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British Medical Bulletin 60:69-88 (2001)
© 2001 Oxford University Press
The malnourished baby and infant
Relationship with Type 2 diabetes
MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton, UK
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Abstract |
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Abstract
Fetal nutritionThe growth of a baby is constrained by the nutrients and oxygen it receives from the mother. A mother's ability to nourish her baby is established during her own fetal life and by her nutritional experiences in childhood and adolescence, which determine her body size, composition and metabolism. Mother's diet in pregnancy has little effect on the baby's size at birth, but nevertheless programmes the baby. The fetus adapts to undernutrition by changing its metabolism, altering its production of hormones and the sensitivity of tissues to them, redistributing its blood flow, and slowing its growth rate. In some circumstances, the placenta may enlarge. Adaptations to undernutrition that occur during development permanently alter the structure and function of the body.
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Fetal nutrition |
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The supply of nutrients to the fetus is the major influence that regulates its growth. It depends on the mother's body composition and size, her nutrient stores, what she eats during pregnancy, transport of nutrients to the placenta and transfer across it. This long and vulnerable series of steps is known as the fetal supply line. The fetus becomes undernourished when its demand for nutrients exceeds its supply. Either the supply may be low, for example when the mother is thin or starving or when the placenta fails, or demand may be high because the fetus is growing rapidly.
Early in development, before implantation, the embryo comprises two groups of cells, the inner cell mass which becomes the fetus and the outer cell mass which becomes the placenta. Experiments in animals indicate that the allocation of cells between the two masses is influenced by nutrition and by hormones1
,2. In experimental animals, maternal undernutrition at the time of conception leads to fewer cells in the inner cell mass, which is associated with reduced birth weight and postnatal growth, altered organ/body weight ratios and the development of hypertension3. Better periconceptual nutrition is thought to raise the fetal growth trajectory4 which is established in early gestation when the fetus’ absolute requirement for nutrients is small. A more rapid growth trajectory leads to an increased demand for nutrients in late gestation, when requirements are relatively large and when the progressive reduction in the ratio of placental to fetal size reduces placental reserve capacity5. The fetus' ability to sustain growth during a period of undernutrition depends on its previous growth rate, more rapidly growing fetuses with a high demand for nutrients being less able to sustain growth6,7. Males grow more rapidly than females and are, therefore, less able to withstand undernutrition.
Because the fetus' requirements for nutrients are small in early gestation, it is often assumed that undernutrition will not influence growth until late gestation, when substrate supply becomes inadequate to meet increasing fetal demand for tissue building blocks. This is not, however, the case. When, for example, female pigs are fed low protein diets from the time of mating the weight and length of their fetuses are already reduced at mid-gestation8. This indicates that fetal undernutrition can affect fetal growth through mechanisms other than lack of substrate supply to growing tissues.
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Fetal adaptations to undernutrition |
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In common with other living things, the human fetus is able to adapt to undernutrition. Its responses include metabolic changes, redistribution of blood flow and changes in the production of fetal and placental hormones which control growth9
. They are shown in Figure 1. Its immediate metabolic response to undernutrition is catabolism: it consumes its own substrates to provide energy8. More prolonged undernutrition leads to a slowing in growth rate. This enhances the fetus' ability to survive by reducing the use of substrates and lowering the metabolic rate. Slowing of growth in late gestation leads to disproportion in organ size since organs and tissues that are growing rapidly at the time are affected the most. For example, undernutrition in late gestation may lead to reduced growth of the kidney which is developing rapidly at that time. Reduced replication of kidney cells may permanently reduce cell numbers, because after birth there seems to be no capacity for renal cell division to ‘catch-up’10,11.
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Animal studies show that a variety of different patterns of fetal growth result in similar birth size. For example, a fetus that grows slowly throughout gestation may have the same size at birth as a fetus whose growth was arrested for a period and then ‘caught up’. Different patterns of fetal growth will have different effects on the relative size of different organs at birth, even though overall body size may be the same. This emphasises the severe limitation of birth weight as a measure of fetal growth.
