Chapter Contents
Introduction 115
Emerging care of the premature infant 115
Feeding the premature infant 116
Early versus late feeding 116
Thermoregulation and the premature infant 116
Thermoregulation 116
The metabolic response to a cool environment 117
The neutral thermal environment for newborn babies 117
Respiratory distress syndrome 117
Pulmonary mechanics and surfactant 117
Antepartum glucocorticoids for the prevention of respiratory distress syndrome 118
Treatment of respiratory distress syndrome 118
Intraventricular haemorrhage 119
Periventricular leukomalacia 119
Necrotising enterocolitis 120
Retinopathy of prematurity 120
Birth asphyxia 121
Greater tolerance of the young to asphyxia 121
Effect of environmental temperature 121
Circulation and cardiac glycogen 121
Sequence of circulatory and respiratory changes following asphyxia 121
Assessment of vital signs at birth and resuscitation 121
Birth asphyxia and brain damage 122
Birth asphyxia and neonatal encephalopathy 122
Rhesus haemolytic disease 122
Introduction
This chapter focuses on how our understanding of certain neonatal disorders has emerged and describes the research that underpinned it. Most advances are not the result of serendipitous discovery but are due instead to the gradual accumulation of research-based knowledge over an extended timeframe. Along the way, landmark publications appear and are highlighted in this chapter, but they need to be reviewed in the context of their building blocks.
Emerging care of the premature infant
The importance of feeding and warmth to the survival of premature infants had been known for centuries but it was not until the second half of the 19th century that serious efforts were made to improve their outcome. Two obstetricians, Stéphane Tarnier and Pierre Budin, led the way in Paris, France, at the Maternité and the Hôpital de la Charité.
Tarnier introduced hygienic measures at the Maternité which substantially reduced mortality from puerperal sepsis. He developed a closed incubator, and introduced gavage feeding in 1884. His pupil, Pierre Budin, had remarkably prescient ideas that were to occupy the minds of paediatricians into the 20th century. He developed what was probably the first follow-up clinic for infants and wrote about the outcome for premature babies in his treatise, The Nursling , which was originally published in 1900 and included information on breastfeeding and mother–infant bonding, hygiene, hypothermia and cyanotic episodes ( ).
Feeding the premature infant
The compromised ability of the feeble newborn to feed adequately, together with sepsis, were important causes of mortality before the 20th century. Methods of feeding premature babies included the trickling of milk into the infant’s mouth directly from the mother’s breast or from a wet nurse, and the use of spoons, small cups, droppers and quills.
Otto Heubner (1843–1926) is best known for the name of the branch of the anterior cerebral artery. An internal physician by training, he was subsequently appointed as Professor of Paediatrics in Berlin, Germany. His research with Max Rubner using indirect calorimetry to determine the caloric needs of infants promoted feeding according to requirements rather than empirical observations ( ; cited by ). The chemical composition of milk and its calorific value were known by the close of the 19th century and many felt that 100–150 cal/kg/day were optimal for growth, largely based on Rubner and Heubner’s observations.
Although formula feeds based on evaporated cow’s milk and approximating in composition to human milk were used by the second quarter of the 20th century, it was still widely considered that human milk was superior for premature infants. When highlighted caloric loss in the stools resulting from the premature infant’s difficulty in absorbing fat, their observations led to the increasing use of half-skimmed cow’s milk preparations. In order to meet caloric needs the protein content had to be increased and the formulas also had a higher electrolyte and mineral content than human milk. and later others showed that babies fed a half-skimmed milk formula gained weight more rapidly than those fed breast milk. The relatively high protein intakes were associated with raised blood urea levels ( ).
However, there remained a concern that premature infants exclusively fed on expressed breast milk did not grow as well as those who received formula feeds. In a randomised trial observed that babies of 28–32 weeks’ gestation fed on expressed breast milk had significantly slower rates of head and linear growth in the first month of life compared with formula-fed infants.
