Folate Deficiency in Premature Infants

Zuelzer and Ogden first clearly defined the syndrome of megaloblastic anaemia in infants, which responds to folic acid, as long ago as 1946. They concluded: 'In an analysis of etiologic conditions, infections and nutritional deficiencies appear significant while age, race and possibly prematurity and maternal anemia are predisposing factors'. 5 ofthe 25 infants they described had been born prematurely, but it is only in the past few years that the particular susceptibility of premature babies to folate deficiency has been adequately documented. The exact frequency with which premature babies in well-nourished communities develop the deficiency is still uncertain. Strelling et al. (1966), examining buffy coat preparations, found megaloblastic changes in 7 of 54 premature babies and suspected it in a further 4. The incidence of the abnormality was highest in the smallest babies since all 6 babies weighing less than 1500 g. at birth and 3 of the 18 weighing between 1500 g. and 1800 g. had a definite or 'probable' megaloblastic change. All 11 infants with megaloblastic changes were said to show a reticulocyte response with a rise in haemoglobin in response to folic acid therapy, but these responses were not recorded by the authors. Gray and Butler in 1965 described 3 premature infants who developed megaloblastic anaemia between the 3rd and 7th week of life, and they clearly showed that in each infant the anaemia responded well to folic acid therapy. Other cases of premature infants developing megaloblastic anaemia responding to folic acid therapy have been described by Zuelzer and Ogden (1946), Zuelzer and Rutzky (1953), Kho and Odang (1959), and Vanier and Tyas (1967). The incidence of biochemical abnormalities due to folate deficiency is more fully documented than the incidence of haematological changes. As in other conditions in which folate deficiency occurs, biochemical abnormalities are found far more frequently than overt megaloblastic anaemia since megaloblastic anaemia occurs only when the deficiency is extremely severe. Thus Shojania and Gross (1964) found that 28% of all premature babies and as many as 68% of those weighing less than 1700 g. at birth developed low serum folate levels between 1 and 3 months of age. Vanier and Tyas (1967) extended these observations. In their series 65% of premature babies aged between 2 and 3 months had subnormal serum folate levels, 40% had subnormal red cell folate levels, and 24% excreted raised amounts of formiminoglutamic acid (Figlu) after a histidine load. Clinically the deficiency in premature babies differs from that in full-term infants in two respects. First, the deficiency tends to develop in premature babies within the first few weeks or months of life. This contrasts with the peak age incidence of folatedeficient megaloblastic anaemia in full-term infants, which is in the second 6 months of life. Secondly, the deficiency may occur in premature babies but not in full-term infants without an external cause such as infection, general malnutrition, or a diet of abnormally low folate content being implicated. Folate deficiency occurs in premature babies because demands for growth exceed intake of the vitamin and thus use up stores of folate. Serum and red cell folate levels at birth, both in premature and in full-term infants, are higher than normal adult values (Grossowicz et al., 1960; Shojania and Gross, 1964; Vanier and Tyas, 1966, 1967). After birth, the serum and red cell folate levels drop rapidly in all infants, but the fall is both more rapid and more severe in infants born prematurely (Matoth et al., 1964; Shojania and Gross, 1964; Vanier and Tyas, 1967). The steepest falls occur in the smallest babies. Serum folate falls more rapidly than red cell folate, the lowest levels being reached between 4 and 8 weeks, and in the series of Roberts et al. (1969) all but one of 13 premature infants had a serum folate less than 6-0 ng. /ml. at 7 weeks of age. The data of Roberts et al. (1969) also suggest that the smallest prematures may be born with lower folate levels than larger premature babies, but the numbers analysed were insufficient for this to be definitely established. The newborn infant's requirements for folate have been estimated to be of the order of 20-50 Xug. per day, about 4-10 times adult requirements based on body weight (Matoth et al., 1964; Sullivan, Luhby,