Neonatal medicine

Management of threatened preterm delivery

Whenever possible, the aim is to deliver the infant at full term whilst ensuring the well-being of both mother and infant. The decision to deliver infants less than 28 weeks' gestation is especially difficult, and should involve the obstetrician, neonatologist and parents after detailed assessment of the risks to mother and infant.

Management known to improve neonatal outcome includes:

• Antenatal steroids – reduces rate of respiratory distress syndrome, intraventricular haemorrhage and neonatal death (see Box 1.4 for details)

• Magnesium sulphate – shown to reduce the risk of cerebral palsy in infants <32 weeks' gestation. Its mechanism of action is poorly understood.

Following PPROM, there is increased risk of neonatal morbidity and infection. It is associated with ascending maternal infection from the lower genital tract, with one third having positive amniotic cultures. Antibiotics are given to the mother to treat chorio­amnionitis and reduce the risk of neonatal infection.

Tocolytics are often used to suppress contractions to allow time for antenatal corticosteroids or maternal transfer to a perinatal centre, but there is no clear evidence that they improve outcome.

Overview of the preterm infant

The preterm infant at 23–25 weeks' gestation differs markedly in size, appearance and development from babies born at later gestations. Typical birth weight at 24 weeks is only 620 g for females, 700 g for males (50th centile). Their skin is red, thin and gelatinous, making them prone to high evaporative heat loss and is easily damaged, making it a potential portal for infection. They adopt an extended posture with uncoordinated movements, reflecting their early stage of neural development (see Chapter 28 , Neurology). Their eyelids may be fused or partially open, with infrequent eye movements, in contrast to the term infant who looks and follows faces. They are unlikely to breathe without respiratory support because of surfactant deficiency and lung immaturity. They are unable to coordinate sucking and will require nasogastric feeding, often augmented by parenteral nutrition; the ability to suck and coordinate swallowing usually only develops at 34–35 weeks. Babies born weighing less than 1.5 kg are at increased risk for a range of complications ( Table 11.2 ).

Respiratory distress syndrome

Respiratory distress syndrome (RDS) is the most common lung problem that accompanies prematurity. It may lead to severe respiratory failure and death. It is caused by deficiency of surfactant, which leads to higher surface tension at the alveolar surface, difficulty in achieving adequate functional residual capacity and interferes with the normal exchange of respiratory gases. The incidence and severity of RDS is inversely proportional to gestational age because of the smaller number of functional alveoli with decreasing gestational age. The airways of the preterm infant are also incompletely formed and lack sufficient cartilage to remain patent. This contributes to collapse of lungs and increased airway resistance. The higher surface tension requires greater distending pressure to inflate the alveoli, according to Laplace's law: P = 2T/r, where P is the pressure, T is the surface tension and r is radius ( Figs 11.1 – 11.2 ). The chest wall of the preterm newborn is also more compliant than the lungs, thus tending to collapse when the infant attempts to increase negative intrathoracic pressure.

In summary, functional abnormalities which contribute to respiratory failure in preterm newborns include:

• Decreased compliance

• Increased resistance

• Ventilation–perfusion imbalance

• Impaired gas exchange

• Increased work of breathing.

Nutrition

Human breast milk is the optimal form of nutrition even for extremely preterm infants. Its gastrointestinal tolerance is better and the incidence of necrotizing enterocolitis and the risk of systemic infection are lower than in infants fed with infant formula. Even minimal volumes may help prime bacterial colonization of the gut.

Lack of success in producing sufficient breast milk is often a problem, which may be aggravated by physical separation of mother and baby, difficulty in maintaining milk supply over a long period, lack of motivation and inadequate support. Frequent expression, kangaroo care or skin-to-skin contact and relaxation tapes improve the volume and duration of breastfeeding. Breast pumping, massage prior to pumping and dopamine antagonists may improve production. Expressed donor milk (DBM), which has been pooled and pasteurized, is increasingly used when mother's milk is not available. If these options are not available then preterm infant formula can be given. It has been modified to meet the increased nutrient requirements of extremely preterm infants and results in faster weight, length and head circumference growth, reduced incidence of hyponatraemia, bone disease of prematurity, hypophosphataemia and hyperbilirubinaemia than breast milk. However, tolerance of feeds is poorer and risk of NEC (necrotizing enterocolitis) is increased.

