending on the proportion of haemoglobin that is fetal, and the arterial pH (a drop in pH of 0.2 eliminates the left shift produced by 70% of the haemoglobin being fetal). Thus, in the newborn period, respiratory failure can also be dened in terms of oxygen saturation, but there are no widely accepted criteria. Hypoxaemia in the neonatal period can result from multiple mechanisms6:  Ventilation/perfusion mismatch, often distinguished by a good response to supplementary oxygen (also referred to as intrapulmonary shunting).  Inadequate pulmonary surface area (e.g. pulmonary hypoplasia, diaphragmatic hernia).

Thermoregulation
At birth, babies have a high surface area:mass ratio and lose heat quickly. They are born wet into a relatively cool environment, having been kept warm by their mother until the time of birth. Fetal thermogenesis is normally inactive; however, fetal basal heat production is approximately twice that of an adult. After birth, the temperature falls

Fetal-to-neonatal maladaptation  Increased physiological dead space, such as: e respiratory distress syndrome, e pneumonia, e meconium aspiration syndrome.  Extrapulmonary (right-to-left) shunting, distinguished by relatively little improvement with supplementary oxygen and found in: e persistent pulmonary hypertension, e cyanotic congenital heart disease. Hypoventilation (reduced alveolar ventilation, reduction in tidal volume and/or frequency) can be recognised by high PaCO2, often in association with hypoxaemia and occurs in the following conditions:  Reduced respiratory compliance (e.g. respiratory distress syndrome [RDS], pneumonia).  Reduced lung volume (e.g. RDS, pulmonary hypoplasia).  Compressed lungs (e.g. pneumothorax, pleural effusion, lobar emphysema, cystic adenomatoid malformation).  Ventilatory pump failure (e.g. reduced central drive following a high level of maternal sedation, cerebral ischaemia, intracerebral haemorrhage, apnoea of prematurity, and central alveolar hyperventilation syndrome).  Impaired ventilatory muscle function.  Miscellaneous conditions (e.g. disuse atrophy, protein calorie malnutrition, neuromuscular disorders, diaphragmatic problems, phrenic nerve palsy, etc.).  Pre-existent central nervous system injuries or anomalies; these may prevent the infant from achieving a normal adaptation by hindering spontaneous breathing or control of circulatory function.

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Clinical considerations
Respiratory depression at birth Failure to establish normal respiration soon after birth is associated with the biochemical changes of hypoxemia, hypercapnia, and acidaemia. If all three conditions are present, an asphyxial state is said to exist. The causes can be conveniently divided into central and peripheral. Central causes are more common, particularly reduced respiratory drive secondary to fetal hypoxaemia:  Maternal analgesia and anaesthesia or other depressant drugs.  Severe intrapartum hypoxia: e maternal circulatory collapse, e placental abruption or vascular malformation, e cord accidents.  Severe fetal haemorrhage or anaemia: e feto-maternal haemorrhage, e twin-to-twin transfusion syndrome, e severe haemolytic disease (isoimmunisation).  Severe birth trauma.  Neuromuscular disorders (e.g. myotonic dystrophy).  Severe infection (e.g. group B streptococcus).  Pre-existing central nervous system injury or anomaly. Although the severity of respiratory depression is commonly assessed by using the Apgar score,7 the rational management of such a baby requires an understanding of the pathophysiology of the condition. Soon after the onset of an asphyxial insult, rapid gasps occur, which cease after 1e2 min. This is followed by a period of primary apnoea. Spontaneous deep gasping follows for several minutes, gradually becoming weaker

Figure 2 Birth asphyxia: biochemical and cardiorespiratory changes associated with birth asphyxia and the response to resuscitation (adapted from The Newborn Life Support Provider course manual, Northern Neonatal Network, UK).

170 and terminating in the last gasp (Fig. 2). The time interval between the asphyxial insult and the last gasp is about 8e 10 min. The baby then enters terminal apnoea when circulation falters and the heart rate and blood pressure fall dramatically. A baby who has entered terminal apnoea is more likely to die without resuscitation, and might die despite a properly performed resuscitation. However, a brief period of intermittent positive pressure ventilation and external cardiac compression can sometimes produce a rapid recovery.8,9 In human newborns, the occurrence of a sudden complete asphyxial insult at birth is very rare; intermittent partial asphyxia during labour is far more common. Most babies are born in primary apnoea and rapidly establish normal respiration. The immediate management of birth depression should thus be directed towards rapid and efcient resuscitation, followed by stabilisation of the infants condition. Although the Apgar score is a helpful shorthand way of assessing an infants status at birth, it is more meaningful to distinguish between primary and terminal apnoea. Gasping infants should always be treated as though they are in terminal apnoea:  Primary apnoea: e heart rate > 60 beats/min and accelerating, e some muscle tone, e some spontaneous movement, e preserved gag reex, e gasps in response to lung ination (Heads reex), e spontaneous breathing before skin becomes pink.  Secondary apnoea: e pallor (asphyxia pallidum), e heart rate < 60 beats/min, sometimes decelerating, e no muscle tone, e no spontaneous movement, e no gag reex, e no Heads reex on lung ination, e heart rate and colour improve before the return of spontaneous breathing.