In a review of nutritional studies commented that ‘an optimum diet has been defined as one in which no change can promote greater health and well-being of the populace’. Therein lay an enigma that continues to challenge paediatric nutritional researchers. Is the aim to encourage growth in the early weeks that characterises normal fetal growth ( ); to satisfy some other concept of optimal postnatal weight gain; to permit accumulation of carbohydrate, fat and protein and minerals at a rate observed in the last trimester of pregnancy ( ); to influence later neurodevelopmental outcome in some way ( ; ); or perhaps to minimise the risk of the infants developing adult disease such as hypertension, stroke and diabetes ( )?
Early versus late feeding
By the late 1940s the practice of starting feeds at 24 hours or sooner (‘early feeding’) was causing concern because milk aspiration was considered to be a prominent cause of pneumonia and cyanotic episodes. Generalised oedema in the first week of life was also attributed to early feeding. In the USA and subsequently in the UK it became common practice to delay the first feed. For example, studied 231 premature babies in whom the time of the first feed was determined by the baby’s vigour. The average age when babies in different birthweight categories were offered their first feed ranged from 48 to 73 hours, but in many the delay was more than 100 hours. The authors concluded that a period of starvation was safe. Similarly, described that feeding began on the third day in infants who weighed 3–4 lb (1.4–1.8 kg), and on the fourth day for those under 3 lb (1.4 kg).
During the 1960s evidence accumulated suggesting that early starvation might be causally related to cerebral palsy in premature infants ( ; ). There was also growing experimental evidence in animals of the harmful effects of early malnutrition ( ).
In what proved to be a landmark publication, observed that infants who weighed 1000–2000 g could safely be fed within 2 hours of birth on undiluted breast milk at 60 ml/kg/day, increasing daily to 160 ml/kg/day. They suffered less symptomatic hypoglycaemia and their bilirubin levels were lower than those of infants who were fed later. Similar beneficial effects of early feeding were subsequently reported by others but it was several years before the practice became widely adopted. An excellent historical review of changing attitudes to the first feed and the underlying scientific concepts was written by .
Thermoregulation and the premature infant
The vulnerability of newborn infants exposed to a cold environment has been known from ancient times. Methods used to keep small and feeble babies warm included fireside heat, hot-water bottles, animal skins and plant leaves. Probably the first device which can be considered to be an incubator was a warming tub – a double-walled metal tub with the space between the walls filled with warm water. This was developed in 1835 and used at the Foundling Hospital in St Petersburg. The subsequent history of the development of incubators was addressed by .
The emergence of public viewing of babies nursed in incubators at various fairs and exhibitions in Europe and the USA from around 1896 until 1940 was addressed by in a captivating account. The incubator exhibitions did at least raise the profile of small babies and provide access to warmth and nutrition and for some it was their only hope of survival. Arguably it also stimulated an interest in the science of thermoregulation in infants.
Thermoregulation
From the early 1900s animal physiologists had studied birds and mammals, establishing that there was a critical environmental temperature below which heat production was necessary to maintain a normal body temperature and above which stability of temperature was dependent on physical factors such as changes in insulation and body posture ( ). The critical temperature varied between species and habitat. Given what was known about the lability of body temperature in small infants, and that heat loss occurred by evaporation, conduction, radiation and convection, a key question was how babies might protect themselves when exposed to a cool environment.
In published their results of a detailed study of premature infants aged 4–53 days, in which heat production (oxygen consumption) and different forms of heat loss were measured in relation to environmental temperature. They observed that in cool air vasoconstriction was active but total heat loss per unit area of skin was greater than that of adults. Although infants increased their heat production in cool air, ‘the sustained muscular movement necessary to raise heat production is more difficult for these feeble subjects than for adults’ ( ).
More than a decade later in a randomised controlled trial observed that prematurely born infants nursed in incubators maintained at a temperature of 31.7°C during the first 5 days of life had a better survival rate than those nursed at 28.9°C (84% versus 68%). The beneficial effect was observed in all birthweight categories.
showed that infants from birth, including those of low birthweight, had a very well-developed thermoregulatory control system. They could adjust their peripheral blood flow and sweat secretion and the temperature threshold at which these controls were activated was related to body size. The increased heat production when infants were exposed to a cool environment was the result of non-shivering thermogenesis rather than shivering.
