Foetal circulation

Ductus arteriosus

O2

fully saturated blood

O2

desaturated blood

Lungs

Pulmonary artery

RV

RA Foramenovale

LA

LV

Descendingaorta

Umbilicalarteries

Placenta

Mother

Umbilicalvein

IVC

DV

SaO2

70%

SaO2

55%

SaO2

40%

SaO2

65%

SaO2

60%

Aorticarch

Lower body

Brain and upperbody

BASIC SCIENCE

Foetal to neonatal transition ehow does it take place?Peter Reynolds

AbstractThe rapid adaptation of the newborn baby to respiratory, cardiovascular,

metabolic and neurological independence is only successful because of

a series of evolved critical mechanisms and practised manoeuvres. This

article reviews the physiology of these adaptations. It is particularly

useful for clinicians to understand the underlying physiology as the treat-

ments for maladaptation are based not only on treating the underlying

disease which may be contributing, but also aimed at reversing the

abnormal physiological processes. At the bedside, such understanding

proves to be invaluable.

Keywords Foetal transition; newborn physiology; postnatal adaptation

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

bias is intended.

Introduction

Being born is arguably the most potentially dangerous event that

most of us ever encounter. The foetus develops in an airless,

dark, hypoxaemic environment where full nutrition and waste

needs are met. However his survival depends on a series of rapid

and profound physiological adaptations which must take place at

or soon after delivery. Coupled with an understanding of normal

processes, doctors need to be able to promptly recognize infants

where transition is delayed or abnormal as resuscitation will

invariably be more effective the earlier it is instituted. The

accompanying article will describe the potentially life-threat-

ening consequences of failure to adapt.

How do the environments differ?

In utero is a constant and reliable environment in which there are

minimal fluctuations in temperature, darkness, glucose supply

and nutritional needs, gas exchange and excretion. The upper

airways, lungs and gut are fluid filled. The placenta fulfils the

role of ‘life support machine’ by providing nutrition, regulating

oxygen supply and carbon dioxide removal. The foetal circula-

tion passes through the placenta continuously, there is relative

hypoxia (PO2 3e4 kPa) and there is little perfusion to the lungs

(Figure 1). The temperature is maintained at about 1�C above

maternal core temperature. The foetus passes urine into the

amniotic fluid.

By contrast the ex utero environment is variable and incon-

sistent e temperature variations, periods of fasting and feeding,

requirement for respiratory, cardiovascular, metabolic and

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 1

nutritional ‘independence’ although still dependent on a carer to

help meet these needs. So the normally developed, term newborn

baby faces sudden and dramatic change necessary for survival.

From blue to pink in under a minute

Clearly breathing is fundamental to survival in air, and the

newborn baby has to undergo substantial changes in the lungs

and upper airways to support this.

� Foetal fluid is driven from the lungs and any fluid remaining

in the mouth is usually swallowed.

� There are large increases in lung volume and intrathoracic

pressure, forcing widespread alveolar expansion. This is

facilitated by the release of pulmonary surfactant to reduce

the surface tension at the alveolar airefluid interface.

� Establishment of functional residual capacity and a large

surface area for gas exchange.

As the baby begins to breathe air, the PO2 increases, and as

a result there is a rapid fall in the pulmonary vascular resis-

tance. This in turn greatly increases the pulmonary blood

flow, facilitating better gas exchange in a positive feedback

loop as the baby effectively resuscitates himself, and turns

pink. These adaptations are normally so effective that over

O2

partially saturated blood

saturation of blood at locationSaO2

Figure 1

� 2010 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

90% of babies have established regular air breathing within

a minute of birth.

So how does this all work so well?

Notwithstanding a few hundred thousand years of evolution, the

foetus spends a considerable amount of time preparing for this

moment. The following are key to a successful transition from

foetal to neonatal existence.

Developing sustained breathing

The foetus practises breathing from an early age e 11 weeks, and

keeps breathing until delivery. The breathing movements are

shallow and rapid initially, but by 20 weeks they slow to a rate of

about 50 per minute and become deeper and more regular. They

occur only about 40% of the time, mostly while the foetus is in

rapid eye movement (REM) sleep. If the PCO2 increases, then the

rate increases, but if the PO2 is lowered they decrease and they

become continuous if the PO2 is increased. Foetal breathing is not

just helpful practice for the ‘blue to pink’ transition, it promotes

the correct development of the lungs.