While slowing its rate of growth, the fetus may protect tissues that are important for immediate survival, the brain especially. One way in which the brain can be protected is by redistribution of blood flow to favour it12,13. This adaptation is known to occur in many mammals but in humans it may have exaggerated costs for other tissues, notably the liver and other abdominal viscera, because of the large size of the brain.
It is becoming increasingly clear that nutrition has profound effects on fetal hormones, and on the hormonal and metabolic interactions between the fetus, placenta and mother on whose co-ordination fetal growth depends8. Fetal insulin and the insulin-like growth factors (IGFs) are thought to have a central role in the regulation of growth and respond rapidly to changes in fetal nutrition14. If a mother decreases her food intake, fetal insulin, IGF-1 and glucose concentrations fall, possibly through the effect of decreased maternal growth hormone and IGF. This leads to reduced transfer of amino acids and glucose from mother to fetus, and ultimately to reduced rates of fetal growth15. In late gestation and after birth, the fetus' growth hormone and IGF axis take over, from insulin, a central role in driving linear growth. Whereas undernutrition leads to a fall in the concentrations of hormones that control fetal growth, it leads to a rise in cortisol whose main effect is on cell differentiation9.
The differing effects of undernutrition at different stages of gestation may be summarised as follows16.
Early pregnancy
As has been described already, the concentrations of nutrients in the earliest stages of pregnancy influence growth of the embryo. Animal studies have shown that birth size can be profoundly changed by a brief period of in vitro culture before implantation. Sub-optimal nutrition before implantation retards growth and development, the one-cell embryo being particularly sensitive. The early embryo is selective in its use of nutrients and respires pyruvate, lactate, and amino acids such as glutamine rather than glucose4. Before implantation it switches to a glucose-based metabolism, and low glucose concentrations retard its growth and development17. Paradoxically, perhaps, high glucose concentrations, which accompany maternal diabetes, also delay embryonic growth. This effect contrasts with the accelerated growth associated with high glucose concentrations in late pregnancy.
Mid-pregnancy
The placenta grows faster than the fetus in mid-pregnancy and nutrient deficiency may, therefore, affect fetal growth by changing the interaction between the fetus and the placenta. Whereas maternal undernutrition restricts growth of fetus and placenta, mild undernutrition may lead to increased placental, but not fetal, size18. This placental overgrowth may be an adaptation to sustain nutrient supply from the mother. Localised placental hypertrophy can also be induced experimentally in sheep by reducing the number of implantation sites. Owens and Robinson19 have shown that the compensatory growth at the remaining sites occurs before there is noticeable retardation of fetal growth, and may be a sensitive, early response to reduced nutrient supply.
During undernutrition, fetal growth may be sacrificed to maintain placental function. In animals oxygen, glucose and amino acids may be redistributed, so that the placenta reduces its consumption of oxygen and glucose while maintaining a large output of lactate to the fetus20. The lactate is partly derived from amino acids of fetal origin, and the fetus may waste and be thin at birth20. There is evidence for similar metabolic changes in growth retarded human fetuses, in whom wasting has been observed by ultrasonography21–23.
Late pregnancy
In late gestation, undernutrition results in immediate slowing of fetal growth. Acute undernutrition causes prompt slowing of fetal growth associated with fetal catabolism6, but fetal growth rapidly resumes when nutrition is restored. In contrast, prolonged undernutrition may irreversibly slow the rate of fetal growth in lambs and lead to reduced length at birth24. The basis of this irreversibility is uncertain, but it is reflected in the clinical observation that children with intra-uterine growth retardation who show postnatal growth failure are those with evidence of more prolonged intra-uterine growth retardation25.
