1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Disturbance of normal fetal growth can result in a decrease in weight, or altered body proportion at birth. Fetuses that fail to reach their genetically predetermined growth potential due to intrauterine growth restriction (IUGR) following placental insufficiency are at increased risk for adverse short and long term outcomes that can extend all the way into adult life.1–4 Because of its diverse impacts, placental disease has been the research focus of a variety of biomedical subspecialties. Consequently, considerable information on IUGR has been published outside the obstetric core literature. Many of these observations may not appear salient in the context of clinical prenatal care. However, obstetricians and fetal medicine specialists are the primary caregivers to pinpoint, manage and co-ordinate research in these high risk pregnancies. Research and development on necessary new therapeutic strategies is most likely to be effective if the multiple interactions between fetal condition and outcomes can be identified and successfully modified prenatally. As these relationships are clarified, the focus of clinical fetal medicine is likely to shift from improvement of perinatal mortality and morbidity to enhancing the life-quality in survivors. It is the aim of this review to illustrate the multisystem fetal effects of placental insufficiency and how this information may stimulate future research.

Regulation of fetal growth

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

The placenta is the interface between maternal and fetal compartments. Three overlapping gestational epochs are characterised by important milestones that are necessary for successful maturation of co-ordinated maternal–fetal exchange. Maternal adaptations to pregnancy predominate in the first trimester, while the second trimester is characterised by elaboration of placental function. Successful progression ultimately enables the fetus to reach its growth and developmental potential in the third trimester in preparation to extrauterine life.

Following fertilisation, the cytotrophoblast migrates to form anchoring sites through controlled breakdown of the extracellular matrix by metalloproteinases and localised expression of adhesion molecules. Placental adherence is thus established by the formation of these anchoring villi between the decidua and the uterus. Simultaneously, hypoxia-stimulated angiogenesis contributes to the development of vascular connections between the maternal circulation and the intervillous space. This is necessary to permit a degree of nutrient and oxygen delivery to the growing trophoblast that goes beyond simple diffusion.5,6 With this nutritional and vascular support, the villous trophoblast consisting of a maternal microvillous and fetal basal layer is formed.7 At this point, placental secretory substances have appeared in the maternal circulation and are responsible for several maternal adaptations. These changes include postprandial hyperglycaemia, increased fasting levels of free fatty acids, triglycerides and cholesterol, fat deposition, maternal intravascular volume expansion and relative refractoriness to vasoactive agents.8 Ultimately, these maternal adaptations increase substrate availability and steadiness of nutrient delivery to the placenta. In order to reach the fetal compartment, all nutrients have to pass through the villous trophoblast. For substances such as glucose, amino acids and fatty acids that cannot efficiently pass this bilayer by simple diffusion, several active placental mechanisms regulate transport into the fetal compartment.9–11 Trans-membrane ion pumps such as the Na/H+ pump also develop maintaining cellular homeostasis and therefore normal cellular function.12 With the establishment of a functional fetal circulation, substances that enter the primitive villous circulation are distributed to the fetus via the umbilical vein.13 While the fetoplacental unit may be functional at this point, several additional developments are critical to enable ongoing placental development as well as fetal growth and maturation.

Maintenance of placental function is energy intensive. Under physiologic conditions, the placenta consumes as much as 40% of O2 and 70% of glucose supplied to the uterus.14–16 Optimal fetal growth and development is achieved when nutrient and oxygen delivery is sufficient to allow ideal substrate utilisation in the fetus. This is only possible when the magnitude of nutrient delivery to the uterus exceeds placental demand leaving sufficient surplus for the fetus. The different classes of nutrients that are transported transplacentally have different roles in the fetus. Glucose is the primary oxidative fuel while amino acids are incorporated into proteins. Fatty acids are precursors for bioactive compounds including prostaglandins, thromoboxanes, leucotrienes and are also necessary for maintenance of membrane fluidity and permeability. In addition, long chain polyunsaturated fatty acids such as arachidonic and docosahexanoic acids are essential for normal brain and retinal development. Fetal glucose and amino acids are the primary stimulants of insulin-like growth factors (IGF) I and II, and therefore drive fetal growth and differentiation.17 Leptin co-regulates transplacental amino acid and fatty acid transport and thereby modulates fetal body fat content and proportions.18,19 With advancing gestation magnitude and efficiency of maternal–fetal exchange is increased through developments in all placental compartments (Fig. 1).