At birth however the newborn needs to breathe continuously.

The traditional view has been that the ‘stress’ of labour and

delivery leads to a transient foetal asphyxia, leading to increased

PCO2 and acidosis. It was thought that this gave a stimulus to

peripheral chemoreceptors to induce the first breath, and then

breathing was sustained through other stimuli such as touch,

cold and sensory stimuli.

However more recent evidence has dispelled this view. In

animal experiments, denervation of the carotid and aortic

chemoreceptors does not inhibit the initiation of respiration, and

continual breathing is actually dependant on the rise in PO2 (as in

the foetus) and is independent of rises in PCO2. This is a classic

example of where adult physiology principles were wrongly

applied to newborns. Furthermore, it has been shown that the

placenta produces specific peptides which inhibit more sustained

foetal breathing until the cord is clamped.

Foetal lung fluid reabsorption

Foetal lung fluid is derived from both interstitial fluid within the

lung and vascular fluid in the lung circulation. All it takes to

draw the fluid from the interstitium into the potential air space is

a �5 mV potential generated by chloride pumps in the pulmo-

nary epithelium. Animal models have shown that it is produced

at a rate of about 2 ml/kg/hour at mid-gestation rising to 5 ml/

kg/hour at term (so a 3.5 kg term baby is producing about 420 ml

a day!). About 50% of foetal lung fluid is swallowed, and the rest

mixes with amniotic fluid.

Production is unaffected by pulmonary mechanics, but is affected

by the presence of hormones e for example adrenaline and prosta-

glandin E2 (PGE2) decrease production of lung fluid. Experiments

have shown that adequate lung expansion by foetal lung fluid is

essential for the growth and development of normal lung structure.

It is thus remarkable how quickly fluid-filled lungs become air-

filled. Previously it was thought that the main process of removal

was a mechanical one as the foetal chest was compressed as it

passed through the vaginal canal. Whilst there is some expulsion

of foetal fluid from the mouth at birth, we now know that the

hormonal process of labour itself is a key factor. An interesting

SURGERY 28:1 2

class of membrane-integrated water channels called aquaporins

(AQPs), with several isoforms found in the human lung epithelium

and in vascular endothelium, appears to be important. Movement

of water via AQPs is efficient, osmotically driven by a sodium

gradient actively generated by Naþ, Kþ-ATPase (adenosine

triphosphatase) in the epithelium. Furthermore, AQP production

and activity appears to be dynamic and responsive to hormones,

pH and other factors. Production of foetal lung fluid begins to

diminish two to three days prior to delivery. It is known that

cortisol increases the level of AQP1 in lung endothelium, as does

maternal treatment with corticosteroids. During labour there is

a 50% decrease in secretion and reabsorption of lung fluid

commences. The precise mechanisms and relative contributions to

this remain to be elucidated, but adrenaline, prostaglandin E2

(PGE2), nitric oxide and lung surfactant are involved and the AQPs

appear to play a key role.

Postnatally the reabsorption of foetal lung fluid is very fast as

the lung epithelium switches chloride ion secretion to sodium

absorption into the pulmonary interstitium. There is increased

expression not only of the epithelial sodium channels and

sodium pumps, but also of AQP4 which may be particularly

important in removal of foetal lung fluid at this critical time.

Surfactant production

Human surfactant comprises 90% of lipid and 10% of protein

and is secreted by type II alveolar cells in the lung. It first appears

in the lung at about 22e24 weeks’ gestation and its main role is

to lower the surface tension on the liquid surface of the alveolus

to facilitate alveolar expansion during inspiration (Figure 2). It is

useful to think about the pressure required to maintain a gas

bubble (even though alveoli are not spherical gas bubbles) which

is related to the surface tension and the size, as described by the

Laplace equation:

DP ¼ 2Y=r

where DP ¼ difference in pressure inside and outside the bubble

(Pa), g ¼ surface tension (N/m) and r ¼ radius (m).

