Fetal Nutrition: How We Become What We Are (2001)

Fetal growth is maintained through the complex interplay of maternal and fetal systems, including circulatory, endocrine, and metabolic. Althugh, intuitively, severely compromised fetal growth and nutrition can lead to fetal death, during the past decade it has become increasingly apparent that smaller decrements in growth during the fetal period can have profound consequences for the individual throughout later life. This review will attempt to summarize recent progress, first in the delineation of the consequences of impaired fetal growth, and subsequently in our knowledge regarding the mechanisms by which fetal growth is optimized, and, potentially impaired in pathologic states. FETAL “PROGRAMMING”—THE BARKER HYPOTHESIS Fetal programming denotes the concept that critical periods of rapid fetal cell division exist during which an injury to this process can result in permanent metabolic or structural changes (1). These alterations can have long-term consequences, even in adults. Considerable literature exists in animals regarding the influence of fetal malnutrition on later health. In addition, it has long been known that poor human growth in utero can have adverse effects on growth and development during infancy and childhood. During the past decade, epidemiologic analyses have documented that people who have evidence of poor growth in utero can have increased risk of adult diseases as well. These include cardiovascular disease, hypertension, and type 2 diabetes mellitus. The links were originally elucidated through the work of researcher David Barker and his colleagues. They postulate that there are critical windows in fetal maturation during which inadequate nutrition can “program” the development of adult disease. The novelty of recognizing the influence of fetal growth on future well-being has led to the label “Barker hypothesis.” During these crucial periods of rapid fetal growth, fetal adaptations meant to counteract malnutrition in the short-term can negatively influence long-term health (2). The initial studies of Barker’s group were retrospective analyses of adult British men and women who, as infants, had birth measurements recorded. In one such cohort, from Hertfordshire, Great Britain, data on approximately 16,000 subjects born between 1911 and 1930 were available. Evaluation of this information suggested that the mortality rate (among adults) caused by coronary artery disease was inversely related to birth weight, to a maximum of 9.5 lb (3). Subjects who weighed less than 5.5 lb at birth had a twofold greater risk of death than larger infants. With more than 9.5 lb, relative risks again began to increase, perhaps because of the inclusion of infants of diabetic mothers. These particular infants may have been influenced by a genetic predisposition to diabetes or physiologic effects of prenatal hyperglycemia (4). The data for men are shown in Figure 1. The overall increase in mortality rate was greater if poor growth persisted through 1 year of age (5). Continued meager growth ex utero might represent programmed growth hormone resistance, with its attendant influence on the cardiovascular system (2). Interestingly, the highest mortality rate in women existed in those who were small at birth but above average weight at 1 year of age. A subsequent study of Finnish men also found that increased postnatal growth rate (small at birth but high body mass index at age 7 years and older) increased susceptibility to eventual death from cardiac disease (6). Thus, Seckl (7) has suggested that smallness from in utero malnutrition is a stronger risk factor than the risk associated with genetic code. These findings have been replicated in other populations, both in Europe and abroad (8,9). Hypertension has also been related to alterations in fetal growth. Initial studies suggested an inverse correlation between birth weight and blood pressure (10). Interestingly, the highest risk for hypertension was in small babies with large placentas (three times greater than large babies with small placentas). Placental enlargement has been linked to other adult diseases and may represent evidence of disturbed fetal development (11). Although others have failed to reproduce this association (12), there is widespread documentation of the inverse relation between birth weight and blood pressure (13). Suggested causes for eventual hypertension in small babies include programmed vascular changes and effects of glucocorticoid excess in utero (2,14).FIG. 1.: Standardized mortality ratio for men by birth weight in Hertfordshire study. Data obtained from Osmond C, Barker DJP, Fall CHD, Simmonds SJ. Early growth and death from cardiovascular disease in women. BMJ 1993;307:1521.A study of a group of 468 Hertfordshire men demonstrated that low birth weight correlated with adult development of type 2 diabetes mellitus and impaired glucose tolerance (15). Evaluation of men and women born in Preston, England, confirmed this propensity. Here, the investigators discovered that persons who were small and thin (low ponderal index), and had a smaller head circumference, would be at increased risk of poor glucose metabolism and frank diabetes (16). As might be expected, higher body mass index as an adult increased the risk in both studies. As Barker points out, lifestyle factors, such as obesity, are additive to the effect of intrauterine environment (2). As many as nine other studies have exhibited similar results regarding smallness and thinness at birth and impaired glucose tolerance (17). In an effort