The metabolic response to a cool environment
suggested that brown fat might be a source of heat production in the cold-adapted rat as oxygen consumption of the tissue was high. A major advance was a study by ; these authors observed that exposure to cold was associated with a rise in temperature of brown adipose tissue. Hydrolysis of the fat was associated with a marked rise in plasma glycerol levels and a smaller increase in plasma free fatty acids, suggesting that most of the liberated free fatty acids was metabolised within the brown adipose tissue.
observed that when babies were exposed to a cool environment the nape of the neck was warmer than other sites. The distribution of brown adipose tissue in the human infant at necropsy was studied by , who showed that it was relatively depleted in infants who had died following a history of hypothermia or cold injury.
It is perhaps intuitive that the metabolic response of newborn babies to a cool environment might be influenced by their state of oxygenation. reported that oxygen consumption (metabolic rate) in premature and term babies decreased when they were exposed to 15% oxygen. They speculated that, although this might be a defence mechanism against hypoxia, it might also impair thermoregulation and that a low body temperature in the newborn might be symptomatic of hypoxia. shed light on this issue in laboratory animals when she observed that it was only in a cool environment, when the metabolic rate had already increased to maintain body temperature, that induced hypoxia caused a fall in oxygen consumption and a fall in rectal temperature. In a neutral thermal environment induced hypoxia had no effect on oxygen consumption.
The neutral thermal environment for newborn babies
Additional clinical studies of thermoregulation in newborn babies emerged and closely reflected observation in animals. This culminated in defining the thermal environment for newborn babies that made minimal demands on the infant’s energy reserves with core body temperature being regulated by changes in skin blood flow, posture and sweating ( ). The concept of thermal neutrality was later reviewed further by .
Respiratory distress syndrome
In , reporting on a necropsy study in newborn infants, drew attention to infants whose alveolar ducts and alveoli were coated with a layer of eosinophilic material originally described as myelin. The next half-century saw intense research and debate about the origin and significance of this material, which was subsequently referred to as hyaline (from the Greek for glass). The suggested causes of the hyaline membranes included aspiration of amniotic fluid or vernix caseosa, infection, congenital or developmental anomaly, intrauterine hypoxia, oxygen poisoning, injury and necrosis of bronchiolar epithelium. The various aetiological theories put forward were based almost entirely on histochemical analysis of lung tissue with little in the way of clinicopathological correlation. Distressed breathing in premature infants was recognised but it was generally attributed to ‘congenital atelectasis’ or ‘asphyxia’.
By the 1950s the association of hyaline membranes at necropsy with prematurity and respiratory distress was confirmed and the terms ‘hyaline membrane disease’ and ‘idiopathic respiratory distress syndrome’ became increasingly used. concluded that the membranes were composed of fibrin formed in situ as a result of exudation of fibrinogen from pulmonary capillaries. The radiological features of the disorder were described and the reticular–granular pattern on chest X-ray was distinguished from the coarse opacities associated with amniotic fluid aspiration and pneumonia ( ).
Pulmonary mechanics and surfactant
In compared the pressure–volume curves of air-filled porcine lungs with curves produced after filling the lungs with isotonic gum solution which had the potential to abolish surface tension forces at the air–tissue interface. Based on these experiments he suggested that surface tension forces were more important than elasticity in lung recoil, and that surface forces might interfere with lung expansion. The importance of this was not appreciated at a time when there was still growing preoccupation with the significance of hyaline membranes.
suggested that an unusually high surface tension might be responsible for the uneven pattern of expansion observed in the lungs of premature infants and for resistance to lung inflation. During the 1950s the relationship between the pressure–volume characteristics of lung and surface tension force became clarified. , studying nerve gases at the Ministry of Defence at Porton Down, UK, observed that foam found in the trachea of rabbits with induced acute lung oedema had an altogether peculiar property in that it was unaffected by silicone antifoams. He concluded that the stability of the foam was due to an insoluble surface layer on the foam bubbles which originated from the original lining of the air spaces.