In normal lung extracts, the surface tension is approximately

6 mN/m, thus for an alveolar radius of 50 mm, the DP is 2.4 cm

H2O (where 1 cm H2O ¼ 98.1 Pa). This is about the end expi-

ratory pressure in the normal lung, sufficient to prevent lung

collapse. In extracts of lung deficient in surfactant, the surface

tension is about four times higher, so for the same size of alve-

olus (50 mm) the DP is 9.3 cm H2O.

As the foetus approaches term, there is a surge in surfactant

production around 33e35 weeks’ gestation, with further stimulus

around the time of delivery. The lipid component of surfactant is

80% composed of phosphatidylcholine, of which 60% is 2,3-

dipalmitoyl phosphatidylcholine (DPPC). DPPC is the main

surface tension-lowering lipid. The hydrophobic surfactant

proteins (SP) B and C are also important in lowering surface

tension; SP-A and SP-D are hydrophilic and have a role in immune

defence. Surfactant is recycled by alveolar macrophages and by

endocytosis back into the type II cells. Endogenous and exogenous

steroids increase surfactant production, hence the importance of

giving maternal steroids in threatened preterm labour.

During expiration, the surfactant molecules coalesce tempo-

rarily, reducing the surface tension and thus the pressure

� 2010 Elsevier Ltd. All rights reserved.

Polar structure of surfactant molecules and distribution in the alveolus

hydrophilicpolar head

Surfactant moleculehydrophobic non-polartailsExpiration – molecules

crowd together to reducesurface tension

Inspiration – moleculesseparate, surface tensionclose to water

Figure 2

Blood streaming

To brain, upper body

Pulmonary artery

Pulmonary veinsSVC

IVC Aorta

Figure 3

BASIC SCIENCE

required to maintain alveolar opening is reduced. This enables

the baby to maintain a functional residual capacity in expiration,

and to ensure that the pressures required to re-inflate the alveoli

during inspiration are not so great that exhaustion and respira-

tory failure would ensue.

Conversion from foetal to neonatal circulation

The foetal circulation in Figure 1 is a sophisticated mechanism

that ensures continuous, predictable supply of oxygen and

nutrient and removal of the products of cellular metabolism.

Well-oxygenated blood is directed primarily towards the devel-

oping brain, myocardium and the left ventricle, with less well

oxygenated, low nutrient blood directed towards the right

ventricle. This streaming of blood is vital to ensure optimal

growth and development of the foetus (Figure 3).

The inferior vena cava (IVC) is angled to direct different blood

streams from the lower body (desaturated blood) which is

directed into the right ventricle, and from the ductus venosus

(saturated blood) which crosses the foramen ovale into the left

atrium and the left ventricle.

The superior vena cava (SVC) carries mainly desaturated blood

from the upper body and is angled on the right atrium so that its

flow passes to the right ventricle.

The right ventricle pumps mainly desaturated blood into the

pulmonary artery, most of which then crosses the ductus arteriosus

into the descending aorta. Approximately 10e15% passes through

the pulmonary circulation. Desaturated blood then mixes with

saturated blood, 30% of it passes to the lower body and the rest

returns to the placenta. By allowing blood to largely bypass the lungs,

this prevents excessive strain being placed on the right ventricle.

The left ventricle contains mainly saturated blood, received

from the IVC stream described above. Sixty per cent of this

SURGERY 28:1 3

output is pumped to the brain and upper body, 10% goes to the

myocardium and 30% to the lower body.

The flow of blood is radically altered by a series of events,

commencing with the clamping of the umbilical cord. This

removes the low pressure placental circulation, resulting in an

increase in the left-sided pressure and a drop in the right-sided

pressure. This is accentuated by the taking of the first breath,

which triggers a rapid fall in the pulmonary vascular resistance

and a resulting massive increase in pulmonary blood flow. A

major regulator of vascular tone is nitric oxide (NO), released via

the oxidation of L-arginine by pulmonary vascular endothelium

� 2010 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

nitric oxide synthase (eNOS) in response to increased oxygena-

tion. NO acts via guanylate cyclase to increase cyclic guanosine

monophosphate (cGMP) to cause vasodilation.