Figure 1. In the presence of adequate oxygenation, normal functioning of transplacental transport mechanisms for glucose amino acids and fatty acids ensures availability of substrate for the fetus. Glucose and amino acids are the main stimulants of the insulin, IGF growth axis and stimulate longitudinal fetal growth. In addition, amino acids are utilized for protein synthesis and contribute to the muscle bulk. Fatty acids have roles at many levels serving as precursors for eicosanoids and structural components of cell membranes and myelin sheaths. In the third trimester, accumulation of adipose stores provides a reservoir for essential fatty acids. Endocrine axes including hormones such as cortisol, thyroxin and leptin modulate fetal maturation and differentiation according to substrate availability and may have significant impacts on adult life through fetal programming.

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Invasion of the trophoblast into the maternal spiral arteries results in progressive loss of musculo-elastic media, first in the decidual, then in the myometrial portion of these vessels.20 When this process is successful, a low resistance, high capacitance placental compartment is established that receives up to 600 mL/minute of maternal cardiac output at term.21,22 Throughout the first trimester, there is progressive thinning of the villous trophoblast down to 4 μm by the 16th week. The placental exchange area increases rapidly until 26 weeks, and then at a slower rate, to reach a surface area of up to 12 m2 at term.7 In mid-gestation, intermediary villi appear in the fetal compartment followed by terminal villi which represent the main sites of exchange.23 This mature branching pattern results in low placental blood flow resistance. Through concurrent increases in fetal cardiac output, villous blood flow increases exponentially through the third trimester.7,13 Perfusion matching between the maternal and fetal compartments is further modulated and optimised through placental autoregulation, which is probably mediated through local paracrine factors such as nitric oxide, endothelin, red blood cell adenosine or cyclic guanosine monophoshate and fetal atrial natriuretic peptide. The sum of these changes increases nutrient carrying capacity in maternal and fetal vascular beds and improves the efficiency of active and passive transplacental exchange. Nutrients that have entered the fetal circulation through the umbilical vein are delivered to the liver and heart. Through modulations in shunting through the ductus venosus, 68–82% of umbilical venous blood continues to the liver, while the remainder is distributed to the heart.24 Differential directionality of blood streams entering the right atrium ensures that nutrient-rich blood is distributed to the left ventricle, myocardium and brain while low-nutrient venous return is distributed to the placenta for re-oxygenation and nutrient and waste exchange.25 In addition, several organs modify their blood flow to meet oxygen and nutrient demands through autoregulation.26

If these developmental milestones are reached, placental–fetal growth and development remain closely related throughout gestation27 and follow distinct patterns. The placental growth curve has a sigmoid shape that plateaus in mid-gestation while fetal growth continues exponentially at a rate of 1.5%/day to term.28,29 Initial fetal weight increase is correlated with placental glucose and amino acid transport and therefore mainly due to skeletal and muscle growth. Throughout gestation, essential fatty acids are deposited in the developing brain and retina and account for up to 50% of dry brain weight.30 After 20 weeks of gestation, a notable increase in fatty acid transport and utilisation initiates the deposition of significant fetal adipose tissue.10 From 24 weeks onward, exponential fetal growth and adipose tissue deposition coincide with increasing conversion of glucose into fat, as well as increased utilisation of fatty acids.10,30,31 From 32 weeks to term, fat stores increase from 3.2% of fetal body weight to 16% accounting for the significant reduction in body water content.32,33 Throughout gestation, relative serum concentrations of free fatty acids remain related to maternal dietary intake. However, enhanced transplacental transport of essential polyunsaturated fatty acids and especially their storage in adipose tissue occurs during the period of exponential fetal growth. Therefore, third trimester increase in fetal size is characterised by longitudinal growth accompanied by accumulation of essential body stores in preparation to extrauterine life.

