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Intrauterine growth retardation and subsequent somatic growth and neurodevelopment
I
Intrauterine growth retardation and subsequent
somatic growth and neurodevelopment
Although multiple studies have demonstrated a deleterious effect of fetal growth deceleration on outcome,1-3 most have not adequately controlled for potential confounding genetic and environmental variables. For example, intrauterine growth retardation occurs more commonly in women who are of lower socioeconomic status, who access health care less frequently, and who are not in the prime reproductive years. These known prenatal risk factors may also play an important postnatal role in infant growth and development. Thus the possibility exists that long-term neurodevelopmental deficits in growth-retarded infants are due in part to postnatal environmental factors rather than solely to the biologic effect of fetal growth retardation on the developing fetal brain. In this issue of The Journal, Strauss and Dietz4 revisit this issue through a clever study paradigm designed to limit potential genetic and environmental confounders by comparing infants with IUGR with their siblings who were appropriate for gestational age (and with a general cohort of nonrelated infants who were appropriate for gestational age). There is strong neuropathologic evidence for a deleterious effect of early malnutrition on brain development. IUGR involves profound deficiencies of at least three substrates that are important for normal brain development: oxygen, protein-energy, and iron. Winnick and Rosso’s5 classic studies demonstrated a substantive negative impact on cell number and cell size, resulting in dramatic reductions in head circumference.5 In animal models chronic in-
J Pediatr 1998;133:3-5. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/91243
trauterine hypoxia without protein-energy or iron restriction results in smaller fetuses with lighter brain weights and DNA content.6 Neuronal RNA,7 DNA, and RNA coding for neuronal and glial structural proteins, synapse number,8 ultrastructural changes in synaptic junctions,9 and downregulation of neurotransmitter peptide production10 have been documented after experimental protein restriction in the developing animal. Altered ratios of essential fatty acids affect myelination, brain lipid composition, and learning ability in rats.11 Finally, protein-energy malnutrition negatively affects growth factors important for central nervous system development including IGF-1.
See related article, p. 67. Previous clinical studies of small-forgestational-age human infants have generally borne out the theoretical risks. There has been little debate that IUGR that results in poor prenatal head growth is associated with poor developmental outcome.1-3,12-14 Symmetric IUGR has a deleterious effect on subsequent verbal outcome,12 on visual recognition memory,3 and on general neurodevelopmental outcome at 7 years.13 Of infants born after pregnancies complicated by IUGR and gestational hypertension, 15% have mild neurodevelopmental abnormalities noted at 2 years of age compared with 3% of infants in control groups.15 As the ability to assess neurodevelopment has become more sophisticated and precise, it is interesting to note that cognitive disabilities such as weak novelty preference (a problem in recognition memory) rather than motor disabilities seem particularly prevalent in infants with IUGR.3 This finding is
consistent with more global insults such as hypoxia, protein-energy malnutrition, and iron deficiency. IUGR
Intrauterine growth retardation
In light of strong anatomic evidence and previous clinical studies, the Strauss and Dietz4 study merits close scrutiny. With the registry from The National Collaborative Perinatal Project (19591976), the group had access to the birth and 7-year growth and neurodevelopmental data of more than 45,000 children. The authors made two sets of comparisons to assess the effect of IUGR. First, in a manner similar to previous studies of the effects of IUGR, the 2719 infants with IUGR from the registry were compared with the general population of 43,104 infants who were not small for dates. In this comparison the infants with IUGR had significant growth and developmental deficits, confirming previous studies of IUGR populations. In the second paradigm the authors compared 220 infants with IUGR from the registry who happened to have siblings who did not have IUGR and who were also in the registry. In this comparison growth but not intellectual differences was seen between the groups. The authors conclude that restriction of fetal growth affects longterm weight and length but that neurodevelopment is affected only if microcephaly was present at birth. Furthermore the authors suggest that the neurodevelopmental deficits seen in previous studies of infants with IUGR may have been due to uncontrolled genetic or environmental factors. When compared with their own siblings (who presumably have similar genetic and environmental risk factors), the outcomes 3
