Fetal and Placental Physiology

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.

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.