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Mother's height and smoking |
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Mother's height is related to birth weight: short women have small babies26
. Teleologically, this form of constraint can be viewed as a way of ensuring that the fetus cannot outgrow the size of the mother's pelvis and birth canal. Mother's skeletal size is not, however, related to the long-term changes in the physiology and metabolism of the fetus which are described in this issue16,27. Similarly, while mother's cigarette smoking is associated with reduced birth weight, it does not appear to be associated with long-term changes in glucose/insulin metabolism. Consistent with this, neither mother's height, smoking habits or age are related to cord blood insulin concentrations whereas mother's dietary intakes of carbohydrate and protein are strongly associated with cord blood concentrations of insulin and its precursors28. This chapter, therefore, focuses on other influences that determine delivery of nutrients to the fetus. |
Genes and fetal growth |
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Although the growth of a fetus is influenced by its genes, studies in humans and animals suggest that it is usually limited by the nutrients and oxygen it receives29
,30. The mother seems to exert a stronger effect on fetal growth than the father. Among half siblings, related only through one parent, those with the same mother have similar birth weights, the correlation coefficient being 0.58. The birth weights of half siblings with the same father are, however, dissimilar, the correlation coefficient being only 0.131. Other studies of relatives have shown that first cousins related through the mother tend to have similar birth weights whereas paternal first cousins do not32. Penrose analysed the birth weights of relatives and concluded that 62% of the variation between individuals was the result of the intra-uterine environment, 20% was the result of maternal genes and 18% of fetal genes33. A study of babies born after ovum donation showed that while their birth weights were strongly related to the weight of the recipient mother (Fig. 2), they were unrelated to the weight of the woman who donated the egg34. Studies in domestic animals also suggest that birth size is essentially controlled by the mother rather than the genetic inheritance from both parents26,35–37. In Walton and Hammond's well known experiments, in which Shetland and Shire horses were crossed, the foals were smaller at birth when the Shetland pony was the mother than when the Shire horse was the mother38. As the genetic composition of the two crosses was similar, this implied that the Shetland mother had constrained the growth of the fetus.
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Genes and fetal adaptations |
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Little is known about the genes which underlie the fetal cardiovascular, metabolic and hormonal adaptations to undernutrition. Genes which allow the fetus to adapt successfully to undernutrition are likely to be favoured by natural selection even though they may lead to disease and premature death in post-reproductive life. The fundamental role of genetic information is to enable the cell and organism to maintain homeostasis in the face of environmental changes, that is to maintain the intracellular concentrations necessary for survival, while the supply of these from external sources fluctuate. Common genetic variation results in different individuals in a population having differing ability to maintain homeostasis under different environmental challenges. In response to poor nutrient availability in utero, some fetuses will fail to make appropriate homeostatic responses and will die; some will make responses that will allow growth to continue at the same rate; others will make homeostatic responses that will ensure survival but the growth rates of some tissues and systems will slow. This last group will be at risk of coronary heart disease and other disorders in adult life.
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Maternal–fetal conflict |
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Haig and others have suggested that the relation between mother and fetus can usefully be viewed as genetic conflict39
,40. The effects of natural selection on genes expressed in fetuses may be opposed by the effects of natural selection on genes expressed in mothers. Fetal genes will be selected to increase the transfer of nutrients to the fetus so that it grows larger. Maternal genes will be selected to limit transfer to the fetus to protect the mother, and to ensure her survival and that of her children, born and unborn. What is best for the fetus need not be best for its mother, or so it seems.
The theory of parent–child conflict proposes that children are selected to demand more resources from parents than parents are selected to give. Three sets of genes have different interests: the mother's genes, the fetus' genes derived from the mother, and the fetus' genes derived from the father. If the genes of the fetus make excessive demands on the mother, it will prejudice the mother's ability to pass her genes on to other offspring. It is argued that genes derived from the father have been selected to take more resources from the mother's tissues than the genes derived from the mother41. The conflict between the maternal and paternal genomes over the nutritional demands that the fetus imposes on its mother may explain why genes derived from one parent can ‘imprint’, or override, the expression of those derived from the other42. An example of ‘genomic imprinting’ is that of the genes for insulin-like growth factor II. In the mouse, only those derived from the father are expressed43,44.
An interesting example of the conflict of interests between mother and baby, though it is not genetic conflict, comes from the breeding habits of southern elephant seals45. They come ashore to breed on the island of South Georgia and nourish their pups only from the reserves of fat and protein stored in their bodies on arrival at the beaches. The proportion of the food reserves made available to the pups may be critical to both mother and child. Mothers that expend a large proportion on their pups may compromise their survival to the next breeding season or reduce their subsequent reproductive output. On the other hand, pups that are small and thin have reduced chances of survival to breeding age. The production of small pups by smaller mothers may be a compromise between the future reproductive success of the mother and the survival of the pup. Male pups are heavier at birth than females and the smallest elephant seal mothers only give birth to females, which suggests that they abort male pups. This may be an advantage if they are unable to raise a male pup to a viable size without jeopardising their own survival and reproductive success.
