Fetal Origins of Adult Disease

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The "fetal origins" hypothesis proposes that undernutrition in utero at critical periods of development, programs or permanently alters fetal metabolism and renders the individual susceptible to future cardiovascular disease (CVD) and metabolic derangements of glucose metabolism (Barker et al., 1989a). This hypothesis originated in a retrospective study in which it was noted that men whose birth weights were below the 5th percentile had a higher risk of dying from coronary artery disease than men with a higher birthweight. Subsequent investigations with other populations have confirmed this relationship (Barker et al., 1993a; Martyn et al., 1998) and noted that it also exists in women (Osmond et al., 1993; Osmond et al., 2000; Rich-Edwards et al., 1997).

Low birth weight is reported to be associated with established cardiovascular risk factors including dysglycemia, dyslipidemia, and hypertension (Barker et al., 1993b; Lithell et al., 1996). Upon meta-analysis, however, the association between birth weight and blood pressure or dyslipidemia is weaker than initially thought, with the larger studies showing the smallest relationship (Huxley et al., 2002). In a recent meta-analysis, the pooled relative risk for coronary artery disease among the 6,056 subjects who weighed 5.5 pounds or less at birth was 1.26 (95 percent confidence interval = 1.11 to 1.44) compared with the risk for the 80,802 subjects who weighed more than 5.5 pounds at birth (Raju, 1995). Animal studies have provided supportive evidence in favor of this programming hypothesis, although often after the use of extreme nutritional insults during fetal life (Coates et al., 1983).

Despite the growing number of reports on an association between low birth weight, cardiovascular risk factors and surrogate markers of CVD, most studies investigating the fetal origins of adult disease have used a retrospective design for data collection (Barker et al., 1989a, Barker et al., 1989b, Barker et al., 1993a; Barker et al., 1993b; Barker et al., 1993c; Leeson et al., 2001). Furthermore, many of these studies were conducted with highly selected subgroups of people for whom very little information on pregnancy and perinatal events was available. In addition, most investigators did not differentiate low birth weight from small for gestational age or prematurity, and did not measure postnatal growth. Thus, birth weight and early growth were used as surrogates for overall somatic growth, without data on the presence or the absence of interim growth decelerations or subsequent catch-up growth. Furthermore, social class (paternal occupation) was based on recall by adult subjects 50 to 70 years later and the studies did not control for postnatal modifiers, such as socioeconomic, environmental or behavioral factors, or social deprivation in the early critical period of life (Paneth et al., 1996; Joseph and Kramer, 1996; Paneth, 1994; Paneth and Susser, 1995). In addition, retention rates in most study cohorts were extremely poor with only between 19 and 60 percent of the subjects available for further follow-up (Strauss, 2000; Cooke, 2004; Bhargava et al., 2004).

Only a paucity of studies have been designed to investigate specifically whether the fetal origins hypothesis is also applicable to preterm infants and not just to those who are small for gestational age. Fewtrell and colleagues (2000) examined the relationship between gestational age and size for gestational age on glucose and insulin concentrations at ages 9 to12 years in 385 children who had been born preterm with birth weights less than 1,850 grams. Low birth weight, whether it was due to being born preterm or intrauterine growth restriction, was associated with higher plasma glucose levels 30 minutes after administration of a glucose load in preterm children. Recently, Hofman and colleagues (2004a) have demonstrated that 4- to 10- year- olds born preterm have metabolic abnormalities similar to those observed in infants born full term but small for gestational age and that these occur irrespective of whether the preterm infants are small or appropriate for gestational age. In fact, there did not seem to be an additive effect on reduced sensitivity from being born both preterm and small for gestational age. A subsequent study by the same investigators confirms the reduction in insulin sensitivity, which may be a risk factor for Type II diabetes mellitus (Hofman et al., 2004b). This reduction was similar in infants born between 24 and 32 weeks gestation, suggesting that a critical window exists in the third trimester in which insulin activity is altered. In another study by Hovi et al. (2005), young adults born with birth weights less than 1,500 grams had fasting insulin levels that were 34 percent higher than those for controls, and their mean fasting serum glucose level was also higher (but an oral glucose tolerance test was not done). Unfortunately, these studies examined only 50 percent of the cohort.