S.K. Sinha, S.M. Donn or RDS, previously referred to as hyaline membrane disease. RDS is primarily a disease of prematurity related to the immaturity of the lungs and, to a lesser extent, the airways. The incidence and severity of the disease is inversely related to gestational age and, in its most severe form, can lead to severe respiratory failure and death. The major hallmark is a deciency of surfactant, which leads to higher surface tension at the alveolar surface and interferes with the normal exchange of respiratory gases. The higher surface tension requires greater distending pressure to inate the lungs. The number of functional alveoli (and thus the functional surface area available for gas exchange) normally increases with advancing gestational age but is reduced in prematurity. With extreme prematurity (23e25 weeks), the distance from the alveolus or terminal bronchiole to the nearest adjacent capillary also increases and, thus exacerbates the diffusion barrier and interferes with oxygen transport from lungs to blood. The airways of the extremely preterm infants are also incompletely formed because of decient cartilage and they tend to collapse, thus increasing airway resistance. The chest wall of the premature newborn is also more compliant than the lungs and tends to collapse when the infant attempts to increase negative intrathoracic pressure (Fig. 3). These factors result in a number of functional abnormalities, including decreased lung compliance, increased airway resistance, ventilation/perfusion abnormalities, impaired gas exchange, and increased work of breathing.10 Treatment requires a clear understanding of these anatomical and functional abnormalities, which usually persist for a considerable time in the neonatal period and can vary according to the stage of the illness and comorbidities, which initiate the pulmonary injury sequence. The treatment includes establishment of adequate gas exchange by either increasing the FiO2 to overcome the diffusion block, or the use of distending pressure if the infant is only mildly affected and showing reasonable respiratory effort and effective ventilation. If, however, the infant is exhibiting evidence of alveolar hypoventilation with hypoxaemia and hypercapnia despite receiving supplemental oxygen, some form of positive pressure mechanical ventilation will be needed. Whatever method is used, the goal of mechanical ventilation remains the same: achieve adequate pulmonary gas exchange while decreasing the patients work of breathing. RDS is a disorder of low lung volume, so the approach should be one that delivers an appropriate tidal volume while minimising the risk of complications. The development and use of surfactant replacement therapy has been one of the most signicant milestones in the history of neonatology. Numerous pharmacological preparations are now available (some synthetic, others animal derived) more recently synthetic surfactants containing bioengineered peptides that mimic human surfactant-associated proteins have been developed. Surfactant therapy can be given prophylactically immediately after the birth in at-risk infants, such as those born before 30 weeks gestation, or as a rescue treatment, given after the diagnosis is established.11 Antenatal corticosteroid treatment of the mother has been demonstrated to reduce the incidence and severity of RDS, particularly if given between 28 and 32 weeks gestation.12

Respiratory distress
Respiratory distress in the newborn is a clinical condition characterised by four cardinal signs: grunting, aring of the ala nasi, recession of the accessory muscles of respiration, and tachypnoea. It has many causes and its presence is diagnostically non-specic. Transient tachypnoea of the newborn (TTN) is a selflimiting condition characterised by features of respiratory distress; these are not usually severe. TTN is frequently seen in large premature infants and in term or near-term infants delivered by caesarean section without the mother going into labour. Infants born to diabetic mothers and or infants with poor respiratory drive as a result of excessive maternal analgesics, sedatives, or depressant pharmacological agents (such as magnesium sulphate) are also at risk. The underlying pathophysiology is incomplete or slow resorption of lung uid, and the condition usually requires no more than 30e40% of inspired oxygen for its treatment. More severe signs suggest other pathology, such as congenital pneumonia

Fetal-to-neonatal maladaptation

171

Lung mechanics in RDS

NORMAL RDS

CHEST WALL RIGID

SURFACE TENSION LOW

CHEST WALL SOFT

SURFACE TENSION HIGH

Figure 3

Lung mechanics and surface tension forces in surfactant-decient lung disease.

