Each year, approximately 20 percent of the almost 4 million infants in the United States are born at the low and high extremes of fetal growth. Although most low-birthweight infants are preterm, approximately 3 percent are term. In 2006, 8.3 percent of infants weighed less than 2500 g at birth, whereas 7.8 percent weighed more than 4000 g. The proportion of those < 2500 g has increased by 22 percent since 1984 and by 8 percent since 2000. At the same time, the incidence of macrosomia—defined as birthweight > 4000 g—continues to decline as the distribution has shifted toward lower weights (Martin and colleagues, 2007, 2009).


Human fetal growth is characterized by sequential patterns of tissue and organ growth, differentiation, and maturation. Development is determined by maternal provision of substrate, placental transfer of these substrates, and fetal-growth potential governed by the genome. Steer (1998) has summarized the potential effects of evolutionary pressures on human fetal growth. In humans, there is an increasing conflict between the need to walk—requiring a narrow pelvis—and the need to think—requiring a large brain. Humans may be resolving this dilemma by acquiring the ability to restrict growth late in pregnancy. Thus, the ability to growth restrict may be adaptive rather than pathological.


Lin and Santolaya-Forgas (1998) have divided cell growth into three consecutive phases. The initial phase of hyperplasia occurs in the first 16 weeks and is characterized by a rapid increase in cell number. The second phase, which extends up to 32 weeks, includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetal growth is by cellular hypertrophy, and it is during this phase that most fetal fat and glycogen deposition takes place. The corresponding fetal-growth rates during these three phases are 5 g/day at 15 weeks, 15 to 20 g/day at 24 weeks, and 30 to 35 g/day at 34 weeks (Williams and co-workers, 1982). As shown in Figure 38-1, there is considerable biological variation in the velocity of fetal growth.

Figure 38-1
Graphic Jump Location

Increments in fetal weight gain in grams per day from 24 to 42 weeks' gestation. The black line represents the mean and the outer blue lines depict ±2 standard deviations. (Data courtesy of Dr. Don McIntire.)


Although many factors have been implicated, the precise cellular and molecular mechanisms by which normal fetal growth occurs are not well understood. In early fetal life, the major determinant is the fetal genome, but later in pregnancy, environmental, nutritional, and hormonal influences become increasingly important (Holmes and colleagues, 1998). For example, there is considerable evidence that insulin and insulin-like growth factor-I (IGF-I) and II (IGF-II) have a role in the regulation of fetal growth and weight gain (Chiesa and associates, 2008; Forbes and Westwood, 2008). These growth factors are produced by virtually all fetal organs beginning early in development. They are potent stimulators of cell division and differentiation.


Since the discovery of the obesity gene and its protein product, leptin, ...

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