Workshop Summary:
Fetal Growth:
Its Regulation and Disorders
Pediatrics v.99, n.4, Apr97
William W. Hay, Jr, MD*; Charlotte S. Catz, MD++; Gilman D. Grave, MD§; and Sumner J. Yaffe, MD||
From the * Department of Pediatrics of the University of Colorado School of Medicine; the § Endocrinology, Nutrition and Growth and ++Pregnancy and Perinatology Branches of the || Center for Research for Mothers and Children and the Perinatology Research Branch of the National Institute of Child Health and Human Development.
ABBREVIATIONS. IUGR, intrauterine growth restriction; SGA, small for gestational age; AGA, average for gestational age; LGA, large for gestational age; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; VIP, vasoactive intestinal polypeptide.
This report summarizes a meeting sponsored by the National Institute of Child Health and Development to review important scientific contributions over the past several years that addressed the causes and consequences of intrauterine growth restriction (IUGR). IUGR contributes significantly to perinatal morbidity and mortality. Considerable research has focused on various aspects of fetal growth, particularly with respect to the epidemiology of IUGR, the regulation of fetal growth by intrinsic growth factors and extrinsic nutrient supply, the role of the placenta in fetal growth, and diagnosis and treatment of IUGR. In addition to summarizing many of the advances in each of these important areas of research, a major purpose of the meeting was to consider future directions for research into the causes, consequences, diagnosis, and treatment of IUGR.
At the onset of the meeting, Dr William Hay provided a broad overview of IUGR. Much of the impetus for studying IUGR began with the observation by pediatricians and neonatologists that when classified according to birth weight and gestational age, newborn infants were shown to be small, average, or large for gestational age (SGA, AGA, and LGA, respectively), and that specific morbidities and rates of death were unique to each of these birth weight-gestational age classifications.' SGA infants, for example, were recognized as having more frequent problems with hypoglycemia, hypothermia, polycythemia, and neurodevelopmental handicaps, as well as a higher mortality rate.2 With the advent of improved fetal diagnosis, infants who were small at birth were increasingly recognized as representing a variety of fetal growth patterns. For example, infants who were considered constitutionally small simply grew parallel to, but less than, the 10th percentile for normal rates of fetal growth. Infants with genetic abnormalities or acquired diseases, particularly infections occurring in the first trimester, also grew slowly, and many of these infants progressively failed to keep up with growth rates as gestation proceeded. Still other infants, suffering from nutritional deprivation from causes such as maternal starvation or placental insufficiency, may have started off with normal rates of growth but these decreased in the third trimester, and affected weight more than length or head circumference. Thus, small size at birth was increasingly recognized as either a normal outcome or one that was a result of intrinsic or extrinsic factors that limited fetal growth potential.
Over the past several years, most investigation has focused on decreased rates of fetal growth as an adaptation to inadequate nutrient supply. Nearly all of these fetuses, for example, whether studied experimentally in animal models or in women by cordocentesis (direct umbilical blood sampling), have relatively lower plasma glucose concentrations compared with normally grown fetuses.3,4 Fetal hypoglycemia has several consequences important to fetal adaptation and survival when maternal glucose supply is limited. First, it maintains the maternal/fetal glucose concentration gradient and thus the transport of glucose across the placenta to the fetus.' Additionally, while limiting tissue glucose uptake, it also limits insulin secretion, which initially may allow fetal glucose production to take place (providing glucose for both fetal and placental needs), but subsequently, combined with hypoglycemia, results in increased protein breakdown and decreased protein accretion .6-8 At more reductionist levels, circulating concentrations and tissue-specific growth factors such as insulin-like growth factor (IGF)-I and IGF-II, and different glucose transporters, are variably downregulated or upregulated by hypoglycemia,9,10 reflecting how deficiencies of exogenous nutrient supply lead to molecular and cellular mechanisms that allow the fetus to adapt to nutrient deficiency and to continue development. In this example fetal hypoglycemia in response to a decrease in maternal glucose supply acts to increase nutrient supply and decrease fetal nutrient need. IUGR that results from these conditions is thus seen as a successful adaptation to maintain fetal survival.