Circulatory maladaptation in the newborn

Persistent pulmonary hypertension of the newborn
Persistent pulmonary hypertension of the newborn (PPHN) also known as persistent fetal or transitional circulation (PFC), is an acute neonatal emergency resulting from the failure of the normal post-birth decrease in pulmonary vascular resistance (PVR), which leads to a variable degree of right-toleft shunting of deoxygenated blood through persistent fetal channels (the foramen ovale and patent ductus arteriosus). This, in turn, leads to severe hypoxemia, acidosis, and further pulmonary vasoconstriction. A similar clinical picture can arise from decreased systemic vascular resistance (SVR) or any condition where the PVR: SVR ratio is >1. Potential mechanisms contributing to the pathogenesis of PPHN can be grouped under the following categories13:  Normal pulmonary vascular morphology but presence of myocardial dysfunction or increased vascular reactivity from vasoconstrictive stimuli: e failure to initiate or sustain effective breathing, e meconium aspiration syndrome, e severe RDS, e sepsis/pneumonia, e hyperviscosity syndrome.  Morphologically abnormal pulmonary vasculature: e some cases of meconium aspiration syndrome, e idiopathic PPHN, e structurally abnormal lungs (e.g. congenital diaphragmatic hernia, lung hypoplasia, cystic adenomatoid malformation).  Structurally abnormal heart diseases causing left ventricular outow tract obstruction, such as critical aortic stenosis, interrupted aortic arch or those resulting in obligatory right-to-left shunt (tricuspid atresia, hypoplastic left ventricle).

The differential diagnosis of persistent hypoxaemia in term and near-term newborn infants includes primary lung disease, cyanotic congenital heart disease and PPHN, with or without lung disease. The diagnostic work-up for PPHN requires a detailed echocardiogram, which demonstrates elevated pulmonary artery pressure and delineates the site(s) of shunting. Echocardiography is also useful in excluding structural congenital heart disease and transient myocardial dysfunction. The clinical management of PPHN remains controversial. Ideally, it starts from identication and appropriate obstetric management of at-risk pregnancies associated with PPHN, such as intrapartum difculties, post-datism, and chorioamnionitis; and adequate resuscitation of the affected newborn to facilitate successful adaptation. Although there is no consensus as to what is the best method of ventilating such babies, optimal ventilatory support using appropriate strategies is necessary to establish acceptable gas exchange, while treating the underlying pulmonary disease, if present. Both conventional mechanical ventilation and high-frequency ventilation have been utilised. No matter which approach is chosen, infants with PPHN demonstrate extreme lability and it is always advisable to attempt several small ventilator/FiO2 changes rather than one large one. Ventilatory management might still fail unless correction of the abnormalities that contribute to right-to-left shunting (such as hypotension, hypercarbia and acidosis) are corrected. Given the underlying pulmonary vasoconstriction central to PPHN, it seems sensible to approach this aspect of pathophysiology by employing a vasodilator. Until recent years, a specic pulmonary vasodilator has not been available and treatment relied on general vasodilators, such as tolazoline, with effects on both the systemic and pulmonary circulations. This was an undesirable situation, since systemic hypotension induced by the drug might signicantly worsen the babys overall situation. However, since the early 1990s, inhaled nitric oxide (iNO) has been

172 available as a specic pulmonary vasodilator. Synthesis of NO by vascular endothelium is thought to be essential for modulation of normal vascular tone and decreasing platelet and neutrophil adherence. Inhaled NO produces vasodilation by the same mechanism after diffusing from the alveoli to the pulmonary vasculature. Any excess NO is rapidly inactivated, as it is bound to haemoglobin before metabolism to nitrates and nitrites. This mechanism of action produces a selective dilation of the pulmonary vascular bed. In addition, iNO improves ventilationeperfusion mismatch through its vasodilatory effects on ventilated areas of the lungs, thus reducing the intrapulmonary shunting of venous blood.14 The role of iNO in respiratory failure in preterm infants is still not proven. Current evidence suggests that preterm infants should not be treated with iNO outside the context of a randomised trial.15 Other vasodilatory agents that have been tried for treatment of PPHN include prostacyclin and sildenal, but data regarding safety and efcacy are limited. If mechanical ventilation and supportive therapy are unsuccessful in improving oxygenation (generally indicated by an AaDO2 > 600 mmHg or an oxygenation index of >40, which are predictors of a very high mortality rate), a term or near-term infant might be a suitable candidate for extracorporeal membrane oxygenation (ECMO).16 It is a form of cardiopulmonary bypass that provides support for patients with reversible respiratory and/or cardiac failure. Venoarterial (V-A) ECMO uses two large-gauge catheters (12e14 French), placed in the right common carotid artery and right internal jugular vein. Blood is drained passively from the venous catheter and pumped through the membrane lung. The oxygenated blood is re-warmed and returned to the aorta via the internal carotid artery catheter. This form of ECMO is able to support both pulmonary and cardiac function. Venovenous (V-V) ECMO, using a double-lumen catheter placed in the jugular vein, thus obviating the need for carotid ligation, has become more popular. Oxygen delivery in V-V ECMO relies upon adequate cardiac function. Whilst on ECMO, ventilation is reduced to rest settings, i.e. 5e 10 cmH2O PEEP and 5e10 breaths per minute. This prevents atelectasis, which might follow acute withdrawal of respiratory support, and enhances clearance of secretions.