At the same time researchers from the Department of Physiology at the Harvard School of Public Health were studying pulmonary mechanics and the implication of surface tension forces at the air–liquid interface. calculated the internal surface area of the lungs from their pressure–volume characteristics assuming that surface tension was constant and equal to that of plasma. His calculation of the surface area was much lower than data derived from morphological examination. This anomaly held a clue to the surface-active property of the lung lining.
studied surface films prepared from rat, cat and dog lungs using a modified Wilhelmy balance, which compresses and expands the surface film while measuring surface tension. He showed that surface tension fell to a minimum as the surface area of the film was compressed, but, more importantly, only a 10% expansion from the compressed state restored the surface tension to its maximum value – the surface film was showing hysteresis. In the absence of the specialised surface film, which Clements referred to as pulmonary surfactant, the high surface tension would resist lung expansion, cause small air spaces at high pressure to empty into larger air spaces and promote uneven expansion and atelectasis.
The association of surfactant deficiency with hyaline membrane disease was established by , who measured the surface tension of lung extracts of infants using a Wilhelmy balance. The extracts from infants who weighed more than 1200 g and who had died from causes other than hyaline membrane disease achieved much lower surface tensions than lung extracts from infants who had died from hyaline membrane disease and from smaller babies.
Thus, more than half a century after Hochheim’s original description of hyaline membranes, the underlying physicochemical abnormalities of the lungs were discovered. revisited the histopathological changes in the lung in hyaline membrane disease and measured surface tension in lung extracts. They observed that the presence or absence of osmiophilic granules, which represent stored surfactant within type 2 pneumocytes, did indeed reflect surface tension measurements.
Antepartum glucocorticoids for the prevention of respiratory distress syndrome
, while studying the influence of the fetal endocrine system in promoting parturition in ewes, observed that ablation of the fetal pituitary or hypothalamus led to prolongation of gestation. Stimulation of the fetal adrenals by corticotrophin or infusion of cortisol led to premature parturition ( ). A striking feature was that lambs born at 117–123 days’ gestation following dexamethasone infusion showed partial expansion of their lungs, a feature which is not normally apparent at this gestation and which is dependent on adequate surfactant activity. Liggins suggested that the dexamethasone-treated fetuses may have had accelerated surfactant production.
extended these observations in a novel way. They infused cortisol into one of twin fetal lambs and observed that the lungs of treated lambs were more mature than their untreated twins in terms of pressure–volume curves and surface tension measurements of lung extracts. Similar evidence for hormonal control of fetal lung development has been shown in the rabbit ( ).
Supporting evidence for the hormonal control of pulmonary surfactant development in human fetuses was provided in an autopsy study by . They observed that infants who had died with hyaline membrane disease had lighter adrenal glands than those dying from other causes and infection arising before birth was correlated with the absence of hyaline membrane disease. Anencephalic infants with no adrenal fetal cortical zone had a reduced mass of osmiophilic granules in their type 2 pneumocytes compared with non-anencephalic infants.
The first controlled trial of antepartum glucocorticoid treatment for the prevention of respiratory distress syndrome (RDS) commenced in December 1969 and enrolled 282 mothers admitted in preterm labour or in whom delivery was planned before 37 weeks ( ). RDS was seen significantly less in infants of mothers treated with betamethasone but this was confined to infants under 32 weeks’ gestation whose mothers had been treated for at least 24 hours before delivery. Neonatal mortality was significantly reduced, and there were no deaths with hyaline membrane disease or intraventricular haemorrhage among infants of mothers who had received betamethasone longer than 24 hours before delivery.
This important trial was the forerunner of many others which shed light on whether there was a true gestational age cut-off point below which antenatal glucocorticoids were ineffective, whether repeated doses of glucocorticoids were beneficial, and whether there were maternal contraindications to their use.
Treatment of respiratory distress syndrome
Before the discovery of surfactant deficiency as the underlying cause of RDS, treatment was largely supportive and relied on oxygen, intravenous fluids and the maintenance of acid–base balance. The use of supplemental oxygen suffered a setback with its restrictive use because of fears about retrolental fibroplasia. This was associated at the time with a rise in mortality from RDS ( ).