Mechanisms of placental insufficiency

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Conditions that interfere with placental vascular development account for the majority of IUGR pregnancies.34 Depending on the gestational age and extent of interference with placental development, various clinical scenarios may result in maternal, placental and fetal compartments. At the earliest, unsuccessful placental adherence leads to miscarriage. If sufficient supply to the placental mass can be established further differentiation is possible. However, inefficient elaboration of maternal pregnancy adaptation and deficient nutrient delivery pose limitations to placental metabolic and synthetic activity ultimately interfering with the differentiation of endocrine feedback loops and active transport mechanisms. Similarly, deficient placental vascular differentiation and local paracrine vascular control result in altered diffusion properties and perfusion mismatch at the maternal–fetal interface. Eventually, loss of this placental autoregulation promotes vascular occlusion, infarction and permanent structural damage.35 If adaptive mechanisms permit ongoing fetal survival, early onset growth restriction with manifestations in several organ systems and prominent vascular manifestations is the most likely outcome. The spectrum of fetal manifestations is determined by the range of adaptive and/or decompensatory responses in various organ systems. If compensatory mechanisms are unsuccessful, permanent damage or stillbirth ensues. With successful placental/fetal adaptation, insufficient nutrient availability may remain largely subclinical, only to be unmasked through its restrictive effect on exponential fetal growth in the third trimester. Under these circumstances, vascular manifestation may be less pronounced and physical characteristics may be more apparent—decreased adipose tissue, abnormal body proportions at birth may be the only evidence of growth restriction. While the majority of early onset IUGR fetuses are likely to be symmetrically small, a sizeable proportion of subtle third trimester IUGR neonates may escape detection, particularly if population based, rather than customised weight references are used.4 A wide range of observations in varying degrees of placental dysfunction have been made that provide an increasing level of insight into the complex nature of fetal responses to placental insufficiency.

Fetal metabolic responses

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

In mild placental insufficiency, placental glucose and oxygen utilisation initially remain unaltered while fetal demands have to be met by increased fractional extraction. Only when uterine oxygen delivery falls below a critical value (0.6 mmol/minute/kg fetal body weight in sheep) is fetal oxygen uptake and glucose transfer reduced.36 With the onset of fetal hypoglycaemia, pancreatic insulin responses are blunted, allowing gluconeogenesis from hepatic glycogen stores.37–40 A proportion of fetal glucose and lactate is redirected to the placenta for nutrition. Because hepatic glycogen stores are minimal, persistent or declining nutrient deficit results in worsening fetal hypoglycaemia and the ability to maintain fetal oxidative metabolism and placental nutrition becomes limited. At this stage, down-regulation of active placental transport and the need of the fetus to mobilise other energy sources result in more widespread metabolic responses. Limitation of amino acid transfer and breakdown of endogenous muscle protein to obtain gluconeogenic amino acids results in depletion of branched chain and other essential amino acids.41–43 Simultaneously, lactate accumulates due to the limited capacity for oxidative metabolism. Overall, placental transfer capacity for fatty acids remains unaltered unless there is considerable loss of placental substance. However, selectivity of transport mechanisms especially for essential fatty acids may suffer. In the fetal circulation, free fatty acid and triglyceride levels rise due to reduced fetal utilisation and consequently there is failure to accumulate adipose stores. In this setting of advanced malnutrition, the liver metabolises the majority of accumulating lactate. However, the fetal brain and heart can switch their primary nutrient source from glucose to lactate and ketones44—cardiac metabolism has the capacity to remove up to 80% of the circulating lactate.45,46 Acid–base balance can be maintained as long as acid production is met by sufficient buffering capacity of fetal haemoglobin and a matching removal rate by these organs.

