BJOG: an International Journal of and DOI: 10.1111/j.1471-0528.2004.00273.x October 2004, Vol. 111, pp. 1031–1041

REVIEW

Fetal responses to : an update

Introduction hypoxia-stimulated angiogenesis contributes to the devel- opment of vascular connections between the maternal Disturbance of normal fetal growth can result in a circulation and the intervillous space. This is necessary decrease in weight, or altered body proportion at birth. to permit a degree of nutrient and delivery to the that fail to reach their genetically predetermined growing trophoblast that goes beyond simple diffusion.5,6 growth potential due to intrauterine growth restriction With this nutritional and vascular support, the villous (IUGR) following placental insufficiency are at increased trophoblast consisting of a maternal microvillous and risk for adverse short and long term outcomes that can fetal basal layer is formed.7 At this point, placental se- extend all the way into adult life.1–4 Because of its diverse cretory substances have appeared in the maternal circu- impacts, has been the research focus of a lation and are responsible for several maternal adaptations. variety of biomedical subspecialties. Consequently, consid- These changes include postprandial hyperglycaemia, in- erable information on IUGR has been published outside the creased fasting levels of free fatty acids, triglycerides and obstetric core literature. Many of these observations may cholesterol, fat deposition, maternal intravascular volume not appear salient in the context of clinical . expansion and relative refractoriness to vasoactive agents.8 However, obstetricians and fetal medicine specialists are Ultimately, these maternal adaptations increase substrate the primary caregivers to pinpoint, manage and co-ordinate availability and steadiness of nutrient delivery to the pla- research in these high risk . Research and centa. In order to reach the fetal compartment, all nutri- development on necessary new therapeutic strategies is ents have to pass through the villous trophoblast. For most likely to be effective if the multiple interactions substances such as , amino acids and fatty acids between fetal condition and outcomes can be identified that cannot efficiently pass this bilayer by simple diffu- and successfully modified prenatally. As these relationships sion, several active placental mechanisms regulate trans- are clarified, the focus of clinical fetal medicine is likely to port into the fetal compartment.9–11 Trans-membrane ion shift from improvement of and morbid- pumps such as the Na/Hþ pump also develop maintain- ity to enhancing the life-quality in survivors. It is the aim of ing cellular homeostasis and therefore normal cellular this review to illustrate the multisystem fetal effects of function.12 With the establishment of a functional fetal placental insufficiency and how this information may circulation, substances that enter the primitive villous stimulate future research. circulation are distributed to the via the umbilical vein.13 While the fetoplacental unit may be functional at this point, several additional developments are critical to Regulation of fetal growth enable ongoing placental development as well as fetal growth and maturation. The is the interface between maternal and fetal Maintenance of placental function is energy intensive. compartments. Three overlapping gestational epochs are Under physiologic conditions, the placenta consumes as characterised by important milestones that are necessary for much as 40% of O2 and 70% of glucose supplied to the successful maturation of co-ordinated maternal–fetal ex- uterus.14–16 Optimal fetal growth and development is change. Maternal adaptations to predominate in achieved when nutrient and oxygen delivery is sufficient the first trimester, while the second trimester is character- to allow ideal substrate utilisation in the fetus. This is only ised by elaboration of placental function. Successful pro- possible when the magnitude of nutrient delivery to the gression ultimately enables the fetus to reach its growth and uterus exceeds placental demand leaving sufficient surplus developmental potential in the third trimester in preparation for the fetus. The different classes of nutrients that are to extrauterine life. transported transplacentally have different roles in the Following fertilisation, the cytotrophoblast migrates to fetus. Glucose is the primary oxidative fuel while amino form anchoring sites through controlled breakdown of the acids are incorporated into proteins. Fatty acids are pre- extracellular matrix by metalloproteinases and localised cursors for bioactive compounds including prostaglandins, expression of adhesion molecules. Placental adherence thromoboxanes, leucotrienes and are also necessary for is thus established by the formation of these anchoring maintenance of membrane fluidity and permeability. In villi between the decidua and the uterus. Simultaneously, addition, long chain polyunsaturated fatty acids such as

