Fetal Physiology PDF

12 chapter 32 | Phys...

12 chapter 32 | Physiology Fetal physiology Aris T Papageorghiou Fetal cardiovascular physiology of contractile tissue (30%) than in the adult (60%). Furthermore, fetal myofibrils are fewer in number and The fetal cardiovascular system develops early in fetal not arranged as parallel fibres but more randomly. life, with blood circulation established by week 4. In this Finally the fetal heart is less compliant (more stiff) than section, the heart and vessels are considered separately, in the adult owing to the constraining effects of the but it is important to realise that development of these lungs and chest wall in the absence of air. Owing to structures is synchronous. these factors, the fetal stroke volume is maximal with little functional reserve. The fetal heart has limited cap- the fetal heart acity to increase stroke volume. The principal way that cardiac output in the fetus is increased is, therefore, by Cardiac output an increase in heart rate. Cardiac metabolism In the adult circulation, the circulatory system is in series and there are no shunts. Therefore, stroke volume In the adult heart, long-chain fatty acids are the main of the right ventricle equals that of the left ventricle and source of fuel, with glucose and lactate being minor fuels cardiac output can be defined in terms of the volume of that are usually only used during hypoxia. In contrast, blood ejected by one ventricle (by convention the left) in the fetal heart lacks the enzyme responsible for trans- 1 minute. This can be described by the equation: port of fatty acids into mitochondria, which means that Cardiac output ¼ Stroke volume  Heart rate lactate and carbohydrates are the primary fuel. In the fetus, there is shunting of blood through the Fetal heart rate ductus venosus, foramen ovale and ductus arteriosus (see fetal circulation below). As a result, the stroke The fetal heart rate (FHR) is determined by depolar- volume of the fetal right ventricle is not equal to the isation of the sinoatrial node, which is under sympa- stroke volume of the left ventricle: in fact about two- thetic influence and inhibited by vagal (parasympathetic) thirds of blood returns to the right ventricle and one- stimulation. Vagal tone exerts the major influence, caus- third to the left ventricle. Therefore, cardiac output in ing a fall in heart rate while sympathetic activity causes a the fetus is measured as the total output of both ven- rise in heart rate and myocardial contractility. Other tricles, termed the combined ventricular output. factors influencing the heart rate include hormonal factors (epinephrine and norepinephrine released from Myocardial function the adrenal medulla), drugs and temperature. Finally, baroreceptors in the aortic arch and chemoreceptors The myocardium grows by cell division (hyperplasia) are sensitive to changes in blood pressure and partial until birth and by cell enlargement (hypertrophy) after oxygen pressures, respectively, and mediate heart rate via birth. Fetal heart myocytes have a much smaller amount the autonomic nervous system (Figure 32.1). 449  se ct io n 1 2 : p hysio log y figure 32.1 Fetal heart rate modulators Bradycardia is defined as a heart rate of less than 110 beats/minute lasting 10 minutes or longer. Occasionally this can be the normal heart rate of the fetus, when it is an isolated abnormality with normal beat-to-beat vari- ability and accelerations. If the bradycardia occurs with previously normal heart rate, it is usually the response to fetal hypoxia, in particular if the heart rate is below 100 beats/minute. Possible causes include cord compression, placental abruption, maternal hypotension or uterine hyperstimulation. Fetal heart block is a rare cause of persistent fetal bradycardia. Beat-to-beat variability The interval between successive fetal heart beats varies in normal circumstances. This beat-to-beat variability is defined as fluctuation in the FHR of at least two cycles The FHR decreases with advancing gestation, a reflec- per minute and it increases with gestational age. Beat- tion of the maturing parasympathetic nervous system. to-beat variability is divided into long-term variability The parasympathetic control also influences beat-to- (LTV) and short-term variability (STV). In clinical beat variability via its interaction with the sympathetic interpretation these two are usually reported together, system (a constant ‘push and pull’) and also changing but computerised cardiotocography (CTG) and fetal vagal impulses. As these FHR patterns are controlled by electrocardiogram (ECG) can measure LTV and STV the para-sympathetic and sympathetic nervous systems, separately. The LTV measures the oscillations or fluctu- the FHR is a reflection of the status of the fetal brain ations of the heart rate within its baseline range (exclud- stem’s medulla oblongata. Pathological events, such as ing accelerations or decelerations) and it is measured in fetal hypoxia, that affect these nerve fibre impulses can cycles/minute. STV is measured in milliseconds and therefore be observed in FHR patterns. Other influ- measures the R–R interval between two consecutive ences, such as the fetal sleep and wake states and drugs QRS complexes on the fetal ECG. Although modern may also have effects. external ultrasound devices use standard CTG to give a close approximation, STV can only be correctly meas- Baseline FHR ured using a scalp electrode. The STV therefore reflects the change in the FHR from one beat to the next and is After the early first trimester, the normal baseline FHR the cause of the rapidly changing display in FHR when decreases with gestational age. At term, the normal FHR using fetal scalp electrode monitoring. is 110–150 beats/minute. In