956
Commentary
The Journal of Pediatrics December 1975
Commentary: Intrauterine developmental retardation
Growth is a word of notorious imprecision, but it stoutly defies semantical reform. It may mean increase of length, area, weight or volume; it may mean the act or accomplished fact of reproduction, i.e. increase of number; or it may simply mean development-the adverb is not well chosen--with all that development implies of increasing complexity and elaboration.~ THE CONCEPT of intrauterine growth retardation is now so well established that it has become a part of the jargon of the nursery. It was a major advance to designate small infants who were in fact undergrown for gestational age in contrast to small infants who were appropriate for gestational age and truly premature. The last decade has been characterized by publications which attempted to distinguish these infants by two approaches. The first is based on the assumption that neurologic maturation in the absence of disease is relatively uninfluenced by those factors that determine fetal size. ~ The second relies on the assumption that aspects of skin maturation reflect gestational age more closely than body size? Both of these assumptions have been amply confirmed in the human infant and to some extent in animal models, 4, ~ The word growth, as used by pediatricians, usually denotes size in contrast to maturity. The phrase "growth and development" reflects the pediatrician's desire to distinguish changes in size from changes in maturation after birth. There has been no suitable phrase for delay or acceleration of maturation in utero, in contrast to changes in growth. In fact the concepts of relative advancement in the maturity of one organ system and delay in the maturity of another within the same infant are only now becoming appreciated. ~' 7 Strong supporting evidence for the possibility of selective organ maturation or retardation comes from pharmacologic intervention during pregnancy. For example, administration of phenobarbital to the mother prior to delivery has been shown to result in maturation of liver enzymes which enhance hepatic clearance of bilirubin although the clinical benefit of this approach has not been established. ~ Prenatal glucocorticoids can accelerate the maturation of the lung with
Vol. 87, No. 6, part 1, pp. 956-957
respect to surfactant synthesis without altering aspects of bone age or skin age, or having any significant effect on body size.9' lo The concept of intrauterine developmental retardation or intrauterine developmental acceleration may now be added to the concept of departure from average fetal size. The infant of a diabetic mother illustrates this concept. Most frequently born "large for date," the infant often suffers from pulmonary immaturity, as manifested by an increased incidence of respiratory distress syndrome. 11 The article by Smith and associates 12 on cortisol-insulin antagonism with respect to the maturation of lung cells in tissue culture has significant implications for infants of diabetic mothers. When the fetus is in a hyperinsulinemic state, it is probable that the normal maturational influence of endogenous glucocorticoid is blocked, hence there is a delay in maturation of the lung with respect fo surfactant synthesis. The end result is hyaline membrane disease in the infant. One might then suggest that the infant of the diabetic mother shows intrauterine growth acceleration and intrauterine developmental retardation. With increasing understanding of the regulators of organ maturation we can expect that we will be able to define the degree of maturity of lung, intestine, liver, brain, and other organs. It seems probable from clinical observations that the nervous system and the skin are relatively less influenced by hormonal regulators of maturation than are lung, liver, and intestine. On the other hand much needs to be learned about those events that selectively retard or accelerate growth as well as maturation of each organ system, and presumably each function of each organ. Although the concepts proposed appear to add complexity to the situation it would be assumed that ultimately some simplifying generalizations might emerge. For example, the number of types of accelerators and inhibitors must be finite, and the target organs may well be grouped into those that are cortisol responsive, for example, and those that are cortisol unresponsive. Further understanding of these issues may influence greatly our
Volume 87 Number 6, part 1
Commentary
approach to management of small infants whose environment can presumably be manipulated to be supportive to those functions needing time for development regardless of gestational age.
Mary Ellen Avery, M.D. Ivan Frantz, III, M.D. Children's Hospital Medical Center 300 Longwood A re. Boston, Mass. 02115 REFERENCES 1. Medawar PB: The uniqueness of the individual, New York 1957, Basic Books, Inc., p 108. 2. Amiel-Tison C: Neurological evaluation of the maturity of newborn infants, Arch Dis Child 43:89, 1968. 3. Usher R, McLean F, and Scott KE: Judgement of fetal age. II. Clinical significance of gestational age and an objective method for its assessment, Pediats Clin North Am 13:835, 1966. 4. Dubowitz LMS, Dubowitz V, and Goldberg C: Clinical assessment of gestational age in the newborn infants, J PEDIATR77:1, 1970. 5. Taeusch HW, Wang NS, and Avery ME: Studies on organ
6.
7.
8.
9.
10.
11.
12.
957
maturation; "Skin Age" as an indicator of "'tung age" in fetal rabbits, Pediatrics 49:400, 1972. Kotas RV, Fletcher BD, Torday J, and Avery ME: Evidence for independent regulators of organ maturation in fetal rabbits, Pediatrics 47:57, 1971. Avery ME: Differential organ growth in littermate rabbits in Elliott K, Knight J, editors: Size at birth, Ciba Foundation Symposium 27 (new series), North Holland, Amsterdam, 1974. Trolle D: Decrease of total serum-bilirubin concentration in newborn infants after phenobarbitone treatment, Lancet 2:705, 1968. Kotas RV, and Avery ME: Accelerated appearance of pulmonary surfactant in the fetal rabbit, J Appl Physiol 30:358, 1971. Liggins GC, and Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50:515, 1972. Robert MF, NeffRK, Hubbell JP, Taeusch HW, and Avery ME: The association between maternal diabetes and the respiratory distress syndrome, Pediatr Res 9:370, 1975 (abstr). Smith BT, Giroud CJP, Robert MF, and Avery ME: Insulin antagonism by cortisol action in lecithin synthesis by cultured fetal lung cells, J PEDIATR87"953, 1975.
Commentary
The Journal of Pediatrics December 1975
Commentary: Intrauterine developmental retardation
Growth is a word of notorious imprecision, but it stoutly defies semantical reform. It may mean increase of length, area, weight or volume; it may mean the act or accomplished fact of reproduction, i.e. increase of number; or it may simply mean development-the adverb is not well chosen--with all that development implies of increasing complexity and elaboration.~ THE CONCEPT of intrauterine growth retardation is now so well established that it has become a part of the jargon of the nursery. It was a major advance to designate small infants who were in fact undergrown for gestational age in contrast to small infants who were appropriate for gestational age and truly premature. The last decade has been characterized by publications which attempted to distinguish these infants by two approaches. The first is based on the assumption that neurologic maturation in the absence of disease is relatively uninfluenced by those factors that determine fetal size. ~ The second relies on the assumption that aspects of skin maturation reflect gestational age more closely than body size? Both of these assumptions have been amply confirmed in the human infant and to some extent in animal models, 4, ~ The word growth, as used by pediatricians, usually denotes size in contrast to maturity. The phrase "growth and development" reflects the pediatrician's desire to distinguish changes in size from changes in maturation after birth. There has been no suitable phrase for delay or acceleration of maturation in utero, in contrast to changes in growth. In fact the concepts of relative advancement in the maturity of one organ system and delay in the maturity of another within the same infant are only now becoming appreciated. ~' 7 Strong supporting evidence for the possibility of selective organ maturation or retardation comes from pharmacologic intervention during pregnancy. For example, administration of phenobarbital to the mother prior to delivery has been shown to result in maturation of liver enzymes which enhance hepatic clearance of bilirubin although the clinical benefit of this approach has not been established. ~ Prenatal glucocorticoids can accelerate the maturation of the lung with
Vol. 87, No. 6, part 1, pp. 956-957
respect to surfactant synthesis without altering aspects of bone age or skin age, or having any significant effect on body size.9' lo The concept of intrauterine developmental retardation or intrauterine developmental acceleration may now be added to the concept of departure from average fetal size. The infant of a diabetic mother illustrates this concept. Most frequently born "large for date," the infant often suffers from pulmonary immaturity, as manifested by an increased incidence of respiratory distress syndrome. 11 The article by Smith and associates 12 on cortisol-insulin antagonism with respect to the maturation of lung cells in tissue culture has significant implications for infants of diabetic mothers. When the fetus is in a hyperinsulinemic state, it is probable that the normal maturational influence of endogenous glucocorticoid is blocked, hence there is a delay in maturation of the lung with respect fo surfactant synthesis. The end result is hyaline membrane disease in the infant. One might then suggest that the infant of the diabetic mother shows intrauterine growth acceleration and intrauterine developmental retardation. With increasing understanding of the regulators of organ maturation we can expect that we will be able to define the degree of maturity of lung, intestine, liver, brain, and other organs. It seems probable from clinical observations that the nervous system and the skin are relatively less influenced by hormonal regulators of maturation than are lung, liver, and intestine. On the other hand much needs to be learned about those events that selectively retard or accelerate growth as well as maturation of each organ system, and presumably each function of each organ. Although the concepts proposed appear to add complexity to the situation it would be assumed that ultimately some simplifying generalizations might emerge. For example, the number of types of accelerators and inhibitors must be finite, and the target organs may well be grouped into those that are cortisol responsive, for example, and those that are cortisol unresponsive. Further understanding of these issues may influence greatly our
Volume 87 Number 6, part 1
Commentary
approach to management of small infants whose environment can presumably be manipulated to be supportive to those functions needing time for development regardless of gestational age.
Mary Ellen Avery, M.D. Ivan Frantz, III, M.D. Children's Hospital Medical Center 300 Longwood A re. Boston, Mass. 02115 REFERENCES 1. Medawar PB: The uniqueness of the individual, New York 1957, Basic Books, Inc., p 108. 2. Amiel-Tison C: Neurological evaluation of the maturity of newborn infants, Arch Dis Child 43:89, 1968. 3. Usher R, McLean F, and Scott KE: Judgement of fetal age. II. Clinical significance of gestational age and an objective method for its assessment, Pediats Clin North Am 13:835, 1966. 4. Dubowitz LMS, Dubowitz V, and Goldberg C: Clinical assessment of gestational age in the newborn infants, J PEDIATR77:1, 1970. 5. Taeusch HW, Wang NS, and Avery ME: Studies on organ
6.
7.
8.
9.
10.
11.
12.
957
maturation; "Skin Age" as an indicator of "'tung age" in fetal rabbits, Pediatrics 49:400, 1972. Kotas RV, Fletcher BD, Torday J, and Avery ME: Evidence for independent regulators of organ maturation in fetal rabbits, Pediatrics 47:57, 1971. Avery ME: Differential organ growth in littermate rabbits in Elliott K, Knight J, editors: Size at birth, Ciba Foundation Symposium 27 (new series), North Holland, Amsterdam, 1974. Trolle D: Decrease of total serum-bilirubin concentration in newborn infants after phenobarbitone treatment, Lancet 2:705, 1968. Kotas RV, and Avery ME: Accelerated appearance of pulmonary surfactant in the fetal rabbit, J Appl Physiol 30:358, 1971. Liggins GC, and Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50:515, 1972. Robert MF, NeffRK, Hubbell JP, Taeusch HW, and Avery ME: The association between maternal diabetes and the respiratory distress syndrome, Pediatr Res 9:370, 1975 (abstr). Smith BT, Giroud CJP, Robert MF, and Avery ME: Insulin antagonism by cortisol action in lecithin synthesis by cultured fetal lung cells, J PEDIATR87"953, 1975.
