The purpose of this review is to convince the reader that the rate of growth in utero is exquisitely sensitive to and regulated by substrate availability and that understanding this "supply-side economics" has practical value in at least three areas. First, it should improve both diagnostic ability and accuracy: what does asymmetric growth retardation mean to the baby and what causes it? Likewise, it should help the reader understand intrauterine therapy of this disorder and should emphasize that asymmetric intrauterine growth retardation is primarily a fetoplacental adaptive mechanism to promote survival under less than optimal circumstances.1
WORKING DEFINITION AND CLINICAL CHARACTERISTICS
From a physiological viewpoint, asymmetric intrauterine growth retardation is a persistent downregulation of genetic growth that begins in the latter half of gestation in response to an intermittent or continuous decrease in substrate availability. Clinically, this manifests as a slowing of the rate of growth of the uterus, placenta, and fetus. It is best detected during pregnancy by a single individual manually assessing changes over time.
At birth, diagnostic confirmation requires assessment of the entire morphometric profile because the asymmetrically growth- retarded fetus usually has a birthweight within the normal range. Measures of axial growth and cranial volume are also usually within the normal range. The distinguishing characteristic is a variable degree of soft-tissue wasting, best identified by a decrease in subcutaneous and intra-abdominal fat, a high head circumference/abdominal circumference ratio, and low indices of weight per length (Ponderai or body mass index). Use of this profile reduces the chance of misclassifying the genetically small infant as growth retarded and helps identify the fetus who is growth restricted even though he or she weighs more than the 5th or 10th percentile for gestational age. Recognition of these two situations is difficult if birthweight for gestational age is the only criterion used to assess growth.
CAUSES OF ASYMMETRIC INTRAUTERINE GROWTH RETARDATION
Multiple environmental, maternal, and placental factors can limit substrate availability to cause or occur in conjunction with late-onset growth restriction. All of these factors act through the final common pathway of reducing nutrient availability via their effects on blood flow, transplacental concentration grathents, and functional transfer capacity of the placenta. In contrast, other factors that result in fetal growth restriction such as substance abuse, infection, chromosomal abnormalities, cyanotic heart disease, and chronic pulmonary disease produce a picture of symmetric growth restriction.1 Thus, you can gain insight into the cause of decreased intrauterine growth by determining if it is symmetrical or asymmetrical.
There is a direct correlation between fetoplacental growth rate and the rate of blood flow in the maternal (uterine) and fetal (umbilical) placental circulations. Asymmetric fetal growth retardation can be induced experimentally by suppressing the normal increase in uterine blood flow that occurs as gestation advances.1 Research models have reduced blood flow by mechanical interference with the uterine vascular bed at various levels, as well as maternal hyperthermia, anemia, and hypoxia, which act to decrease blood flow indirectly via adrenergic mechanisms.3'9 TKe human parallels of these experimental manipulations occur in pregnancies complicated by abnormal placentation (acereta, twinning, and previa), maternal hypertension, autoimmune disease, and sickle cell disease. Gravitational stress, inadequate maternal blood volume expansion, maternal autonomie dysregulation with hypotension, and beginning heavy physical work in late pregnancy also appear to lower birthweight by reducing the rate of placental perfusion.10,12 So search for the possible conditions when you have a neonate with asymmetric growth retardation.
Transplacental Concentration Grathent of Glucose
Under normal circumstances, glucose appears to be the major fetal fuel. It is transferred across the placenta by facilitated diffusion, and fetal availability is a function of the transplacental grathent. The latter increases and decreases with changes in maternal blood sugar concentration. Therefore, factors that reduce the average 24-hour maternal blood glucose level decrease fetal glucose availability and growth of the fetus and placenta.
Typical perturbations that reduce the average 24hour maternal blood sugar leading to growth restriction are prolonged maternal fasting and reduced maternal carbohydrate intake, gastrointestinal disease, and exercise.12'20 The most convincing studies are those of Mellor13 in sheep and Langer et al19 in humans. Both demonstrate that changing maternal blood sugar levels by 10% to 20% has rapid and profound effects on intrauterine growth and size at birth.