the absence of any input from the autonomic Fetal tachycardia (at least 160 beats per minute for 10 nervous system, the fetal heart will beat at 110–150 minutes) can be normal at earlier gestation. Depending beats/minute without variability. It is the constant on the cause, it is usually mediated via catecholamine modulation of this basal heart rate by the autonomic release, sympathetic nervous system stimulation or lack nervous system that produces the characteristic pattern of parasympathetic stimulation. Common causes are of beat-to-beat variability. This is usually ascribed to the fetal hypoxia (where it is accompanied by an evolving opposing actions of the sympathetic nervous system picture of loss of beat-to-beat variability and late decel- causing an increase and the parasympathetic causing a erations), maternal pyrexia, chorioamnionitis, tocolysis decrease in the FHR, but it may also be caused by using beta-sympathomimetic drugs or fetal heart rhythm repeated, short-lived parasympathetic impulses. Absent abnormalities. or reduced variability may simply be due to preterm 450  c ha pt er 3 2 : f e ta l p h ys i olo g y gestation, but other causes include the fetal sleep cycle, explained by the gradual compression of umbilical vein 12 fetal metabolic acidosis, drugs (central nervous system and then umbilical vein and artery, followed by a grad- | Physiology depressants such as magnesium sulphate, morphine or ual release in reverse order. As the depth of variable alcohol) or pre-existing neurologic abnormality. decelerations is a reflection of baroreceptor stimulation rather than hypoxaemia, fetal wellbeing should be Fetal heart accelerations assessed based on the baseline rate, variability and pres- ence of accelerations. Fetal heart accelerations are defined as an increase of 15 Late decelerations usually begin before the peak of the beats/minute for at least 15 seconds. Accelerations are contraction and are defined as decelerations where the rarely seen in the presence of fetal hypoxia. Conversely, nadir of the deceleration is after the peak of the contrac- the absence of accelerations for more than 80 minutes tion. They usually have a slow recovery phase. During correlates with increased neonatal morbidity. Acceler- uterine contractions, the blood supply in the placental ations are usually caused by fetal movements or stimu- intervillous spaces temporarily stops. This means that lation (for example, vibroacoustic). Accelerations are gas exchange also ceases temporarily and, if there is thought to occur from direct sympathetic stimulation; reduced fetal reserve or uterine overactivity, this leads repeated accelerations during uterine contractions may to a reduction in oxygen absorption (leading to hypox- be due to mild umbilical vein compression leading to aemia) and accumulation of lactic acid and carbon systemic hypotension, which triggers acceleration of FHR. dioxide (and therefore acidosis). Hypoxaemia causes chemoreceptor stimulation and results in parasympa- Fetal heart decelerations thetic slowing of FHR. In addition, fetal myocardial hypoxia leads to inability of the myocardium to respond Fetal heart decelerations are defined as a decrease of 15 and to further bradycardia. This inability of the fetal beats/minute for at least 15 seconds. Decelerations are heart to respond to autonomic nervous system stimula- subclassified into early, variable and late decelerations. tion often leads to a concomitant reduction in variability. Early decelerations occur during uterine contractions. Fetal head compression leads to a transient reduction in transitional events at birth fetal cerebral blood flow, hypoxia, hypercapna and hypertension. Triggering of baroreceptors causes para- After birth, there is loss of the placental circulation and sympathetic stimulation, resulting in a reduction in shunts between the pulmonary and systemic circulations. heart rate. The cardiac output can then be measured as in the adult. Variable decelerations occur without a regular pattern There is a rapid change in the function of the myocar- in terms of relation with uterine contractions, duration dium, with an increase in myocardial contractility. and depth. They are thought to be caused by umbilical During the first weeks, there is a preferential increase in cord compression or stretching. The differential com- left rather than right ventricular mass. In the myocar- pression of umbilical vein and artery may be responsible dium, there is a switch from lactate and carbohydrate for the variable appearance of the decelerations. Umbil- metabolism to using free fatty acids as the preferred fuel. ical vein compression causes a transient reduction of venous return to the heart and reduction in blood pres- sure. Carotid body baroreceptors are triggered and Fetal circulation stimulation of the sympathetic nervous system causes fetal tachycardia. Umbilical artery compression causes An important prerequisite for the understanding of fetal an increase in systemic vascular resistance and a rise in cardiovascular function is the fetal circulation and the blood pressure, and baroreceptor-mediated parasympa- differences with postnatal function. Unlike the adult thetic stimulation causes fetal bradycardia. The fre- heart, the four chambers of the fetal heart are arranged quently observed picture of an FHR deceleration with as a parallel system where the output of the right and left acceleration before and after its occurrence can be ventricles mix. This is due to shunts that normally close 451  se ct io n 1 2 : p hysio log y at birth. There are three such shunts, which are illus- Before birth, the pulmonary circuit is at high resistance, trated in Figures 32.2 and 32.3: mainly becasue of compression of the pulmonary