|Causes and Consequences of Intrauterine Growth Retardation, Proceedings of an IDECG workshop, November 1996, Baton Rouge, USA, Supplement of the European Journal of Clinical Nutrition (International Dietary Energy Consultative Group - IDECG, 1996, 100 pages)|
|Biological mechanisms of environmentally induced causes of IUGR|
The hormonal regulation of fetal growth is complex. During pregnancy, hormones appear to be important mediators of substrate availability to the fetus. Growth depends on the stage of gestation, and nutrient availability. A normal balance of the functional unit, consisting of uterus, placenta and fetus, is of great importance for fetal growth. Late in gestation some maternal physical factors might constrain fetal growth, as demonstrated by embryo transplants and crossbreeding experiments (Gluckman and Liggins, 1984; Snow, 1989). A common illustration is the reduced mean birth weight in multiple pregnancies.
Fetal growth might be controlled at the level of individual cells and organs by nutrient supplies and/or by locally active factors. For example, IGFs have been described as acting on cell growth via autocrine or paracrine mechanisms (Adamson, 1993; D'Ercole, 1991). Stimulation of mitosis appears to be a major function of IGF-2; its absence results in IUGR mice (DeChiara et al, 1990). IGF-1 is also capable of inducing cell differentiation (Ohlsson et al, 1993). Pituitary growth hormone (GH) is found in the fetal circulation by 12 weeks of gestation (Cornblath et al, 1965). Despite its abundance early in the second trimester, the role of GH in intrauterine growth is not clear. Pituitary aplasia and congenital hypopituitarism do not cause severe IUGR (Lovinger et al, 1975; Goodman HG et al, 1968). Children with abnormal GH receptors, however, are usually short at birth (Laron et al, 1972). GH seems to be involved in the initiation of synthesis of IGF-binding protein, which plays a major role in fetal growth. Pancreatic agenesis is associated with severe growth retardation (Lemons et al, 1979), and fetal hyperinsulinemia leads to fetal mass overgrowth.
Circulating levels of IGF-1 in fetal, and cord blood correlate with fetal size (Lassare et al, 1991). Reduced plasma concentration of IGF-1 has been reported in IUGR (Ashton et al, 1985). When mouse embryos with high plasma IGF-1 concentration are transplanted into unselected maternal recipients, intrauterine growth is larger than that of transplanted embryos with low concentration of IGF-1 (Gluckman et al, 1992). Maternal starvation leads to a rapid decrease in fetal IGF-1 concentration, which is generally associated with the cessation of intrauterine growth (Basset et al, 1990). Glucose is the major regulator of fetal IGF-1 secretion (Oliver et al, 1993).
The above fetal determinants might act independently or in conjunction with maternal determinants. During pregnancy, the maternal hormonal profile might be modified by placental hormones such as human chorionic somatomammotropin. Maternal IGF-1, IGF-2, and insulin do not cross the placenta, and do not have a direct effect on fetal growth, but may have an effect on placental function, thus altering the nutrient exchange between the placenta and the fetus. For example, administration of IGF-1 to pregnant rodents eliminates the maternal physical constraint on fetal growth and alters the relationship between fetal size and placental size (Hall K. et al, 1984). Maternal plasma IGF-1 concentration correlates with fetal growth (Mirlesse et al, 1993; Smith et al, 1992).
The placenta is also an active endocrine organ, secreting steroids and polypeptide hormones. The placenta synthesizes estrogen, and progesterone (Simpson and MacDonald, 1981) and a number of other growth factors involved in autocrine and paracrine mechanisms of fetal development. Recently, the placenta has been shown to express the GH-V gene specifically leading to the production of a placental growth hormone (placental GH) (Chen et al, 1989). Early in pregnancy (15-20 weeks of gestation) pituitary GH is present in the maternal circulation. Later in pregnancy (20 weeks to term) increased placental GH replaces pituitary GH (Frankenne F et al, 1990). Placental GH declines rapidly with the onset of labor and after delivery. Plasma samples of mothers of IUGR babies contain significantly lower concentrations of placental GH (Mirlesse et al, 1993); plasma levels of IGF-1 are also reported to be low, suggesting a relationship between placental GH and the development of the feto-placental unit. However, since placental GH is not detected in the fetal circulation, it does not appear to have a direct effect on fetal growth.
Human placental lactogen (hPL) is detected by six weeks of gestation and its concentration increases progressively throughout gestation (Handwerger S, 1991). hPL stimulates insulin secretion, and causes nitrogen retention during pregnancy (McGarry and Beck, 1972). hPL is also lipolytic, and thus, might help to maintain glucose availability to the fetus during maternal starvation (Walker et al, 1991). However, there is no direct evidence of a role of hPL in fetal growth.
The role of infection
Acute infections may affect the fetus temporarily because of maternal pyrexia Chronic infections may act on the fetus by crossing the placenta, and directly altering fetal cell growth. A few infecting agents may interfere with the utero-placental transfer mechanism and reduce the supply of nutrients. Where malaria is endemic, it is one of the most common causes of IUGR. McGregor et al reported a 20% infiltration of the placenta with extensive villus damage, and reduced birthweight (McGregor et al, 1983).
Cytomegalovirus infection is commonly associated with congenital abnormalities of the fetus, and 40% of the infants born with this condition have IUGR (Stagno et al, 1983). Rubella might limit cell multiplication in the fetus, and damage the vascular endothelium of the villus capillaries, thus impeding normal circulation. Cooper et al found that 60% of infants with congenital rubella had birth weights below the tenth centile. Other virus infections, such as herpes and hepatitis, have occasionally been reported to be associated with IUGR (Waterson, 1979).