Foetal to neonatal transition — what can go wrong?

Introduction 

Failure to successfully adapt to the world outside the womb is not uncommon, but the clinical effects can be devastating unless recognized and managed quickly. Failure to remove foetal lung fluid, to produce adequate surfactant, or to transition from a foetal circulation can all quickly become life-threatening emergencies, whilst babies who are slow to adjust to intermittent nutrition can develop persistently, and occasionally profoundly, low blood sugar levels.

Triggers for maladaptation 

Whilst it is not always clear why some otherwise healthy babies struggle to make the successful transition to extra-uterine life, there are a number of perinatal risk factors which should make all clinicians have a higher index of suspicion. Perinatal asphyxia in particular is associated with these problems, and whilst babies who exhibit moderate or severe degrees of clinical encephalopathy will be medically unwell, mild asphyxia can be more difficult to determine clinically, as the baby may simply appear to be particularly alert and crying because he is ‘hungry’. Likewise babies with intrauterine growth restriction can appear to be very well, albeit small, and clinicians need to be alert to the fact that significant hypoglycaemia can, in the early stages, be ‘silent’. Even simply being born by caesarean section, or being born mildly prematurely for maternal health reasons or multiple pregnancy, can result in significant morbidity which can be unexpected by the obstetrician and the parent. The most common example of this would be transient tachypnoea of the newborn, which is described below.

Transient tachypnoea of the newborn (TTN) 

TTN, or ‘wet lung’ as it is often described radiologically, arises due to delayed clearance of foetal lung fluid. Given the enormity of the achievement to remove foetal lung fluid and fill the lungs with air in an incredibly short time frame, it is perhaps surprising that TTN is not more common than it is, occurring in about 1% of newborn term infants, although there is probably a clinical spectrum of disease when more mild cases do not require admission to the neonatal unit.

It has been shown that the normal process of sodium absorption, driven by increased expression of the epithelial sodium channels (ENaCs) in response to catecholamines and glucocorticoids, can be switched off pharmacologically and this results in respiratory distress. The clinical disease is even more severe in an ENaC knockout mouse model as it leads to death.

Babies born by elective caesarean section are at particular risk of TTN. Previously it had been thought that this was due to the lack of chest compression in the vaginal canal during vaginal birth. However it is now known that TTN arises because they are not exposed to the catecholamine/steroid increases, described in more detail in the accompanying article.

Babies with TTN present soon after delivery with tachypnoea, expiratory ‘grunting’, nasal flaring, sternal and subcostal recession, and in severe cases they may be cyanosed. Expiratory grunting is a descriptive term referring to the expiratory noise that these babies make. It is caused by the baby closing his glottis during expiration, generating increased intrathoracic pressures (in effect positive end expiratory pressure (PEEP)). Through this the baby endeavours to prevent alveolar collapse and maintain gas exchange, but as he tires this will become less effective and respiratory failure can follow. Blood gases may reveal increased PCO2 with acidosis and mild hypoxaemia, and chest X-ray reveals perihilar streaky opacities (Figure 1).

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Figure 1 Typical chest X-ray of an infant with transient tachypnoea of the newborn (TTN) taken at 4 hours after delivery. This shows perihilar streaky appearances, fluid in the horizontal fissure and well-expanded lung fields to positive end expiratory pressure (PEEP) applied exogenously.

The treatment of TTN involves giving oxygen, intravenous fluids if feeds are not tolerated (though often they are to a certain extent, and we always start milk feeds in these babies contrary to typical textbook advice) and the use of non-invasive respiratory support. Traditionally support has been with CPAP (continuous positive airway pressure), but we find the use of high-flow humidified nasal cannulae to be particularly well-suited in this population as term babies can find CPAP prongs to be uncomfortable and therefore irritating, and they will often try to remove them! Trials of diuretics for TTN have not demonstrated benefit.

The acute phase of TTN resolves quickly in most babies – however the illness can have a long ‘tail’ with some babies requiring supplemental low-flow oxygen for several days. There is also an association with subsequent development of asthma. Parents need to be reassured that the prognosis is excellent and that once resolved, the fluid won't return.

Surfactant deficiency – hyaline membrane disease – respiratory distress syndrome (RDS) 

Usually called RDS, this failure to adapt is usually related to immaturity, so in some ways is not a true failure of normal postnatal adaptation. However whilst the severity and incidence is inversely related to gestational age, it can occur in more mature infants and there is a particular association with maternal diabetes. It is primarily caused by insufficient production of pulmonary surfactant to overcome alveolar surface tension leading to widespread atelectasis. The production and role of surfactant in lowering surface tension is described in the accompanying article.