An exciting new area of investigation has focused on the long-term adult consequences of fetal nutrient deprivation and IUGR. Barker", for example, has provided epidemiological data which indicates that diabetes, hypertensive disease, and coronary vascular disease are more common among adults who were smaller than normal at birth and very likely SGA (particularly those who had a high placental to fetal weight ratio) and appeared to have experienced IUGR.
Experimentally, fetal animals with altered pancreatic function, representing either a failure of pancreatic development as a response to nutrient deprivation leading to IUGR or to glucose excess in cases of maternal diabetes, more frequently develop diabetes as adults with impaired insulin secretion and peripheral insulin sensitivity. A specific example in the pregnant rat was discussed by Dr Joseph J. Hoet who presented evidence that programming of the functional activity of the endocrine pancreas can be modulated by feeding an isocaloric low protein (8%) diet to the mother. The neonatal islet cell proliferation is significantly reduced in vitro and in vivo in this model; also the islet cell size and islet insulin content are decreased12 and, when challenged in vitro with secretagogues such as leucine, arginine, and/or theophylline, insulin secretion is depressed.13 Cyclic adenosine monophosphate content also is diminished when challenged with glucose, or leucine and arginine, but is normalized with theophylline or analogues .14 When the low protein diet is maintained in the offspring until adult age, their pancreatic insulin content is dramatically decreased and insulin secretion is significantly depressed when challenged by glucose, amino acids, forskolin, and tetradeconyl phorbol acetate. A normal diet given immediately after birth does restore the insulin secretion to most secretagogues but not to arginine. A low protein diet maintained after birth reduces in vitro insulin secretion to all secretagogues tested .14 The mitochondrial enzyme glycerophosphate dehydrogenase, which is reduced in 0-cells of Type II diabetics, also is diminished with the low protein diet, suggesting that mitochondrial adenosine triphosphate production in this specific experimental condition may play a role in insulin secretion.15 When offspring were exposed to low protein isocaloric diets during fetal life and after birth, they show impaired glucose tolerance with low plasma insulin levels as adults. This is true for males or females. When exposed only during fetal life, only the female offspring have impaired glucose tolerance with low insulin levels as adults (preliminary unpublished results: J. Hoet, et al). These results indicate that several alterations induced during fetal development remain after birth and affect glucose tolerance at adult age. Female offspring seem to be more sensitive than males; this experimental observation may clarify the intergenerational effects, which may include a possible genetic predisposition.
Dr Hay pointed out that these examples indicate that certain adult pathologies may be unavoidable consequences of environmentally imposed conditions that lead to fetal growth restriction to ensure successful fetal survival. IUGR, therefore, is increasingly seen as an adaptive physiological process, even though it can produce adverse fetal, neonatal, and potentially adult consequences.
If this is the case, then it becomes increasingly important to be able to diagnose slower rates of fetal growth in pregnant women, to allow more accurate estimation of whether slower rates of fetal growth represent constitutional conditions and therefore should be considered normal, or adaptations to pathological influences. This would allow a more rational approach to providing therapy as techniques of fetal intervention become more successful.
DEFINITION OF IUGR
Dr Tim Chard focused discussion on the definition of IUGR, making the point that infants who are smaller than average, are, for the most part, quite normal and healthy. There are, of course, some cases of IUGR that are the result of specific causes such as congenital infection, pre-eclampsia, gross maternal malnutrition, and placental damage resulting in a preterm delivery; the significance of these specific causes of IUGR is not in dispute. However, most cases of so-called IUGR are small term babies with no obvious cause. Dr Chard pointed out the confusion in diagnosis. Thus, defining IUGR as a birth weight below the 5th to 10th percentile of a population norm, even when corrected for factors such as gender, ethnicity, fetal number, and so forth, confuses an anthropometric outcome with a variety of possible processes that might lead to altered fetal growth rate.16
Several lines of evidence presented by Dr Chard suggest that the small term infant is at low-risk for serious neonatal morbidity or long-term adverse outcome. First, this group of infants has no difference in mortality and morbidity rates compared with AGA infants at term gestation. Second, there is no statistical evidence for a subpopulation of at-risk IUGR infants among otherwise normal term SGA infants. Third, focusing on infants less than the 10th percentile would miss most cases of IUGR: for example, the genetically-destined 4000-g infant born as 3500 g).17 Fourth, the concept of symmetric and asymmetric IUGR is probably an artifact resulting from the failure to appreciate the normal relationship of birth weight and body proportionality, ie, smaller infants tend to be thinner and larger infants, fatter. Dr Chard further emphasized the importance of defining IUGR as a failure of normal fetal growth, particularly in those cases that result from pathological processes. Future attempts at screening, diagnosis, and treatment must be directed at identifying such infants and the adverse pathophysiology rather than just their size.