capil- laries by the collapsed lung, the smooth muscle layer of 6 ductus venosus: directs blood to the inferior the pulmonary arteries and the vasoconstrictive effects vena cava of low fetal partial pressure of oxygen (PO2). At the 6 foramen ovale: allows blood to pass from the right to same time, the systemic circulation is at low resistance the left atrium to blood flow, owing to the large placental bed. The 6 ductus arteriosus: connects the pulmonary artery to presence of shunts, high pulmonary resistance and low the aorta. It carries the output of the right ventricle systemic resistance allows blood to be diverted from the owing to the higher pressure of the pulmonary lungs to the placenta. compared with the systemic circulation. figure 32.2 Main characteristics of the fetal circulation showing the fetal shunts Ductus arteriosus Pulmonary vein Superior vena cava V Pulmonary vein Crista dividens IV Foramen ovale III Pulmonary artery II Inferior vena cava Descending aorta Ductus venosus I Portal vein Inferior vena cava Umbilical vein Umbilical arteries Red = fully oxygenated blood | blue = deoxygenated blood | red/blue = mixed blood | Shunts in italic Source: Murphy PJ. The fetal circulation. Continuing Education in Anaesthesia, Critical Care & Pain 2005;5:107–12. 452  c ha pt er 3 2 : f e ta l p h ys i olo g y figure 32.3 Comparison of fetal and adult circulatory systems 12 | Physiology arteriosus A Fetal (parallel) Right Left Body heart heart Foramen ovale B Adult (series) Right Left Body heart heart Adapted with permission from: Blackburn ST. Maternal, Fetal and Neonatal Physiology. 2nd ed. St Louis: Saunders; 2003. An important feature of the fetal circulation is that, ductus venosus has a small diameter (0.5mm at mid- although there is mixing of oxygenated and deoxygenated gestation to about 2mm at later gestation) and this blood, this does not result in homogenous semioxygenated narrowing causes an acceleration in blood velocity. This blood. Rather, preferential streaming of oxygenated blood high-velocity blood flow allows preferential streaming of occurs from the umbilical vein via the ductus venosus and the oxygenated blood coming from the ductus venosus foramen ovale into the left ventricle and proximal aorta, and via the IVC by exerting pressure on the flap-valve of allowing highly oxygenated blood to reach the coronary the foramen ovale. About 30% of the umbilical blood is and carotid arteries. Deoxygenated blood enters the right shunted through the ductus venosus at midgestation atrium from the inferior and superior vena cava, through and this drops to about 20% at 30–40 weeks. This is the tricuspid valve into the right ventricle, pulmonary likely to be because of the development of the fetal liver trunk and ductus arteriosus, entering the descending aorta at later gestations requiring a larger proportion of the and the umbilical arteries. The physiology of the three fetal umbilical venous blood. shunts allows this preferential streaming of blood. foramen ovale ductus venosus The foramen ovale is a communication between right The ductus venosus connects the umbilical vein to the and left atria and is formed by the overlap of the septum inferior vena cava (IVC) at the inlet to the heart. The secundum over the septum primum, producing a 453  se ct io n 1 2 : p hysio log y flap-valve. The higher pressure in the right atrium 41 weeks if normalised for fetal weight. The resistance ensures that the valve is maintained open and allows a to blood flow through the placental vascular bed has no right-to-left flow of blood. Blood enters the right atrium neural regulation and catecholamines have little effect. from the IVC. Within the IVC, blood flow is not uni- form, with the highly oxygenated blood that originated control of fetal circulation from the umbilical vein flowing anteriorly and to the left within the IVC. As blood enters the atrium from the The control of the fetal circulation is complex and IVC, it is divided into two streams by the free edge of poorly understood. The peripheral circulation of the the atrial septum (the crista dividens). The high-velocity fetus is under a tonic adrenergic influence (predomin- oxygenated blood is shunted towards the left, through antly vasoconstriction), probably mediated by circulat- the foramen ovale and into the left atrium. The lower ing catecholamines and in particular by norepinephrine. velocity, less oxygenated blood is shunted towards the Other factors such as arginine vasopressin, the renin– right, mixing with blood from the superior vena cava angiotensin system and prostaglandins also have a role. and coronary sinus. Baroreceptors in the aortic arch and carotid arteries are The net result of this is that blood in the left ventricle sensitive to changes in arterial blood pressure. Chemo- is more highly oxygenated than in the right ventricle. receptors that are sensitive to changes in the oxygen The highly oxygenated blood in the left ventricle is content ensure that, during hypoxaemia, the blood flow pumped into the ascending aorta and 90% of it flows increases to the brain, myocardium and adrenals and into the coronary arteries, left carotid and subclavian decreases to the lungs and lower body. This phenom- arteries; the remaining 10% flows via the aortic arch and enon of arterial redistribution is used in clinical practice into the descending aorta, mixing with blood from the in the monitoring of fetal growth restriction. ductus arteriosus. meeting fetal oxygen needs ductus arteriosus The mixing of oxygenated and deoxygenated blood in The ductus arteriosus connects the pulmonary trunk to the fetal circulation means that oxygen content is lower the descending aorta. This allows blood to bypass the in the fetus than in postnatal life. The mechanisms