International Perspectives

With continuing advances in preterm baby care, survival rates are increasing in very low-birthweight (VLBW) and very low gestational age newborns in both developed countries and large centers in developing countries. Preterm babies have metabolic characteristics and many diseases and complications due to immaturity that make provision of appropriate nutrition a challenge. Even greater difficulties are encountered with microelements, known also as trace elements or oligoelements, and vitamins because basic needs are not always perfectly defined. There are also no evident clinical signs of deficiency during the neonatal period, so the neonatologist is not always aware of a need to supplement them.Several situations contribute to deficiencies in these nutrients among VLBW preterm babies: human milk fortifiers do not contain all the necessary micronutrients or contain them in insufficient quantities; formula milks have different ingredients in different countries, with the most suitable ones often not available; and formulas for parenteral nutrition do not provide the necessary micronutrients, such as selenium. Recently, supplementation of minerals such as selenium and vitamins A and E, which have antioxidant properties, has been evaluated clinically for the possible prevention of preterm infant diseases in which free radicals have pathophysiologic importance. Also, many studies have been undertaken on mineral and vitamin supplements for pregnant mothers in poorer countries that are aimed at reducing low birthweight and perinatal and infant mortality.The important microelements in human nutrition are zinc, copper, selenium, chromium, molybdenum, manganese, iodine, and iron. Although they only represent a small fraction of the human body’s total mineral content, they play important roles in various metabolic routes. Preterm babies can present with deficiencies, even without clinical signs, due to low concentrations of the elements at birth because these minerals are only incorporated in the last trimester of pregnancy.The importance of selenium increases in all ages as a component of the selenoenzymes, which have distinct functions. For example, glutathione peroxidase is an important antioxidant enzyme in cell membranes. Such enzymes prevent the formation of free radicals, reducing the lipid peroxides and hydrogen peroxide and protecting the organism from oxidative aggression. Another of selenium’s properties is its role in immunocompetence. Neutrophils and macrophages from animals deficient in selenium have low glutathione peroxidase concentrations, which can affect their antimicrobial properties. (1)(2)Selenium concentrations in the soil vary considerably in different geographic areas, and concentrations in pastures, animals, and humans reflect these variations. Concentrations in human milk follow these regional variations. (3) Human milk has much higher selenium concentrations than nonsupplemented preterm formulas. These preterm formulas, therefore, are not recommended for VLBW preterm infants.The VLBW preterm infant is vulnerable to conditions that involve an attacking free radical pathophysiology, such as bronchopulmonary dysplasia (BPD), retinopathy of prematurity, periventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia. The frequency with which such infants receive oxygen makes them susceptible to oxidative stress and the subsequent production of reactive oxygen. Although selenium deficiency may participate in such diseases in preterm babies, data to support its actual importance are lacking. In a review, Klein (1) referred to clinical studies linking selenium to diseases in preterm babies. For example, eight preterm babies who developed respiratory distress syndrome and did not receive parenteral or oral selenium experienced a rapid decrease in blood selenium concentrations 2 weeks after birth. In another study, preterm infants who had chronic lung disease (CLD) and did not receive selenium supplement experienced an accentuated decrease in selenium concentrations. In New Zealand, a country where the soil and foods are poor in selenium, low selenium concentrations in 79 VLBW preterm infants were associated with increased respiratory morbidity, and plasma concentrations were significantly lower in children dependent on oxygen at 28 days after birth. The consequences of low selenium levels in newborns have not been determined, although it has been suggested that they represent a risk factor for CLD and retinopathy of prematurity. However, there is uncertainty as to whether selenium supplementation reduces the risk of these diseases.The mechanisms that control the maternal-fetal transfer of selenium still are not fully clear. Transfer through the placenta is limited, making fetal concentrations relatively low; cord blood concentrations are about 65% those of the maternal serum. We found no significant differences in cord selenium concentrations between VLBW preterm and term newborns who were appropriate (AGA) or small for gestational age (SGA), with selenium concentrations corresponding to approximately 80% of maternal