Mechanical ventilation
The experimental use of positive-pressure mechanical ventilation for newborn infants with hyaline membrane disease was reported by . During the 1960s, with further experience limited to a few specialist neonatal units, the practical problems became apparent, especially the challenge of prolonged mechanical ventilation including endotracheal tube instability and problems maintaining nutrition. Intuitively it was felt that the treatment carried huge risks and that it was a last resort for infants dying with hyaline membrane disease. The third child of President John F Kennedy died of RDS, having been delivered at 34 weeks weighing 2.11 kg in August 1963. His obituary in the New York Times stated that all that could be done was to ‘monitor the infant’s blood chemistry and to try to keep it near normal’. The following year, described their experience of mechanical ventilation of severely acidaemic and apnoeic infants with ‘terminal’ hyaline membrane disease and concluded that the best hope of success with this treatment was its application in the preterminal rather than the terminal state.
The growth of neonatal intensive care units and the development of regional referral centres in the UK during the 1970s led to an increasing experience of mechanical ventilation in infants with RDS. A major concern was the occurrence of pneumothoraces and bronchopulmonary dysplasia, which had originally described. For staff on the emerging intensive care units assisted ventilation was a steep learning curve because ventilators had hitherto been machines used by anaesthetists – not paediatricians. An important advance, certainly in the UK, were publications by and describing the effect of alterations of ventilator settings on pulmonary gas exchange in hyaline membrane disease and the use of strategies that might minimise high inspired concentrations of oxygen and high peak inspiratory pressures.
reported the successful use of continuous positive airway pressure (CPAP) in spontaneously breathing infants with RDS. Different methods of applying CPAP emerged but the influence on clinical practice was that it drew attention to the benefits of respiratory support of some kind before the infant had reached a terminal state of respiratory failure.
During the subsequent decades advances occurred at a rapid pace. Non-invasive continuous blood gas monitoring facilitated the earlier detection of deteriorating infants. Interest grew in different ventilator strategies aimed at reducing the risk of barotrauma. Sedative drugs and muscle relaxants were increasingly used. However, the major advance – the one that really improved survival rates in RDS – was surfactant replacement therapy.
Surfactant replacement therapy
Based on their notion that pulmonary ischaemia was very important in the pathogenesis of RDS, conducted a detailed cardiorespiratory function study of infants with the disease. Intravenous acetylcholine was associated with an increase in effective pulmonary flow and appeared to have other beneficial functional effects. Administration of dipalmitoyl lecithin by aerosol was followed by an increase in lung compliance but this occurred even in infants who subsequently died and there was no apparent clinical benefit.
The effect of natural surfactant derived from rabbit and bovine lung was tested on premature animals during the 1970s with encouraging results. treated 10 premature infants with severe hyaline membrane disease by intratracheal administration of an artificial surfactant modified from bovine lung tissue. Oxygenation improved and it was possible to reduce the ventilator settings. Eight infants survived.
During the 1980s synthetic and bovine or porcine-derived surfactants were used in many randomised controlled trials and treatment reduced mortality and pulmonary air leaks. Further trials have compared different types of surfactant, examined more critically the role of multiple versus single dosage and shown that prophylactic treatment soon after delivery is more beneficial than rescue treatment. has provided an excellent review of the development of surfactant replacement therapy.
Intraventricular haemorrhage
During the early part of the 20th century it became clear that intraventricular haemorrhage (IVH) was seen more commonly in premature infants. drew attention to the association of IVH and premature birth ‘even when the delivery had been easy and natural’ and he attributed this to ‘the great delicacy of the vessels in the premature fetus’. The early debate about the cause of IVH essentially focused on the anatomical origin of the bleeding. It was thought that the source of the bleeding was engorged veins of the choroid plexus or from the subependymal region with leakage into the ventricular cavity. Attention was focused on engorgement of the terminal vein which drains the subependymal region.