D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology www.blackwellpublishing.com/bjog 1032 REVIEW arachidonic and docosahexanoic acids are essential for of exchange.23 This mature branching pattern results in normal brain and retinal development. Fetal glucose and low placental flow resistance. Through concur- amino acids are the primary stimulants of insulin-like rent increases in fetal cardiac output, villous blood flow growth factors (IGF) I and II, and therefore drive fetal increases exponentially through the third trimester.7,13 growth and differentiation.17 Leptin co-regulates transpla- Perfusion matching between the maternal and fetal com- cental and fatty acid transport and thereby partments is further modulated and optimised through modulates fetal body fat content and proportions.18,19 With placental autoregulation, which is probably mediated advancing gestation magnitude and efficiency of maternal– through local paracrine factors such as nitric oxide, endo- fetal exchange is increased through developments in all thelin, adenosine or cyclic guanosine mono- placental compartments (Fig. 1). phoshate and fetal atrial natriuretic peptide. The sum of Invasion of the trophoblast into the maternal spiral these changes increases nutrient carrying capacity in ma- arteries results in progressive loss of musculo-elastic me- ternal and fetal vascular beds and improves the efficiency dia, first in the decidual, then in the myometrial portion of of active and passive transplacental exchange. Nutrients these vessels.20 When this process is successful, a low that have entered the fetal circulation through the umbilical resistance, high capacitance placental compartment is vein are delivered to the liver and heart. Through modu- established that receives up to 600 mL/minute of maternal lations in shunting through the ductus venosus, 68–82% of cardiac output at term.21,22 Throughout the first trimester, umbilical venous blood continues to the liver, while the there is progressive thinning of the villous trophoblast remainder is distributed to the heart.24 Differential direc- down to 4 Am by the 16th week. The placental exchange tionality of blood streams entering the right atrium ensures area increases rapidly until 26 weeks, and then at a slower that nutrient-rich blood is distributed to the left ventricle, rate, to reach a surface area of up to 12 m2 at term.7 In mid- myocardium and brain while low-nutrient venous return is gestation, intermediary villi appear in the fetal compartment distributed to the placenta for re-oxygenation and nutrient followed by terminal villi which represent the main sites and waste exchange.25 In addition, several organs modify