Human milk fortifiers containing protein, energy, macrominerals, trace minerals and a range of vitamins are widely used to supplement expressed breast milk to meet the additional nutritional requirements. They provide short-term improvements in weight gain, linear and head growth, but evidence is lacking for long-term benefits. As they are based on cows' milk, their precise biological properties differ from that of human milk. More recently, ‘humanized’ milk fortifier and infant formula, produced from pooled donor breast milk, have been developed and appear to have a lower risk of necrotizing enterocolitis compared to preparations based on cows' milk.

Parenteral nutrition is required if adequate enteral feeding is not possible, as extremely preterm infants have very limited ability to withstand starvation due to their low protein, fat and carbohydrate stores. Further details about nutrition in preterm infants are covered in Chapter 13 , Nutrition.

Patent ductus arteriosus (PDA)

The role of the ductus arteriosus in the fetus and its functional and anatomical closure after delivery are described in Chapter 10 , Perinatal medicine. Its patency is maintained by high blood flow, hypoxia and locally derived prostaglandin E2. In preterm infants, the ductal wall is thinner, the lumen is larger and postnatal constriction does not wholly obliterate the lumen. The incidence of functional PDA varies inversely with gestational age. Predisposing risk factors are respiratory distress syndrome, sepsis and fluid overload.

Infection

Preterm infants are particularly vulnerable to early-onset and nosocomial (hospital-acquired) infection. This is partly due to lack of maternal IgG antibody transfer across the placenta (fetal IgG rises from approximately 10% of the maternal concentration at 17–22 weeks' gestation to 50% at 28–32 weeks' gestation; Fig. 11.3 ) and breach of natural defence barriers from invasive central and peripheral lines, catheters and tubes, including artificial ventilation. Transplacental transfer of antibodies is an active process that results in fetal IgG levels in excess of maternal levels by full term. Breast milk is another important source of passive immune protection for infants and is rich in IgA but contains little or no IgG.

Following birth, a preterm infant should receive their immunizations at the same postnatal age as a term baby. Whilst immune response in very preterm infants may be suboptimal, these infants are also at increased risk of infection, so vaccination should not be delayed. Primary protection against infectious diseases at birth is provided mainly by maternal antibodies. However, these antibodies can hamper the humoral antibody response of the infant to vaccination, so the timing of vaccination should take their presence into consideration. The timing for childhood immunizations is based upon a complex risk–benefit analysis that takes account of this effect, which is why, for example, primary MMR vaccination is delayed until 12 months of age.

Necrotizing enterocolitis

About 5% of all very-low-birthweight (VLBW) infants will develop necrotizing enterocolitis (NEC), with mortality ranging from 15–25%. It is a clinical diagnosis of abdominal distension and tenderness, bilious aspirates, bloody stools and intramural air (pneumatosis intestinalis) on abdominal X-ray. It may progress to peritonitis and bowel perforation.

The exact cause is unknown but is probably multifactorial, including loss of bowel mucosal integrity leading to macromolecular absorption and bacterial translocation. There is significant deficiency of secretory IgA, with increased permeability to small and large molecules. Antenatal glucocorticoid therapy improves intestinal maturation and reduces permeability and hence offers a degree of protection. Infection may initiate mucosal injury leading to invasion of gas-producing bacteria, which can result in pneumatosis intestinalis. This gas in the bowel wall is mainly nitrogen and hydrogen. There may also be gas in the portal venous system. Histologically, there is necrosis of the mucosa with microthrombus formation, patchy mucosal ulceration, oedema and haemorrhage. Cytokines and inflammatory markers such as interleukins, tumour necrosis factor alpha (TNFα) and platelet activating factors (PAF) have an important role and enterocyte death may be induced due to imbalance in the pro- and anti-inflammatory mediators and increased pro-apoptotic protease activity. Any part of the small or large bowel may be affected, but the terminal ileum or sigmoid colon is usually involved. Risk factors for the development of NEC are shown in Figure 11.4 .