Placental Functional Capacity
Placental capacity for transport of diffusible substrate is a function of surface area, vascular supply, and thickness of the membrane. Transporter number and function also play a major role in facilitating diffusion and the active transpon of amino acids. Conditions that limit one or more of these parameters usually are associated with fetal growth restriction and a concomitant decrease in placental perfusion.21,24
In animal models, this has been illustrated by restricting placental growth in early pregnancy.21 In humans, pregnancy complications such as pregnancyinduced hypertension, hemorrhagic endovasculitis, inadequate villous vascularization, intervillous space thrombosis, placental angiomas that interfere with placental function are associated with a strong correlation between placental weight and birthweight.22,24 Furthermore, mid-trimester placental growth is highly predictive of third-trimester fetal growth and appears to be a major determinant of size at birth.25,27 Likewise, histomorphometric studies of freshly delivered placentae show clear evidence of a direct link between membrane surface area and thickness, or maternal and fetal vascular volumes, and size at birth.28-31
These findings underscore the high degree of interdependence and balance between placental and fetal growth. Placental adaptations and signaling probably play a significant role in minimizing the impact of late-onset intrauterine growth retardation due to changes in blood flow and maternal substrate levels.
HOW THE SYSTEM WORKS
Asymmetric intrauterine growth is an active response that matches demand with supply. Evidence suggests the central regulatory mechanism that balances demand and the available supply of nutrient lies at the logical place, ie, within the placenta. The placenta appears to use classical endocrine mechanisms to induce endocrine, paracrine, and autocrine signaling in both maternal and fetal tissues, which ultimately produce maternal and fetal metabolic, hemodynamic, endocrine, and growth responses. Furthermore, growth suppressive rather than growth stimulating signals appear to regulate the various interactions (Table).
Briefly, an increase or decrease in substrate delivery is sensed in an as yet unknown way by the placenta, which responds by either decreasing or increasing its tonic release of one or more growth suppressive compounds. In turn, these alter the placenta! production and release of multiple regulatory compounds as well as the production of insulin-like growth factors (IGFs) and binding proteins (IGFBPs) in the maternal and fetal liver and other fetal tissues. As a result, there are balanced tissue-specific changes in growth, metabolism, and hemodynamics within the fetus and placenta accompanied by complementary changes in maternal function.
The experimental support for this scheme lies in four areas.32-42 First, growth-retarded animal fetuses have high levels of growth suppressive activity in the umbilical blood returning from the placenta to the fetus. The magnitude of this growth suppressive aerivi' ty is directly proportional to the severity of the fetal growth restriction. Second, fetal-placental growth can be up regulated by increasing substrate delivery even in the face of progressive placental damage. Third, in polyoccuous species, it appears that local nutrient availability is a critical determinant of early placental growth, which ultimately is a major determinant of size at birth. Finally, there is a large body of recent data suggesting that placental growth hormone, placental lactogen, IGF I and IGF II and their binding proteins, especially IGFBP I, appear to be potent autocrine and paracrine signaling mechanisms within the maternal and fetoplacental unit. They clearly are responsive to nutrient and oxygen availability and capable of growth regulation at a tissue level. For example, it appears that increased production of IGFBP I, resulting in increased binding of IGF I, is a major mechanism for suppressing the growth-promoting effects of IGF I.
THE VALUE OF USING THE PRINCIPLES OF 'SUPPLY SIDE ECONOMICS' IN CLINICAL CARE
There is clear evidence for a rapid, sensitive, and balanced growth response to acute and chronic changes in substrate delivery. This response is accompanied by equally rapid and balanced maternal, placental, and fetal cardiovascular, metabolic, and endocrine responses that act to maintain physiological equilibrium at all levels.1,17,32,37,42,46 This turns out to have numerous positive and practical clinical ramifications.
First, it means that an alteration in growth rate is the primary rather than a secondary or tertiary adaptation to a change in substrate availability. Thus, precise, serial assessment of the incremental growth of the uteroplacental-fetal tissue mass should be an invaluable clinical screening technique for assessing the overall normality of the pregnancy because it reflects the entire maternal adaptive response (cardiovascular, metabolic, and endocrine) as well as fetal growth per se.
Overview of the Regulatory System
When this is put into a clinical context, it suggests that the commonly used multiple examiner, cross-sectional approach to growth assessment (small- or largefor-gestational age compared with populace norms) should be replaced by a single examiner using a longitudinal approach (measuring interval growth rate). The cross-sectional approach does not allow the clinician to reliably detect a change in the rate of growth until it is far advanced. Conversely, the longitudinal approach allows the clinician to establish an early diagnosis and etiology for the change in growth rate, which, in turn, should maximize the value of therapeutic intervention. An important clinical corollary is that a diagnosis of a decreased growth rate from serial abdominal palpation and fundal height measurements by a single examiner will be much better than that obtained by a single ultrasound examination.