to immature lungs. After right ventricular contraction, ensure adequate oxygen delivery are: blood flows mainly through this vessel and into the descending aorta, with about 13% of the combined 6 preferential delivery of oxygen-rich blood to the cardiac output entering the pulmonary circulation, to myocardium and brain by presence of shunts support lung development. After 30 weeks, the propor- 6 preferential shunting of oxygen-poor blood to the tion of blood flow to the lungs increases to about 20% of placenta for oxygenation the combined cardiac output. The patency of the ductus 6 high heart rate arteriosus is maintained by the vasodilator effects of 6 fetal haemoglobin, which results in oxygen binding prostaglandins (PGE1 and PGE2) and prostacyclin even at a low PO2, which results in high saturation, (PGI2) and reduced fetal oxygen tension. even at low oxygen tensions. fetoplacental circulation transitional events at birth Blood flow from the fetus to the placenta is via the Shortly after birth, the low-resistance placental circula- umbilical arteries and this represents about 33% of the tion is lost. This loss of blood flow through the placenta combined ventricular output at 20 weeks of gestation means that the systemic resistance is approximately and about 20% after 32 weeks. With increasing fetal doubled and pressures in the aorta, left ventricle and growth, the absolute volume of umbilical blood flow left atrium increase. At the same time, with the first increases throughout gestation, but it is lowest at breath of air there is lung expansion, vasodilation in 454  c ha pt er 3 2 : f e ta l p h ys i olo g y the pulmonary vascular bed due to higher oxygen ten- patent foramen ovale can lead to paradoxical embolic 12 sion and a fall in the pulmonary vascular resistance. events in later life. | Physiology The changes in the relative pressures between pul- monary and systemic systems mean that there is a change from the parallel (fetal) system with placental Fetal respiratory physiology respiration to a neonatal circulatory system in series with pulmonary respiration. Normal fetal lung development depends on normal ana- The fall in pulmonary and rise in systemic pressures tomical development, fetal breathing movements, absorp- cause a massive reduction in blood flow through the tion of lung fluid at birth and surfactant production. ductus arteriosus. The ductus arteriosus then closes spontaneously, on average 2 days after birth, most anatomical development likely because of the increase in oxygen tension. Failure of the closure of the ductus arteriosus can lead to the Lung development occurs in five stages, which are common problem of ‘patent ductus arteriosus’ in the described below and in Table 32.1. postnatal period and this is more common in premature The embryonic phase is characterised by an out- infants or those with low oxygen tensions from continu- pouching of the ventral wall of the foregut. This is ing hypoxia. The ductus arteriosus is sensitive to the separated from the oesophagus by a septum and the influence of prostaglandin E2, which maintains the lung bud divides into the two main bronchi and subse- patency of the vessel. Administration of prostaglandin quently subdivides into the tracheobronchial tree. Pul- synthase inhibitors (such as indometacin) can be used monary arteries, which develop from the sixth aortic postnatally in cases of patent ductus arteriosus for thera- arches, develop alongside these airways. peutic purposes, but can cause severe constriction of the During the pseudoglandular phase, there is continued ductus arteriosus antenatally if administered during the branching of both airways and blood vessels. By 16–17 third trimester. weeks of gestation, this branching is complete and the The ductus venosus usually closes 1–3 weeks after total number of pre-acinar airways will not change birth in term infants. Unlike closure of the ductus arter- further. iosus, it is thought that in the ductus venosus this is During the canalicular stage, the acinar structures are mechanical. Finally, there is functional closure of the formed. These will give rise to the gas-exchanging struc- flap-like opening of the foramen ovale due to the tures of the lung and contain the terminal bronchioles, increase in left atrial pressure. Anatomical closure of alveolar ducts and primitive alveoli. the septum primum and septum secundum occurs in The saccular phase is characterised by enlargement of the majority of cases by the age of one year. Persistent the peripheral airways and thinning of the airway walls table 32.1 Stages of fetal lung development Stage Time period Developmental events Embryonic Conception to 7 weeks of gestation Formation of main bronchi and bronchopulmonary segments Pseudoglandular 7–17 weeks Branching of airways and blood vessels, forming the conducting airways of the lung Canalicular 17–27 weeks Formation of the acini, the gas-exchanging parts of the lung Saccular 28–36 weeks Enlargement of peripheral airways, thinning of the airway walls to form terminal sacs Alveolar 36 weeks of gestation to 2 years Formation of definitive alveoli post-birth 455  se ct io n 1 2 : p hysio log y to form a large number of terminal sacs. This allows a alveolar surfaces. Surfactant protein A and surfactant large increase in the surface area of the lung. protein D have pathogen-recognising functions and aid The formation of definitive alveoli marks the alveolar innate immunity. stage, which continues well into the postnatal period. Glucocorticoids, such as betamethasone and dexa- About 1000 alveoli will form per acinus. methasone, allow accelerated surfactant synthesis and lung maturation. Other factors that have been shown to fetal breathing movements stimulate lung maturity are thyroid