These increasing degrees of metabolic compromise have been documented through cordocentesis in human fetuses. Hypoglycaemia and hypoxaemia with decreased levels of essential amino acids occur first. In worsening placental dysfunction, increasing hypoxaemia and lactate production are exponentially correlated to the degree of acidaemia. Overt hypoaminoacidaemia, hypercapnia, hyperlacticaemia and triglycidaemia therefore accompany the development of acidaemia.43,47–49 Amniotic fluid elevation of the glycine/valine ratio and ammonia elevation are additional markers of this state of protein energy malnutrition (Table 1).50,51 This degree of metabolic deterioration is associated with elevated transaminases as evidence of hepatic dysfunction, and may be precipitated by a significant decline of hepatic blood flow as a result of excessive shunting at the level of the ductus venosus.52,53 Fetuses that manifest growth restriction in the third trimester are more likely to have less severe metabolic and acid–base disturbance and only subtle changes in lipid metabolism.54

Table 1.  Summary of metabolic responses to placental insufficiency.
GlucoseDecreased proportional to the degree of fetal hypoxaemia.
Amino acidsSignificant decrease in branched chain amino acids (valine, leucine, isoleucine) as well as lysine and serine. In contrast, hydroxyproline is elevated. The decrease in essential amino acids is proportional to the degree of hypoxaemia.
Elevated amniotic fluid glycine to valine ratio.
Elevations in amniotic fluid ammonia with a significant positive correlation to the ponderal index.
Fatty acids and triglyceridesDecrease in long chain polyunsaturated fatty acids (docosahexanoic and arachidonic acid).
Decrease in overall fatty acid transfer only with significant loss of placental substance.
Hypertriglyceridaemia due to decreased utilization.
Lower cholesterol esters.
Oxygen and CO2Degree of hypoxaemia proportional to villous damage and correlates significantly with hypercapnia, acidaemia and hypoglycaemia and hyperlacticemia.

Fetal endocrine responses

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

The immediate effect of decreased fetal glucose and amino acid levels is the down-regulation of the principal endocrine growth axis involving insulin, IGF I, IGF II and transforming factor beta.55,56 This may be further exacerbated by pancreatic cellular dysfunction that is evident through a decreased insulin/glucose ratio and impaired fetal glucose tolerance.43,57 Elevations in serum glucagon and stimulation of the fetal adrenal axis promote the mobilisation of hepatic glycogen stores and peripheral gluconeogenesis.58 Corticotropin releasing hormone, adreonocorticotrophic hormone and cortisol levels are significantly elevated relating both to the level of hypoglycaemia and to the degree of placental vascular compromise.43,59,60 However, elevations of cortisol down-regulate IGF I activity and may therefore have additional negative impacts on linear growth as well as the potential to limit the capacity for postpartum catch-up growth.61,62 In addition to the glucocorticoid axis, significant elevations of adrenaline and noradrenaline levels are also found in IUGR fetuses, while aldosterone levels appear unaltered.63–65

Disturbances at all levels of thyroid function have been documented in IUGR fetuses and correlate with the degree of hypoxaemia.66,67 Thyroid gland dysfunction may develop as indicated by low levels of thyroxine and T3 despite elevated thyroid stimulating hormone levels. In other instances, central production of thyroid stimulating hormones may be responsible for fetal hypothyroidism.68 Finally, down-regulation of thyroid hormone receptors may limit the biologic activity of circulating thyroid hormones in specific target tissues such as the developing brain.69

IUGR fetuses also show evidence of disturbed endocrine regulation of bone formation. Serum levels of active vitamin D and osteocalcin are significantly decreased and may be responsible for decreased bone mineralisation as well as decreased bone growth.70,71

Fetal vascular responses

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Doppler ultrasound allows the assessment of vascular effects of placental dysfunction in the placental and fetal vasculature. The presence of an early diastolic notch in the uterine arteries at 12–14 weeks suggests delayed trophoblast invasion of the maternal spiral arteries,72 while persistence of ‘notching’ beyond 24 weeks provides confirmatory evidence.73 These findings indicate that blood flow resistance in the maternal compartment remains elevated thus jeopardising uterine perfusion. In the fetal circulation, changes in blood flow are related to placental blood flow resistance, fetal oxygenation, organ autoregulation and vascular reactivity. A reduction of umbilical venous blood flow volume may be the earliest Doppler sign of subtle decreases in fetal villous perfusion.74 Abnormal villous branching, or progressive villous vascular occlusion, results in elevated blood flow resistance that is reflected in the umbilical artery waveform. A decrease of the umbilical artery end-diastolic velocity becomes apparent when some 30% of the fetal villous vasculature is abnormal.75 Absence, or even reversal of end-diastolic velocities (AREDV), can occur after 60–70% of the villous vascular tree is damaged.76 The risk for fetal hypoxaemia and acidaemia is proportional to the severity of umbilical artery Doppler abnormality.77,78