When animals breed before they are mature maternal–fetal conflict may be enhanced. James has suggested that whereas the hormonal responses to pregnancy in adult women seem geared to optimising the flow of nutrients to the fetus, the opposite seems to occur when adolescent girls are pregnant46. Paradoxically, feeding young pregnant adolescent lambs leads to a selective channelling of nutrients to the mother who thrives at the expense of the fetus.
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Maternal nutrition and body size at birth |
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Fetal nutrition must be distinguished from maternal nutrition. Experience in famine shows that even extreme restrictions in mother's food intake during pregnancy have only modest effects on birth weight. From this it cannot be concluded that fetal growth is not regulated by its nutrient supply. Rather it suggests that maternal nutrient intakes during pregnancy have relatively small effects on birth size, which may depend more on mother's nutritional state before pregnancy – on the turnover of her protein and fatty acid stores in her muscle and fat. Birth weight is a crude measure of fetal growth: babies of the same weight may, for example, be short and fat or long and thin, and may be markedly different in organ size and structure, physiology and metabolism. The next sections describe what is known about the effects of maternal body composition and diet on birth size, body proportions at birth, and placental growth.
Mother's body size before pregnancy
A mother's body size before pregnancy is the most important determinant of the size of her baby. The variation in body form around the world is changing rapidly, which must have profound consequences for fetal growth. Whereas in Western countries many women are slim by choice, around the world most women with low body weight in relation to their height have been chronically undernourished since childhood. Women who have low body weight before pregnancy have small babies47–50. Chronic undernutrition also influences birth weight through its effect on maternal stature, independent of body weight26,51. It may also be associated with deficiencies in specific nutrients which influence fetal growth, including vitamins A, C, and D, folate, iron and zinc52.
Among chronically undernourished mothers, high weight gain during pregnancy partly offsets the effects of low weight before pregnancy, although the babies' weights still tend to remain below average53,54. The mother stores fat in the first half of pregnancy and mobilises it in the second under the influence of placental growth hormone and other hormones. In this way she spares glucose for the fetus by switching to fat as her primary energy source. Observations on weight gain in obese women point to the importance of pre-pregnant weight in determining birth weight. Those who gain little weight during pregnancy, or even lose weight, still have babies of average or above average weight53–57.
Differences in the proportions of fat in different parts of the body are known to be linked to differences in metabolism and hormonal profile. Deposition of fat on the abdomen, for example, is associated with resistance to insulin and an altered balance of sex hormones58, and fat at different sites on the body makes varying amounts of oestrogen. The effects that the hormonal and metabolic variations which are linked to body fat distribution have on the fetus are largely unknown.
Weight gain and diet during pregnancy
In Europe, mothers gain around 12 kg (26 lb) in weight during pregnancy. The maternal component of this averages 7.7 kg (17 lb) and comprises increases in fat, extracellular fluid, uterine and breast tissue. Maternal fat stores of around 3 kg (7 lb) are mostly laid down during the first half of pregnancy and provide an energy store for the fetus in late gestation. The extracellular fluid volume is increased by 3 l. Half of this increase is due to expansion of the plasma volume which, together with a fall in the peripheral resistance and increase in heart rate, leads to an increase in cardiac output. The cardiac output increases by 40% during the first trimester. Plasma volume increases more if the fetus is large and the mother's cardiovascular adaptations, which determine the perfusion of the placenta, are important determinants of fetal nutrition. We know little about the effects of the mother's body composition and nutrition before pregnancy on these adaptations59.
In Western countries, except in extreme circumstances, maternal undernutrition during pregnancy, reflected in low maternal weight gain, leads to only modest reductions in birth weight60–63. Indeed, the weak relationship between maternal weight gain in pregnancy and birth size has contributed to the myth that, in affluent populations, nutrition has little effect on fetal growth64. This myth arises from failure to understand the importance of maternal body composition, itself determined by nutrition, failure to distinguish fetal from maternal nutrition, and the use of crude indicators of fetal growth such as birth weight.