A recent proposal is that anaemia leads to compromise of the mesenteric blood flow causing intestinal hypoxia and mucosal injury. Transfusion-related reperfusion gut injury (TRAGI) of the hypoxaemic gut has been postulated to predispose anaemic preterm infants to NEC. Probiotics with or without prebiotics to help promote normal gut flora have been studied extensively; their benefit remains unproven.

Current management of NEC is to stop feeds and place a large bore naso/orogastric tube for intestinal decompression, start broad spectrum antibiotics and provide supportive care. Surgical intervention may be required for bowel perforation or failure of medical treatment, with peritoneal drainage at the bedside or resection of non-viable bowel and anastomosis or ileostomy or colostomy.

Periventricular-intraventricular haemorrhage

Periventricular-intraventricular haemorrhage (PVH-IVH) is the most common neurological complication of preterm infants (the incidence is inversely related to gestational age) and is an important risk factor for neurodevelopmental impairment and death. It is caused by rupture of the fragile capillary network in the subependymal (also called germinal) matrix of the developing brain, which overlies the head of the caudate nucleus. The haemorrhage may be confined to the subependymal region (germinal matrix haemorrhage; GMH) or may extend into the body of the lateral ventricles (intraventricular haemorrhage) or involve the cerebral cortical parenchyma (parenchymal haemorrhage). The parenchymal lesion is not an extension of the haemorrhage as previously thought, but is a venous infarct related to obstruction to the venous drainage of the white matter. The parenchymal lesion subsequently undergoes cystic degeneration and by term there is a porencephalic cyst. Intraventricular haemorrhage is typically classified by grade (1–4) based on ultrasound appearances ( Box 11.2 ). Serial cranial ultrasound is used to detect intraventricular haemorrhage, porencephalic cysts and ventricular dilatation or hydrocephalus, a complication of intraventricular haemorrhage. The agreement between ultrasound and autopsy diagnosis has been reported to be >90%.

The pathogenesis is multifactorial but key factors are thought to be the immature germinal matrix capillary network, impaired cerebral autoregulation (failure to maintain cerebral blood flow within the normal limits in spite of wide fluctuations in blood pressure), and abnormal coagulation. This is summarized in Figure 11.5 .

Preterm infants with GMH-IVH have a higher mortality compared to those without. Uncomplicated IVH (grades I and II) can also cause motor and cognitive sequelae, with about 9% risk of developing cerebral palsy. About a quarter of infants with grade III and half with grade IV develop cerebral palsy (CP) at two years of age.

Periventricular leukomalacia

Periventricular leukomalacia (PVL) is periventricular white matter injury, which usually results from a combination of ischaemia from hypoperfusion of the periventricular white matter and inflammation resulting in oligodendroglial injury and failure of myelination (see Fig. 11.5 ). In cystic PVL, there are focal macroscopic areas of necrosis in the periventricular white matter leading to small bilateral periventricular cysts which may be visible on cranial ultrasound from about two weeks of birth. The incidence of cystic PVL is 3% of very-low-birth-weight babies. It has a significant impact on neurodevelopmental outcome with a high incidence of diplegic CP, poor visual spatial skills and low IQ scores. More commonly, the focal lesions are microscopic in size and evolve to small glial scars, which are not usually detected on ultrasound but can be identified on MRI scan. It may well be responsible for some of the characteristic cognitive difficulties many extremely preterm babies have at school age, rather than cerebral palsy.

Osteopenia of prematurity

Preterm infants are prone to poor bone mineralization. This is caused by phosphate deficiency and results in reduced bone mineralization with widening and cupping of the wrists, knees and ribs on X-ray (as with rickets), a failure in linear growth and fractures, particularly of ribs and long bones.