Fig. 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. D RCOG 2004 Br J Obstet Gynaecol 111, pp. 1031–1041 REVIEW 1033 their blood flow to meet oxygen and nutrient demands determined by the range of adaptive and/or decompensa- through autoregulation.26 tory responses in various organ systems. If compensatory If these developmental milestones are reached, placen- mechanisms are unsuccessful, permanent damage or still- tal–fetal growth and development remain closely related birth ensues. With successful placental/fetal adaptation, throughout gestation27 and follow distinct patterns. The insufficient nutrient availability may remain largely sub- placental growth curve has a sigmoid shape that plateaus in clinical, only to be unmasked through its restrictive effect mid-gestation while fetal growth continues exponentially at on exponential fetal growth in the third trimester. Under a rate of 1.5%/day to term.28,29 Initial fetal weight increase these circumstances, vascular manifestation may be less is correlated with placental glucose and amino acid trans- pronounced and physical characteristics may be more port and therefore mainly due to skeletal and muscle apparent—decreased adipose tissue, abnormal body pro- growth. Throughout gestation, essential fatty acids are de- portions at birth may be the only evidence of growth posited in the developing brain and retina and account for restriction. While the majority of early onset IUGR fetuses up to 50% of dry brain weight.30 After 20 weeks of ges- are likely to be symmetrically small, a sizeable proportion tation, a notable increase in fatty acid transport and uti- of subtle third trimester IUGR neonates may escape detec- lisation initiates the deposition of significant fetal adipose tion, particularly if population based, rather than customised tissue.10 From 24 weeks onward, exponential fetal growth weight references are used.4 A wide range of observations and adipose tissue deposition coincide with increasing in varying degrees of placental dysfunction have been conversion of glucose into fat, as well as increased utilisa- made that provide an increasing level of insight into the tion of fatty acids.10,30,31 From 32 weeks to term, fat stores complex nature of fetal responses to placental insufficiency. 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 Fetal metabolic responses fatty acids remain related to maternal dietary intake. However, enhanced transplacental transport of essential In mild placental insufficiency, placental glucose and polyunsaturated fatty acids and especially their storage in oxygen utilisation initially remain unaltered while fetal adipose tissue occurs during the period of exponential fetal demands have to be met by increased fractional extraction. growth. Therefore, third trimester increase in fetal size is Only when uterine oxygen delivery falls below a critical characterised by longitudinal growth accompanied by ac- value (0.6 mmol/minute/kg fetal body weight in sheep) is cumulation of essential body stores in preparation to extra- fetal oxygen uptake and glucose transfer reduced.36 With uterine life. the onset of fetal hypoglycaemia, pancreatic insulin responses are blunted, allowing gluconeogenesis from he- patic glycogen stores.37 – 40 A proportion of fetal glucose Mechanisms of placental insufficiency and lactate is redirected to the placenta for nutrition. Because hepatic glycogen stores are minimal, persistent Conditions that interfere with placental vascular devel- or declining nutrient deficit results in worsening fetal opment account for the majority of IUGR pregnancies.34 hypoglycaemia and the ability to maintain fetal oxidative Depending on the gestational age and extent of interference metabolism and placental nutrition becomes limited. At this with placental development, various clinical scenarios may stage, down-regulation of active placental transport and the result in maternal, placental and fetal compartments. At the need of the fetus to mobilise other energy sources result in earliest, unsuccessful placental adherence leads to miscar- more widespread metabolic responses. Limitation of amino riage. If sufficient supply to the placental mass can be acid transfer and breakdown of endogenous muscle protein established further differentiation is possible. However, to obtain gluconeogenic amino acids results in depletion inefficient elaboration of maternal pregnancy adaptation of branched chain and other essential amino acids.41 –43 and deficient nutrient delivery pose limitations to placental Simultaneously, lactate accumulates due to the limited metabolic and synthetic activity ultimately interfering with capacity for oxidative metabolism. Overall, placental trans- the differentiation of endocrine feedback loops and active fer capacity for fatty acids remains unaltered unless there is transport mechanisms. Similarly, deficient placental vascu- considerable loss of placental substance. However, selec- lar differentiation and local paracrine vascular control tivity of transport mechanisms especially for essential fatty result in altered diffusion properties and perfusion mis- acids may suffer. In the fetal circulation, free fatty acid and match at the maternal–fetal interface. Eventually, loss of triglyceride levels rise due to reduced fetal utilisation and this placental autoregulation promotes vascular occlusion, consequently there is failure to accumulate adipose stores. and permanent structural damage.35 If adaptive In this setting of advanced malnutrition, the liver metabo- mechanisms permit ongoing fetal survival, early onset lises the majority of accumulating lactate. However, the growth restriction with manifestations in several organ fetal brain and heart can switch their primary nutrient systems and prominent vascular manifestations is the most source from glucose to lactate and ketones44 —cardiac likely outcome. The spectrum of fetal manifestations is metabolism has the capacity to remove up to 80% of the D RCOG 2004 Br J Obstet Gynaecol 111, pp. 1031–1041 1034 REVIEW circulating lactate.45,46 Acid–base balance can be main- gluconeogenesis.58 Corticotropin releasing hormone, adreo- tained as long as acid production is met by sufficient nocorticotrophic hormone and cortisol levels are signifi- buffering capacity of fetal haemoglobin and a matching cantly elevated relating both to the level of hypoglycaemia removal rate by these organs. and to the degree of placental vascular compromise.43,59,60 These increasing degrees of metabolic compromise have However, elevations of cortisol down-regulate IGF I activ- been documented through cordocentesis in human fetuses. ity and may therefore have additional negative impacts on Hypoglycaemia and hypoxaemia with decreased levels of linear growth as well as the potential to limit the capacity essential amino acids occur first. In worsening placental for postpartum catch-up growth.61,62 In addition to the dysfunction, increasing hypoxaemia and lactate production glucocorticoid axis, significant elevations of are exponentially correlated to the degree of acidaemia. and noradrenaline levels are also found in IUGR fetuses, Overt hypoaminoacidaemia, , hyperlacticae- while aldosterone levels appear unaltered.63 –65 mia and triglycidaemia therefore accompany the develop- Disturbances at all levels of thyroid function have been ment of acidaemia.43,47 –49 elevation of the documented in IUGR fetuses and correlate with the degree / ratio and elevation are additional of hypoxaemia.66,67 Thyroid gland dysfunction may devel- markers of this state of protein energy malnutrition op as indicated by low levels of thyroxine and T3 despite (Table 1).50,51 This degree of metabolic deterioration is as- elevated thyroid stimulating hormone levels. In other in- sociated with elevated transaminases as evidence of hepatic stances, central production of thyroid stimulating hor- dysfunction, and may be precipitated by a significant de- mones may be responsible for fetal hypothyroidism.68 cline of hepatic blood flow as a result of excessive shunting Finally, down-regulation of thyroid hormone receptors at the level of the ductus venosus.52,53 Fetuses that manifest may limit the biologic activity of circulating thyroid hor- growth restriction in the third trimester are more likely to mones in specific target tissues such as the developing have less severe metabolic and acid–base disturbance and brain.69 only subtle changes in lipid metabolism.54 IUGR fetuses also show evidence of disturbed endocrine regulation of bone formation. Serum levels of active vita- min D and osteocalcin are significantly decreased and may Fetal endocrine responses be responsible for decreased bone mineralisation as well as decreased bone growth.70,71 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 Fetal vascular responses transforming factor beta.55,56 This may be further exacer- bated by pancreatic cellular dysfunction that is evident Doppler ultrasound allows the assessment of vascular through a decreased insulin/glucose ratio and impaired effects of placental dysfunction in the placental and fetal fetal glucose tolerance.43,57 Elevations in serum vasculature. The presence of an early diastolic notch in the and stimulation of the fetal adrenal axis promote the uterine arteries at 12–14 weeks suggests delayed tropho- mobilisation of hepatic glycogen stores and peripheral blast invasion of the maternal spiral arteries,72 while