Childhood weight gain has also been shown to be an important predictor of measures of insulin secretion and resistance in some studies (Fewtrell et al., 2000). Singhal and colleagues (2003a) have shown that preterm infants with birth weight less than 1,850 grams who received nutrient-enriched formula had higher fasting 32-33 split pro-insulin levels at adolescence. This effect of postnatal diet was a proxy for greater weight gain in infants in the first 2 weeks of life, independently of birth weight, gestational age, and other sociodemographic factors. The authors propose that relative undernutrition in preterm infants early in life may actually have beneficial long-term effects on insulin resistance. Similar beneficial effects on vascular structure and endothelial function were also observed (Singhal et al., 2004). These studies have raised further controversy regarding the nutritional management of very preterm infants and what should be considered 'optimal' catch-up growth.

Other studies have also shown high rates of Type II diabetes in individuals who were small for gestational age at birth and who later became overweight as adults (Bavdekar et al., 1999; Newsome et al., 2003; Eriksson et al., 1999). In a recent prospective longitudinal study of 1,492 Indian subjects 26 to 32 years of age, the growth of children in whom IGT or diabetes later developed was characterized by a low body mass index between birth and 2 years of age, followed by an early adiposity rebound and a sustained and accelerated increase in body mass index until adulthood (Bhargava et al., 2004). In two other studies with young adults, individuals who experienced the largest increase in body mass index and those who remained overweight over time had evidence of vascular change manifest by increased CIMT (Oren et al., 2003; Eriksson et al., 2001). Thus the association of low birth weight and later CVS and metabolic factors is very likely modified by postnatal factors, although this has not been adequately studied.

Body composition, specifically the distribution of the fat and lean bone mass compartments, may also be important predictors of risk of CVD, hypertension and diabetes in adult life. Fat mass and fat-free mass were lower in 8 to 12 year old children born with birth weights less than 1,850 grams than in children born with normal birth weights (Fewtrell et al., 2004). Such findings may reflect programming of body composition by early growth and nutrition. Indeed, a higher birth weight was associated with a greater fat free mass in adolescents (Singhal et al., 2003b). The authors suggest that an association of low birth weight and lower lean mass may be the underpinnings of programming for suboptimal insulin sensitivity, lower metabolic activity, and a subsequent propensity to greater adiposity and risk of CVD (Singhal et al 2003b).

Using whole-body magnetic resonance, Uthaya and colleagues (2005) have recently shown that by the time that infants born preterm reached their term age, they had a highly significant decrease in subcutaneous adipose tissue and significantly increased levels of intraabdominal adipose tissue. They caution that preterm infants may be at risk of metabolic complications later in life through this increased and aberrant adiposity. In a cohort of 132 20-year-old individuals who had been born small for gestational age and average for gestational age and who were born full term (Levitt et al., 2005), the association between low birth weight and expression of adult chronic cardio-metabolic disease was not dependent on birth weight alone, but was also dependent on its interaction with subsequent fat accumulation (either generally or abdominally) (Levitt et al., 2005).

Fewer studies have explored the association of preterm birth and CVS disease in adulthood. Irving and colleagues (2000) investigated 61 young adults who had been born with low birth weights less than 2,000 grams at a mean age of 24 years and showed that those who were small because of prematurity were also at risk of hypertension, an adverse metabolic profile (higher plasma insulin triglyceride and total cholesterol levels and lower high-density lipoprotein cholesterol levels) and hyperglycemia as adults. Among the preterm cohort, those who were small for gestational age were not measurably more disadvantaged than those who were average for gestational age. CIMT studies, however, were not performed. A study conducted in The Netherlands attempted to elucidate the effects of prenatal and infancy growth on the lipid and CIMT measures in a very preterm cohort at age 19 years (Martin et al 2006). Their findings support an effect of current body composition rather than early growth on CVD risk. Two recent studies (Doyle et al., 2003; Hack et al., 2005) have shown higher systolic blood pressure among very low birth weight infants in late adolescence and young adulthood. However, no relationship was found between intrauterine growth and blood pressure. Not all studies have found higher blood pressure in preterm subjects in childhood (Morley et al., 1994) or at young adulthood (Saigal et al., 2005). Further prospective, long-term studies of preterm infants monitored to adulthood are warranted to confirm whether preterm infants are at increased risk for CVD and metabolic problems as adults.

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