Investigations show a low phosphate with calcium being either normal or elevated initially in conjunction with a markedly elevated alkaline phosphatase (a marker of bone turnover). It can be prevented by giving additional phosphate in parenteral nutrition and by giving oral phosphate or using preterm milk fortifier. Providing sufficient phosphate if on long-term parenteral nutrition can be difficult. Treatment is with oral phosphate and vitamin D supplements.

Retinopathy of prematurity

Retinopathy of prematurity (ROP) is an important cause of visual impairment and blindness in the preterm newborn (see Chapter 30 , Ophthalmology). The risk of its development should be minimized by avoiding hyperoxaemia (maintain oxygen saturation 91–95%), hypoxaemia and wide fluctuations in oxygen saturations.

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is defined clinically on the basis of clinical signs and dependence on ambient oxygen either at 28 days or more usually at 36 weeks post menstrual age. Although oxygen supplementation has routinely been used as a surrogate for assessing the severity of the underlying lung disease, this is subjective and it is not surprising that prevalence of BPD varies markedly between units and this variation has hampered epidemiological research. To rectify this, a stricter physiologic definition has been proposed in which infants receiving less than 30% supplemental oxygen are subjected to a stepwise 2% reduction of supplemental oxygen until they are breathing room air. The outcome of this allows the identification of:

• No BPD – oxygen saturation >90% for 60 minutes in room air

• BPD – if saturation <90% during the observation period

Babies undergoing an oxygen challenge test are monitored for apnoea, bradycardia and increased oxygen requirement. If any of these events occur and require treatment, this is considered a test failure and categorized as BPD. This method provides an objective assessment of the presence and severity of underlying lung disease. Using this physiological definition, the incidence of BPD is only about 10% of very-low-birthweight infants compared to 25% using the standard criteria.

Its pathogenesis is multifactorial and includes:

• Underdeveloped lungs due to prematurity

• Initial injury to the lung due to primary disease process, e.g. RDS

• Ventilator-induced lung injury mediated through barotrauma (high pressure)

• Volutrauma (inappropriately high or low tidal delivery)

• Oxygen toxicity

• Inflammatory cascade

• Inadequate nutrition

The pathophysiology and underlying pulmonary mechanics in infants with BPD includes reduction in lung compliance as well as increased airway resistance leading to increased work of breathing. Later, expiratory flow limitation may become more significant. Functional residual capacity may be reduced initially because of atelectasis but can increase in later stages from air trapping and hyperinflation. More recent findings in extremely premature infants reveal alveolar simplification, a reduction in the overall surface area for gas exchange, and failure of secondary alveolar crest to form normal alveoli (epithelial and endo­thelial cell growth abnormalities).

Once BPD has developed, treatment is only supportive. Most infants ultimately achieve normal lung function and thrive. They are at higher risk of death in the first year of life and long-term complications such as reactive airway disease, increased susceptibility to viral infection, particularly RSV (respiratory syncytial virus) infection, growth failure and neurodevelopmental abnormalities.

Outcomes in preterm infants

This includes survival to discharge from hospital, key morbidities and neurodevelopmental outcomes. With advances in perinatal medicine such as use of ante­natal steroids, advanced ventilation techniques, good intensive care and decreased sepsis, the survival rate of extremely premature infants has increased markedly. However, they are at increased risk of medical problems at and following discharge and of neurodevelopmental problems. Medical problems at and following discharge include increased risk of:

• Poor growth – at discharge, over 90% of VLBW infants are below the 10th centile for weight, length and head circumference. Many show some catch-up growth in the first 2–3 years

• Pneumonia/wheezing/asthma

• Bronchiolitis from RSV (respiratory syncytial virus) infection (hospitalization is reduced by giving RSV monoclonal antibody, palivizumab)

• Bronchopulmonary dysplasia – may require supplemental oxygen therapy at home

• Gastro-oesophageal reflux – especially with bronchopulmonary dysplasia

• Complex nutritional and gastrointestinal disorders – following necrotizing enterocolitis or gastrointestinal surgery

• Inguinal hernias – require surgical repair.

