Introduction
The subject of fetal and placental physiology encompasses a large and complex branch of the reproductive sciences, and any one of the subsections below could form the subject of an entire textbook. The concepts described here should aid the understanding of how fetal and placental physiology influence clinical assessment of fetal wellbeing, as well as diseases of prematurity and the unwell term neonate.
Understanding of the physiology of the fetus and placenta is inextricably linked to the developmental stage of the pregnancy. Unlike the chapters on maternal physiology, where in the absence of maternal disease, complete structural (anatomical) and functional maturation can be assumed, both must be considered in relation to gestational age (GA) of the fetus at birth. Throughout their development, fetal organ systems continue to modify their function to meet the demands of in utero, compared to postnatal life, while also maturing the fetal body for the transition into neonatal life.
Fetal Development and Preparation for Birth
Cardiovascular
The primitive heart tube is formed during the third week of pregnancy, with a heartbeat detectable from around the third to fourth week. A complex pattern of folding, rotation and remodelling results in the four-chamber heart with multiple arterial and venous connections and which anatomically resembles the adult heart, but contains additional fetal vascular shunts to support the unique requirements of the fetus ( Fig. 4.1 ).
In utero, the source of oxygenated blood is the placenta not the lungs, so oxygen-rich blood is delivered by umbilical vein (UV) to the inferior vena cava (IVC) and right atrium through the first of the fetal shunts, the ductus venosus (DV), instead of the left atrium via the pulmonary vein. The DV allows newly oxygenated blood to bypass the portal sinus supplying the liver significant depletion of its oxygen content, before passing through the second of the fetal shunts, the foramen ovale into the left atrium, then ventricle. Deoxygenated blood from the fetal brain also enters the right atrium via the superior vena cava (SVC) with a downward flow pattern. This angle of entry is different to that of the blood from the IVC, which stays medial and is directed towards the medially placed foramen ovale. This ensures that there is minimal mixing of partially deoxygenated blood from the SVC, which enters the right ventricle, and well-oxygenated blood.
The oxygen-rich blood is pumped by the left ventricle into the ascending aorta and the aortic arch, where it supplies the first four branches of the aorta: the coronary arteries, the brachiocephalic trunk, the left common carotid artery and the left subclavian artery. Partially deoxygenated blood is pumped from the right ventricle through the third of the fetal shunts, the ductus arteriosus (DA), which links the pulmonary artery to the descending aorta: this allows blood to bypass the non-gas-exchanging fetal lungs and high-pressure pulmonary arteries. The DA inserts at the aortic isthmus, just distal to the origin of the subclavian artery, allowing mixing of richly oxygenated blood coming from the aortic arch with partially deoxygenated blood to deliver oxygen to the remainder of the fetal organs via arterial branches of the descending aorta before returning to the placenta via the umbilical arteries, which arise from the internal iliac arteries.
It is important to recognise that the fetal ventricles beat in parallel, with no temporal offset in closure of pulmonary and aortic valve. Additionally, both sides of the heart supply the systemic circulation, unlike in postnatal life. Therefore the convention is to refer to combined cardiac output (CCO) during fetal life rather than to consider left ventricular output equal to cardiac output as in the adult. Fetal ventricular output is unequal, with around 55% of cardiac output coming from the right ventricle and 45% coming from the left in normal conditions, although the balance becomes inverted during fetal compromise. This organisation of the fetal cardiovascular system lends a degree of plasticity to the fetal circulation, allowing it to respond to in utero acute and chronic hypoxic or hypotensive challenges in a different way to postnatal life, when ventilatory responses can also be made, referred to as cardiovascular defence mechanisms or fetal brain sparing.
Cardiovascular Defence Mechanisms
The fetus has several mechanisms to protect itself against acute hypoxia. Firstly, fetal heart rate (FHR) decreases due to parasympathetic nervous system (PNS) activation (causing a deceleration or bradycardia), so reducing myocardial oxygen consumption. CCO is maintained as the longer diastolic filling time increases the stroke volume (SV) and myocardial contractility (Starling’s law), which offsets the effect of reduced heart rate (CCO = SV × FHR). Secondly, blood flow is redistributed away from the peripheries to the central circulation, ensuring adequate oxygenation to brain and heart, known as ‘fetal brain sparing’. Hypoxia and the resultant hypercapnia, sensed by peripheral chemoreceptors, trigger peripheral vasoconstriction due to sympathetic nervous system (SNS) activity. Cerebral vasodilation also occurs under paracrine control, and the combination of high peripheral pressure and low central pressure directs blood preferentially into the central circulation. Finally, oxygen consumption is downregulated: fetal movements and breathing movements cease. These mechanisms mature from the second trimester onwards in line with the maturation of the PNS and SNS; immaturity or failure of these processes is associated with adverse pregnancy outcomes.