EPIDEMIOLOGICAL CONSIDERATIONS
Regardless of the definition of IUGR, the problem is widespread among developed as well as undeveloped countries and populations. Dr Robert Goldenberg reviewed a variety of potential risk factors for their association with IUGR. The major risk factors for IUGR include small maternal size (height and prepregnancy weight) and low maternal weight gain. Low maternal body mass index, defined as [weight (kg)]/[height (cm)]2 is a major predicator of IUGR, but more importantly, this characteristic interacts with other risk factors to impact on fetal growth, especially in thin women. Smoking has only half the impact on fetal growth in obese women compared with thin women, and in black versus white women.18 Low doses of aspirin has been shown to enhance fetal growth, but only in thin women, 19 while low blood pressure has a detrimental impact on fetal growth, with most of the effect occurring in thin women .20 Moderate obesity, therefore, protects against most growth-inhibiting risk factors except for black race and female gender. This pattern also holds for certain therapies. For example, zinc supplementation has a major impact on fetal growth in black women who have relatively low plasma zinc levels early in pregnancy, with all of the impact occurring in relatively thin women .21
Perhaps the most important epidemiological consideration for infants who have experienced IUGR is their long-term neurodevelopmental outcome. As reviewed by Dr Maureen Hack, with certain exceptions of defined pathologic conditions, the small term infant carries little excess long-term neurodevelopmental risk and recent surveys demonstrate that the term SGA infant is not doing as poorly as indicated earlier .22
Outcome studies of the effects of IUGR have been confounded by the heterogeneity of the populations studied. This includes various causes and definitions of intrauterine growth failure, the effects of the associated perinatal and neonatal complications on outcomes, the age the children are studied, and the postnatal influences on the children, especially those related to sociodemographic factors .23 The older studies of intrauterine growth included children with intrauterine infections and congenital malformations, and lacked the elements of modern neonatal intensive care that have decreased the rates of complications such as asphyxia and hypoglycemia.
Intrauterine growth failure is associated with higher rates of gestational age-specific neonatal mortality 24 Studies of term children who are born SGA reveal, in general, overall normal intelligence, but with a tendency to lower IQs when compared with normal birth weight children. The rates of major disability are low; however, higher rates of minimal cerebral dysfunction in children with normal intelligence have been reported .25,26 Outcomes of term children also have been examined with consideration of the timing and severity of intrauterine brain growth failure (measured via antenatal ultrasound). Outcomes are significantly poorer for children whose brain growth failure occurred before 26 weeks gestation.27 Subtle behavioral differences are also noted in children whose growth failure occurred before 35 weeks gestation .28 Similarly, cerebral palsy is more common among infants who experienced more severe growth restriction .29 A difficulty in sorting out which infants are at increased risk is also reflected by different outcomes among many of the studies, eg, head growth, ponderal index, evidence of fetal and/or neonatal asphyxia, hypertensive disease, multiple birth, or mixed neonatal complications.30
Among these several outcomes head size and head growth at birth have been of particular concern because of the common assumption that head circumference less than the 3rd percentile more commonly relates to long-term neurodevelopmental handicaps.31 Subnormal head size appears to be far more representative of abnormal outcome among AGA than SGA preterm infants. Preterm AGA infants have far more cerebral palsy than similar birth weight infants who are older in gestation but growth-restricted .32
The outcomes of preterm children with intrauterine growth failure vary widely depending on whether they are compared with birth weight or gestational age-matched controls. No differences in outcomes are found when birth weight is matched, whereas poorer outcomes for children of lower gestational ages have been reported .33,34
Dr Hack concluded that the effects of intrauterine growth failure are affected by the quality of perinatal care and sociodemographic factors. Outcome studies are furthermore confounded by the heterogeneity of perinatal and postnatal conditions and varying methodology.
