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.
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, there has been interest in maternal and fetal serum leptin levels. Fetal concentrations increase during the first two trimesters, and they correlate with birthweight (Catov, 2007; Sivan, 1998; Tamura, 1998; and all their colleagues). This relationship, however, is controversial in growth-restricted fetuses (Kyriakakou, 2008; Mise, 2007; Savvidou, 2006, and all their associates). Angiogenic factors have also been studied. For example, higher levels of sFlt-1 at 10 to 14 weeks are associated with small-for-gestational age infants (Smith and co-workers, 2007).
Fetal growth is also dependent on an adequate supply of nutrients. As discussed in Chapter 4, Fetal Nutrition, glucose transfer has been extensively studied during pregnancy. Both excessive and diminished maternal glucose availability affect fetal growth. Excessive glycemia produces macrosomia, whereas diminished glucose levels have been associated with fetal-growth restriction. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) found that elevated cord c-peptide levels, which reflect fetal hyperinsulinemia, have been associated with increased birthweight even in women with maternal glucose levels below the threshold for diabetes.
There is less information concerning the physiology of maternal-fetal transfer of other nutrients such as amino acids and lipids. Ronzoni and colleagues (1999) studied maternal-fetal concentrations of amino acids in 26 normal pregnancies. These investigators reported that an increase in maternal amino acid levels led to an increase in fetal levels. In growth-restricted fetuses, amino acid disturbance similar to the biochemical changes seen in postnatal protein-starvation states has also been detected (Economides and colleagues, 1989b). In a study of 38 growth-restricted infants, Jones and colleagues (1999) found impaired use of circulating triglycerides consistent with peripheral adipose depletion.
Low-birthweight infants who are small-for-gestational age are often designated as having fetal-growth restriction. The term fetal-growth retardation has been discarded because “retardation” implies abnormal mental function, which is not the intent. It is estimated that 3 to 10 percent of infants are growth restricted.
In 1963, Lubchenco and co-workers published detailed comparisons of gestational ages with birthweights in an effort to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco (1967) then classified small-for-gestational-age (SGA) infants as those whose weights were below the 10th percentile for their gestational age. Such infants were shown to be at increased risk for neonatal death. For example, the neonatal mortality rate of SGA infants born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights.
Many infants with birthweights less than the 10th percentile, however, are not pathologically growth restricted but are small simply because of normal biological factors. Indeed, Manning and Hohler (1991) and Gardosi and colleagues (1992) concluded that 25 to 60 percent of SGA infants were in fact appropriately grown when maternal ethnic group, parity, weight, and height were considered.