During the past 50 years, numerous studies have examined whether the quality of the diet eaten by a pregnant woman influences the birth weight of the baby. The results have been various and contradictory65. The relationship between calorie intake in pregnancy and birth weight, found in observational studies and trials, is of varying size and generally less than had been expected66. In one of the best known studies in Aberdeen, Scotland, the diets of primagravid women were recorded by weighed food intakes and food diaries during the seventh month of pregnancy67. Calorie intake was associated with birth weight in that women who consumed less than 1800 calories per day had babies who weighed 240 g (0.5 lb) less than those of mothers who ate 3000 and more calories, but this is a small effect.
The Dutch hunger winter lasted for 5 months and daily calorie intakes fell below 1000. Babies exposed to the famine during the first half of gestation, who were born after the famine was lifted, had normal birth weight. Those exposed during the second half of gestation had lower birth weight, being 327 g (0.7 lb) lighter than babies born before the famine68,69. The effect of the famine in Wuppertal, Germany, during 1945–1946 was less. Calorie intake was reduced to around 2400 a day and birth weight was reduced by around 185 g (0.4 lb)70. The exceptionally severe famine in Leningrad (now St Petersburg) during 1941–1943 led to a 530 g (1.2 lb) fall in mean birth weight71. The German blockade of Leningrad between September 1941 and January 1944 prevented supplies from reaching the city for 900 days. During the siege, approximately 1 million Leningrad citizens died from a total population of 2.4 million. Most of these deaths occurred during the ‘hunger winter’ of November 1941 to February 1942 when the siege was in full force and the average daily ration was about 300 calories, composed almost entirely of carbohydrate. Nearly 50% of all term infants exposed to famine during the second half of gestation weighed less than 2.5 kg (5.5 lb).
In some trials, supplementation of the mother's diet has led to an increase in mean birth weight, though generally of small size. One trial of protein-calorie supplementation, among poorly nourished mothers in New York City, produced a fall in mean birth weight72. This unexpected result led to a re-analysis of all reported supplementation trials73. Supplements with a low percentage of calories as protein were found to have increased birth weight whereas supplements with a high protein density reduced birth weight.
A number of studies support the idea that the inconsistency in the results of different trials could be the result of differing effects in women whose nutritional status differed before pregnancy. Underweight women with high calorie intakes during pregnancy have babies of similar size to those of overweight women with low calorie intakes. A trial among Asian women living in England suggested that the babies of women whose triceps skinfold thickness did not increase in mid-pregnancy benefited most from protein and energy supplementation74. In The Gambia, energy supplementation increased birth weight only during the wet season, a time when food is scarce and women work hard planting crops75. In the New York study, only the babies of mothers who smoked cigarettes benefited72; whether this reflected the different diets of smokers and non-smokers is not known.
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Maternal nutrition and body proportions at birth |
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Animal studies show that fetal undernutrition at different times in gestation may lead to new-borns with different overall body size or with similar body size but marked differences in the proportional size of different organs. In sheep, for example, undernutrition in late pregnancy increases the weight of the heart without altering body size. Chronic nutritional deprivation sustained from early pregnancy is associated with proportionate growth failure in head size, length, and weight5
,36. Undernutrition in mid or late gestation is associated with disproportionate growth, reflected in thinness or shortness at birth. This is, of course, an over-simplification. Though thinness at birth may result from failure of nutrient supply in late pregnancy, this failure may originate from influences affecting placental development in early gestation76. The guinea pig fetus becomes thin only if the mother is continuously undernourished from early or mid pregnancy to term, while it will become short if the mother is undernourished in early or mid pregnancy only.
There is limited information about the maternal influences that determine different body proportions at birth. Figure 3 shows that the babies of mothers who had low birth weight tend to be thin irrespective of the mother's current body size77. In that particular study, maternal stature had no additional effect, though Kramer has found that taller mothers tend to have longer, thinner babies78. The father's birth weight did not influence ponderal index but taller fathers have longer, thinner babies77. Low dairy protein intake in late pregnancy is also associated with thinness at birth and Dutch babies exposed to wartime famine in the last trimester were thin69,79. Other studies have shown that reduced protein intake in pregnancy is associated with shortness at birth80.