EDITORIALS
of “head-spared” infants with IUGR are no worse. This study and others that have preceded it conclude that long-term growth is affected by fetal growth restriction. In toto, these studies support the concept that critical windows of time are present in human development during which certain growth processes (e.g., fat or muscle accretion, bone growth) must occur. Permanent deficits may result if growth failure occurs during these critical time periods. The neurodevelopmental data presented in this study are not as clear-cut as the growth data, and for good reason. First, the measurement of weight and length is well defined and precise. Neurodevelopmental assessment is far more difficult because of the need to accurately evaluate the multiple cognitive domains that can be affected by prenatal insults. Gross effects can be relatively easily quantified by global and nonspecific tests; subtle or more discrete lesions are more problematic. Thus it was not surprising in this study that infants born with microcephaly had significantly lower IQ and Bender-Gestalt scores at 7 years of age when compared with either control cohort. These findings confirm previous studies documenting the detrimental effect of “non-head-spared IUGR”12-14 and are likely due to the overt effects of fetal growth restriction on brain composition described in animal models.6-11 Whether IUGR without overt microcephaly is detrimental to the developing brain has not been settled by this study. On the surface the comparison of the infants with IUGR with their siblings suggests that although both groups have generally poorer neurodevelopment (presumably as a result of environmental factors such as less prenatal care, more maternal smoking, and hypertension or genetic factors), there is no additional decrement in the IUGR group simply from exposure to a hostile intrauterine environment. The authors should be congratulated on a study design that controls for several nonnutritional factors that potentially affect fetal nutrition and brain development. Nevertheless, two alternate explanations for these findings can be consid4
THE JOURNAL OF PEDIATRICS JULY 1998 ered. First, despite an initially large database (54,000 pregnancies), the cohorts ultimately used to test the hypothesis about potentially subtle neurodevelopmental differences were relatively small. Thus the possibility of a beta error exists (that is, finding no difference when one actually exists because of lack of adequate numbers of subjects). This possibility is suggested by the finding that the siblings with IUGR had lower mean values for both IQ and Bender-Gestalt, the effect being 20% to 30% as robust as the decrement seen in the population cohort part of the study. The p values of 0.18 and 0.19 for the comparisons with the non-IUGR siblings are not significant but certainly suggest (with 82% and 81% assurance) that the findings may not be due to chance and that a biologic process may play a role in these differences. This trend is worth further investigation by increasing the number of the cohort. The second potential explanation for the negative findings is that mild IUGR affects neurodevelopmental behaviors not adequately assessed by IQ and Bender-Gestalt tests. Choosing the correct assessment instrument in neurodevelopmental outcomes research is as crucial as choosing the correct assay in a physical science experiment. As recently reviewed by Singer,16 “the (psychologic) assessment must (1) be standardized (i.e., have a uniform set of procedures for administration and scoring), (2) be reliable (i.e., measure a cohesive construct in a similar fashion across...time), and (3) be valid (i.e., measure the construct it purports to).” In addition, the test must be appropriate for the pathophysiology of the biologic event affecting the outcome (e.g., if perinatal hypoxia-ischemia specifically affects the hippocampus, tests assessing recognition memory that are mediated by the hippocampus are appropriate). The IQ and Bender-Gestalt tests are broad-based evaluations that yield a single composite score based on multiple subtests of diverse skills. As such, they are good screening tools that provide a summary of overall developmental abilities. However, without subtest analyses, little other than a general picture is gained for them. Moreover, they provide no information about