The pathological anatomy was advanced by the study of , who used a dye injection and stereomicroscopic method to examine the brains of babies who had died within 10 days of birth. Among premature infants with subependymal haemorrhage or IVH they were unable to confirm rupture of the terminal vein or germinal layer infarction. They observed a rich capillary network within the germinal layer which was supplied by Heubner’s artery, a branch of the anterior cerebral artery. Injection of the carotid artery caused prominent leaks within the germinal layer capillary bed. The authors speculated that the capillaries might rupture by a rise in arterial pressure in conditions of hypercapnia or hypoxia.
Enlarging on this, suggested an integrated model which might explain both haemorrhagic and ischaemic lesions in the preterm brain. The model took into account the state of development of the cerebral vessels and the effects thereon of increased or decreased perfusion pressure in precipitating haemorrhagic and ischaemic lesions.
As the use of mechanical ventilation for babies with RDS was evolving, death from IVH appeared to be an important limiting factor. A major advance was the ability to diagnose IVH in life by computed tomographic brain scanning ( ) and ultrasound imaging ( ). The importance of the paper by was their grading of the extent of the IVH (grades I–IV).
Ultrasound imaging proved to be more convenient as a cot-side investigation and it became established as an important research tool. Many studies were published seeking to relate obstetric and neonatal factors with IVH. A plethora of ‘risk factors’ emerged which were difficult to interpret because of confounding variables but they appeared to have had their basis in altered regulation of cerebral blood flow, sudden changes in blood volume and coagulation abnormalities.
Ultrasound imaging made it possible to assess the effects of various agents for reducing the risk of IVH such as phenobarbital ( ), vitamin E ( ), etamsylate ( ) and indometacin ( ). None of those agents became firmly established or stood the test of time, although indometacin has enjoyed a recent revival. This was possibly because the background incidence of IVH fell as a result of improvements in obstetric and neonatal care such as the use of antenatal corticosteroids, surfactant replacement and efforts to promote circulatory stability. Long-term outcome studies from the various prophylaxis regimens were few.
Periventricular leukomalacia
The pattern of pathology that we now term ‘periventricular leukomalacia’ (PVL) was described in the 19th century under a different name ( ). The first comprehensive description of PVL was by and was based on postmortem examinations of infants set against a review of neuropathological observations that had been made in the 19th century. They used the term ‘periventricular leukomalacia’ to reflect their observation of bilateral ‘necrosis of the white matter dorsal and lateral to the external angles of the lateral ventricles’ and suggested a relationship with a compromised arterial supply.
The vascular anatomy and its relationship to PVL were clarified by , who showed that the lesions were located in the periventricular arterial border zones between the ventriculopetal and ventriculofugal branches of the deep penetrating arteries and suggested that impaired perfusion was an aetiological factor. In a postmortem study of infants with PVL, observed that most had suffered perinatal complications or had been born prematurely. They noted that haemorrhage occurred within infarcts in some infants and differentiated this from subependymal-related haemorrhage. They observed that cavity formation in the infarcted areas was associated with degeneration of the corticospinal tracts and speculated that this may form an anatomical basis for spastic hemiplegia or quadriplegia.
During the 1980s descriptions of the cerebral ultrasound appearance of PVL appeared. The ultrasound characteristics of haemorrhagic periventricular leukomalacia and their correlation with autopsy findings were described by ). The reported incidence of PVL ranged from less than 5% ( ) to 18% ( ). As with IVH, these studies allowed associated clinical factors to be explored. Subsequent reports suggested that neonatal cranial ultrasound expressions of white-matter damage were reasonably good predictors of neurodevelopmental outcomes ( ).
Meanwhile both experimental and clinical evidence accumulated to suggest an association between a maternal or fetal inflammatory response and white-matter injury. had shown that intraperitoneal injection of lipopolysaccharides into kittens caused white-matter changes not dissimilar to that seen in humans. Elevated levels of proinflammatory cytokines in umbilical cord plasma and amniotic fluid ( ) were reported to be associated with PVL, and other studies showed that clinical markers of intra-amniotic infection preceding premature birth are linked to white-matter damage.
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