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An important difference between fetal growth in non-industrialised countries and that in Western countries is that proportionate growth retardation is common in the non-industrialised countries whereas disproportionate, or ‘asymmetrical’, growth retardation prevails in Western countries36
. Babies with proportionate growth retardation may be more prone to neurodevelopmental impairment, whereas those with disproportionate growth retardation may be more at risk of perinatal death81–83. |
Maternal nutrition and the placenta |
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Placental size and the ratio of placental weight to birth weight have been found to be associated with type 2 diabetes and impaired glucose tolerance. Among 7086 men and women born in Helsinki, those who developed type 2 diabetes tended to have had low placental weight as well as low birth weight84
. In contrast, glucose tolerance tests performed on 226 men and women born in Preston, UK, showed that those with impaired glucose tolerance or type 2 diabetes had an increased ratio of placental weight to birth weight85.
Maternal undernutrition has variable effects on placental growth. In general, it has little effect in early and late gestation: in mid-gestation its effects vary. Some animal studies have shown that maternal undernutrition in mid-pregnancy reduces placental weight86,87. Others have shown increased placental weight (in sheep), or an increase in the ratio of placental to fetal weight (in guinea-pigs)18,88,89. The findings in sheep are not readily reproducible and McCrabb suggested that this might be the result of different maternal nutritional reserves before conception89. Subsequently, Robinson and colleagues in Adelaide showed that good nutrition around the time of conception followed by a restricted diet in mid-pregnancy, stimulated placental growth in sheep, whereas mid-pregnancy undernutrition in an already poorly nourished ewe restricted placental growth90. These observations on the effect of a changing plane of nutrition during pregnancy are consistent with empirical practices in sheep farming, whereby ewes are moved from rich pasture to poor pasture after mating. If they are then returned to rich pasture in later pregnancy, the lambs are heavier than those whose mothers were on rich pasture throughout. These surprising observations inevitably raise questions about the effects of nausea and anorexia in human pregnancy.
In humans, there is some evidence that high food intakes in mid-pregnancy may also suppress placental growth. A study of the diets of an unselected group of pregnant women suggested that high intakes of carbohydrates in mid-pregnancy, especially simple carbohydrates such as are found in soft drinks, suppressed placental growth91. This was especially marked if high carbohydrate intake in mid-pregnancy was followed by low dairy protein intake in late pregnancy. Differential effects of carbohydrates on placental size were also found in a recent trial. In this instance, however, ‘aboriginal’ carbohydrates, which are associated with a lower blood sugar after ingestion led to reduced placental and fetal size92.
In contrast to the apparent suppressive effect of carbohydrate, Beischer showed that anaemia during pregnancy was associated with increased placental size93. In a study of 8684 pregnant women in Oxford, those whose haemoglobin concentrations fell to lower values during pregnancy had larger placentas94. Subsequent studies showed that among women with low haemoglobin, placental volume was already increased at 18 weeks of pregnancy95. Furthermore, Wheeler and colleagues showed that maternal haemoglobin concentrations between 9–11 weeks of pregnancy were inversely related to the maternal serum concentrations of chorionic gonadotrophin and placental lactogen – hormones synthesised by the placenta96. The associations between maternal haemoglobin and placental size and function are not explained by the effects of haemodilution. They may reflect the effects of a reduced oxygen content in maternal blood. Hypoxia may stimulate blood vessel formation in the growing placenta by increasing the expression of angiogenic growth factors such as vascular endothelial growth factor.
The mild hypoxaemia associated with life at high altitude is also associated with an increase in the ratio of placental to fetal weight97,98. Clapp has shown that if mothers exercise vigorously in early pregnancy the volume of the placenta in mid-pregnancy is increased99. Cigarette smoking suppresses both placental and fetal growth but suppression of the placenta is less and the ratio of placental to fetal weight at birth is therefore increased97. These effects may also be mediated by hypoxia, though other influences must also affect the ratio of placental to fetal weight, which is raised if the mother has a high body mass100.