REGULATION OF FETAL GROWTH
aIntrinsic growth factors, either circulating in the fetal plasma or part of fetal cellular structure, also are important regulators of fetal growth. Such growth factors may regulate normal growth processes as part of their normal developmental expression; they also lead to abnormal growth when genetic variation in expression is present. Additionally, such growth factor expression can be modified by extrinsic factors such nutrient substrate supply to the fetal plasma. Dr Joseph D'Ercole reviewed the role of IGF-I in brain development using information developed in his laboratory from transgenic models. Such models have shown that increased expression of IGF-I is associated with increased brain growth .35,36 Similarly, although insulin-like growth factor binding protein (IGFBP)-1 is not normally expressed in the brain, a transgenic model in which IGFBP-1, an inhibitor of IGF action, is expressed results in an inhibition of brain growth .37 In general, the regions of the brain most overgrown in the IGF-I transgenic model are most undergrown in the IGFBP-1 transgenic model, presumably because the most affected regions are those most sensitive to the actions of IGF-II Furthermore, the results of these transgenic studies suggest the IGF-I has profound effects on myelination.38 IGF-I stimulates an increase in total brain myelin content which is accomplished by stimulating increased expression of myelin associated protein genes as well as by increasing the number of oligodendrocytes. This results in a increased number of myelinated axons and in the thickness of their myelin sheaths. IGF-I also appears to stimulate an increase in neuronal number, at least in the trigeminal somatosensory system (Gutierrez-Ospina et al, 1996, unpublished observation). IGF-I also increases the volume of barrel structures in the somatosensory cortex: they are doubled in the IGF-I transgenic model and reduced to half the normal size in the IGFBP-1 transgenic model. These effects of IGF-I may be due to increased neuronal outgrowth with increased dendritic arborization and axon terminal fields. Because IGF-I is decreased directly by reduced nutrient supply, particularly glucose, and IGFBP-1 is decreased under these circumstances, Dr D'Ercole speculated that the smaller, more densely packed neuronal structure of the malnourished brain may have been mediated by nutrient regulation of IGF-I and IGFBP-1 expression.
Dr Victor Han focused additional attention on IGF-II and IGFBP-2 with respect to fetal growth. IGFBP-2 is abundantly expressed in fetal life in every tissue in the first part of gestation, but only in liver and kidney in the second part of gestation, reflecting persistent sites of autocrine and paracrine action.39 Although serum concentrations of IGF-II may not correlate with fetal size at birth in human infants, it has been shown conclusively that targeted mutation of the IGF-II gene reduces fetal size in mice .4° Furthermore, IGF-II is the predominant IGF that is expressed in the tissues of embryos and fetuses of all species. As with IGF-I and IGFBP-1, transgenic overexpression of IGF-II and IGFBP-2 show that cellular growth is dependent on the balance between the binding protein and the IGF molecule itself. Dr Han also reviewed the importance of IGFBP-3. IGFBP-3 is the predominant binding protein in several mammalian species including humans, rhesus monkeys, and sheep, but it is not detectable in some other mammalian species, particularly rodents, rats, and mice. This species difference in fetal concentrations brings into question the significance of circulating IGFBP-3. Although IGFBP-3 is not detectable in the plasma of these latter animals, the message is known to be expressed in their tissues .41,42 IGFBP-3 has been shown to be reduced in cord blood of infants with IUGR.43 In this respect, measurements of circulating as well as cellular-bound IGFs and IGFBPs are critical, not only to understand their potential regulatory influences within a given animal model, but also to compare and contrast the vast differences in the expression and effects of these substances that occur among species. Dr Han particularly stressed a multispecies approach to understanding the role of IGFs and their binding proteins in human development in that any one model may be quite different from that of the human.