hormones, prolactin and catecholamines. Delayed lung maturation is seen in Fetal breathing movements occur from the end of the maternal diabetes and it is unclear whether this is an effect first trimester and increase in frequency and strength of insulin administration or hyperglycaemia. Androgens with gestation. It is thought that fetal breathing move- also delay lung maturation, which may explain why male ments regulate lung growth by lung fluid regulation and infants are more likely to develop respiratory distress than lung cell growth. The importance of fetal breathing female infants of similar gestational age. movements has been demonstrated in animal experi- ments, which have shown that ablation of the phrenic transitional events at birth nerve, which innervates the diaphragm, leads to lung hypoplasia. Fetal breathing movements increase after a Even before the onset of labour, lung fluid secretion falls maternal meal, maternal glucose administration and con- and reabsorption of fluid from the alveolar spaces ditions of acidosis. They are decreased by fetal hypoxia, begins. With the first breath of air into the lungs, an maternal consumption of alcohol and sedative drugs. air/liquid interface is created and surfactant facilitates the formation of the alveolar lining. The pulmonary lung fluid fluid continues to be replaced by air and most has been actively absorbed (across the alveolar wall into capillar- Lung fluid is mainly formed from secretions of alveolar ies and lymphatics) within 2 hours of breathing. The epithelial cells and this begins at the canalicular stage of transition from fetal breathing movements to normal development. Fluid is swallowed or released into the ventilation is triggered by a series of tactile and thermal amniotic fluid, but lung fluid only contributes a small stimuli. The first breaths are important in inflating the amount to amniotic fluid volume. Lung fluid is essential fluid-filled lungs. These initial inflation breaths generate for normal lung development and lung hypoplasia can pressures that are 10–15 times greater than that needed result if lung fluid is decreased or there is an absence of for subsequent breathing. Once the alveoli are aerated, amniotic fluid. breathing requires minimal negative intrathoracic pres- sure to maintain a normal tidal volume and alveolar surfactant surface tension is stabilised by the surfactant released by distension and ventilation of the lungs. Surfactant is a lipoprotein produced by type II pneumo- cytes. About 90% is made of lipids, with two-thirds of Fetal haematology this being dipalmitoylphosphatidylcholine (DPPC). The remaining 10% of surfactant is made of proteins, includ- Fetal haematopoiesis occurs in three overlapping periods: ing surfactant proteins A–D. Surfactant has a major role in pulmonary function. Its main functions include redu- 6 mesoblastic period: in the yolk sac, from 14 days to cing the surface tension part of elastic recoil, thus 12 weeks increasing pulmonary compliance and allowing normal 6 hepatic period: from 6 weeks and peaking from 10 to inflation. The same mechanism prevents lung collapse 18 weeks, when it is the main source of fetal at the end of expiration. The surface tension is mainly haematopoiesis regulated by DPPC, with surfactant protein B and sur- 6 myeloid period: from 8 weeks through to the adult factant protein C allowing surfactant spread over the period. Blood cells develop from stem cells, which 456  c ha pt er 3 2 : f e ta l p h ys i olo g y first appear in the yolk sac but migrate to these fetal figure 32.4 Oxygen dissociation curves for fetal and adult blood 12 tissues where they give rise to primitive cells in the | 100 Physiology first instance, followed by definitive cells. 80 Fetal formation of fetal blood cells haemoglobin Percentage saturation Fetal red blood cell formation occurs independently of 60 Normal the mother and is controlled endogenously. While haemoglobin primitive cells contain embryonic haemoglobin, which 40 is not controlled by erythropoietin (EPO), definitive red blood cells containing mainly fetal haemoglobin (HbF) 20 are regulated by EPO. Fetal EPO, produced initially from the liver and then the kidneys, increases from 0 20 weeks onwards and increased EPO production 0 2 4 6 8 10 12 14 occurs in hypoxic conditions such as placental insuffi- Partial pressure of oxygen (kPa) ciency and severe maternal anaemia. Fetal white blood cell formation begins at 6 weeks in the liver, but they are also produced in the spleen, thymus and lymphatic (2,3-DPG) reducing its oxygen affinity, while HbF does system. Circulating granulocytes increase rapidly in the not bind 2,3-DPG. The differences in affinity between third trimester and at birth they are equal to or greater HbA and HbF can be shown graphically using the oxygen than found in adults. Platelet production begins in the saturation curve (Figure 32.4). The value of P50 is the yolk sac at 6 weeks and in the liver from 8 weeks. partial pressure of oxygen at which Hb is 50% saturated: the lower the P50, the greater the affinity for oxygen. The fetal haemoglobin value of P50 for HbF is 3.6kPa, whereas for HbA P50 is about 4.8kPa. The oxygen saturation curve is therefore Adult haemoglobin (Hb) is made of two alpha (or shifted to the left for HbF when compared with HbA. This alpha-like) and two beta (or beta-like) globulin chains. greater affinity of HbF allows oxygen transfer across the During development, embryonic haemoglobins placenta. Although this also reduces the ability to release (HbGower 1, HbGower 2, HbPortland) are replaced oxygen to the tissues, fetal tissue acid–base balance aids from 10 weeks by HbF, which consists of two alpha oxygen delivery (Table 32.2). and two gamma chains. This is the predominant