deficits that are pathophysiologically related to the process of IUGR (i.e., by assessing behaviors subserved by areas of the brain that were targeted by the process of IUGR). Thus the tests used in this study lack sufficient specificity or sensitivity to identify any subtle effects on items such as spatial working memory, recognition memory, or memory strategy as examples. This is particularly relevant given other studies that suggest an effect of IUGR on these cognitive domains.3 Ultimately, deficits in these areas may have important effects on school performance without any obvious effect on IQ. In defense of this study, these metrics were either not available or not routinely performed in the creation of the database, and thus no definitive conclusion can be made about any subtle effects of fetal growth restriction on neurodevelopmental outcome. In summary, IUGR has an incontrovertible effect on long-term growth. The effect on neurodevelopment remains difficult to pin down. Certainly, a small head circumference at birth is a harbinger of future neurodevelopmental problems. Whether head sparing completely eradicates the neurodevelopmental risk associated with IUGR is unclear until more specific and sensitive assessments are applied to this group of infants. Until that time it seems prudent to continue to consider these infants at risk for mild neurodevelopmental sequelas that may affect school or social performance despite grossly normal IQs at 7 years of age. Michael K. Georgieff, MD Associate Professor of Pediatrics and Child Development University of Minnesota Minneapolis, Minnesota
REFERENCES 1. Low JA, Galbraith RS, Muir D, Killen H, Pater B, Karchmar J. Intrauterine growth retardation: a study of long-term morbidity. Am J Obstet Gynecol 1982; 142:670-7. 2. Harvey D, Prince J, Bunton J, Parkinson C, Campbell S. Abilities of children who were small-for-gestationalage babies. Pediatrics 1982;69:296-300. 3. Gottleib SJ, Biasini FJ, Bray NW. Visual recognition memory in IUGR and
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 1
4.
5.
6.
7.
8.
normal birthweight infants. Infant Behav Devel 1988;11:223-8. Strauss RS, Dietz WH. Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr 1998; 133:67-72. Winnick M, Rosso P. The effect of severe early malnutrition on cellular growth of the human brain. Pediatr Res 1969; 3:181-4. DeGruaw TJ , Myers RE, Scott WJ . Fetal growth retardation in rats from different levels of hypoxia. Biol Neonate 1984;46:10-3. Bass NH, Netsky MG, Young E. Effect of neonatal malnutrition on the developing cerebrum. Arch Neurol 1970;23:289-302. Cragg BH. The development of cortical synapses during starvation in the rat. Brain 1972;95:143-50.
EDITORIALS
9. Jones DG, Dyson SE. Synaptic junction in the undernourished rat brain. An ultrastructural investigation. Exp Neurol 1976;51:529-35. 10. Wiggens RC, Fuller G, Enna SJ. Undernutrition and the development of brain neurotransmitter systems. Life Sci 1984;35:2085-94. 11. Yamamamoto N, Saitoh M, Moriuchi A, Nomura M, Okuyama H. Effect of dietary linolenate/linoleate balance on brain lipid compositions and learning ability of rats. J Lipid Res 1987;28:144-51. 12. Pollitt E, Gorman KS. Nutritional deficiencies as developmental risk factors. In: Nelson CA, editor. Infants and children at risk: integrating biological, psychological and social risk factors. Minnesota Symposia on Child Psychology, New Jersey: Lawrence Erlbaum Assoc. Hillsdale, 1994;27:121-44.
13. Berg AT. Indices of fetal growth retardation, perinatal hypoxia-related factors and childhood neurological morbidity. Early Hum Dev 1989;19:271-83. 14. Lin CC, Su SJ, River LP. Comparison of associated high-risk factors and perinatal outcome between symmetric and asymmetric fetal intrauterine growth retardation. Am J Obstet Gynecol 1991;164: 1535-41. 15. Spinello A, Stronati M, Ometto A, Fazzi E, Lanzi G, Guaschino S. Infant neurodevelopmental outcome in pregnancies complicated by gestational hypertension and intra-uterine growth retardation. J Perinat Med 1993;21:195-203. 16. Singer LT. Methodological considerations in longitudinal studies of infant risk. In: Dobbing J, editor. Developing brain and behaviour. London: Academic Press; 1997. p. 209-31.