Through modulations in ductus venosus shunting umbilical venous blood increasingly bypasses the liver and is channelled toward the heart. Because of the parallel arrangement of the fetal circulation, changes in cardiac afterload determine how this increased blood volume is distributed in the downstream circulation.79–81 Elevation of right ventricular afterload or decrease in left ventricular afterload allows preferential distribution of cardiac output towards the left ventricle and therefore the coronary circulation and brain.82 This is achieved in two principal ways. Firstly, peripheral arterial vasoconstriction in the trunk and elevated placental blood flow resistance lead to elevations in thoracic and descending aortic Doppler resistance indices (‘hind limb reflex’) and therefore increased right ventricular afterload.83,84 Secondly, a decline in cerebral blood flow resistance (‘brain sparing’)85,86 decreases left ventricular afterload. The changing balance between right and left ventricular afterload results in a decline of the cerebroplacental Doppler index ratio87 or a measurable decline in end-diastolic velocities in the aortic isthmus.88,89 Concurrently, blood flow resistance in peripheral pulmonary arteries,90 celiac axis,91 mesenteric vessels,92,93 renal,94,95 femoral and iliac arteries96 may be elevated. Individual vital organs such as the adrenal glands97 and spleen98 may show evidence of enhanced blood flow. The overall impact of these changes is an improved distribution of well-oxygenated blood to the heart and brain with preferential streaming of descending aortic blood flow to the placenta for re-oxygenation (Table 2). However, such degrees of circulatory abnormalities are associated with elevations of endothelin, vasoactive intestinal peptide, vasopressin and renin–angiotensin levels.99–101 A decrease of the thromboxane to prostacyclin ratio provides evidence of endothelial dysfunction while elevations in nitric oxide production indicate a compensatory response.102,103 It is likely that the degree of vascular reactivity is not only responsible for the high complication rate following invasive procedures, but also contributes to the clinical progression by impacting on blood flow resistance in many vascular beds.104–107

Table 2.  Summary of fetal vascular responses to placental insufficiency.
ResponseFeaturesDoppler evidence
Hind limb reflexDiversion of blood flow away from the carcass at the expense of the lower body. Achieved through increase in right ventricular afterload proximal to the umbilical arteries as well as increased blood flow resistance distally. In addition to centralisation (see below), descending aortic blood flow is also preferentially distributed to the placenta.Elevation of blood flow resistance in the thoracic aorta and iliac artery.
CentralisationA measurable shift in the relationship between right and left ventricular afterload, that results in redistribution of cardiac output in favour of the left ventricle (i.e. the heart and the brain).Decrease in the cerebroplacental Doppler ratio.
Direct measurement of cardiac output. Reversal of end-diastolic velocity in the aortic isthmus. Inferred through absence or reversal of umbilical artery end-diastolic velocity.
Brain sparingCerebral vasodilatation in response to perceived hypoxaemia.Decrease in the carotid or middle cerebral artery Doppler index.
Liver sparingPreferential arterial blood supply to the fetal liver invoked when increased diversion of umbilical venous blood through the ductus venosus jeopardises hepatic perfusion.Measured dilation of the ductus venosus with elevated Doppler index accompanied by a decreased hepatic artery Doppler index.
Adrenal sparingEnhanced adrenal perfusion is triggered as part of the fetal stress response to chronic or acute-on-chronic malnutrition.Decreased Doppler index in the adrenal artery flow velocity waveforms.
Heart sparingMarked augmentation of coronary blood flow in situations of acute-on-chronic hypoxaemia that is achieved through up-regulation of coronary vascular reserve and vasodilatation.Sudden ability to visualize and measure coronary. Blood flow in a setting of deteriorating venous Doppler indices in a premature IUGR fetus.

