The problem of maternal diabetes and the increased population risk of obesity is becoming a greater problem not only in the developed areas of the world but also in developing countries with large populations and high birth rates. Because the increased risk of diabetes and obesity is now becoming manifest in adolescents and even children as young as 2-5 years,1 the concept of in utero fetal programming assumes even more importance. Fetal programming is the effect of the in utero environment on events which have a permanent effect the organism's physiology or metabolism. In this chapter we will review normal fetal growth, fetal growth in infants of women with diabetes and fetal growth in infants of obese women.
Based on the studies of Hytten, greater than two-thirds of fetal growth occurs in the third trimester, with the fetus increasing weight from approximately 1000 to 3400 g.2 Multiple factors contribute to the variability in fetal growth. These include ethnic, geographic and socio-economic factors. In the early 1960s the WHO reported that birthweight in various Indian populations was affected by socio-economic status, with neonates of women in lower socio-economic classes having smaller offspring than their more affluent counterparts.3 Relative to geographic issues, high altitude has long been recognized as a factor resulting in decreasing birthweights as compared with those infants born at sea level; the decrease in oxygen tension at higher altitudes being the most ready explanation for the decreased birthweight.4 Lastly, differences in various ethnic groups accounts for much of the variation in birthweight with Asian and African women having lighter babies in comparison with their Caucasian counterparts.4
Within the aforementioned parameters, however, the maternal environment during pregnancy has profound affects on in utero fetal growth. There is a strong correlation between maternal height and weight and fetal growth. In general, the taller and heavier a woman is prior to conception, the more her infant will weigh at birth.5 These correlations are more robust in nulliparous as compared with multiparous women.6 Similarly, there are also significant increases in birthweight related to maternal weight gain during gestation.6 The interaction of maternal pregravid weight and weight gain on fetal growth are interesting relative to the underlying physiology of fetal growth. Based on the studies of Abrams and Laros,7 lean or underweight women will need to have a significant increase in weight gain in pregnancy in order to have a normally grown fetus. In contrast, the overweight and/or obese women will more likely have a larger baby, even with little or no weight gain. Maternal parity also has an affect on fetal growth. Increasing parity results in an increase of approximately 100 g with each successive pregnancy.8 The effect appears to plateau after the fifth pregnancy. This may be related to increased maternal weight retention after successive pregnancies but does not appear to be related to maternal age, once adjusted for other co-variables.
The issue of maternal nutrition and fetal growth has been addressed in many animal studies, mostly addressing the issue of fetal programming in growth restricted models, although more recent work has focused on the problem of maternal obesity and obesogenic diets. In the human, the studies of Barker have addressed the issue of fetal programming in the human intrauterine growth restricted (IUGR) model.9 The Barker hypothesis notes that poor nutrition in utero leads to fetal adaptations that produce permanent changes in insulin and glucose metabolism. For example, intra-uterine growth restriction followed by increased availability of food and/or decreased activity result in dysregulation such as the metabolic syndrome.10 Lucas et al., however, suggested that size in early life is related to health outcomes only after adjustment for current size, it is probably the change in size between these points rather than fetal biology that is implicated.11
For example, in the Early Bird Study12 300 British children were followed longitudinally. Insulin resistance was the same in children who had high birthweight and remained at an elevated birthweight centile through age 5 years, compared with those who had a lower birthweight but attained a similar centile at age 5. In fact, the IUGR model for the fetal programming hypothesis is more robust relative to aspects of the metabolic syndrome such as hypertension rather than obesity.13 Unfortunately, the human studies addressing the issue of maternal under nutrition in pregnancy mostly relate to starvation conditions during wartime. The best documented of these are the Dutch famine studies of 1944-1945.14
Starvation conditions had specific dates of onset and, with liberation, specific dates on the relief of starvation conditions. Nutritional developments in early pregnancy followed by increased access to food in later pregnancy results in babies being heavier at birth as compared with babies born either before or after the famine. This may represent in utero catch-up growth. In contrast, if the famine occurred during late gestation, the babies weighed less and were thinner at birth, with no change in length. Nutritional supplementation can improve birthweight. Based on the Guatemalan studies, the type of supplementation, i.e. protein or carbohydrate, may not make a difference in the increase in birthweight, assuming minimal protein requirements are achieved.15
Relative to maternal factors, paternal anthropometric factors have limited impact on fetal growth. Morton reported that half siblings of with the mother as the common parent, the correlation of birthweight between the half siblings was r = 0.58. In contrast, the correlation of birthweights between half siblings where the father was the common parent was only r = 0.19.16 Animal cross-breeding studies support these findings. Walton and Hammond cross-bred Shetland ponies with shire horses. The size of the foals was approximately the same size as the foals of the maternal pure breed.17 Thus, maternal regulation was more important in determining intrauterine growth than paternal factors. Lastly, Klebanoff using a Danish population registry, reported that paternal birthweight, adult height and weight together explained approximately 3% of the variance in birthweight, compared with 9% for the corresponding maternal factors.18 In summary maternal factors, most importantly maternal pregravid weight has the strongest correlation with birthweight.
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