5
Intrauterine growth retardation and subsequent
somatic growth and neurodevelopment
Although multiple studies have demonstrated a deleterious effect of fetal growth deceleration on outcome,1-3 most have not adequately controlled for potential confounding genetic and environmental variables. For example, intrauterine growth retardation occurs more commonly in women who are of lower socioeconomic status, who access health care less frequently, and who are not in the prime reproductive years. These known prenatal risk factors may also play an important postnatal role in infant growth and development. Thus the possibility exists that long-term neurodevelopmental deficits in growth-retarded infants are due in part to postnatal environmental factors rather than solely to the biologic effect of fetal growth retardation on the developing fetal brain. In this issue of The Journal, Strauss and Dietz4 revisit this issue through a clever study paradigm designed to limit potential genetic and environmental confounders by comparing infants with IUGR with their siblings who were appropriate for gestational age (and with a general cohort of nonrelated infants who were appropriate for gestational age). There is strong neuropathologic evidence for a deleterious effect of early malnutrition on brain development. IUGR involves profound deficiencies of at least three substrates that are important for normal brain development: oxygen, protein-energy, and iron. Winnick and Rosso’s5 classic studies demonstrated a substantive negative impact on cell number and cell size, resulting in dramatic reductions in head circumference.5 In animal models chronic in-
J Pediatr 1998;133:3-5. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/91243
trauterine hypoxia without protein-energy or iron restriction results in smaller fetuses with lighter brain weights and DNA content.6 Neuronal RNA,7 DNA, and RNA coding for neuronal and glial structural proteins, synapse number,8 ultrastructural changes in synaptic junctions,9 and downregulation of neurotransmitter peptide production10 have been documented after experimental protein restriction in the developing animal. Altered ratios of essential fatty acids affect myelination, brain lipid composition, and learning ability in rats.11 Finally, protein-energy malnutrition negatively affects growth factors important for central nervous system development including IGF-1.
See related article, p. 67. Previous clinical studies of small-forgestational-age human infants have generally borne out the theoretical risks. There has been little debate that IUGR that results in poor prenatal head growth is associated with poor developmental outcome.1-3,12-14 Symmetric IUGR has a deleterious effect on subsequent verbal outcome,12 on visual recognition memory,3 and on general neurodevelopmental outcome at 7 years.13 Of infants born after pregnancies complicated by IUGR and gestational hypertension, 15% have mild neurodevelopmental abnormalities noted at 2 years of age compared with 3% of infants in control groups.15 As the ability to assess neurodevelopment has become more sophisticated and precise, it is interesting to note that cognitive disabilities such as weak novelty preference (a problem in recognition memory) rather than motor disabilities seem particularly prevalent in infants with IUGR.3 This finding is
consistent with more global insults such as hypoxia, protein-energy malnutrition, and iron deficiency. IUGR
Intrauterine growth retardation
In light of strong anatomic evidence and previous clinical studies, the Strauss and Dietz4 study merits close scrutiny. With the registry from The National Collaborative Perinatal Project (19591976), the group had access to the birth and 7-year growth and neurodevelopmental data of more than 45,000 children. The authors made two sets of comparisons to assess the effect of IUGR. First, in a manner similar to previous studies of the effects of IUGR, the 2719 infants with IUGR from the registry were compared with the general population of 43,104 infants who were not small for dates. In this comparison the infants with IUGR had significant growth and developmental deficits, confirming previous studies of IUGR populations. In the second paradigm the authors compared 220 infants with IUGR from the registry who happened to have siblings who did not have IUGR and who were also in the registry. In this comparison growth but not intellectual differences was seen between the groups. The authors conclude that restriction of fetal growth affects longterm weight and length but that neurodevelopment is affected only if microcephaly was present at birth. Furthermore the authors suggest that the neurodevelopmental deficits seen in previous studies of infants with IUGR may have been due to uncontrolled genetic or environmental factors. When compared with their own siblings (who presumably have similar genetic and environmental risk factors), the outcomes 3