The foramen ovale closes within minutes as a result of the

increase in left-sided pressure and the fall in right-sided pressure,

but permanent closure occurs more slowly over weeks to

months.

Simultaneously the flow in two foetal vessels falls dramati-

cally e flow in the ductus arteriosus falls, with functional closure

occurring usually within hours of birth. This closure is mediated

by increased intraluminal oxygen tension and reduction in

prostaglandin E2 causing constriction of ductal vascular smooth

muscle. Closure is also dependent on muscular maturity, nutri-

tional reserves, ATP stores and autonomic nervous system

activity. Once closed, ATP depletion and cell death lead to

permanent remodelling of the ductus wall.

Flow in the ductus venosus is reduced by 95% as the cord is

clamped, again resulting in closure within hours and permanent

closure within 7e14 days. Again, increased oxygen tension is

thought to play a role in the closure of this vessel.

Thus it is pressure changes at birth which are mainly

responsible for the change from foetal to neonatal circulation.

Nutritional independence

The nutritional demands of the foetus are met entirely by the

placenta, and the foetus does not need to control its fluid intake or

output. Glucose is the predominant substrate for the foetus,

provided primarily via the placenta but also, towards the end of

gestation, by gluconeogenesis in the foetal liver as preparation for

neonatal existence. There is also a step-up in ketone body

production at 34e36 weeks’ gestation. The sudden transition from

continuous maternal glucose to intermittent breast milk triggers

mild hypoglycaemia leading to production of adrenalin, growth

hormone and glucagon and a fall in insulin level. This leads to

gluconeogenesis, lipolysis and glycogenolysis so the newborn is

not only able to produce glucose at a rate of 4e6 mg/kg/minute in

the postnatal period, but also to utilize other substrates such as

ketone bodies (acetoacetate and 3b-hydroxybutyrate) and lactic

acid during the postnatal phase and during fasting. Thus neonatal

ketogenesis does not reflect starvation, but is a normal part of the

adaptive response.

Renal maturation

Foetal urine, which comprises about 50% of the amniotic fluid

composition, is extremely dilute. Immature glomeruli have high

SURGERY 28:1 4

vascular resistance and nephrons continue to form until they

reach adult numbers at about 34e35 weeks, so the foetal renal

blood flow and glomerular filtration rate are low. The foetus is in

positive sodium and water balance, which are essential for

growth. After birth, the blood pressure rises as described above

and continues to rise over the first few days. Renal vascular

resistance falls with greater flow and rapid maturation of the

glomeruli takes place. Increased expression of renal AQPs play

an important role in the concentrating capacity of the kidney

which does not fully mature until 18 months.

Gastrointestinal maturation

The foetus starts swallowing amniotic fluid from 11 weeks, and

from 18 weeks’ gestation more complex sucking movements can

be seen. This is not just practice for postnatal life, it is also

essential for the development of the gut in utero. Swallowing

matures at about 37 weeks at the same time as gastric emptying

cycles strengthen and become fewer and more prolonged in

preparation for intermittent milk feeds and satiety.

Ophthalmological adaptation

Foetal eye movements are seen at 16e18 weeks and eyes

develop despite no visual stimulus, suggesting that these

movements are essential to enable the maturation and func-

tional connections.

Haematological adaptation

During foetal life, haemoglobin F (HbF) accounts for over 90% of

the total haemoglobin. HbF has a different dissociation curve to

HbA, binding oxygen with greater avidity. Towards term, there is

increasing production of HbA so that it accounts for 15e50% of

the total at birth, and this continues postnatally so that by 2 years

it accounts for about 98% of the total.

Summary

At birth a series of practised physiological events occur rapidly to

ensure that the foetus can make the successful transition from

the intrauterine fluid-filled environment to the ex utero one. The

reader should now have an insight into these processes, which

will help in further understanding the principles of resuscitation

and disease processes which take place when the adaptive

processes do not proceed adequately. The accompanying article

considers the most common and/or clinically severe examples

when babies fail to adapt to the postnatal environment. A

� 2010 Elsevier Ltd. All rights reserved.