haemoglobin from 10 weeks and peaks at over 90% of Acid elution of fetal haemoglobin and the haemoglobin at 32 weeks, declines to 60–80% of haemo- Kleihauer test globin at birth and is present until 3–6 months postna- tally. Adult haemoglobin (HbA) is present from HbF is more resistant to alkali denaturation and acid 10 weeks of gestation in small amounts and increases elution than HbA and this forms the basis of the Klei- rapidly in the third trimester. The switch from HbF to hauer test. In this test, a maternal blood smear is pre- HbA as the predominant haemoglobin occurs between pared and an acid bath removes HbA. Staining of HbF birth and 12 weeks of postnatal life. allows pink-stained fetal cells to be seen on microscopy, while HbA-containing maternal cells appear as pale Oxygen affinity of fetal haemoglobin ‘ghost cells’. A simple count allows estimation of the amount of fetal blood in the maternal circulation, as All forms of haemoglobin bind oxygen, but the affinity may occur after a fetal–maternal haemorrhage. with which this occurs varies. An important feature of Persistence of maternally derived HbF in the maternal HbF is that it binds oxygen with greater affinity than HbA. blood cells, as can occur in haemoglobinopathies, needs This is because HbA binds with 2,3-diphosphoglycerate to be taken into account to avoid false interpretation. 457  se ct io n 1 2 : p hysio log y table 32.2 Maternal–fetal PO2 gradient placenta results in a significant increase in blood volume Maternal Fetal and red blood cell mass. Whether this is of benefit is controversial. In preterm infants it has been suggested PO2 80–100mmHg Umbilical artery that hyperbilirubinaemia may result from excessive pla- 45mmHg (20mmHg) cental transfusion; however, hypovolaemia may result if (placental pool) Umbilical vein (30mmHg) immediate clamping occurs. Haemoglobin levels in newborns are usually around 16.5–17.5g/dl with a Hb 12g/dl 17g/dl haematocrit of around 53% and mean white blood cell Blood O2 content 15ml/100ml 25ml/100ml counts are 15000/mm3. Red blood cell and white blood cell counts increase in the initial hours after birth before Hb, haemoglobin O2, oxygen, PO2, partial pressure of oxygen decreasing by day 4–7. Platelet counts are similar to Postnatally the ability of the Kleihauer test to assess fetal adult values but increase throughout the first month of red cells in the maternal circulation will depend on the postnatal life. Platelet activity is reduced in the neonate persistence of the cells. If the mother and fetus are ABO, and the risk of bleeding and coagulopathy is increased, incompatible fetal red blood cells may be eliminated particularly in preterm infants. This is compounded by from the maternal bloodstream very quickly and a Klei- the low levels of vitamin K-dependent clotting factors. hauer test should be performed as soon as possible in these circumstances. Fetal renal physiology fetal immune development Functionally, urine production begins at 9–10 weeks Precursors of the immune system develop in the embry- and reabsorption in the loop of Henle begins by 12 onic yolk sac and migrate to the liver, spleen, bone weeks. Unlike the adult (where about 20% of cardiac marrow and thymus. Lymphoid stem cells give rise to output reaches the kidneys), only 2–3% of fetal cardiac B lymphocytes (from the liver) and T cells (from the output goes to the kidneys; fetal fluid and electrolyte thymus). B cells appear in peripheral blood from balance is mainly under the control of the placenta 12 weeks and mature T cells from 14 weeks. Although rather than the kidney. Urine production is present immunoglobulin synthesis begins at 12 weeks of gesta- and after 18 weeks fetal urine is the major contributor tion, production remains low throughout fetal life and to amniotic fluid, while before 16 weeks most amniotic the rise in immunoglobulin (Ig) G seen in the second fluid is produced by the fetal skin and placenta. There- trimester is caused by placental transfer of maternal fore, reduced urine production from midgestation is an IgG. As IgM does not cross the placental barrier, any important cause of reduced amniotic fluid volume and increase in IgM is fetal in origin and may be due to can be seen in fetal growth restriction. intrauterine infection. Although neutrophils and macro- The fetal kidney has limited ability in concentrating phages can be isolated from 14 weeks, their levels in fetal urine and fetal urine is hypotonic. The ability to concen- peripheral blood remain low until the last trimester. trate urine increases with fetal renal maturation and From 32 weeks, the function of the immune system advancing gestation. Although the number of nephrons rapidly approaches that of a term infant, whereas before is similar to the adult from about 34 weeks of gestation, this time the system is largely immature, an important their functional maturity is not established until post- aspect of care of the preterm infant. natal life. Preterm infants are therefore less able to maintain fluid and electrolyte balance. transitional events at birth transitional events at birth The neonatal blood parameters change depending on the degree of placental transfusion. Late clamping of the After birth, there is a dramatic increase in renal blood cord and holding the newborn below the level of the flow to the kidney, increasing from 2–3% of combined 458  c ha pt er 3 2 : f e ta l p h ys i olo g y ventricular output in the fetus to about 10% of cardiac table 32.3 Functional development of the fetal gastrointestinal 12 output at age 4 days. With renal blood flow, glomerular system | Physiology filtration rate also increases at birth and this continues Development Gestational age (weeks) with a doubling by 2 weeks of neonatal life. SUCKING