Secondary surfactant deficiency may be caused by perinatal asphyxia, meconium aspiration, congenital pneumonia and pulmonary haemorrhage.

The clinical presentation of RDS is with tachypnoea, tachycardia, chest recession, grunting and nasal flaring, and in more severe cases there may be cyanosis and increasing frequent apnoeas leading to eventual collapse. The foetus will rapidly progress to respiratory failure followed by circulatory collapse and death unless prompt intervention occurs. Babies whose mothers have not received antenatal steroids may have more severe disease; other antenatal conditions such as pregnancy induced hypertension, chorioamnionitis and intrauterine growth restriction may actually reduce the severity of RDS (although having other important consequences for the newborn).

Blood gases will show raised PCO2 with acidosis, and hypoxaemia. The classical radiological appearance on chest X-ray shows small volume, poorly expanded lungs with a ‘ground glass’ appearance of the lung fields representing widespread alveolar collapse, with larger airways visible as air bronchograms because of the homogeneous appearance of the lungs. It can be difficult to see the cardiac borders (Figure 2).

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Figure 2 Chest X-ray of respiratory distress syndrome (RDS), showing poorly expanded lungs with a homogeneous, ground glass appearance. Air bronchograms are visible in both lung fields and the cardiac outline is difficult to see.

Intratracheal administration of surfactant soon after birth mitigates the severity of surfactant deficiency, but is invasive and clinicians are engaged in a myriad of studies worldwide to minimize the requirement for intubation. The use of immediate CPAP/HFNC (high-flow nasal cannula) after birth has been shown to be effective but not in all cases, and further attempts will continue to define which babies must be intubated and which can be managed in a less invasive way. Likewise small trials of a nebulized surfactant have been encouraging but further work is required before widespread use. Until such time, the author's preference is for Curosurf™ 200 mg/kg administered immediately after birth with early subsequent extubation to CPAP or HFNC, but many different, appropriate, local protocols also exist.

Classically RDS increases in severity over the first two to three days, and ADH secretion means that urine output is reduced and there may be mild oedema, often seen in the eyelids. Recovery is typically heralded by a diuresis, although exogenous surfactant administration seems to modify the disease process.

Persistent pulmonary hypertension of the newborn (PPHN, persistent foetal circulation (PFC)) 

There are several reasons why the pulmonary vascular resistance may not decrease normally after birth. Abnormalities of the lung parenchyma are the most common cause, meconium aspiration syndrome, congenital pneumonia, hyaline membrane disease are all associated with PPHN, which occurs in approximately 1–2/1000 live births. Lung hypoplasia secondary to, for example, congenital diaphragmatic hernia (CDH) is also typically seen. PPHN can also less commonly arise as a primary condition.

As a result of the high pulmonary blood pressure, right-to-left shunting occurs mainly through the foramen ovale and the ductus arteriosus. This results in hypoxaemia which can be profound. Over time there is thickening of the pulmonary vascular smooth muscle and reduced expression of eNOS (endothelial nitric oxide synthase).

Diagnosis of PPHN may not always be straightforward, and doctors need to be aware that in any baby (preterm or term) where the risk factors given above exist, and where oxygenation remains poor despite apparently adequate ventilation, that PPHN may be present. Measurements of preductal (right hand) and postductal (left hand or either foot) saturations may reveal a significant difference due to the right-to-left shunting of desaturated blood through the duct. Echocardiography is also useful to measure tricuspid regurgitation (TR), caused by the high pulmonary arterial pressures, from which an estimation of the right-sided pressure can be made using the Bernoulli equation — RV pressure = RA pressure + (4 × (TR jet velocity)2) — and bowing of the interventricular septum may also be seen. Chest X-ray may show slight cardiac enlargement and reduced pulmonary vascularity.

Treatment is directed at the primary cause, but also at reducing, the pulmonary pressures and shunting. General stabilization will include the need for several interventions which may include paralysis or heavy sedation, volume support, ventilation (although if there is no lung parenchymal pathology beware of over-ventilation), surfactant, antibiotics and, in the case of CDH, surgery to repair the defect. Treatment includes:

Sildenafil, a phosphodiesterase inhibitor type 5, also appears to be a safe and effective treatment, but oral preparations may take several hours to organize and dosing regimes are still being evaluated. It may have a particular role in developing countries where NO availability is more limited. One dosage regime used by the author is to start at 0.5 mg/kg per dose, increasing to 1 mg/kg per dose after 30 minutes if no response, and finally to 2 mg/kg per dose after another 30 minutes if no response. The response is measured by an increase in SaO2 of 10% or increase in PaO2 by 3 kPa. The sildenafil is given 6 hourly at the response dose until the FiO2 (fraction of inspired oxygen) is less than 0.6 and is then weaned by 0.5 mg/kg every 12–24 hours. However routine use cannot be recommended until more definitive evidence is available.