values. (4) However, Makhoul and associates, (5) evaluating cord blood selenium in newborns born between the 24th and 42nd weeks of gestation, found an association with gestational age, with a significant increase in concentration after 36 weeks.There are no data on fetal selenium content, but incorporation is estimated to be 1 mcg/kg per day. Selenium is stored in the fetal liver between gestational weeks 20 and 40, which may be why low concentrations are seen in preterm newborns. Studies of selenium concentrations in VLBW preterm infants have shown that plasma concentrations of selenium and glutathione peroxidase correlate with birthweight and that glutathione peroxidase levels in VLBW preterm newborns are one third those of term infants. (6)For preterm infants who had respiratory diseases and were receiving parenteral nutrition without selenium supplement for the first 14 postnatal days, concentrations of the element declined in the first few days after birth. (7) Except for one newborn who developed BPD, concentrations increased when feeding with selenium-supplemented formula was initiated. Other authors have shown a progressive decline in glutathione peroxidase activity in erythrocyte and plasmatic selenium in preterm newborns from the second postnatal week when fed standard milk formula.In a cross-sectional study at Botucatu School of Medicine’s Neonatal Unit, São Paulo, Brazil (UNESP), (4) we evaluated serum selenium concentrations for the first 30 days after birth in three groups of newborns: VLBW preterm, term AGA, and term SGA. From each infant we collected between two and five blood samples at different times. The infants did not receive selenium supplementation in parenteral nutrition, maternal milk with fortifier, or preterm formula. Cord selenium values were less than maternal values in all three groups. The only differences were significantly lower levels in the VLBW preterm infants on day 3 in relation to term AGA infants and an accentuated progressive decrease in selenium concentrations in preterm infants on days 15 and 30 in relation to both term groups (FigureF1). The underweight term newborns had no differences in behavior compared with the normal-weight term newborns. This study was performed in a region of São Paulo State that has average soil levels of selenium. We concluded that VLBW preterm infants require selenium supplement in both parenteral and enteral nutrition.This finding was confirmed by Darlow and associates (8) in a multicenter, randomized, double-blind trial of 534 VLBW preterm infants evaluated at 28 days after birth and 36 weeks after conception. The treatment group received 7 mcg/kg per day selenium parenterally and 5 mcg/kg per day added to maternal or formula milk. The authors observed that glutathione peroxidase and plasma selenium concentrations were significantly lower in the nonsupplemented group at both time points. This study was performed in New Zealand, which has very low soil selenium levels.In a randomized study, 38 preterm infants whose average birthweight was 1,171g received 3 mcg/kg per day selenium-supplemented parenteral nutrition and were followed for the first 6 weeks after birth. (9) They were compared with preterm infants receiving nonsupplemented parenteral nutrition and a reference group of term newborns receiving human milk or formula. Supplementation slowed selenium depletion, although they did not reach the concentrations seen with the term breastfed group, who had increased selenium levels. (9) This study also was performed in a country that has low selenium soil levels, South Australia.In the United States, Tyrala and associates (10) performed a randomized, controlled, blinded study in VLBW preterm infants. Seven infants received preterm infant formula supplemented with 3.5 mcg/100 kcal selenium, followed by term formula supplemented with 2.6 mcg/100 kcal selenium. The control group consisted of 10 children fed preterm formula with 1.2 mcg/100 kcal selenium and then a term formula containing 1.3 mcg/100 kcal selenium up to 12 weeks after birth. Plasma selenium concentrations only declined in the nonsupplemented group, although erythrocyte selenium declined in both groups. Also, glutathione peroxidase concentrations only increased in the supplemented group. The investigators concluded that selenium supplementation is required in preterm formulas. In Brazil, the same preterm infant formula was supplemented with 2 mcg/100 kcal selenium.Whether supplementation prevents diseases in newborns still requires study. In a meta-analysis by Darlow and Austin, (11) three studies fulfilled the requirements and included 297 newborns given selenium supplementation and 290 controls. Two studies included extremely preterm babies. Complications evaluated included the need for oxygen at 28 days, sepsis episodes, death while in hospital, chronic pulmonary disease (the need for oxygen at 28 d and postconceptual age of 36 wk), and retinopathy of prematurity. The authors concluded that selenium supplementation reduced one or more episodes of late-onset sepsis, but did not have a significant effect on the other diseases or complications.There