AND SWALLOWING Swallowing 10–14 Gastrointestinal physiology Immature suck–swallow 33–36 STOMACH Although nutrition is provided by the placenta, func- Motility and secretion 20 tional development of the gut during fetal life begins early in gestation and swallowing movements are seen PANCREAS from 12 weeks. The rate of swallowing increases with Zymogen granules 20 age and reaches 250ml/day at term, making swallowing LIVER an important aspect of amniotic fluid volume regula- tion. Intestinal villi start developing from 7 weeks of Bile metabolism 11 gestation and by 20 weeks these are well developed. Bile secretion 22 Peristaltic motility develops gradually and is mature by SMALL INTESTINE the third trimester; intestinal absorptive processes are only partially available before 26 weeks of gestation. The Active transport of amino acids 14 fetal liver is mainly a haemopoietic organ during intra- Glucose transport 18 uterine life and functionally it is the placenta that Fatty acid absorption 24 handles metabolic processes. Liver and pancreatic secre- tions develop early in gestation. Although the nutri- Adapted with permission from: Blackburn ST. Maternal, Fetal and Neonatal tional value of amniotic fluid and cells are in doubt, Physiology. 2nd ed. St Louis: Saunders; 2003. these enzymes are thought to play a role in preventing bowel obstruction due to cellular debris. Functional development of the gastrointestinal tract is summarised associated stress factors (for example, hypoxia and in Table 32.3. infection). Meconium-stained amniotic fluid is present in about 12% of all deliveries, but its incidence increases with meconium gestational age and it is present in 30% of post-term pregnancies. Meconium aspiration syndrome occurs in Meconium is composed of water (about 75%), intestinal about 5% of infants with meconium-stained amniotic secretions, squamous cells, lanugo hair, bile pigments fluid. It is dependent on the presence of both meconium (responsible for the green colour), pancreatic enzymes and fetal hypoxia and is thought to be caused by gasping and blood. It appears from about 10–12 weeks of gesta- actions of the fetus causing aspiration of meconium into tion and slowly moves into the colon by 16 weeks. the lungs. This causes a combination of mechanical Meconium passage is a normal developmental event and blockage of small airways and production of chemical 98% of newborns pass meconium in the first 48 hours pneumonitis by the inhaled meconium particles. In after birth. addition, meconium directly inhibits pulmonary func- Although the relationship between fetal hypoxia and tion by displacing surfactant and inhibiting its function increased intestinal peristalsis has been considered for and promotes lung tissue inflammation by activating many years, the precise mechanism of how stress or neutrophils and macrophages. If postnatal hypoxia con- hypoxia results in meconium passage is unclear. The tinues, meconium contributes to pulmonary vasospasm, effects of meconium depend on the concentration of hypertrophy of the pulmonary musculature and pul- meconium, duration of exposure and the presence of monary hypertension. 459  se ct io n 1 2 : p hysio log y transitional events at birth Myelinisation begins in midgestation (around 24 weeks), peaks at birth and, especially in the corpus Gut maturation continues postnatally and is partly callosum, continues throughout childhood. Biochem- under the influence of gastrointestinal hormones and ical activity in the fetal brain is evident from 16 weeks. neuropeptides. A major stimulus for their release is Spontaneous electroencephalographic activity appears commencement of enteral feeding and human milk, at around 20 weeks and becomes synchronised at 26 which is rich in trophic factors and antibodies, is the weeks, while wake/sleep cycles are seen from 30 weeks. preferred feeding option. peripheral nervous system Fetal skin physiology Derived from cells of the neural crest, ganglia appear at 4–5 weeks of gestation. Nerve fibres grow from the Skin is permeable to water until midpregnancy, with a spinal plate and form the ventral root (motor fibres) net loss of water across the skin by transudation. Ini- and dorsal root (sensory fibres). tially, the water content of skin is close to 100% but this Motor movements depend not only on innervation begins to decrease from 20 weeks owing to keratinisation but also intact muscle cells; body movements appear in the epidermis and an increase in connective tissue and from 7 weeks and limb movements from 9 weeks of vernix caseosa. This thin fatty film forms from 17 weeks gestation. Motor movements become more coordinated and is made up of sebaceous gland secretions and des- as gestation advances and complex movements are seen quamated skin cells. Although this film prevents loss of in the third trimester. Maternal perception of movements water and electrolytes, the fetal skin continues to con- occurs from around 16 weeks in multiparous women but tribute to amniotic fluid production. may be as late as 24 weeks in the first pregnancy. There is a steady increase in movements, but a gradual reduction near term is common, most likely owing to reduced Fetal neurological system space within the uterus. A marked reduction in the quality or frequency of movements experienced by the The fetal central nervous system is one of the earliest mother can reflect fetal hypoxia (as in fetal growth systems to begin development but also the latest to restriction) or fetal anaemia (as in rhesus disease). mature. Lower level structures, including the basal gan- The earliest sensory abilities are touch sensation and glia, thalamus, midbrain and brainstem form first, while afferent synapses develop from 10 weeks. However, the cerebrum and cerebellum