EDITORIALS
of “head-spared” infants with IUGR are no worse. This study and others that have preceded it conclude that long-term growth is affected by fetal growth restriction. In toto, these studies support the concept that critical windows of time are present in human development during which certain growth processes (e.g., fat or muscle accretion, bone growth) must occur. Permanent deficits may result if growth failure occurs during these critical time periods. The neurodevelopmental data presented in this study are not as clear-cut as the growth data, and for good reason. First, the measurement of weight and length is well defined and precise. Neurodevelopmental assessment is far more difficult because of the need to accurately evaluate the multiple cognitive domains that can be affected by prenatal insults. Gross effects can be relatively easily quantified by global and nonspecific tests; subtle or more discrete lesions are more problematic. Thus it was not surprising in this study that infants born with microcephaly had significantly lower IQ and Bender-Gestalt scores at 7 years of age when compared with either control cohort. These findings confirm previous studies documenting the detrimental effect of “non-head-spared IUGR”12-14 and are likely due to the overt effects of fetal growth restriction on brain composition described in animal models.6-11 Whether IUGR without overt microcephaly is detrimental to the developing brain has not been settled by this study. On the surface the comparison of the infants with IUGR with their siblings suggests that although both groups have generally poorer neurodevelopment (presumably as a result of environmental factors such as less prenatal care, more maternal smoking, and hypertension or genetic factors), there is no additional decrement in the IUGR group simply from exposure to a hostile intrauterine environment. The authors should be congratulated on a study design that controls for several nonnutritional factors that potentially affect fetal nutrition and brain development. Nevertheless, two alternate explanations for these findings can be consid4
THE JOURNAL OF PEDIATRICS JULY 1998 ered. First, despite an initially large database (54,000 pregnancies), the cohorts ultimately used to test the hypothesis about potentially subtle neurodevelopmental differences were relatively small. Thus the possibility of a beta error exists (that is, finding no difference when one actually exists because of lack of adequate numbers of subjects). This possibility is suggested by the finding that the siblings with IUGR had lower mean values for both IQ and Bender-Gestalt, the effect being 20% to 30% as robust as the decrement seen in the population cohort part of the study. The p values of 0.18 and 0.19 for the comparisons with the non-IUGR siblings are not significant but certainly suggest (with 82% and 81% assurance) that the findings may not be due to chance and that a biologic process may play a role in these differences. This trend is worth further investigation by increasing the number of the cohort. The second potential explanation for the negative findings is that mild IUGR affects neurodevelopmental behaviors not adequately assessed by IQ and Bender-Gestalt tests. Choosing the correct assessment instrument in neurodevelopmental outcomes research is as crucial as choosing the correct assay in a physical science experiment. As recently reviewed by Singer,16 “the (psychologic) assessment must (1) be standardized (i.e., have a uniform set of procedures for administration and scoring), (2) be reliable (i.e., measure a cohesive construct in a similar fashion across...time), and (3) be valid (i.e., measure the construct it purports to).” In addition, the test must be appropriate for the pathophysiology of the biologic event affecting the outcome (e.g., if perinatal hypoxia-ischemia specifically affects the hippocampus, tests assessing recognition memory that are mediated by the hippocampus are appropriate). The IQ and Bender-Gestalt tests are broad-based evaluations that yield a single composite score based on multiple subtests of diverse skills. As such, they are good screening tools that provide a summary of overall developmental abilities. However, without subtest analyses, little other than a general picture is gained for them. Moreover, they provide no information about