Further evidence that the placental enlargement may be an adaptive response to lack of oxygen or nutrients comes from a study of babies that were unusually small (below the 10th centile) for their gestational age101. Their ratio of placental to birth weight was higher than that of babies whose size was appropriate to their gestational age.
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Intergenerational constraints on fetal growth |
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In addition to the effects of mother's body composition and diet on birth weight, mothers' birth weights are related to those of their children and even their children's children102
–107. Women who were small for gestational age at birth are at twice the risk of having a small for gestational age baby and their babies are more likely to die in the perinatal period107,108. Women who had low birth weight also tend to have thin babies. The father's birth weight has no effect on ponderal index77, though it influences placental weight. These observations have led to the conclusion that mothers constrain fetal growth and that the degree of constraint they exert is set when they themselves are in utero109. ‘Maternal constraint’ is thought to reflect the limited capacity of the mother to deliver nutrients to her fetus110. Sisters, who experience a common level of constraint in utero, exert a similar level of constraint on their own fetuses. Although low birth weight is a feature of the families of mothers who have growth retarded babies, it is not a feature of the families of the fathers. Studies of babies who are unusually large at birth have shown, however, that large birth weight is common in the families of both parents. One interpretation of this is that the father influences the fetal growth trajectory only when maternal constraint is relaxed109. We do not know the mechanisms by which a mother's poor fetal growth impairs the fetal growth of her offspring, but one possibility is that a reduced uterine vasculature is laid down in utero and this impairs placentation in the next generation.
Fifty years ago, Mussey wrote111: ‘it must be borne in mind that the diet of a given generation may affect the offspring several generations hence’. This has been demonstrated experimentally in animals. Stewart undernourished a colony of rats with a protein deficient diet over 12 generations. When he re-fed them with a normal diet, it took 3 generations before fetal growth and development were restored to normal112. Similarly, the adverse effects of exercise in pregnancy on fetal growth in rats are evident in the second generation113. It follows that in humans who move from poorly nourished to well nourished communities, Indian migrants to Europe for example, it will take more than one generation before fetal growth increases to the level of the host country114.
The realisation that a mother's physiological capacity to nourish her fetus was established when she herself was in utero is not new. Mellanby wrote115: ‘it is certain that the significance of correct nutrition in child-bearing does not begin in pregnancy itself or even in the adult female before pregnancy. It looms large as soon as a female child is born and indeed in its intra-uterine life’. Hence the fetus adapts its rate of growth, and the life-long structure and function of its body, not only to its mother, but to the environment its grandmother provided for its mother. Sensitivity to more than one generation allows the fetus to adapt to the level of nutrition which has prevailed over many years rather than only to that at the time of its conception. This may be important in places where there is periodic famine.
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Long-term effects of maternal nutrition on glucose-insulin metabolism |
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In the Dutch famine study, it was people born to mothers who had low body weight who had the highest plasma glucose concentrations 2 h after a standard glucose load116
. A study of middle-aged men and women in Scotland suggested that an association between low maternal body mass index and insulin resistance in the offspring might underlie this observation117. This observation has been confirmed in a study of men and women in Beijing, China (Table 1), and found to apply to body mass index in both early and late pregnancy118. An interpretation of this is that the association between maternal body mass and insulin resistance is initiated in early pregnancy. Table 2 shows similar findings in a group of older men and women in Finland119. In these people, the associations between low maternal body mass index and offspring's plasma glucose, insulin and pro-insulin concentrations were independent of the offspring's body size at birth and during childhood. The particular aspect of maternal metabolism that is associated with low body mass index and leads to insulin resistance is not known, but low protein turnover is one possibility. The relationship between mother's diet in pregnancy and the glucose-insulin metabolism of the offspring in middle age was examined in the Scottish study. The offspring of mothers with high intakes of fat and protein in late pregnancy had a reduced plasma insulin increment between fasting and 30 min117. This was independent of the association between high maternal body mass and low insulin increment, an association which studies of gestational diabetes suggest may be mediated by raised maternal plasma glucose concentrations (see Fall, this issue).
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Footnotes |
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Correspondence to: Prof. David J P Barker, MRC Environmental Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
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