However, when exposed to chronic hypoxia, as in fetal growth restriction (FGR), only the fetal brain sparing response persists. The FHR returns to normal, even without recovery of normal oxygenation as PNS activity attenuates, and SNS activity converts to an perpetuated endocrine response. Fetal movements and breathing movements recommence and may be perceived as normal. Ongoing reduction in supply of oxygen and nutrients to the peripheral circulation has adverse effects on the development of organs, notably the kidneys, pancreas and intestines, which mature slower than anticipated, and leads to asymmetric growth restriction. Persistent high peripheral resistance causes remodelling of the cardiomyocytes and resetting of arterial baroreflex functions. Prolonged SNS activation causes dysregulation of the fetal autonomic system, with reduction in FHR variability and blunting of bradycardic responses to further episodes of superadded acute hypoxia. Unsurprisingly, such a wide-ranging series of compromises to maintain central oxygenation, while beneficial in utero, persist postnatally, when they present a risk of adult disease (see later).
Heart Rate Variability
The fetal heart shows beat-to-beat differences in rate, which results in variability in the baseline FHR, excluding periods of acceleration and deceleration. This variability can be assessed using cardiotocography (CTG), can be quantified using computerised CTG as short- or long-term variation (STV, LTV), and is understood to be a powerful predictor of fetal wellbeing. FHR fluctuates under the influence of basal sympathetic and parasympathetic tone, different fetal sleep states, and has some intrinsic diurnal variability. The sympathetic tone predominates for much of the third trimester, with parasympathetic tone only increasing near term. FHR variability increases with advancing gestation and is higher in active sleep states (associated with fetal body and eye movements) and lower in quiet sleep states (Fetal rest). FGR has been suggested to impair the expected increases in FHR variability with GA. Chronic reduction in STV particularly has been associated with adverse pregnancy outcomes, although the mechanisms underlying this remains to be understood. Animal models suggest that autonomic system dysregulation, potentially through an action on the fetal brain stem or desensitisation to catecholamines, plays a key role.
Postnatal Cardiovascular Changes
Following delivery, the source of oxygenated blood shifts from the placenta to the lungs, and the circulation needs to divide into systemic (left-sided) and pulmonary (right-sided) aspects. This change relies on closure of the fetal shunts and removal of the umbilical arteries and veins from the circulation. While the umbilical cord is often clamped and cut to achieve this, this is not the evolutionary solution, and anatomical remodelling of the cord remnant is also required regardless. The Wharton’s jelly which surrounds the vessels in the umbilical cord vessels swells in response to lower temperatures, promoting vascular closure. The umbilical arteries constrict due to serotonin and thromboxane A 2 release within minutes of delivery, achieving functional closure, before degenerating into the median umbilical ligaments over months. The UV remains open after birth, allowing passive flow of blood from the placenta to the neonate, before it degenerates over days into the ligamentum teres hepatis. Finally, the umbilical cord remanent detaches spontaneously leaving the umbilicus.
The DA closes within hours of birth: its smooth muscle is sensitive to the bradykinins, endothelin, and acetylcholine released as a result of respiration and rising oxygen content in the fetal lungs and blood; the effect can be reversed using a prostaglandin-E infusion if patency of the DA is required in the neonate for clinical reasons (usually in the context of congenital heart disease). Until functional closure is achieved, peripheral saturations in the neonate are interpreted as pre-ductal (higher) or post-ductal (lower), and oxygen saturation in the right hand may be compared to the feet to illustrate this difference. Functional closure is followed by anatomical closure: the DA becomes the ligamentum arteriosum over months. Patent DA causes left-to-right shunting (differences in systolic pressure cause reversal of flow) and may result in pulmonary hypertension and right heart failure if untreated.