deficits that are pathophysiologically related to the process of IUGR (i.e., by assessing behaviors subserved by areas of the brain that were targeted by the process of IUGR). Thus the tests used in this study lack sufficient specificity or sensitivity to identify any subtle effects on items such as spatial working memory, recognition memory, or memory strategy as examples. This is particularly relevant given other studies that suggest an effect of IUGR on these cognitive domains.3 Ultimately, deficits in these areas may have important effects on school performance without any obvious effect on IQ. In defense of this study, these metrics were either not available or not routinely performed in the creation of the database, and thus no definitive conclusion can be made about any subtle effects of fetal growth restriction on neurodevelopmental outcome. In summary, IUGR has an incontrovertible effect on long-term growth. The effect on neurodevelopment remains difficult to pin down. Certainly, a small head circumference at birth is a harbinger of future neurodevelopmental problems. Whether head sparing completely eradicates the neurodevelopmental risk associated with IUGR is unclear until more specific and sensitive assessments are applied to this group of infants. Until that time it seems prudent to continue to consider these infants at risk for mild neurodevelopmental sequelas that may affect school or social performance despite grossly normal IQs at 7 years of age. Michael K. Georgieff, MD Associate Professor of Pediatrics and Child Development University of Minnesota Minneapolis, Minnesota
REFERENCES 1. Low JA, Galbraith RS, Muir D, Killen H, Pater B, Karchmar J. Intrauterine growth retardation: a study of long-term morbidity. Am J Obstet Gynecol 1982; 142:670-7. 2. Harvey D, Prince J, Bunton J, Parkinson C, Campbell S. Abilities of children who were small-for-gestationalage babies. Pediatrics 1982;69:296-300. 3. Gottleib SJ, Biasini FJ, Bray NW. Visual recognition memory in IUGR and
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 1
4.
5.
6.
7.
8.
normal birthweight infants. Infant Behav Devel 1988;11:223-8. Strauss RS, Dietz WH. Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr 1998; 133:67-72. Winnick M, Rosso P. The effect of severe early malnutrition on cellular growth of the human brain. Pediatr Res 1969; 3:181-4. DeGruaw TJ , Myers RE, Scott WJ . Fetal growth retardation in rats from different levels of hypoxia. Biol Neonate 1984;46:10-3. Bass NH, Netsky MG, Young E. Effect of neonatal malnutrition on the developing cerebrum. Arch Neurol 1970;23:289-302. Cragg BH. The development of cortical synapses during starvation in the rat. Brain 1972;95:143-50.
EDITORIALS
9. Jones DG, Dyson SE. Synaptic junction in the undernourished rat brain. An ultrastructural investigation. Exp Neurol 1976;51:529-35. 10. Wiggens RC, Fuller G, Enna SJ. Undernutrition and the development of brain neurotransmitter systems. Life Sci 1984;35:2085-94. 11. Yamamamoto N, Saitoh M, Moriuchi A, Nomura M, Okuyama H. Effect of dietary linolenate/linoleate balance on brain lipid compositions and learning ability of rats. J Lipid Res 1987;28:144-51. 12. Pollitt E, Gorman KS. Nutritional deficiencies as developmental risk factors. In: Nelson CA, editor. Infants and children at risk: integrating biological, psychological and social risk factors. Minnesota Symposia on Child Psychology, New Jersey: Lawrence Erlbaum Assoc. Hillsdale, 1994;27:121-44.
13. Berg AT. Indices of fetal growth retardation, perinatal hypoxia-related factors and childhood neurological morbidity. Early Hum Dev 1989;19:271-83. 14. Lin CC, Su SJ, River LP. Comparison of associated high-risk factors and perinatal outcome between symmetric and asymmetric fetal intrauterine growth retardation. Am J Obstet Gynecol 1991;164: 1535-41. 15. Spinello A, Stronati M, Ometto A, Fazzi E, Lanzi G, Guaschino S. Infant neurodevelopmental outcome in pregnancies complicated by gestational hypertension and intra-uterine growth retardation. J Perinat Med 1993;21:195-203. 16. Singer LT. Methodological considerations in longitudinal studies of infant risk. In: Dobbing J, editor. Developing brain and behaviour. London: Academic Press; 1997. p. 209-31.
5