Table 1. Summary of metabolic responses to placental insufficiency.

Substrate Change

Glucose Decreased proportional to the degree of fetal hypoxaemia.

Amino acids Significant decrease in branched chain amino acids (valine, , ) as well as and . 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 triglycerides Decrease 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 CO2 Degree of hypoxaemia proportional to villous damage and correlates significantly with hypercapnia, acidaemia and hypoglycaemia and hyperlacticemia.

D RCOG 2004 Br J Obstet Gynaecol 111, pp. 1031–1041 REVIEW 1035 persistence of ‘notching’ beyond 24 weeks provides con- Firstly, peripheral arterial vasoconstriction in the trunk and firmatory evidence.73 These findings indicate that blood elevated placental blood flow resistance lead to elevations flow resistance in the maternal compartment remains in thoracic and descending aortic Doppler resistance in- elevated thus jeopardising uterine perfusion. In the fetal dices (‘hind limb reflex’) and therefore increased right ven- circulation, changes in blood flow are related to placental tricular afterload.83,84 Secondly, a decline in cerebral blood blood flow resistance, fetal oxygenation, organ autoregu- flow resistance (‘brain sparing’)85,86 decreases left ventric- lation and vascular reactivity. A reduction of umbilical ve- ular afterload. The changing balance between right and left nous blood flow volume may be the earliest Doppler sign ventricular afterload results in a decline of the cerebropla- of subtle decreases in fetal villous perfusion.74 Abnormal cental Doppler index ratio87 or a measurable decline in end- villous branching, or progressive villous vascular occlu- diastolic velocities in the aortic isthmus.88,89 Concurrently, sion, results in elevated blood flow resistance that is blood flow resistance in peripheral pulmonary arteries,90 reflected in the umbilical artery waveform. A decrease of celiac axis,91 mesenteric vessels,92,93 renal,94,95 femoral and the umbilical artery end-diastolic velocity becomes appar- iliac arteries96 may be elevated. Individual vital organs such ent when some 30% of the fetal villous vasculature is as the adrenal glands97 and spleen98 may show evidence of abnormal.75 Absence, or even reversal of end-diastolic enhanced blood flow. The overall impact of these changes velocities (AREDV), can occur after 60–70% of the villous is an improved distribution of well-oxygenated blood to vascular tree is damaged.76 The risk for fetal hypoxaemia the heart and brain with preferential streaming of descend- and acidaemia is proportional to the severity of umbilical ing aortic blood flow to the placenta for re-oxygenation artery Doppler abnormality.77,78 (Table 2). However, such degrees of circulatory abnormal- Through modulations in ductus venosus shunting umbil- ities are associated with elevations of endothelin, vasoac- ical venous blood increasingly bypasses the liver and is tive intestinal peptide, vasopressin and renin–angiotensin channelled toward the heart. Because of the parallel ar- levels.99 –101 A decrease of the thromboxane to prostacyclin rangement of the fetal circulation, changes in cardiac ratio provides evidence of endothelial dysfunction while afterload determine how this increased blood volume is elevations in nitric oxide production indicate a compensa- distributed in the downstream circulation.79 – 81 Elevation of tory response.102,103 It is likely that the degree of vascular right ventricular afterload or decrease in left ventricular reactivity is not only responsible for the high complication afterload allows preferential distribution of cardiac output rate following invasive procedures, but also contributes to towards the left ventricle and therefore the coronary circu- the clinical progression by impacting on blood flow resis- lation and brain.82 This is achieved in two principal ways. tance in many vascular beds.104 –107

Table 2. Summary of fetal vascular responses to placental insufficiency.