Although IGFs and their binding proteins may have a dominant role in fetal growth regulation, as does insulin itself, there are many other growth-regulating factors that need evaluation, particularly at different periods of embryonic and fetal growth. As one example, Dr Joanna Hill reviewed new information about the growth-regulating potential of vasoactive intestinal polypeptide (VIP). Interest in VIP as a regulator of various aspects of embryo and fetal growth developed from cell culture observations in which low concentrations of VIP support survival of neurons in culture (concentrations too low to stimulate adenyl cyclase and the more common actions of VIP).44 Receptors for VIP have been found in the nervous system but not the rest of the fetal body when studied in rat embryos.45 When VIP is added to embryo cultures, however, both brain and body growth are increased .46 Because receptors are only in the central nervous system, it appears that VIP enhances embryonic body growth via a central nervous system regulated process. Specificity of VIP has been tested by showing that antagonists to VIP introduced in pregnant mice also produced smaller fetuses that were particularly microcephalic.47 Neurons in these neonatal mice had reduced mitosis and reduced migration. The affects of VIP are confined to the first half of gestation, particularly the late embryonic and early fetal period. This critical period also reflects a unique stage in which VIP is transiently increased to rather high concentrations in the maternal plasma reflecting a marked increase in VIP production in maternal tissues .48 This suggests that maternal VIP can be transferred to the embryo and regulate embryonic growth at an early period in embryonic development when VIP receptors are expressed. Dr Hill also discussed recent observation which indicated that growth inhibition by the GP120 viral protein of the human immunodeficiency virus may reflect the mechanism by which women infected with the human immunodeficiency virus produce growth-restricted fetuses. In culture studies, GP120 was neurotoxic and also inhibited growth. This could be prevented by the addition of VIP.
ROLE OF THE PLACENTA IN FETAL GROWTH
A major role of the placenta is to transmit nutrient substances to the fetus, thereby providing essential regulation of fetal metabolism and growth. Epidemiological, clinical, and experimental studies have demonstrated a direct relationship between growth of the placenta and growth of the fetus. Both processes depend on an adequate supply of maternal blood to the placenta, which in turn depends on cytotrophoblast invasion of the uterus and its arterioles. As reviewed by Dr Susan Fisher, cytotrophoblast invasion is actually a differentiation process whereby the cells lose the ability to proliferate and modulate their expression of state-specific antigens. These antigens include members of the integrin family of cell-extracellular matrix receptors which are required for invasion .49,50 Preeclampsia, which is commonly associated with IUGR, is characterized by shallow cytotrophoblast invasion and abnormal differentiation as evidenced by the cells' inability to switch their integrin repertoire." Culturing normal cytotrophoblast cells in an hypoxic environment has replicated several aspects of this abnormal phenotype.''- Such studies have shown a marked increase in the cells' incorporation of H-thymidine and bromodeoxyuridine. Moreover, the cells failed to invade extracellular matrix substrates, attributable at least in part to their inability to switch their integrin repertoire. These results suggest that hypoxia alters the balance between cytotrophoblast proliferation and differentiation/ invasion, thus setting the stage for later pregnancy complications.
At more advanced stages of placental development, placental production of growth factors and growth-regulating hormones develop, leading to significant placental regulation of fetal growth processes. Dr Stuart Handwerger reviewed the role of human placental lactogen as one example. Human placental lactogen, which is synthesized and secreted by the syncytiotrophoblast cells of the placenta, is a member of the placental lactogen, growth hormone, prolactin gene family.53 Studies from many laboratories indicate a role for human placental lactogen in the regulation of fetal growth. 54 The growth-promoting actions of placental lactogen are mediated by stimulation of IGF production in the fetus and by increasing the availability of nutrients to fetal tissues. Although placental lactogen acts a fetal growth hormone and is a member of the same gene family as growth hormone, the factors that regulate the synthesis and release of placental lactogen are different from those that regulate growth hormone. Recent investigations strongly suggest a novel role for apolipoprotein A1, the major protein component of high-density lipoprotein, in the regulation of placental lactogen gene expression .55 Thyroid hormone, retinoic acid, vitamin D3, and the cytokines interleukin-6 and interleukin-1 also are implicated in the regulation of placental lactogen gene expression.