to place these data in context, Barker and Hales, in 1992, proposed the “thrifty hypothesis,” whereby permanent metabolic and endocrine modifications (nutritional thrift) occurring in utero as a result of inadequate nutrition are detrimental to the developing pancreas, and thus create a predisposition for the eventual development of diabetes (18). Phillips would later suggest that when nourishment is scarce these fetal metabolic adaptations might include development of tissue insulin resistance to prevent glucose metabolism and cell growth (19). This insulin resistance could become permanently programmed and persist into adult life, thus contributing to the development of type 2 diabetes. Other associations have also been suggested through epidemiologic analyses. Low birth weight correlates with death as a result of cerebrovascular accidents in some series (20,21). In addition, poor fetal growth has been linked to high serum cholesterol, apolipoprotein B, fibrinogen, and factor VII levels (22,23). Smaller abdominal circumference at birth was also associated with higher cholesterol and fibrinogen levels, prompting speculation that an effect on liver development may be responsible for these findings (2). Finally, there may be a link between some cancers, such as breast and testicular, and poor nutrition in utero; but this requires further investigation (4). As body tissues and organ systems develop at different stages of gestation, Barker proposes particular consequences, in utero and as adults, of malnutrition during early, mid, and late pregnancy (2). For instance, injuries during the second trimester can lead to disturbances in the insulin axis and infants born with thin body habitus. As adults, these individuals have a propensity for development of hypertension and type 2 diabetes. Epidemiologic data accounts for most of the knowledge acquired regarding fetal nutrition and adult outcomes. Future endeavors will likely include further population-based studies in addition to animal research to uncover the metabolic pathways responsible for phenotypic changes. These should consider the influence of maternal nutrition and cumulative intergenerational effects (24). Use of birth weight alone as a marker for fetal malnutrition has obvious limitations that must be considered. Although the majority of data discussed above deals with the impact of fetal growth on adult well-being, information also exists regarding the impact of suboptimal fetal growth on childhood growth and neurodevelopment. For example, low birth weight has been repeatedly correlated with higher blood pressure in children (25–27), although less consistently in adolescence (13). Hofman et al. demonstrated evidence of insulin resistance in children who were small for their gestational age (28). In fact, multiple endocrine axes seem to be influenced by intrauterine growth retardation (IUGR), including that of growth hormone (29). These disturbances may account for the lack of catch-up growth that occurs in the minority of IUGR patients (30). Finally, although much less well-studied, fetal programming may also play a role in children with evidence of overnutrition in utero. Generally, infants who are large for their gestational age are heavier and taller throughout childhood and are at higher risk for obesity (31,32). This propensity to obesity persisted through adolescence in one large study; here, macrosomic infants (who did not have diabetic mothers) had higher body mass indices at 17 years of age when compared with nonmacrosomic infants (33). More recently, investigators have even found a positive correlation between birth size and risk for future asthma and atopy (34). OVERVIEW OF FETAL NUTRITION These discussions are meant to introduce the concept that fetal growth is important not only in the neonatal period, but throughout life. As such, it is of importance to understand the mechanisms by which fetal growth occurs. Early fetal development occurs predominantly by cell hyperplasia. During the embryonic period (the first 2 months after conception), organogenesis is the main focus of the developing embryo. Absolute growth is not significant during this time. Subsequently, in the fetal period, intense growth is present, and cells undergo hypertrophy, while organ systems begin to mature. A graph representing normal intrauterine weight gain appears in Fig. 2. Peak growth velocity occurs during the second and third trimesters and slows near term.FIG. 2.: Graph of intrauterine weight gain by gestational age. Data obtained from O’Rahilly R, Mueller F. Human Embryology and Teratology. 2nd edition. New York: Wiley-Liss; 1996.The mechanisms by which the fetus receives nutrition can be divided into two phases: initially histiotrophic and later hemotrophic. Before implantation, the conceptus is dependent on exogenous nutrients found in ductal and uterine secretions. After implantation occurs around day 4 or 5, the trophoblast has surface cells that aggressively invade the surrounding tissue and absorb nutrients through phagocytosis and pinocytosis. In preparation to host the embryo, the maternal endometrium becomes rich in glycogen and lipids—a process called decidualization. In addition, uterine glands increase in size and activity. Lacunae soon appear in the invading trophoblast tissue and fill with secretions and tissue debris for embryonic utilization. The role of the yolk sac in early embryonic nutrition is not fully known, but it is probably involved with the transfer of nourishment to the developing embryonic mass. 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