The initial epidemiological studies linked birthweight to subsequent disease risk. Later studies examined these risks in relationship to various body proportions at birth such as ponderal index (thinness), abdominal circumference, etc.58,59 This appears to have occurred because in many cases these measures are more closely related to disease risk than is birthweight itself. Such apparent post hoc analysis is in practice an attempt to get closer to the origin of the association; that fetal nutrition as a programming stimulus affects fetal growth rather than birthweight.60 This distinction between fetal growth and birthweight is difficult to make in human pregnancy, although repeated ultrasound measures of fetal size during pregnancy are beginning to assist here. However, the distinction can be readily demonstrated in animals. Fetal sheep growing rapidly in late gestation slow their growth promptly in response to 10 days of maternal undernutrition and resume growth on maternal (and hence fetal) refeeding. When examined after 10 days of refeeding, these fetuses have the same birthweight and length as control fetuses of well-fed ewes, but have increased heart and kidney size and increased blood pressure.45,61 In this case fetal weight does not reflect the direct causal relationship between fetal nutrition, fetal growth and altered physiology. A similar situation can be imagined in human pregnancy where fetuses of similar birthweight may arrive at that point via very different growth trajectories (Figure 2). It seems likely that these trajectories would be associated with different patterns of physiological function and likely programming and thus disease risk, although this remains to be demonstrated.
If fetal growth is poorly reflected in birthweight, then it seems likely that body proportions would be more informative. Although this seems a reasonable hypothesis, there are few data to assist, and many common assumptions in this area are excessively simplistic.
One common assumption is that body proportions provide information about the timing of nutritional insults leading to the limitation of fetal growth. Thus a baby which is proportionately small in weight, length and head circumference at birth is presumed to have suffered from nutrient limitation in early pregnancy, while a baby of similarly low birthweight who is relatively long and thin is presumed to have suffered nutrient limitation in late pregnancy.62–64 These two patterns are commonly referred to as symmetrical and asymmetrical growth restriction, respectively, and are described in the clinical literature as having different origins and different clinical problems. However, careful examination of large human data sets have failed to find any evidence of two distinct populations in this regard.65 Instead, a continuum of changes in body proportions has been demonstrated. Furthermore, measurement of fetal growth by ultrasound showed no clear differences in timing or pattern of growth changes in babies found at birth to be either symmetrically or asymmetrically growth restricted.66 Such findings are consistent with a continuum of nutritional limitation affecting fetal growth, but not with the assumptions about distinct timing. Indeed, studies of maternal undernutrition in sheep have shown that reduced ponderal index (thinness) is seen in fetuses exposed to undernutrition from early or mid gestation through to term, but not in fetuses exposed only in late gestation. Contrary to expectation, exposure only in early or mid gestation results in increased ponderal index.67
Another common assumption is that nutrient limitation to the fetus at a given stage of development is likely to have maximum effect on organs growing rapidly at that stage. However, simple limitation of substrates to growing organs leading to reduced size of that organ does not explain the complex effects observed. Maternal protein restriction in pigs results in reduced fetal weight and length at mid-gestation at a time when the fetus is extremely small and fetal protein requirements for growth are most unlikely to have been limiting by this time.68 Similarly, maternal undernutrition in either early or late gestation in sheep, leading to fetal undernutrition and limiting nutrient supply to growing organs, does not explain the observed increase rather than decrease in size of the heart and kidneys (Table 3).69
Further assumptions have been made in the literature regarding the significance of altered body proportions at birth. Reduced abdominal circumference has been assumed to reflect reduced liver size63
and this has been used as a possible explanation of the relationship observed between abdominal circumference at birth and lipid metabolism in adulthood. This apparently reasonable assumption has recently been questioned by findings that ultrasound measurements of growth restricted human fetuses show little relationship between liver size and abdominal circumference.70
We have found in fetal sheep, using direct measures of organ weight, that abdominal circumference is strongly related to weight of the fetal gut as well as that of the liver. There is a need for more extensive pathological studies to determine the true relationship between birth measurements and organ size in human infants.
In a similar vein, relative preservation of head circumference at birth (‘head sparing’) is commonly assumed to occur as a consequence of blood flow redistribution in fetal life. There is certainly good evidence of redistribution of cardiac output in fetuses exposed to hypoxia, with maintenance of blood flow to essential organs such as the brain and heart at the expense of other organs such as the gut and skin.71 There is also ultrasound evidence that such redistribution does occur in chronically hypoxaemic intrauterine growth restricted (IUGR) human fetuses, and can be partly reversed by administration of oxygen.72,73 However, this is not the only mechanism by which brain growth may be maintained during periods of fetal substrate limitation, and indeed may not be the most common. Hypoxaemia appears to occur late in the process of growth restriction in human fetuses, and many IUGR fetuses are not hypoxaemic on direct measurement in utero although head sparing can be demonstrated in these fetuses.74 Indeed, if IUGR is induced by feed restriction in sheep, fetal growth is impaired and relative head sparing is observed with no evidence of hypoxia.46
Other nutritional mechanisms may allow relative preservation of brain growth in the substrate limited fetus. Glucose uptake into many tissues is mediated by insulin, and fetal insulin secretion is regulated by glucose and amino acid supply. However glucose uptake into the brain does not require insulin. Thus limitation of glucose and amino acid supply to the fetus will reduce circulating insulin concentrations and glucose uptake into peripheral tissues such as muscle, sparing the available glucose for uptake into the brain which is insulin independent.
In addition, as described above, fasting in women increases the supply of ketones to the fetus47 and the fetal brain has been shown to preferentially take up and oxidize ketones.57,75 Similarly, maintenance of fetal lactate supply by the placenta of the undernourished pregnant sheep may allow continued growth of the fetal heart which will preferentially utilize lactate as an oxidative fuel.76 Thus altered body proportions at birth, and particularly relative preservation of brain and heart size, may reflect altered distribution of cardiac output in utero. However, it is likely to reflect also complex metabolic adaptations to limitations in fetal nutrient supply including an altered hormone environment and altered substrate availability.