Workshop Summary: Fetal Growth: Its Regulation and Disorders

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.1 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.34Fetal 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.5Additionally, 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,910reflecting 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. Barker11, 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 decreased12and, 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 β-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.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.16Several 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.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.21Perhaps 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.22Outcome 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.2526 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.32The 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.3334Dr Hack concluded that the effects of intrauterine growth failure are affected by the quality of perinatal care and sociodemographic factors. Outcome studies are confounded by the heterogeneity of perinatal and postnatal conditions and growth either circulating in the fetal plasma or of fetal cellular also are important of fetal growth. growth factors may normal growth processes as of their normal they also lead to abnormal growth when genetic in is such growth factor can be by extrinsic factors such nutrient supply to the fetal Dr Joseph reviewed the role of in brain development developed in from models have shown that increased of is associated with increased brain Similarly, insulin-like growth factor protein is not normally in the a in which an of is results in an of brain In general, the of the brain most in the are most in the because the most affected are those most sensitive to the of the results of these studies suggest the has effects on an increase in brain content which is by increased of associated protein as well as by the of This results in a increased of and in the of their also appears to an increase in number, at in the et unpublished also the of in the they are in the and reduced to half the normal size in the These effects of may be to increased with increased and is decreased by reduced nutrient supply, particularly glucose, and is decreased these Dr that the more of the brain may have been by nutrient regulation of and focused on and with respect to fetal growth. is in fetal life in tissue in the first of but only in and in the of of and concentrations of may not with fetal size at birth in infants, it has been shown that of the reduces fetal size in is the that is in the of and of all As with and of and show that cellular growth is on the the protein and the Dr also reviewed the importance of is the protein in several and but it is not in some other particularly and This difference in fetal concentrations into the significance of circulating is not in the plasma of these the is to be in their has been shown to be reduced in blood of infants with this of circulating as well as and are not only to their potential influences a given animal but also to and the differences in the and effects of these that among Dr particularly a approach to the role of and their in development in that one may be quite different from that of the and their may have a role in fetal growth as does insulin there are many other factors that particularly at different of and fetal growth. As one example, Dr reviewed new the potential of in as a of various aspects of and fetal growth developed from cell in which low concentrations of survival of in low to and the more common of for have been found in the but not the of the fetal body when studied in rat When is to however, both brain and body growth are are only in the it appears that body growth via a of has been by that to in pregnant also smaller that were particularly in these neonatal had reduced and reduced The of are to the first half of particularly the and early fetal This also a unique in which is increased to rather high concentrations in the maternal plasma a increase in production in maternal This that maternal can be to the and growth at an early in development when are Dr also discussed recent observation which indicated that growth by the protein of the may the by which women with the produce In studies, was and also growth. This be by the addition of major role of the placenta is to nutrient to the providing regulation of fetal and growth. and experimental studies have a relationship growth of the placenta and growth of the processes on an supply of maternal blood to the which in on of the and As reviewed by Dr is a the the to and their of These include of the of which are for which is commonly associated with IUGR, is by and abnormal as by the to their normal in an has several aspects of this abnormal studies have shown a increase in the and the failed to at in to their to their These results suggest that the proliferation and thus the for more of placental placental production of growth factors and leading to placental regulation of fetal growth processes. Dr reviewed the role of placental as one placental which is and by the of the is a of the placental growth Studies from many indicate a role for placental in the regulation of fetal The of placental are by of production in the fetus and by the of to fetal placental acts a fetal growth and is a of the as growth the factors that the and of placental are different from those that growth suggest a role for the major protein of in the regulation of placental and the and also are in the regulation of placental major advances in how fetal growth as well as the causes, and consequences of IUGR, therapy for IUGR an is an important however, and one that should research in animal and as as approach to this was presented by Dr who reviewed the importance of as a that fetal growth but also has important influences on maternal according to studies, also may play a role in the regulation of placental and the of maternal and fetal Studies in the pregnant in Dr have shown that into the fetus acts as an important of fetal growth. is and specific nutritional regulation upregulated by both insulin and has and in the fetus and may nutrient glucose and supply to fetal on the maternal in pregnant has shown on but particularly at low rates and low plasma Dr studies have indicated that may increase blood glucose concentration by insulin secretion and insulin placental production at because of the maternal on such Dr that maternal of be considered as a approach to IUGR. This be or by maternal plasma glucose concentration by and/or for IUGR is growth treatment to the may have the potential to increase fetal weight et of The for this approach is that at the that increased in the so does placental growth and production of growth of both and growth therefore, particularly in women who are to increase nutritional may represent that be considered for IUGR. animal are to more the mechanisms by which these may affect nutrient concentrations in the maternal placental and to the fetus of such as well as fetal and fetal growth is in growth that can be by Similarly, some of which may be to the such that it is obvious has in the therefore, reflected the to develop and techniques to the fetus that would and with even minimal in growth and in physiological of fetal blood and blood supply are to this particularly with respect to the placental recent research have focused on placental in which pregnant women of a IUGR infant can be given a of of normally across the placenta such as glucose and amino acids, by cordocentesis to placental of these This can be compared with that from normal with normal placental and fetal growth is also important that techniques are developed to damage is by the pathophysiology associated with more cases of intrauterine growth examples include of blood and and response to on such advances in fetal diagnosis, it may be possible to whether in fetal growth and fetal pathophysiology associated with IUGR are in as serious and of future as postnatal studies have should lead to to IUGR. more research is to when and with damage to the fetus can be or have been and experimentally in animal models to maternal and fetal and to enhance development by of the include that have been to both the and the fetus to increase with potential to the of other fetal the the the and the is to brain development with such as well as long-term growth and development of all affected has been with to increase there are mixed of it is important to consider whether it is to normal among by more is to how altered of development during fetal life are and how they may or normal fetal to be an important problem in perinatal advances at all levels of investigation have improved of how fetal growth place and causes fetal growth to be to the point at which normal fetal is fetal fetal development is and neonatal and long-term outcome become significantly Much more research in all of these areas is to of IUGR to the point techniques and can be and Hay is in by and from the National of for in up the and in the of this were as National Institute of Child Health and Tim and The Joseph of of J. of of of of Robert of National Institute of Child Health and Maureen Hack, Health William of of National Institute of Child Health and Joseph J. Hoet, of and of and of of National Institute of Child Health and and J.