Response Features Doppler evidence

Hind limb reflex Diversion of blood flow away from the carcass Elevation of blood flow resistance in the thoracic aorta and at the expense of the lower body. Achieved iliac artery. 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.

Centralisation A measurable shift in the relationship between right and Decrease in the cerebroplacental Doppler ratio. left ventricular afterload, that results in redistribution of Direct measurement of cardiac output. Reversal of end-diastolic cardiac output in favour of the left ventricle velocity in the aortic isthmus. Inferred through absence or (i.e. the heart and the brain). reversal of umbilical artery end-diastolic velocity.

Brain sparing Cerebral vasodilatation in response to perceived hypoxaemia. Decrease in the carotid or middle cerebral artery Doppler index.

Liver sparing Preferential arterial blood supply to the fetal liver invoked Measured dilation of the ductus venosus with elevated when increased diversion of umbilical venous blood through Doppler index accompanied by a decreased hepatic the ductus venosus jeopardises hepatic perfusion. artery Doppler index.

Adrenal sparing Enhanced adrenal perfusion is triggered as part of the fetal Decreased Doppler index in the adrenal artery stress response to chronic or acute-on-chronic malnutrition. flow velocity waveforms.

Heart sparing Marked augmentation of coronary blood flow in situations Sudden ability to visualize and measure coronary. of acute-on-chronic hypoxaemia that is achieved through Blood flow in a setting of deteriorating venous up-regulation of coronary vascular reserve and vasodilatation. Doppler indices in a premature IUGR fetus.