form later. Neuronal pro- spinothalamic connections do not occur until midgesta- liferation, migration, organisation and myelination are tion and myelination not until 30 weeks. The develop- overlapping processes that continue throughout fetal life ment of smell, taste, hearing and vision all begin at into the postnatal period: in particular, glial prolifer- about 23–26 weeks. ation remains active throughout childhood. Neurons proliferate from 8–20 weeks of gestation, fetal pain with the most active period from 12–16 weeks. Neurons begin migration from the periventricular germinal areas Although nociceptors first appear at 10 weeks of gesta- from 8 weeks, in a radial fashion into areas where grey tion in the fetus, their presence alone is not sufficient for matter is established. By 20 weeks, the cortex has the fetus to experience pain – electrical activity also has acquired the majority of neurons, while, in the cerebel- to be conducted from the nociceptors via the spinal cord lum, proliferation and migration continue until 1 year to the brain. postnatally. Organisation, including synapse formation, Although the fetus may display a physiological stress begins at 12 weeks of gestation and peaks in the last response to painful stimuli (activation of the fetal trimester of pregnancy. Alignment and orientation of hypothalamic–pituitary–adrenal axis) from around cortical neurons continues well into the postnatal period. 19 weeks and the cortex is thought to be able to process 460  c ha pt er 3 2 : f e ta l p h ys i olo g y sensory input from 24 weeks, controversy remains as to the fetus. The amount of amniotic fluid is about 50ml at 12 whether the fetus can perceive noxious stimuli at the 12 weeks and 150ml at 16 weeks. It then increases by | Physiology cortical level as painful. Using activation of the hypo- roughly 50ml/week until 34 weeks (about 1000ml) thalamic pituitary–adrenal axis as a surrogate indicator before a decrease to about 500 ml at term. of fetal pain has limitations. Pain perception during fetal (or indeed neonatal) development does not engage the production and removal same structures involved in pain processing as those used by human adults and this supports the argument There are six areas where exchange of amniotic fluid that the fetus does not feel pain until late gestation. occurs: the fetal renal system production, lung, skin, gastrointestinal tract, across the uterine wall and across transitional events the placenta/membranes and umbilical cord. Amniotic fluid production is initially from the amniotic mem- The main transitional event in nervous system activity is brane and transfer via the fetal skin occurs before during the change from the intrauterine to the extra- keratinisation begins at 20 weeks. In the second trimes- uterine environment. The nervous system continues to ter, the two primary sources of amniotic fluid are fetal mature, but requires adaptation to independent urine and lung liquid. Fetal urine is the main contribu- breathing, oral nutrition, thermoregulation by the auto- tor of amniotic fluid at this stage, with reduced produc- nomic nervous system, movements against gravitational tion owing to urinary tract abnormalities leading to effects and adaptation to sensory stimuli by the motor oligohydramnios, which is not usually evident before and sensory systems. 16 weeks. Amniotic fluid removal is caused by fetal swallowing and absorption into fetal blood across the surface of the Physiology of amniotic fluid placenta. Passive exchanges across the fetal skin and umbilical cord and via the transmembranous pathway Amniotic fluid has protective, thermoregulatory and (across the uterine wall) are not significant during the nutritive effects and allows movements and growth of latter half of gestation (Figure 32.5). figure 32.5 Summary of fluid flow in to and out of the amniotic space in late gestation figure 32.6 Composition of amniotic fluid Fetus Lung fluid Urine flow 340 800–1200 Intra- Swallowing membranous 500–1000 170 Head 200–500 25 170 Amniotic fluid Transmembranous 10 Arrow sizes are proportional to the flow rate | All measurements are in ml/day 461  se ct io n 1 2 : p hysio log y composition to amniotic fluid, the osmolarity decreases slightly com- pared with fetal blood. After keratinisation of the fetal Over 98% of amniotic fluid is water. Minerals (mainly skin, amniotic fluid osmolarity decreases further. The sodium, potassium, chloride), carbohydrates (glucose, osmolarity of the amniotic fluid decreases with advan- fructose), proteins (albumin and globulins), lipids cing gestation, owing to the contribution of hypotonic (chol-esterol, lecithin), hormones, enzymes (mainly fetal urine, and sodium as well as chloride levels alkaline phosphatase) and suspended materials (bile decrease with improving fetal kidney function. Amni- pigments, skin debris, vernix caseosa, lanugo hair) make otic fluid is thought to have antibacterial properties, up the remainder. The composition varies with gesta- mainly due to the presence of lysozymes and peroxidase tional age; as fetal urine production begins to contribute (Figure 32.6). further reading M O O R E K L, P E R S A U D T V N. The Developing Human: Clinically Oriented Embryology, 8th ed. St Louis: Saunders; 2007. B L A C K B U R N S T. Maternal Fetal and Neonatal Physiology, 3rd ed. St Louis: Saunders; 2007. Royal College of Obstetricians and Gynaecologists. Fetal Awareness – Review of Research and Recommendations for DU P L E S S I S A J. Cerebral blood flow and metabolism in the Practice. Report of a Working Party. London: RCOG; 2010. developing fetus. Clin Perinatol 2009;36:531–48. M A R T I N C B. Normal fetal physiology and behavior, and adaptive responses with hypoxemia. Semin Perinatol 2008;32:239–42. 462