TREATMENT OF IUGR
Despite major advances in understanding how fetal growth takes place, as well as the causes, pathophysiology, and consequences of IUGR, therapy for IUGR remains an elusive goal. It is an important goal, however, and one that should attract considerable creative thinking, research trials in animal models, and clinical trials as soon as appropriate. One approach to this issue was presented by Dr Peter Gluckman who reviewed the importance of IGF-I as a hormone that controls fetal growth but also has important influences on maternal metabolism.56 IGF-I, according to preliminary studies, also may play a role in the regulation of placental metabolism and the compartmentalization of nutrients between maternal and fetal plasma. Studies in the pregnant sheep model in Dr Gluckman's laboratory have shown that IGF-I infusion into the fetus acts as an important regulator of fetal growth. It is under rapid and specific nutritional regulation being upregulated by both insulin and glucose .57 It has anabolic and anticatabolic affects in the fetus and may alter fetal/ placental nutrient partitioning favoring glucose and lactate supply to fetal tissues.58 IGF-I infusion on the maternal side in pregnant sheep has shown variable affects dependent on dosage, but particularly at low infusion rates and low plasma concentrations, Dr Gluckman's studies have indicated that IGF-I may increase blood glucose concentration by inhibiting insulin secretion and decreasing insulin concentration. Simultaneously, placental lactate production increases, at least because of the maternal hyperglycemia.59 Based on such information, Dr Gluckman postulated that maternal administration of IGF-I could be considered as a therapeutic approach to treating IUGR. This could be done directly or by raising maternal plasma glucose concentration by enteral and/or parenteral nutrition. Another candidate hormone for IUGR therapy, is human growth hormone, which, like IGF-I treatment to the mother,
may have the potential to increase fetal weight (unpublished observations, Gluckman et al, University of Auckland, Auckland, New Zealand). The rationale for this approach is that at the same time that increased nutrition in the mother upregulates IGF-I, so does placental growth and production of growth hormone. Infusions of both IGF-I and growth hormone, therefore, particularly in women who are unable to increase nutritional intake significantly, may represent hormonal therapies that could be considered for treating IUGR. Obviously animal model trials are necessary to establish more clearly the mechanisms by which these hormones may affect nutrient concentrations in the maternal plasma, placental metabolism and transfer to the fetus of such nutrients, as well as fetal metabolism and growth.
THE FUTURE OF DIAGNOSIS AND TREATMENT OF IUGR
Altered fetal growth rate is seldom dramatic, lacking sudden changes in growth that can be detected easily by ordinary clinical means. Similarly, pathophysiology, some of which may be damaging to the fetus, often develops insidiously, such that once it is obvious clinically, injury has already taken place. An overriding theme in the discussion, therefore, reflected the need to develop and apply diagnostic techniques to the fetus that would establish accurately and with sensitivity even minimal changes in growth rate and coordinated changes in physiological function. Currently, Doppler ultrasound measurements of fetal cardiac output, systemic blood flow, and organ blood supply are getting closer to achieving this goal, particularly with respect to the placental circulation.60 Other recent research trials have focused on quantifying placental transfer functions in which pregnant women suspected of carrying a severely IUGR infant can be given a cocktail of stable isotopes of nutrients normally transported across the placenta such as glucose and selected amino acids, followed by timed cordocentesis to measure placental transfer characteristics of these substrate isotopes.61 This information can be compared with that from normal pregnancies with normal placental function and fetal growth rates.
It is also important that diagnostic techniques are developed to assess what damage is being done by the pathophysiology associated with more extreme cases of intrauterine growth restriction. Current examples include magnetic resonance imaging, Doppler measurements of blood flow, 60 cordocentesis,62-65 and neurological and neuromuscular response to vibroacoustic stimulation .66 Based on such advances in fetal diagnosis, it soon may be possible to assess whether detected changes in fetal growth rate and measured fetal pathophysiology associated with IUGR are in fact as serious and prognostically indicative of future handicap as careful postnatal follow-up studies have indicated.