Breathing changes the relative pressures of the left and right atria, pushing the atrial septum primum against the septum secundum, functionally closing the foramen ovale. The two septa fuse over weeks (anatomical closure): the resulting tissue becomes the fossa ovalis. Patent foramen ovale (PFO) is common, usually of little clinical significance as left atrial pressures typically remain higher than right atrial pressures, preventing shunting, although PFO may allow paradoxical embolus to occur.
The DV shrinks progressively during fetal life, as hepatic blood supply increases with gestation, and collapses at birth once the UV is obliterated. Over months, it becomes the ligamentum venosum, and prolonged patency leads to a portocaval shunt and liver failure, although this remains rare.
Respiratory
The development of the lung in utero is divided into four stages defined by GA: pseudoglandular, canalicular, terminal sac and alveolar.
In the pseudoglandular stage (5 to 16 weeks GA), the embryonic fetal lung develops into five bronchopulmonary segments with branched airways, lined by respiratory epithelium. The pulmonary vasculature, cartilage, smooth muscle and connective tissue also form by 16 weeks. Progressive branching of the airways is directly proportional to the exposure of the endodermal lung buds to surrounding mesenchymal tissue, but also requires the presence of amniotic fluid to expand the lungs. Hence, processes leading to oligo- or anhydramnios during this period of development represent the most significant risk of pulmonary hypoplasia. The mesenchyme is also required to allow the first differentiation of lung epithelium into cilia in proximal airways and alveolar type II pneumocytes in the bronchi.
In the canalicular stage (16 to 25 weeks GA), the gas-exchanging function of the lung develops. Around 20 weeks GA the respiratory epithelium differentiates into type I pneumocytes and inclusion bodies storing surfactant are found in type II pneumocytes. There is a decrease in interstitial tissue thickness, growth of the capillary network of the lungs, as well as elongation and widening of existing airways. Pulmonary blood vessels are formed from mesenchyme, which are thick walled with high vasomotor tone. This stage of development corresponds to the potential for gaseous transfer, and so ex-utero survival to occur, although the respiratory function of the lungs remains underdeveloped. While amniotic fluid remains important in distending fetal lungs during this period and stimulating normal growth, oligohydramnios from this stage onwards produced less profound pulmonary hypoplasia than when it occurs during the pseudoglandular stage.
From 26 weeks until birth, the lungs enter the terminal sac stage, during which the surface area for gaseous exchange increases and interstitial tissue continues to thin. During this phase of development, sporadic breathing (diaphragmatic) movements begin to occur; the resultant stimulation of mechanoreceptors allows the lungs to continue to grow in physical size, and without these breathing movements, pulmonary hypoplasia can still occur.
Surfactant Production
The terminal branches of the primitive airways do not yet resemble adult alveoli, and remain as primitive saccules. Numbers of type I and II pneumocytes increase, as do numbers of inclusion bodies containing pulmonary surfactant. Surfactant is a monomolecular phospholipid layer which coats the bronchioles and small airways of the lung to reduce the work of breathing by preventing the collapse of alveoli and air spaces. The stability of the lung at birth depends on the number of inclusion bodies present in type II pneumocytes and their activity in producing surfactant; without adequate surfactant respiratory distress syndrome (RDS) results. Surfactant production is developmentally regulated, controlled by several hormones, the best known of which are thyroid hormones and cortisol. As such, exogenous glucocorticoids are used antenatally to stimulate surfactant production when early preterm delivery is anticipated. Surfactant can also be deactivated in the term infant by the presence of meconium in the airways, pulmonary haemorrhage, Fetal hyperinsulinemia, and pulmonary or alveolar oedema. RDS secondary to deficiency can be corrected with the use exogenous surfactant more reliably than RDS secondary to deactivation.
Postnatal Respiratory Function
The alveolar stage of lung development typically occurs postnatally but can occur near term. It is marked by the development of primitive saccules into functioning alveoli, usually completed by 5 weeks after birth, although the number of alveoli present continue to increase into childhood.