With further deterioration, ductus venosus shunting away from the liver may compromise hepatic perfusion to a degree that interferes with organ function. Steep elevation in blood lactate and transaminases, as well as sudden compensatory hepatic artery vasodilatation, have been reported under such conditions.52,53,108 When the increased metabolic demands of cardiac work cannot be met, myocardial dysfunction supervenes. Declining cardiac function results in a failure to accommodate venous return and leads to increased venous Doppler indices as evidence of increased central venous pressure.109 In extreme cases, atrial pressure waves may be transmitted all the way back into the free umbilical vein resulting in pulsatile flow. When venous Doppler indices become elevated, a significant rise in atrial natriuretic peptide occurs, probably as a compensatory mechanism to regulate blood volume.110,111 When forward cardiac function declines significantly, coronary vasodilatation becomes exaggerated to recruit all the available coronary blood flow reserve.112 If this fails to support myocardial nutrition sufficiently, cardiac dysfunction may become critical. Cardiac dilatation with holosystolic tricuspid regurgitation and loss of cerebral autoregulation (normalising cerebral Doppler indices) are observed at this level of compromise and indicate loss of cardiovascular homeostasis.113 Elevations of troponin I, S100B protein levels and transaminases provide evidence of cellular damage in the myocardium, brain and liver.114–116 An increased risk for necrotising enterocolitis in survivours has been attributed to bowel injury secondary to chronic underperfusion.117 If the fetus remains undelivered, spontaneous late decelerations of the fetal heart rate and stillbirth ensue.

Fetal biophysical responses

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Normal fetal behavioural development proceeds sequentially with the appearance of movement, coupling, cyclicity of behaviour and finally the integration of movement patterns into stable behavioural states. Autonomic reflexes originating from the brainstem are superimposed on intrinsic cardiac activity and determine fetal heart rate characteristics. With the maturation of the nervous system, modulation of these reflexes through several key elements becomes more refined as gestation advances. These elements include ambient oxygen tension, signals from higher brain centres and the reticular activating system as well as peripheral sensory inputs. Successful maturation of these connections is reflected by decreasing baseline heart rate, increasing heart rate variability and variation, coupling between episodic accelerations with fetal movement and the superimposed impact of behavioural states. This level of central integration of fetal heart rate characteristics with fetal behaviour is normally accomplished by 28 weeks of gestation.118

IUGR fetuses with chronic hypoxaemia exhibit a delay in all aspects of central nervous system maturation, which probably relates to altered myelination as well as changes in central neurotransmitter availability.119–123 The delayed development of behavioural milestones and their central integration with fetal heart rate are primary determinants of lower short and long term variation (on computerised analysis) and delayed development of heart rate reactivity that is observed in IUGR fetuses.124–128 Despite the maturational delay of some aspects of central nervous system function, several centrally regulated responses to acid–base status are preserved. Chronic hypoxaemia is associated with a decline in global fetal activity.129 If the severity of hypoxaemia increases, fetal breathing, gross body movements and tone decrease further and are generally lost when acidaemia develops. Similarly, decreases in fetal heart rate variation and variability as well as onset of decelerations are triggered by worsening hypoxaemia. The decline of these biophysical variables is determined by the central effects of hypoxaemia/acidaemia independent of the cardiovascular status.130–133

Amniotic fluid volume is determined by the effects of hypoxaemia and vascular status on renal perfusion and therefore on fetal urine production. Progressive deterioration of acid–base status and vascular status is accompanied by a progressive decline in amniotic fluid volume.

Haematologic responses

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Fetal hypoxaemia is a trigger for erythropoietin release and stimulation of red blood cell production, through both medullary and extramedullary sites, resulting in polycythemia.134–137 Increased extramedullary haematopoiesis may be physiologic until 28 weeks, but can also be induced by prolonged tissue hypoxaemia and/or acidosis after this gestational age. Extramedullary sites have larger capillary fenestrations that permit the escape of large nucleated red blood cells. Thus, elevated nucleated red blood cell counts correlate with metabolic and cardiovascular status and are independent markers for poor perinatal outcome.138–141 With advancing compromise complex haematologic abnormalities suggest dysfunctional erythropoiesis. Fetal anaemia despite increased nucleated red blood cell release and overt decrease in red cell progenitors could reflect down-regulation of pro-erythropoietic cytokines, vitamin B12 and ferritin deficiency or a combination of these.142–145