Such diagnostic modalities should lead directly to developing therapeutic approaches to IUGR. Considerably more research is necessary to determine when and with what approaches damage to the fetus can be reversed or ameliorated. Some efforts have been made clinically and experimentally in animal models to improve maternal and fetal nutrition 67 and to enhance development by organ-specific hormone targeting." Examples of the latter include glucocorticoids that have been administered (as betamethasone) to both the mother and the fetus to increase lung surfactant maturity,69 with additional potential benefits to the maturation of other fetal organs including the gut, the heart, the adrenals, and the kidneys .68 Continued work is necessary to assess brain development with such treatments, as well as long-term growth and development of all affected organs. Thyroid-releasing hormone has been administered along with corticosteroids to increase lung maturity, although currently there are mixed reports of its effectiveness.'° More philosophically, it is important to consider whether it is wise to change normal developmental relationships among organs by using organ-specific hormone therapy; more information is needed to determine how altered patterns of organ development during fetal life are beneficial and how they may promote, or hinder, normal fetal development.
CONCLUSIONS
IUGR continues to be an important problem in perinatal medicine. Remarkable advances at all levels of biological investigation have improved understanding of how fetal growth takes place and what causes fetal growth to be delayed to the point at which normal fetal function is inhibited, fetal injury takes place, fetal development is adversely affected, and neonatal and long-term outcome become significantly impaired. Much more research in all of these areas is necessary to advance understanding of IUGR to the point where newer diagnostic techniques and therapeutic approaches can be safely and effectively used.
APPENDIX
The workshop participants were as follows:
Charlotte Catz, MD, National Institute of Child Health and Development,
Bethesda, Maryland; Tim Chard, MD, St Bartholomew's Hospital Medical college and
The London Hospital Medical College, London, United Kingdom; A. Joseph D'Ercole,
MD, University of North Carolina School of Medicine, Chapel Hill, North
Carolina; Gore Ervin, PhD, Harbor-UCLA Medical Center, Torrance, California;
Susan J. Fisher, PhD, University of California, San Francisco, California;
Janina Galler, MD, Boston University School of Medicine, Boston, Massachusetts;
Peter Gluckman, MD, University of Auckland School of Medicine, Auckland, New
Zealand; Robert Goldenberg, MD, University of Alabama, Birmingham, Alabama;
Gilman Grave, MD, National Institute of Child Health and Development, Bethesda,
Maryland; Maureen Hack, MD, Case Western Reserve University, Cleveland, Ohio;
Victor Han, MD, St Joseph's Health Centre, London, Ontario, Canada; Stuart
Handwerger, MD, Children's Hospital Medical Center, Cincinnati, Ohio; William W.
Hay, Jr, MD, University of Colorado School of Medicine, Denver, Colorado; Joanna
M. Hill, MD, National Institute of Child Health and Development, Bethesda,
Maryland; Joseph J. Hoet, MD, University of Louvain, University Hospital St-Luc,
Brussels, Belgium; Alan Jobe, MD, Harbor-UCLA Medical Center, Torrance,
California; Satish Kalhan, MD, Rainbow Babies and Children's Hospital,
Cleveland, Ohio; Roberto Romero, MD, Georgetown University Medical Center,
Washington, DC; Raymond Stark, MD, Columbia University College of Physicians and
Surgeons, New York, New York; Randall B. Wilkening, MD, University of Colorado
School of Medicine, Denver, Colorado; Linda Wright, MD, National Institute of
Child Health and Human Development, Bethesda, Maryland; and Sumner J. Yaffe, MD,
National Institute of Child Health and Human Development, Bethesda, Maryland.
ACKNOWLEDGMENTS
Dr Hay is supported in part by grants HD20761, HD28794, and RR00069 from the National Institutes of Health.
We thank Ms Barbara Cantilena for her administrative expertise in setting up the workshop and in the preparation of this manuscript.
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