Readmission to hospital during the first year of life is increased approximately four-fold, mainly for respiratory disorders and surgical repair of inguinal hernias.

About 5–10% of VLBW infants develop cerebral palsy, but the most common impairments are learning difficulties. The prevalence of cognitive impairment and of other associated difficulties increases with decreasing gestational age at birth, and is greatest if born at very early gestational age (<26 weeks' gestation). It becomes increasingly evident when the individual child is compared to their peers at nursery or school. In addition, children may have difficulties with:

• fine motor skills, e.g. threading beads

• concentration, with short attention span

• behaviour, especially attention deficit disorders

• abstract reasoning, e.g. mathematics

• processing several tasks simultaneously.

A small proportion also have hearing impairment, with 1–2% requiring amplification, or visual impairment, with 1% blind in both eyes. A greater proportion have refraction errors and squints and therefore require glasses.

Focusing on preterm babies born at 22–25 weeks' gestation, the most recent population-based outcome study from all those births in England in 2006 (EPICure 2) found that of 3133 deliveries, there were 2034 live births, 1686 neonatal admissions and 1041 discharges from hospital.

Survival rates of live-born infants were:

The evolution of disability up to 11 years of the babies born at 22–25 weeks in the UK in 1995 (EPICure 1) is shown in Figure 11.6 . This outcome data is important to inform debate about ethical decisions concerning babies born at gestational age at the limit of viability (see Chapter 35 , Ethics).

Respiratory distress

The clinical features of respiratory distress in newborn infants are tachypnoea (respiratory rate >60/min), nasal flaring, grunting, chest recession with variable cyanosis depending upon severity of illness. The differential diagnosis is wide ( Table 11.3 ).

Meconium aspiration syndrome

Meconium stained amniotic fluid (MSAF) occurs in around 13% of all deliveries, but meconium aspiration syndrome (MAS) occurs only in only a small percentage of them. Aspiration most commonly occurs in utero and with thick MSAF consistency. Of affected infants, 30–60% require mechanical ventilation, 10–25% develop pneumothoraces and 2–5% die. Some 50–70% of infants with persistent pulmonary hypertension of the newborn have MAS as an underlying disorder.

The pathophysiology of MAS is complex, with proximal and distal airway obstruction and air trapping. There is also pulmonary parenchymal injury due to inflammatory cascade, which in turn can lead to surfactant inactivation. Those babies who suffered from chronic hypoxaemia before delivery may also have remodelling of their pulmonary vasculature leading to persistent pulmonary hypertension of the newborn (PPHN).

Of the various management strategies, few have been adequately evaluated. The mainstay is to provide adequate respiratory support to maintain oxygenation in the normal range, prevent air leaks using newer styles of ventilation including high frequency ventilation and treatment of PPHN with inhaled nitric oxide or extracorporeal membrane oxygen (ECMO). Most babies who survive have normal outcome unless MAS was a result of antenatal or intrapartum asphyxia. Such babies are at risk of subsequent neurodevelopmental delay.

Thoracic air leaks

This refers to a collection of gas outside the pulmonary space and includes pneumothorax, pneumo­mediastinum, pneumoperitoneum, and subcutaneous emphysema.

Several conditions increase the risk of pulmonary air leaks:

• Respiratory distress syndrome (incidence 5–20%, the commonest cause)

• Meconium aspiration syndrome (incidence 20–50%)

• Congenital diaphragmatic hernia (14%)

• Previous pneumothorax (risk of developing contralateral pneumothorax 45%)

