BASIC SCIENCE

Foetal to neonatal transitione what can go wrong?Peter Reynolds

AbstractFailure of the foetus to make a successful transition from the intrauterine

environment can be life threatening. Prompt recognition of problems can

enable critical, life-saving interventions to take place. Whilst there are

numerous adaptations of the newborn at birth, this article focuses on

those which are the most common and/or clinically urgent, and describes

not only the conventional treatments but also emerging therapies. The

article therefore covers maladaptive processes in the normal newborn,

not those with genetic or other congenital problems which cause malad-

aptation due to the underlying disease. Likewise, it is outside the scope

of this article to discuss neonatal jaundice, as it is arguably not a malad-

aptation, and may also not be the ‘design flaw’ that it has previously been

considered to be, as bilirubin may have a physiological role as the main

antioxidant in the newborn in the first week of postnatal life. I have

described five neonatal conditions: transient tachypnoea of the newborn,

respiratory distress syndrome, persistent pulmonary hypertension, which

can all cause significant hypoxaemia, patent ductus arteriosus which is

usually not clinically significant but is common and often causes consider-

able parental anxiety, and transient hyperinsulinaemia which can cause

profound hypoglycaemia.

It is recommended that the reader has an understanding of the normal

physiological adaptive processes which are described in greater detail in

the accompanying article.

Keywords Failure of postnatal adaptation; hyaline membrane disease;

neonatal hyperinsulinaemia; persistent foetal circulation (PFC); persistent

pulmonary hypertension of the newborn (PPHN); respiratory distress

syndrome (RDS); surfactant

The foetus is referred to in the male gender for convenience; no

bias is intended.

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,

Peter Reynolds MBBS PhD FRCPCH is a Consultant Neonatologist at St Peter’s

Hospital, Chertsey, Surrey, UK. Conflicts of interest: none declared.

SURGERY 28:1 5

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 encephalop-

athy will be medically unwell, mild asphyxia can be more diffi-

cult 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 reces-

sion, 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).

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

� 2010 Elsevier Ltd. All rights reserved.

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.

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.

BASIC SCIENCE

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 e

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 e hyaline membrane disease e 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 post-

natal 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 dia-

betes. It is primarily caused by insufficient production of pulmo-

nary 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, tachy-

cardia, 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).

SURGERY 28:1 6

Blood gases will show raised PCO2 with acidosis, and hypo-

xaemia. 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 broncho-

grams because of the homogeneous appearance of the lungs. It

can be difficult to see the cardiac borders (Figure 2).

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 mini-

mize 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 1e2/

1000 live births. Lung hypoplasia secondary to, for example,

� 2010 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

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 desa-

turated 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

d RV pressure ¼ RA pressure þ (4 � (TR jet velocity)2) d 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-venti-

lation), surfactant, antibiotics and, in the case of CDH, surgery to

repair the defect. Treatment includes:

1. Enhancement of left-sided blood pressure using inotrope

infusions. Dopamine and dobutamine are most commonly

used at doses of 10e20 mg/kg/h; adrenaline and noradren-

aline may also be useful in difficult cases.

2. Reduction of right-sided pressures. Inhaled nitric oxide (iNO)

is widely available in level 3 units in the UK and, if PPHN is

suspected in term infants, iNO should be instituted early as

50% or more of cases will respond, and it has been shown to

reduce death and the need for ECMO (extracorporeal

membrane oxygenation). However its use in PPHN associ-

ated with CDH is not recommended as it is associated with

a worse outcome for reasons that are not yet clear. The

current recommended starting dose is 20 parts per million

(ppm) in term infants. Although PPHN may be present in

preterm infants, studies have failed to show any benefit of

iNO in disease modification or reduction in chronic lung

disease.

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

SURGERY 28:1 7

12e24 hours. However routine use cannot be recommended

until more definitive evidence is available.

The evidence of the use of magnesium sulphate and adeno-

sine 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.

3. Optimization of alveolar ventilation through use of 100%

oxygen, high PEEP and appropriate ventilation settings.

There is no evidence that high frequency oscillation venti-

lation is superior to conventional ventilation.

4. Improvement of pulmonary blood flow through normaliza-

tion of arterial pH (range 7.35e7.45) using sodium bicar-

bonate provided CO2 clearance is adequate. Deliberate

over-ventilation to induce respiratory alkalosis with low

PCO2, as used to be commonly recommended, is now

considered less desirable since low PCO2 is associated with

reduced cerebral blood flow and ventilator-associated

alveolar damage should be minimized.

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 (40e60%) 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 6e8 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

� 2010 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

else he risks severe hypoglycaemia with potential neuro-

developmental consequences. Whilst there are an increasingly

described number of genetic conditions that can cause hyper-

insulinaemia, there are also perinatal risk factors which can

disrupt the normal transition events.

Suboptimally controlled maternal diabetes mellitus is a rela-

tively 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 hypo-

glycaemia. 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 keto-

genesis 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 main-

tain 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 10e15 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

SURGERY 28:1 8

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. A

FURTHER READING

Abman SH. Recent advances in the pathogenesis and treatment of

persistent pulmonary hypertension of the newborn. Neonatology

2007; 91(4): 283e90.

de Rooy L, Hawdon J. Nutritional factors that affect the postnatal meta-

bolic adaptation of full-term small- and large-for-gestational-age

infants. Pediatrics 2002 Mar; 109(3): E42.

Rawlings JS, Smith FR. Transient tachypnoea of the newborn. An

analysis of neonatal and obstetric risk factors. Am J Dis Child 1984

Sep; 138(9): 869e71.

Sweet D, Bevilacqua G, Carnielli V, et al. European consensus guidelines

on the management of neonatal respiratory distress syndrome.

J Perinat Med 2007; 35: 175e86.

� 2010 Elsevier Ltd. All rights reserved.