Coinciding with the abnormalities in red cell indices, platelet counts also decrease. Although platelet activating factor is inhibited,146 abnormal villous vasculature as indicated by umbilical artery AREDV may pose on overwhelming stimulus for placental platelet activation and aggregation.147 Under these circumstances, the incidence of thrombocytopenia increases over 10-fold.148 In addition to villous vascular abnormality, increasing anaemia and hypoxaemia are independent risk factors for decreasing platelet counts.149 Increase in whole blood viscosity,150,151 decrease in red blood cell membrane fluidity152 and platelet aggregation may be important cofactors for accelerating placental vascular occlusion and dysfunction.

IUGR fetuses also show evidence of immune dysfunction at the cellular and humoral level. Decreases in immunoglobulin and absolute B-cell counts have been long recognised.153 Reduction in total white blood cell counts and neutrophil, monocyte and lymphocyte subpopulations occurs.154 Selective suppression of T-helper and cytotoxic T-cells have been observed.155 These abnormalities are related to the degree of acidaemia and explain the higher susceptibility to infection after delivery.

Multiple avenues of deterioration require an integrated approach

  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References

Several other abnormalities such as vitamin A , zinc and copper deficiency or elevation of the purine nucleotide breakdown product hypoxanthine with increasing hypoxaemia further illustrate the diverse fetal impacts of placental insufficiency.156–160 It is apparent that IUGR is a complex multisystem disease in which the balance and range of compensatory efforts determines the manifestation and progression. Although many fetal responses have been presented in a sequential manner in this review, our knowledge on their spectrum and relationships continues to evolve. There is no uniform clinical picture. For example, vascular reactivity, blood viscosity, red cell plasticity and platelet aggregation determine blood flow dynamics at multiple levels. Peripheral blood flow dynamics, metabolic milieu, filling state of the circulation all influence the efficiency of cardiac forward function and delivery of oxygen, nutrients and waste to their destined sites. Nutrient deprivation, endocrine imbalance and hypoxaemia potentially alter many aspects of organ function and maturation. Deficient body storage limits available nutrient resources after delivery. It is extremely unlikely that all these factors superimposed on the dynamic process of fetal growth produce a uniform clinical presentation and progression.

Currently used fetal evaluation tools are too crude to match the diversity of the possible fetal impacts. This calls for an integrated approach to IUGR on multiple levels. Diagnosis of IUGR becomes most accurate if information about the parental body characteristics, birth order and race are integrated into the growth assessment.4 There is evidence that this approach could be enhanced even further when placental Doppler studies are integrated.161 In the third trimester, integration of middle cerebral artery Doppler and subcutaneous fat thickness measurements are likely to identify those fetuses with more subtle placental vascular abnormality and deficient adipose tissue as their manifestation of IUGR.162,163 Once IUGR is diagnosed prenatally, therapeutic approaches need to be refined for patients identified by this approach and may include maternal antiplatelet therapy and dietary substitution particularly with folate and omega-3 and -6 essential fatty acids.34 Assessment of fetal status for timing of delivery is most comprehensive when evaluations of vascular and behavioural responses are integrated.164 Evaluation of nutritional, metabolic, endocrine and haematologic responses at birth and their relationship to fetal proportions, Doppler and behavioural parameters will refine our understanding of the condition. Neonatal management is most likely to be most effective when knowledge of fetal status and an appreciation of the spectrum of fetal consequences of placental insufficiency are integrated to guide evaluation and management. A uniform prenatal diagnostic standard and a comprehensive integrated management approach that bridges fetal and neonatal periods is most likely to impact on adult health focussing on the small fetus at risk and sparing normally developed babies from iatrogenic interventions. Our current level of knowledge could be an effective platform for launching observational studies and randomised, intervention trials needed to test these hypotheses.


  1. Top of page
  2. Introduction
  3. Regulation of fetal growth
  4. Mechanisms of placental insufficiency
  5. Fetal metabolic responses
  6. Fetal endocrine responses
  7. Fetal vascular responses
  8. Fetal biophysical responses
  9. Haematologic responses
  10. Multiple avenues of deterioration require an integrated approach
  11. References
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