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With further deterioration, ductus venosus shunting away probably relates to altered myelination as well as changes from the liver may compromise hepatic perfusion to a in central neurotransmitter availability.119 – 123 The delayed degree that interferes with organ function. Steep elevation development of behavioural milestones and their central in blood lactate and transaminases, as well as sudden integration with fetal heart rate are primary determinants of compensatory hepatic artery vasodilatation, have been lower short and long term variation (on computerised reported under such conditions.52,53,108 When the increased analysis) and delayed development of heart rate reactivity metabolic demands of cardiac work cannot be met, myo- that is observed in IUGR fetuses.124 –128 Despite the mat- cardial dysfunction supervenes. Declining cardiac function urational delay of some aspects of central nervous system results in a failure to accommodate venous return and leads function, several centrally regulated responses to acid–base to increased venous Doppler indices as evidence of in- status are preserved. Chronic hypoxaemia is associated creased central venous pressure.109 In extreme cases, atrial with a decline in global fetal activity.129 If the severity of pressure waves may be transmitted all the way back into the hypoxaemia increases, fetal breathing, gross body move- free umbilical vein resulting in pulsatile flow. When venous ments and tone decrease further and are generally lost when Doppler indices become elevated, a significant rise in atrial acidaemia develops. Similarly, decreases in fetal heart rate natriuretic peptide occurs, probably as a compensatory variation and variability as well as onset of decelerations mechanism to regulate blood volume.110,111 When forward are triggered by worsening hypoxaemia. The decline of cardiac function declines significantly, coronary vasodilata- these biophysical variables is determined by the central tion becomes exaggerated to recruit all the available coro- effects of hypoxaemia/acidaemia independent of the car- nary blood flow reserve.112 If this fails to support myocardial diovascular status.130 –133 nutrition sufficiently, cardiac dysfunction may become crit- Amniotic fluid volume is determined by the effects of ical. Cardiac dilatation with holosystolic tricuspid regurgi- hypoxaemia and vascular status on renal perfusion and tation and loss of cerebral autoregulation (normalising therefore on fetal urine production. Progressive deteriora- cerebral Doppler indices) are observed at this level of com- tion of acid–base status and vascular status is accompanied promise and indicate loss of cardiovascular homeostasis.113 by a progressive decline in amniotic fluid volume. Elevations of troponin I, S100B protein levels and trans- aminases provide evidence of cellular damage in the myo- cardium, brain and liver.114 – 116 An increased risk for Haematologic responses necrotising enterocolitis in survivours has been attributed to bowel injury secondary to chronic underperfusion.117 If Fetal hypoxaemia is a trigger for re- the fetus remains undelivered, spontaneous late decelera- lease and stimulation of red blood cell production, through tions of the fetal heart rate and ensue. both medullary and extramedullary sites, resulting in .134 – 137 Increased extramedullary haemato- poiesis may be physiologic until 28 weeks, but can also be Fetal biophysical responses induced by prolonged tissue hypoxaemia and/or after this gestational age. Extramedullary sites have larger Normal fetal behavioural development proceeds sequen- capillary fenestrations that permit the escape of large tially with the appearance of movement, coupling, cyclicity nucleated red blood cells. Thus, elevated nucleated red of behaviour and finally the integration of movement blood cell counts correlate with metabolic and cardiovas- patterns into stable behavioural states. Autonomic reflexes cular status and are independent markers for poor perina- originating from the brainstem are superimposed on intrin- tal outcome.138 –141 With advancing compromise complex sic cardiac activity and determine fetal heart rate charac- haematologic abnormalities suggest dysfunctional eryth- teristics. With the maturation of the nervous system, ropoiesis. Fetal anaemia despite increased nucleated red modulation of these reflexes through several key elements blood cell release and overt decrease in red cell progenitors becomes more refined as gestation advances. These ele- could reflect down-regulation of pro-erythropoietic cyto- ments include ambient oxygen tension, signals from higher kines, vitamin B12 and ferritin deficiency or a combination brain centres and the reticular activating system as well as of these.142 –145 peripheral sensory inputs. Successful maturation of these Coinciding with the abnormalities in red cell indices, connections is reflected by decreasing baseline heart rate, platelet counts also decrease. Although platelet activating increasing heart rate variability and variation, coupling factor is inhibited,146 abnormal villous vasculature as between episodic accelerations with fetal movement and indicated by umbilical artery AREDV may pose on over- the superimposed impact of behavioural states. This level whelming stimulus for placental platelet activation and of central integration of fetal heart rate characteristics with aggregation.147 Under these circumstances, the incidence fetal behaviour is normally accomplished by 28 weeks of of thrombocytopenia increases over 10-fold.148 In addition gestation.118 to villous vascular abnormality, increasing anaemia and IUGR fetuses with chronic hypoxaemia exhibit a delay hypoxaemia are independent risk factors for decreasing in all aspects of central nervous system maturation, which platelet counts.149 Increase in whole blood viscosity,150,151 D RCOG 2004 Br J Obstet Gynaecol 111, pp. 1031–1041 REVIEW 1037 decrease in red blood cell membrane fluidity152 and platelet and omega-3 and -6 essential fatty acids.34 Assessment of aggregation may be important cofactors for accelerating fetal status for timing of delivery is most comprehensive placental vascular occlusion and dysfunction. when evaluations of vascular and behavioural responses IUGR fetuses also show evidence of immune dysfunc- are integrated.164 Evaluation of nutritional, metabolic, en- tion at the cellular and humoral level. Decreases in immu- docrine and haematologic responses at birth and their rela- noglobulin and absolute B-cell counts have been long tionship to fetal proportions, Doppler and behavioural recognised.153 Reduction in total white blood cell counts parameters will refine our understanding of the condition. and neutrophil, monocyte and lymphocyte subpopulations Neonatal management is most likely to be most effective occurs.154 Selective suppression of T-helper and cytotoxic when knowledge of fetal status and an appreciation of the T-cells have been observed.155 These abnormalities are spectrum of fetal consequences of placental insufficiency related to the degree of acidaemia and explain the higher are integrated to guide evaluation and management. A susceptibility to infection after delivery. uniform prenatal diagnostic standard and a comprehensive integrated management approach that bridges fetal and neonatal periods is most likely to impact on adult health Multiple avenues of deterioration require an focussing on the small fetus at risk and sparing normally integrated approach developed babies from iatrogenic interventions. Our cur- rent level of knowledge could be an effective platform for Several other abnormalities such as vitamin A , zinc and launching observational studies and randomised, interven- copper deficiency or elevation of the purine nucleotide tion trials needed to test these hypotheses. breakdown product hypoxanthine with increasing hypoxae- mia further illustrate the diverse fetal impacts of placental 156 – 160 Dr Ahmet Alexander Baschat insufficiency. It is apparent that IUGR is a complex Department of Obstetrics, Gynaecology and Reproductive multisystem disease in which the balance and range of Sciences, University of Maryland School of Medicine, compensatory efforts determines the manifestation and Baltimore, Maryland, USA 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 exam- References ple, vascular reactivity, blood viscosity, red cell plasticity and platelet aggregation determine blood flow dynamics at 1. Battaglia FC, Lubchenco LO. A practical classification of newborn multiple levels. Peripheral blood flow dynamics, metabolic infants by weight and gestational age. J Pediatr 1967;71:159–163. milieu, filling state of the circulation all influence the 2. 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