The evidence of the use of magnesium sulphate and adenosine for the treatment of PPHN is sparse and they are not routinely recommended, but may be considered in refractory cases. Older drugs such as prostacyclin, tolazoline and sodium nitroprusside are now not used as they are not as effective and have greater side-effect profiles.

Weaning of treatment, based usually on oxygen requirements, needs to be done cautiously and slowly as the pulmonary vasculature remains labile during the illness. PPHN remains associated with significant morbidity and mortality, and early recognition and treatment remain the mainstay of management.

Patent ductus arteriosus (PDA) 

In the majority of infants, the ductus arteriosus closes soon after birth. In a few term infants (and in many preterm infants) it remains patent, but persistent patency in term infants is rare. In the absence of pulmonary hypertension the flow of blood is from left to right, so that it does not cause problems with cyanosis. However it is commonly detected as a murmur on the postnatal wards in the absence of any other problems, and whilst it may, in term babies, not be clinically significant it will cause parental anxiety when they are told that their newborn baby has a heart murmur. The most common causes (40–60%) of murmurs in the newborn are PDA and mild peripheral pulmonary artery stenosis.

Our local protocol is that if the murmur is clinically insignificant (systolic, soft and localized) with lower limb oxygen saturations >95%, and the general physical examination including pulses is otherwise normal, the baby should be reviewed 24 hours later and can go home and return to clinic if the second examination does not reveal any more concerning findings. The majority of PDA murmurs will have disappeared by 6–8 weeks, and these cases do not usually require echocardiography or other investigations. Less commonly, a PDA will persist and become clinically significant over time as the additional flow causes left-sided strain. Rarely, if left untreated, it could cause cardiac failure.

The management of PDA in the preterm neonate is not considered here as it is not generally considered to be a failure of postnatal adaptation, more a consequence of prematurity.

Transient hyperinsulinaemia 

The clamping of the umbilical cord abruptly ceases the previous continuous intravenous glucose supply that the foetus has been receiving. The foetus has been producing a steady stream of insulin which he must switch off as his blood sugar levels fall, or else he risks severe hypoglycaemia with potential neurodevelopmental consequences. Whilst there are an increasingly described number of genetic conditions that can cause hyperinsulinaemia, there are also perinatal risk factors which can disrupt the normal transition events.

Suboptimally controlled maternal diabetes mellitus is a relatively common cause of abnormal adaptation. The high blood glucose foetal environment causes the foetal pancreas to produce high levels of insulin (in effect to try to ‘control’ the mother's blood glucose level) and when the cord is clamped, this excessive insulin production continues but is usually very transient. Such babies may also be polycythaemic which aggravates the hypoglycaemia. Perinatal asphyxia and intrauterine growth restriction can also trigger more prolonged hyperinsulinaemia which not only inhibits gluconeogenesis and glycolysis, but also removes glucose into insulin-responsive tissues such as adipose tissue, the liver and skeletal muscle. Additionally, insulin inhibits ketogenesis and lipolysis, depriving the baby of additional substrates that he could use for brain metabolism and explaining why the neurodevelopmental outcome of these cases can be so poor if it is not promptly treated. Treatment consists of early provision of high concentrations of continuous intravenous glucose to maintain blood sugars over 3.5 mmol/litre (higher level set as cannot use alternative energy sources). Glucose is usually administered via an umbilical vein or percutaneous long line, and glucose requirements of 10–15 mg/kg/minute are typical in such cases. Initial investigations include measurement of insulin, growth hormone and cortisol levels whilst hypoglycaemic (confirmed on a laboratory sample). Higher or prolonged glucose requirements or diagnostic uncertainty should trigger specialist advice.

‘Transient’ usually means a few days but can be weeks or even months, and can be severe enough to require treatment with diazoxide and chlorothiazide, which in combination are the most commonly used medical treatment for these transient hyperinsulinaemias. Doctors need to be aware of the typical risk factors for hypoglycaemia in the newborn so that investigations and treatment are initiated early.

Summary 

Failure to adapt rapidly to the extra-uterine environment is not uncommon and can lead to medical emergencies which require high levels of intensive care and skill to stabilize and manage. Recognition of those at particular risk of maladaptation, and prompt treatment of babies who are not following the expected postnatal course are the mainstays of treatment. Treatment is based not only on treating the underlying cause but also reversing abnormal physiology, emphasizing the scientific basis on which neonatal care is founded.