Investigations of protein metabolism in human pregnancy: the term foetus and placenta studied using stable isotope labelled amino-acids

Abstract

Because the placenta functions as a very efficient provider of ‘total parenteral nutrition’, the foetus enjoys a rapid growth rate in relation to its body weight (14). The growth rate exceeds that of any other time during life, including the adolescent growth spurt (12). In human pregnancy, maternal plasma total a-amino nitrogen is reduced from about 3.0 to 2.3mM, however, the total a-amino nitrogen in foetal plasma is 3.8mM, giving a F:M ratio of 1.7 (31). Thus, in fact, all the free amino-acid concentrations in the umbilical artery are higher than in the maternal ante-cubital vein (30), so the placental transfer of amino-acids to the foetus must occur against a concentration gradient, i.e. be due to some process of active transport (22), probably Na-linked. Widdowson et al (29) measured the amino-acid composition of the body and organs of a few human foetuses of accurately known gestational ages (79 days-term), and although such values included the small amount of amino-acids in the free pool as well as the larger amount of aminoacids incorporated into the protein, they clearly showed that nitrogen does not begin to increase rapidly until about 160 days of gestation. Thereafter, the foetus gains weight quickly with rapid nitrogen (mainly protein) deposition: from midgestation to term, the human foetus grows at an average rate of 1.5% per day (19); for a birth weight at term gestation of 3.5 kg, this equals a final growth velocity of 15 g/kg birth weight/day. Amino-acids are the obligatory precursors for body protein, and naturally they are utilised by the foetus for growth but, despite their obvious importance, it is only relatively recently that we have information concerning their metabolism in utero. In sheep, it has been found that the rate of amino-acid provision to the foetus exceeded its rate of accretion in tissue proteins (2, 3). This suggested that amino-acids might also be used as fuel for oxidation or as substrates for lipid, neurotransmitter and nucleic acid synthesis and possibly for gluconeogenesis in the kidney but not in the liver, which is poorly developed. Studies in fasting pregnant sheep using 14C labelled leucine have shown that the ratio of the foetal leucine oxidation rate to the leucine disposal rate was doubled when compared to the fed state (27). Foetal oxidation of alanine, glycine and lysine has also been observed (19). Results of experiments using 14C lysine and 14C leucine in foetal lambs have also shown that the fractional protein synthetic rate in late gestation is twoor three-fold higher than the fractional growth rate, confirming the hypothesis that foetal protein turnover is likely to be high (19). Starting from a low base, the last 10 years have seen an increasing amount of information being gathered on the rates of growth and protein turnover in human neonates, almost exclusively for mature infants. In studies using the 15N glycine/ NH3-urea end product method on very low birth weight premature infants (< 1500g) receiving 483 kJ/kg/day and 3g protein/kg/day as breast or formula milk, the total body protein accretion rate was found to be 1.8 g/kg/day and the observed average weight gain was found to be 15 g/kg/day (8). This agrees closely with the value of 1.9g of protein gained/kg/day obtained from studies using L-[l-13C] leucine (4) in a continuous infusion plasma kinetics protocol. Studies to measure whole blood umbilical V-A concentration differences and umbilical blood flow in chronic unstressed foetal lamb have been performed by the group of Battaglia and Meschia: