Eariy Human Development, 29 (1992) 193-197 Elsevier Scientific Publishers Ireland Ltd.
193
EHD 01273
Intrauterine feeding of the growth retarded fetus: can we help? J. Harding, L. Liu, P. Evans, M. Oliver and P. Gluckman Department
of Paediatrics,
University
of Auckland,
Auckland
(New
Zealand)
Summary Intrauterine feeding of the growth retarded fetus appears an attractive therapeutic possibility. However the factors which determine the reversibility of intrauterine growth retardation are poorly understood. While fetal substrate supply is the tinal common pathway by which many factors restrict fetal growth, improving fetal substrate supply does not always lead to improved fetal growth. Similarly, fetal substrate supply is an important regulator of fetal endocrine status, such as circulating IGF-1 levels, but again, improving fetal substrate supply does not always alter fetal endocrine status or fetal growth. The relationship between substrate supply, endocrine status and growth is regulated in a complex way by placental function. Understanding the role of the placenta in this regulation is essential if in the future we are to help the growth retarded fetus. Key words: intrauterine
growth retardation;
placenta fetal nutrition;
IGF-1
Introduction Intrauterine growth retardation is a major clinical problem, second only to prematurity as a cause of perinatal mortality and morbidity. Some infants who have grown slowly before birth show postnatal catch-up growth and appear to have suffered little harm in the longer term. However many infants appear to have irreversible growth retardation and are at high risk of long-term physical and neurological morbidity [l]. Because these infants do not grow well postnatally, attention has been directed to intrauterine treatment in an effort to reverse growth failure before permanent damage is done and thus improve outcome. Most studies have been directed towards feeding the fetus in utero; improving substrate supply to the fetus either indirectly such as by improving placental blood supply, or more directly by supplying Correspondence to: J. Harding, Auckland, New Zealand.
Department
of Paediatrics, University of Auckland,
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
Private Bag,
194
essential substrates such as glucose and amino acids. However such approaches are not without risk and there is little evidence to date that they are effective [2]. More recently the relationship between fetal growth and the circulating levels of the insulin-like growth factors (IGFs) has raised the possibility that manipulating fetal endocrine status by supplementing the intrauterine growth retarded fetus with growth factors may be a more effective and perhaps less risky means of improving fetal growth in utero. As yet this hypothesis remains untested. Is it possible, then, to help the intrauterine growth retarded fetus by intrauterine fetal feeding? The evidence presented in this paper suggests that although substrate supply has an important influence on fetal growth, improving substrate supply to the fetus does not always improve fetal growth. Similarly, although substrate supply is an important regulator of fetal endocrine status, changes in fetal substrate supply do not always result in changes in fetal IGF levels or in fetal growth. The nature of the relationship between fetal substrate supply, endocrine status and growth is regulated in a complex way by placental function and the nature of this regulation is poorly understood. Greater understanding of the role of placental function in determining the reversibility of intrauterine growth retardation is essential if we are to be able in the future to help the growth retarded fetus (Fig. 1). Fetal nutrition and fetal growth Fetal substrate supply is the final common pathway by which many diverse factors may act to restrict fetal growth. Many common causes of intrauterine growth retardation may act at multiple sites along the fetal supply line. For example, smoking has been shown to alter maternal nutritional intake, to reduce circulating maternal amino acid levels, to decrease uterine blood flow, to decrease placental amino acid transport and oxygenation and to decrease fetal umbilical blood flow and fetal oxygenation. Clearly each of these different steps may contribute to reduced substrate supply to the fetus and ultimately to reduced fetal growth. Although in humans simple maternal under-nutrition does not inhibit fetal growth unless it is very severe, there is anecdotal evidence that in severe maternal starvation, improved maternal nutritional status may be associated with improved fetal growth [3]. Such changes are more easily studied in experimental animals where daily changes in nutritional status and fetal growth can be carefully monitored. In pregnant sheep, maternal under-nutrition in the second half of pregnancy, carefully regulated by Growth
&U
Hormones
Fig. 1. The relationship between fetal growth, nutrition and hormones is regulated by placental function.
195
monitoring maternal blood glucose levels, is usually associated with a prompt fall in fetal growth rate which resumes on maternal refeeding. However this is not always the case, If maternal under-nutrition is prolonged for more than 19 days, there is no change in fetal growth on refeeding and the fetal growth retardation is apparently irreversible [4]. The cause of this irreversibility is unknown, but we believe it is related to changes in placental function. Simple maternal under-nutrition in sheep is associated with decreased circulating levels of glucose and amino acids in the mother. However in the fetus, while glucose is decreased, amino acid and lactate levels rise, suggesting changes in feto-placental metabolism to compensate for the reduced glucose supply. Such changes are very similar to those reported in the growth retarded human fetus [5] and may even be associated with fetal wasting as fetal proteins are broken down to maintain placental metabolic requirements. High placental metabolic needs may also foil attempts to improve substrate supply to the fetus. Large amounts of glucose infused to the mother may result in relatively small changes in the blood glucose of the growth retarded fetus as placental consumption is high [6]. Similarly, maternal refeeding after a period of under-nutrition in sheep results in large rises in lactate concentrations, apparently reflecting changes in placental metabolism which adapt only slowly to changes in substrate supply (Fig. 2). Thus placental function is an important mediator in the relationship between fetal nutrition and fetal growth. Fetal nutrition and fetal endocrine status It is well established over a wide range of species that size at birth correlates with circulating fetal IGF-1 levels. Recent data suggests that fetal IGF-1 levels directly intluence fetal growth. In turn, IGF-1 levels are influenced by fetal nutrition. Maternal starvation results in a fall in fetal IGF-1 levels, whereas maternal refeeding leads to a rise in fetal IGF-1 [7]. Such changes can be shown even if glucose is supplied only to the fetus while maternal starvation continues, suggesting a direct effect of fetal nutrition on fetal IGF-1 levels [8]. However once again, changes in fetal IGF-1 seen in the chronically growth retard-
3,
Blood 2 Lactate . MM1 l-
Fetal
Maternal
Fig. 2. Maternal refeeding after 10 days of under-nutrition trations.
causes a large rise in blood lactate concen-
196
ed fetus may not necessarily be reversed by improving fetal nutrition. In the chronically undernourished sheep, refeeding of the mother is associated with improved fetal growth and rise in fetal IGF- 1 levels. In irreversible growth retardation, however, refeeding results in no change in either fetal IGF-1 or fetal growth. Measurable arterio-venous differences for IGF-1 across the umbilical circulation also suggest that the placenta might be an important regulator of fetal IGF-1 levels and thus once again the mediator between fetal nutrition, IGF-1 levels and growth. The placenta as mediator If placental function, then, is important in regulating fetal nutrition, IGFs and growth, might we influence placental function in order to improve fetal growth? Some clues may be found in studying the different responses to under-nutrition in fetal sheep. Some fetuses respond to short periods of under-nutrition with slowing of fetal growth, whereas other fetuses show no slowing. Careful examination of these two groups of animals shows that those with no change in growth rate upon undernutrition are already growing slowly (Fig. 3) and have adapted to slow in utero growth with increased placental lactate production and decreased fetal IGF-1 levels. Further investigation of the nature and regulation of such adaptation may allow us to find useful interventions for the growth retarded fetus. Finally, there is some evidence that maternal endocrine status may be important in the regulation of placental function. In rats treated with supplemental maternal IGF-1 throughout pregnancy, the normal phenomenon of maternal constraint upon fetal growth is abolished, as shown by the abolition of the normal negative relationship between fetal size and fetal number. However the normal negative relationship between placental size and fetal number is not abolished, suggesting that maternal IGF-1 has altered fetal growth by altering placental function [9]. The nature of this change is as yet unknown, but is likely to be of critical importance in developing strategies for the intrauterine treatment of the growth retarded fetus.
Girth
Catheter Increment (mm)
20
0
-20
-40 -5
15
Gays From
&art
of lJn%nuMtion
Fig. 3. Differing fetal growth responses to chronic maternal under-nutrition. Normally growing fetuses slow their growth, whereas those that are already growing slowly do not change their growth rate.
197
Can we, then, help the intrauterine growth retarded fetus by intrauterine feeding? It seems likely that the answer will be yes, but not simply by nutritional manipulation of the fetus. Rather, we need to find a means of influencing placental function in such a way that the complex interactions between fetal nutrition, fetal endocrine status and fetal growth can be manipulated to improve fetal growth in utero. References Fancourt, R., Campbell, S., Harvey, D. and Norman, A.P. (1976): Follow-up study of small-for-dates babies. Br. Med. J., 1, 1435-1437. Harding, J.E. and Charlton, V.E. (1991): Experimental nutrition supplementation for intrauterine growth retardation. In: The Unborn Patient: Prenatal Diagnosis and Treatment, 2nd edn, pp. 598-613. Editors: M.R. Harrison, M.S. Golbus and R.A. Filly. W.B. Saunders, Philadelphia. Herbert, W.N.P., Seeds, J.W., Bowes, W.A. and Sweeney, CA. (1986): Fetal growth response to total parental nutrition in pregnancy. J. Reprod. Med., 31, 263-266. Mellor, D.J. and Murray, L. (1982): Effects on the rate of increase in fetal girth of refeeding ewes after short periods of severe under-nutrition during late pregnancy. Res. Vet. Sci., 32, 377-382. Nicolaides, K.H., Economides, D.L. and Thorpe-Beeston, G. (1989): Treatment of fetal growth retardation. Fetal Growth, pp. 333-361. Editors: F. Sharp, R.B. Fraser and R.D.G. Mimer. Royal College of Obstetricians & Gynaecologists, London. Harding, J.E., Jones, C.T. and Robinson, J.S. (1985): Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus. J. Dev. Physiol., I, 427-442, Bassett, N.S., Oliver, M.H., Breier, B.H. and Gluckman, P.D. (1990): The effect of maternal starvation on plasma insulin-like growth factor 1 concentration in the late gestation ovine fetus. Pediatr. Res., 27, 401404. Oliver, M.H., Harding, J.E., Breier, B.H., Evans, P.C. et al. (1991): Fetal insulin-like growth factor (IGF)-I responses to fasting and physiological glucose replacement. International Symposium on Growth and Development, Auckland, p. 10. Gluckman, P.D., Morel, P., Breier, B.H., Blair, H. and McCutcheon, S. (1992): Maternal IGF-I alters the pattern of fetal growth by removing maternal constraint. J. Endocrinol., (in press).
193
EHD 01273
Intrauterine feeding of the growth retarded fetus: can we help? J. Harding, L. Liu, P. Evans, M. Oliver and P. Gluckman Department
of Paediatrics,
University
of Auckland,
Auckland
(New
Zealand)
Summary Intrauterine feeding of the growth retarded fetus appears an attractive therapeutic possibility. However the factors which determine the reversibility of intrauterine growth retardation are poorly understood. While fetal substrate supply is the tinal common pathway by which many factors restrict fetal growth, improving fetal substrate supply does not always lead to improved fetal growth. Similarly, fetal substrate supply is an important regulator of fetal endocrine status, such as circulating IGF-1 levels, but again, improving fetal substrate supply does not always alter fetal endocrine status or fetal growth. The relationship between substrate supply, endocrine status and growth is regulated in a complex way by placental function. Understanding the role of the placenta in this regulation is essential if in the future we are to help the growth retarded fetus. Key words: intrauterine
growth retardation;
placenta fetal nutrition;
IGF-1
Introduction Intrauterine growth retardation is a major clinical problem, second only to prematurity as a cause of perinatal mortality and morbidity. Some infants who have grown slowly before birth show postnatal catch-up growth and appear to have suffered little harm in the longer term. However many infants appear to have irreversible growth retardation and are at high risk of long-term physical and neurological morbidity [l]. Because these infants do not grow well postnatally, attention has been directed to intrauterine treatment in an effort to reverse growth failure before permanent damage is done and thus improve outcome. Most studies have been directed towards feeding the fetus in utero; improving substrate supply to the fetus either indirectly such as by improving placental blood supply, or more directly by supplying Correspondence to: J. Harding, Auckland, New Zealand.
Department
of Paediatrics, University of Auckland,
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
Private Bag,
194
essential substrates such as glucose and amino acids. However such approaches are not without risk and there is little evidence to date that they are effective [2]. More recently the relationship between fetal growth and the circulating levels of the insulin-like growth factors (IGFs) has raised the possibility that manipulating fetal endocrine status by supplementing the intrauterine growth retarded fetus with growth factors may be a more effective and perhaps less risky means of improving fetal growth in utero. As yet this hypothesis remains untested. Is it possible, then, to help the intrauterine growth retarded fetus by intrauterine fetal feeding? The evidence presented in this paper suggests that although substrate supply has an important influence on fetal growth, improving substrate supply to the fetus does not always improve fetal growth. Similarly, although substrate supply is an important regulator of fetal endocrine status, changes in fetal substrate supply do not always result in changes in fetal IGF levels or in fetal growth. The nature of the relationship between fetal substrate supply, endocrine status and growth is regulated in a complex way by placental function and the nature of this regulation is poorly understood. Greater understanding of the role of placental function in determining the reversibility of intrauterine growth retardation is essential if we are to be able in the future to help the growth retarded fetus (Fig. 1). Fetal nutrition and fetal growth Fetal substrate supply is the final common pathway by which many diverse factors may act to restrict fetal growth. Many common causes of intrauterine growth retardation may act at multiple sites along the fetal supply line. For example, smoking has been shown to alter maternal nutritional intake, to reduce circulating maternal amino acid levels, to decrease uterine blood flow, to decrease placental amino acid transport and oxygenation and to decrease fetal umbilical blood flow and fetal oxygenation. Clearly each of these different steps may contribute to reduced substrate supply to the fetus and ultimately to reduced fetal growth. Although in humans simple maternal under-nutrition does not inhibit fetal growth unless it is very severe, there is anecdotal evidence that in severe maternal starvation, improved maternal nutritional status may be associated with improved fetal growth [3]. Such changes are more easily studied in experimental animals where daily changes in nutritional status and fetal growth can be carefully monitored. In pregnant sheep, maternal under-nutrition in the second half of pregnancy, carefully regulated by Growth
&U
Hormones
Fig. 1. The relationship between fetal growth, nutrition and hormones is regulated by placental function.
195
monitoring maternal blood glucose levels, is usually associated with a prompt fall in fetal growth rate which resumes on maternal refeeding. However this is not always the case, If maternal under-nutrition is prolonged for more than 19 days, there is no change in fetal growth on refeeding and the fetal growth retardation is apparently irreversible [4]. The cause of this irreversibility is unknown, but we believe it is related to changes in placental function. Simple maternal under-nutrition in sheep is associated with decreased circulating levels of glucose and amino acids in the mother. However in the fetus, while glucose is decreased, amino acid and lactate levels rise, suggesting changes in feto-placental metabolism to compensate for the reduced glucose supply. Such changes are very similar to those reported in the growth retarded human fetus [5] and may even be associated with fetal wasting as fetal proteins are broken down to maintain placental metabolic requirements. High placental metabolic needs may also foil attempts to improve substrate supply to the fetus. Large amounts of glucose infused to the mother may result in relatively small changes in the blood glucose of the growth retarded fetus as placental consumption is high [6]. Similarly, maternal refeeding after a period of under-nutrition in sheep results in large rises in lactate concentrations, apparently reflecting changes in placental metabolism which adapt only slowly to changes in substrate supply (Fig. 2). Thus placental function is an important mediator in the relationship between fetal nutrition and fetal growth. Fetal nutrition and fetal endocrine status It is well established over a wide range of species that size at birth correlates with circulating fetal IGF-1 levels. Recent data suggests that fetal IGF-1 levels directly intluence fetal growth. In turn, IGF-1 levels are influenced by fetal nutrition. Maternal starvation results in a fall in fetal IGF-1 levels, whereas maternal refeeding leads to a rise in fetal IGF-1 [7]. Such changes can be shown even if glucose is supplied only to the fetus while maternal starvation continues, suggesting a direct effect of fetal nutrition on fetal IGF-1 levels [8]. However once again, changes in fetal IGF-1 seen in the chronically growth retard-
3,
Blood 2 Lactate . MM1 l-
Fetal
Maternal
Fig. 2. Maternal refeeding after 10 days of under-nutrition trations.
causes a large rise in blood lactate concen-
196
ed fetus may not necessarily be reversed by improving fetal nutrition. In the chronically undernourished sheep, refeeding of the mother is associated with improved fetal growth and rise in fetal IGF- 1 levels. In irreversible growth retardation, however, refeeding results in no change in either fetal IGF-1 or fetal growth. Measurable arterio-venous differences for IGF-1 across the umbilical circulation also suggest that the placenta might be an important regulator of fetal IGF-1 levels and thus once again the mediator between fetal nutrition, IGF-1 levels and growth. The placenta as mediator If placental function, then, is important in regulating fetal nutrition, IGFs and growth, might we influence placental function in order to improve fetal growth? Some clues may be found in studying the different responses to under-nutrition in fetal sheep. Some fetuses respond to short periods of under-nutrition with slowing of fetal growth, whereas other fetuses show no slowing. Careful examination of these two groups of animals shows that those with no change in growth rate upon undernutrition are already growing slowly (Fig. 3) and have adapted to slow in utero growth with increased placental lactate production and decreased fetal IGF-1 levels. Further investigation of the nature and regulation of such adaptation may allow us to find useful interventions for the growth retarded fetus. Finally, there is some evidence that maternal endocrine status may be important in the regulation of placental function. In rats treated with supplemental maternal IGF-1 throughout pregnancy, the normal phenomenon of maternal constraint upon fetal growth is abolished, as shown by the abolition of the normal negative relationship between fetal size and fetal number. However the normal negative relationship between placental size and fetal number is not abolished, suggesting that maternal IGF-1 has altered fetal growth by altering placental function [9]. The nature of this change is as yet unknown, but is likely to be of critical importance in developing strategies for the intrauterine treatment of the growth retarded fetus.
Girth
Catheter Increment (mm)
20
0
-20
-40 -5
15
Gays From
&art
of lJn%nuMtion
Fig. 3. Differing fetal growth responses to chronic maternal under-nutrition. Normally growing fetuses slow their growth, whereas those that are already growing slowly do not change their growth rate.
197
Can we, then, help the intrauterine growth retarded fetus by intrauterine feeding? It seems likely that the answer will be yes, but not simply by nutritional manipulation of the fetus. Rather, we need to find a means of influencing placental function in such a way that the complex interactions between fetal nutrition, fetal endocrine status and fetal growth can be manipulated to improve fetal growth in utero. References Fancourt, R., Campbell, S., Harvey, D. and Norman, A.P. (1976): Follow-up study of small-for-dates babies. Br. Med. J., 1, 1435-1437. Harding, J.E. and Charlton, V.E. (1991): Experimental nutrition supplementation for intrauterine growth retardation. In: The Unborn Patient: Prenatal Diagnosis and Treatment, 2nd edn, pp. 598-613. Editors: M.R. Harrison, M.S. Golbus and R.A. Filly. W.B. Saunders, Philadelphia. Herbert, W.N.P., Seeds, J.W., Bowes, W.A. and Sweeney, CA. (1986): Fetal growth response to total parental nutrition in pregnancy. J. Reprod. Med., 31, 263-266. Mellor, D.J. and Murray, L. (1982): Effects on the rate of increase in fetal girth of refeeding ewes after short periods of severe under-nutrition during late pregnancy. Res. Vet. Sci., 32, 377-382. Nicolaides, K.H., Economides, D.L. and Thorpe-Beeston, G. (1989): Treatment of fetal growth retardation. Fetal Growth, pp. 333-361. Editors: F. Sharp, R.B. Fraser and R.D.G. Mimer. Royal College of Obstetricians & Gynaecologists, London. Harding, J.E., Jones, C.T. and Robinson, J.S. (1985): Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus. J. Dev. Physiol., I, 427-442, Bassett, N.S., Oliver, M.H., Breier, B.H. and Gluckman, P.D. (1990): The effect of maternal starvation on plasma insulin-like growth factor 1 concentration in the late gestation ovine fetus. Pediatr. Res., 27, 401404. Oliver, M.H., Harding, J.E., Breier, B.H., Evans, P.C. et al. (1991): Fetal insulin-like growth factor (IGF)-I responses to fasting and physiological glucose replacement. International Symposium on Growth and Development, Auckland, p. 10. Gluckman, P.D., Morel, P., Breier, B.H., Blair, H. and McCutcheon, S. (1992): Maternal IGF-I alters the pattern of fetal growth by removing maternal constraint. J. Endocrinol., (in press).