S.K. Sinha, S.M. Donn complications, with efforts directed at establishing normal gas exchange and circulatory function.

Practice points
 Maladaptation is often a sign of a serious underlying problem such as a cardiac, respiratory, neurological or infectious disorder.  Do not assume that the baby is in primary apnoea; commence appropriate resuscitative measures immediately.  Respiratory maladaptation may involve RDS in the preterm infant, and TTNB or pneumonia in the term infant.  Circulatory maladaptation may result from or lead to PPHN.  If a newborn fails to respond to an appropriately performed resuscitation, consider an underlying neurological problem, which may involve the central nervous system, peripheral nervous system, neuromuscular junction, or peripheral nerve.

References
1. Oliver RE. Strang LB: Ion uxes across the pulmonary epithelium and the secretion of lung uid in the foetal lamb. J Physiol 1974;241:327e57. 2. Rigatto H. Control of ventilation in the newborn. Annu Rev Physiol 1984;46:661. 3. Kiserud T. Physiology of fetal circulation. Semin Fetal Neonat Med 2005;10:493e503. 4. Musewe NN, Poppe D, Smallhorn JF, Hellman J, Whyte H, Smith B, et al. Doppler echocardiographic measurement of pulmonary artery pressure from ductal Doppler velocities in the newborn. J Am Coll Cardiol 1990;15:446. 5. Dukarm RC, Steinhorn RH, Morin FC. The normal pulmonary vascular transition at birth. Clin Perinatol 1996;23(4): 711e26. 6. Boynton BR, Hammond MD. Pulmonary gas exchange: basic principles and effects of mechanical ventilation. In: Boynton B, Carlo WA, editors. New therapies for neonatal respiratory failure: a physiologic approach. Cambridge: Cambridge University Press; 1994. p. 115. 7. Catlin EH, Carpenter MV, Bran BS, Mayeld SR, Shaul PW, Goldstein M. The APGAR score revisited: inuence of gestational age. J Pediatr 1986;109:865e8. 8. Godfrey S. Respiratory and cardiovascular changes during asphyxia and resuscitation of foetal newborn rabbits. Q J Exp Physiol 1968;53:97e118. 9. Gorfrey S. Blood gases during asphyxia and resuscitation of fetal and newborn rabbits. Resp Physiol 1968;4:309e21. 10. Harris TR, Wood BR. Physiology and principles. In: Goldsmith JP, Karotkin EH, editors. Assisted ventilation of the neonate. 3rd ed. Philadelphia: WB Saunders Co; 1996. p. 48. 11. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Articial surfactant therapy in hyaline-membrane disease. Lancet 1980;1(8159):55e9. 12. Jobe AH, Mitchell BR, Gunkel JH. Benecial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 1993 Feb;168(2):508e13.

Conclusion
Adaptation, or transition, is a highly complex biological event that enables the fetus to become an independent being and able to exist separate and apart from the uteroplacental unit. In the overwhelming majority of cases, this process occurs normally and without consequence. However, in some situations, prior or ongoing pathology might hinder successful adaptation and place the newborn at jeopardy for death or long-term disability. Recognition of conditions that can lead to maladaptation and prompt institution of corrective measures are the best means of avoiding or limiting further consequences. Affected infants require meticulous surveillance for

Fetal-to-neonatal maladaptation
13. Abman SH. New developments in the pathogenesis and treatment of neonatal pulmonary hypertension. Pediatr Pulmonol Suppl 1999;18:201e4. 14. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic res: The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med 1997;336(9):597e604.

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15. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2001; (4). CD000509. 16. UK Collaborative ECMO Trail Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 1996;348(9020):75e82.