The fact that growth is both down and up regulated to match demand with supply indicates that therapeutic efforts should attempt to improve the availability of substrate and oxygen, and these should rapidly improve growth rate. Thus, therapy should focus on improving uterine perfusion by increasing central blood volume and reducing venous stagnation (position, hydration, and compressive stockings) as well as maximizing maternal circulating levels of substrate and oxygen.38,47,48 Another focus should be the aggressive treatment of underlying diseases, which may further compromise substrate delivery (cardiovascular, pulmonary, gastrointestinal, etc). Finally, a word of caution: while bed rest is often recommended as a mechanism for acutely improving central blood volume and uterine perfusion, it may well have the opposite effect if maintained for a week of more. Prolonged bed rest has multiple adverse effects, including a marked decrease in blood volume.49
Assessing Therapeutic Response
The second clinical ramification of this "supplyside" regulatory mechanism is that it is quickly reversible.13,16 Thus, the same longitudinal approach can be used to assess the response to a given therapy, using evidence of improved substrate availability and growth rate, but you must have an accurate picture of growth. If the more traditional cross-sectional approach is used, the response of the intervention may be obscured by comparing the fetus to the population norm rather than itself.50,51
The third clinical ramification is that the rapid metabolic and circulatory adjustments to changes in substrate availability (a slowing or cessation tn the rate of increase in the demand for oxygen, substrate, and blood flow) will maintain fetal pH, PO2, PCO2, substrates, and flow velocities at normal levels, unless the underling problem is extremely persistent or rapidly progressive. Matching demand with supply avoids intermittent hypoxia and acidosis that may occur when decreases in blood flow and nutrient availability are sudden and profound.2 Over time, the metabolic and cardiovascular savings of growth cessation are on the order of 30% to 50%. This has real survival value because growth cessation prevents acidosis and tissue damage. Growth cessation also allows time for secondary adaptive mechanisms to come into play,2,8,43,45 providing time for improving placental perfusion and flow redistribution within the fetus. These latter responses also have survival value as they act to maintain growth, development, and function at the highest level possible in the most important tissues (placenta, brain, heart, lung, and adrenal gland) while maintaining a baseline supply of nutrient to other tissues.
The rapid physiological adjustment of demand to the level of supply has several important ramifications for interpreting a variety of tests. For example, when cordocentesis is performed, it should be no surprise that values are often in the normal range despite clear evidence of growth restriction.52,53 Low oxygen tension and pH do not occur until late, so normal values should not create a false sense of security. The same appears true for fetal monitoring to detect abnormalities in heart rate pattern, behavior, or velocity flow profiles. The rapid, ongoing circulatory balance of demand to supply may keep these within the normal range until late in the course.
Nonetheless, a failing supply line eventually will cause fetal oxygen tensions, substrate, and hormonal levels to fall. Blood oxygen and glucose will drop, while lactate, hemoglobin, and alanine levels rise, and the hormonal milieu becomes similar to that seen with growth suppression and hypoxia after birth. When the compensatory mechanisms are no longer adequate, tissue hypoxia and rapidly progressive acidosis develop just prior to demise.25
Timing of Delivery
As noted above, at some point in time the adaptive mechanisms of growth cessation and flow redistribution are no longer adequate to maintain the balance between supply and demand. This point will vary. What findings can or should be used to time delivery? Too soon means prematurity, but too late means a risk of hypoxic tissue damage and acute tubular necrosis, necrotizing enterocolitis, brain and myocardial injury, or death. The point when secondary circulatory adaptations are needed to maintain homeostasis may be the optimal time for delivery.52,55 The most promising and least invasive approach appears to be to identify the time when the ratio of changes in the velocity profiles in the cerebral and either the renal or umbilical circulations (indicating redistribution of cardiac output) are altered. This occurs before severe fetal compromise. In contrast, by the time there are changes in the biophysical profile, amniotic fluid volume, and heart rate pattern, the fetus may have significant acidosis and organ ischemia.
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Overview of the Regulatory System