• Pulmonary hypoplasia

• Pulmonary interstitial emphysema

Air leak syndrome arises via a common pathway that involves damage of the respiratory epithelium, which in turn allows air to enter the interstitial space, causing pulmonary interstitial emphysema. With continued high transpulmonary pressures, air dissects towards the visceral pleura and/or hilum by the peribronchial or perivascular space. Pneumothorax occurs when the pleural surface is ruptured resulting in the leakage of air into the pleural space. Acute pneumo­thorax is a serious complication causing collapse of the underlying lung, mediastinal shift and cardiovascular compromise due to reduced venous return and cardiac output. Diagnosis is made on suspicion from deterioration of clinical condition or increased oxygen requirement, clinical signs (reduced air entry, mediastinal shift), positive transillumination and chest radiograph. Needle aspiration can be used to treat a symptomatic pneumothorax. However, chest tube drainage (thoracostomy) is usually needed for continuous drainage of pneumothoraces that develop in infants receiving positive pressure ventilation, because the air leak may be persistent.

Persistent pulmonary hypertension of the newborn (PPHN)

Under normal circumstances, pulmonary vascular resistance (PVR) falls rapidly after birth. If this does not occur, PPHN ensues and this leads to a variable degree of right-to-left shunt of blood through the foramen ovale and ductus arteriosus, which together with intrapulmonary shunting results in severe hypoxaemia. A similar clinical picture can arise from decreased systemic vascular resistance (SVR) or any condition in which the PVR : SVR ratio is more than one. PVR may be elevated as a result of an ‘appropriate’ response to an underlying acute pathological state (for example, pneumothorax or pneumonia), or as a result of structural abnormalities of the pulmonary vascular bed.

A number of non-structural (and therefore more reversible) factors may also impact on pulmonary vascular reactivity and pressure. Hypoxia, hypercarbia and acidosis cause vasoconstriction and elevate pulmonary artery pressure, and their presence may lead to failure of adaptation from fetal to neonatal (adult type) circulation. Conditions which cause increased pulmonary vascular resistance are of two types:

• Where the pulmonary vascular morphology is normal, as seen in association with asphyxia, meconium aspiration syndrome, severe parenchymal lung disease, and sepsis/pneumonia

• Increased pulmonary vascular resistance associated with morphologically abnormal pulmonary vasculature in association with pulmonary hypoplasia, congenital diaphragmatic hernia and congenital pulmonary airway malformations (CPAM). It may also occur in structurally abnormal heart disease, as for example in left ventricular outflow tract obstruction and anomalous pulmonary venous drainage.

Differential diagnosis of persistent hypoxaemia in the term/near term infant includes:

• Primary lung disease

• Cyanotic congenital heart disease

• PPHN, with or without lung disease.

Echocardiography is helpful in confirming the presence of PPHN and identifying congenital heart disease. Treatment includes general supportive measures, mechanical ventilation and pharmacotherapy including pulmonary vasodilators, mainly inhaled nitric oxide. If there is an inadequate responsive to these measures, extracorporeal membrane oxygenation (ECMO) has been shown to significantly reduce death without causing any increase in adverse neurological outcome in later life.

Developmental anomalies

Congenital anomalies in the lung can be categorized as malformations in:

• The tracheo-bronchial tree

• Distal lung parenchyma

• Abnormalities in the pulmonary arterial and venous trees and the lymphatics

Most pulmonary malformations arise during the embryonic and the pseudoglandular stages of lung development. However, acute lung injury in the neonatal period may alter subsequent alveolar and airway growth and development. The most common pulmonary and extra pulmonary malformations are congenital diaphragmatic hernia (CDH), congenital pulmonary airway malformations (CPAM), tracheo-oesophageal fistula (TOF), bronchopulmonary sequestration (BPS) and congenital hydrothorax.

Tracheo-oesophageal fistula

This occurs in 1 in 3000–4500 live births and results from failure of the process of separation of the primitive foregut into the respiratory and gastrointestinal tract at 3–6 weeks of gestation ( Fig. 11.7 ). It is usually found in combination with various forms of oesophageal atresia, the most common combination being oesophageal atresia with distal tracheo-oesophageal fistula (about 91%). Tracheo-oesophageal fistula without oesophageal atresia (H-type fistula) is extremely rare and usually presents after the neonatal period.