The alveolar stage overlaps with the changes that are required in the fetal lung at birth to support ex utero life. Until birth, the fetal lungs are hyperextended with fluid, which is produced within the fetal lungs and removed via the trachea. This maintains high extraluminal pressures and keep pulmonary blood flow low. The pulmonary vasculature has a high resistance and a low blood flow, receiving only around 13% of the CCO at 20 weeks gestation. In preparation for delivery, pulmonary fluid drains from lungs into pulmonary vasculature or lymphatics, under the influence of rising endogenous adrenaline, vasopressin and cortisol, or is mechanically displaced by uterine contractions even preceding vaginal delivery. However, this reduction in extraluminal pressure only increases pulmonary blood flow to around 25% of CCO. Historically, both cord occlusion and removal of facial immersion were thought to be involved in increasing pulmonary blood flow, but neither have been shown in translational models to have an effect.
Pulmonary vascular resistance falls due to activation of pulmonary mechanoreceptors in response to insufflation of the lungs with air, mediated by endothelially derived nitric oxide. The resultant 35% fall in pulmonary vascular resistance with the first breaths causes up to a 400% increase in pulmonary blood flow but does not change pulmonary arterial pressure. Dysfunction of this nitric oxide release from the pulmonary vascular bed leads to persistent pulmonary hypertension of the newborn. Pulmonary arterial pressure is partially reduced by exposure to oxygen, and the vasculature becomes more reactive to hyperoxygenation as gestation increases. Ventilation with an increased inspired fraction of oxygen can result in up to a further 10% fall in pulmonary vascular resistance. At the same time, there is a rapid reorganisation of pulmonary vessel walls after birth, with a reduction in wall thickness, and ongoing vascular remodelling mediated by vasoactive nitric oxide, prostaglandin I 2 and enodothelin-1, leading to a permanent reduction in pulmonary arterial pressure.
Renal and Amniotic Fluid
The fetal kidney is functional by around the 12 weeks gestation, although nephrons continue developing until around 36 weeks. Before birth the fetal kidney produces urine but has minimal filtration capacity, relying on the materno-placental interface for removal of waste usually renally excreted. The renal blood flow is around 5% of the CCO of the fetus and the glomerular filtration rate (GFR) at term is around 30% of the adult. The urine produced is isotonic, as is the amniotic fluid in which the fetus is bathed. In animal models, increases in maternal urea, creatinine and haematocrit have been shown to increase the osmolality of amniotic fluid and fetal urine due to increased fetal production of arginine vasopressin, while maintaining a stable amniotic fluid volume.
After birth, the kidney needs to be able to concentrate urine to a greater degree and excrete nitrogenous waste products. Much of the expected 5% to 10% loss in birth weight over the first week of life is due to diuresis from the immature kidney, also resulting in increased sodium excretion. Renal blood flow increases to around 25% of the neonatal cardiac output, which, coupled with increases in surface area and permeability of the glomerular basement membrane, leads to increased blood flow in the kidneys and transfer of plasma into the nephrons. The GFR increases threefold in the first weeks of life, before reaching adult levels around 2 years of age.
Amniotic Fluid Regulation
While the fetal kidney is functional from early second trimester, amniotic fluid volume is not solely dependent on fetal urination and swallowing ( Fig. 4.2 ). During embryogenesis, amniotic fluid generation far exceeds what would be expected related to embryonic size and comes from passage of maternal plasma through the fetal membranes, before becoming proportionate to fetal size in the second trimester. During this phase of development, the amnion, placenta and umbilical cord remain permeable to water and solutes, as does the fetus until keratinisation of the skin at around 20 weeks, allowing diffusion to occur based on hydrostatic and osmotic pressures. After keratinisation of the fetal skin, amniotic fluid is generated by fetal urine (around 300 mL/kg fetal weight/day) and secretion of fluids from the airway due to fetal breathing (around 75 mL/kg fetal weight/day) but removed by fetal swallowing (200 to 250 mL/kg fetal weight/day). While intra-membranous (direct absorption into cord and placenta) and transmembranous transfer of maternal plasma to amniotic fluid still occurs, this accounts for a much smaller proportion of change in amniotic fluid volume than earlier in pregnancy. Amniotic fluid reaches its maximum volume in early third trimester, before declining naturally as the fetus approaches term, despite increasing fetal size. It appears likely that a control mechanism for amniotic fluid volume exists, although this has not been fully elucidated; intra-membranous absorption of amniotic fluid is increased in animal models with oesophageal atresia, and only two thirds of fetuses with oesophageal or intestinal atresia show increased amniotic fluid volume.