is no doubt that selenium supplementation in parenteral nutrition and formulas is recommended. However, the ideal dose remains unclear. The primary question is whether umbilical cord concentrations should be the reference value, as suggested by Makhoul and associates, (5) or concentrations should be maintained similar to those in term breastfed newborns.Different quantities of selenium are used in preterm infant supplementation. The recommendation in the United States is 2 mcg/kg per day in parenteral nutrition, but meta-analysis suggests 3 mcg/kg per day is needed to maintain cord levels and much higher concentrations to attain similar levels to term breastfed newborns, as reported by Darlow and Austin. (11) A panel of specialists convened by the United States Food and Drug Administration and the American Society for Nutritional Sciences (1) recommends selenium concentrations between 1.8 mcg/100 kcal and 5.0 mcg/100 kcal in formulas for preterm infants.Zinc deficiency has been seen in suckling infants and children from developing countries who have growth and development deficiencies and immunity problems that result in increased morbidity and death from infectious diseases. (12) A randomized, controlled, double-blind study of 1,154 term undersize newborns conducted in New Delhi, India, in which the infants received zinc, vitamin, and mineral supplements from postnatal day 15, showed that only those receiving zinc had reduced mortality with a relative risk (RR) of 0.32 (95% confidence interval CI: 0.12 to 0.89 and P=0.028). (13)Keeping in mind the high prevalence of low-birthweight newborns in less developed countries and the high neonatal and infant mortality, there is worldwide interest in nutrition supplementation with micronutrients during pregnancy, primarily zinc, to reduce low birthweight. Many studies on zinc and other micronutrient supplementation during pregnancy have been undertaken in developing countries, but there are difficulties analyzing results due to different protocols, the intensity of the zinc deficiency, and differences in zinc dose and introduction time during pregnancy. (14) Some clinical studies show a reduction in the number of preterm births, increase in gestation time, and improved Apgar scores, but other researchers have not confirmed whether zinc supplementation during pregnancy affects immunocompetence, resulting in a long-term effect on mortality. Analysis of eight controlled, randomized clinical studies from less developed countries showed no beneficial effect of maternal zinc supplementation on fetal birthweight. (12)Zinc is probably the most intensely studied microelement in newborn nutrition because it is important for cell growth and differentiation. It performs various functions in protein, carbohydrate, and lipid metabolism. It also has a role in hormonal structure and genetic transcription factors. (15) Signs of subclinical zinc deficiency can occur, but they resemble those of deficiencies from other dietary components, especially if the preterm infant is receiving long-term parenteral nutrition without zinc supplement. The most characteristic signs occur after 3 months of age and include weight loss, growth difficulties, dermatitis around orifices, glossitis, and increased susceptibility to infections. (2) Preterm birth is one of the factors contributing to the appearance of deficiency, depriving the newborn of incorporated fetal zinc, similar to other micronutrients that accumulate in the third trimester of pregnancy. Such infants also have immature gastrointestinal tracts, resulting in a negative zinc balance with zinc excretion by the intestines. Studies with isotope markers have shown that the preterm infant has the ability to acquire exogenous zinc, thereby increasing absorption and reducing excretion. Preterm infants can absorb 25% to 40% of their zinc from diet. (1) In addition to less enteral absorption and less hepatic reserves, components in milk formula such as iron can affect zinc bioavailability when the iron:zinc ratio is high. Interference by iron on zinc can be seen in adults but is debatable in preterm infants. However, Klein (1) reported that formulas must use a iron:zinc ratio of 2:1, with a maximum of 3.0 mg iron to 1.5 mg zinc per 100 kcal.Because zinc bioavailability is higher in human milk than cow milk, zinc concentrations in formula should be increased. This difference in bioavailability is due to the strong binding between zinc and casein. (1) It has been shown that 60% of the zinc in preterm human milk is absorbed compared with 36% in supplemented preterm human milk and 14% in preterm infant formula. The concentration of zinc in is but it after the zinc concentration of human milk is is the factor for zinc requirements in preterm infants. for preterm infants between and 28 weeks gestational age that they need to to attain growth to a of weeks postconceptual zinc in a newborn preterm infants have lower reserves, and around to 36 dietary zinc that needs to be for growth is mcg/kg per day at approximately weight and weeks postconceptual age, mcg/kg per day for newborns between to to wk), and to mcg/kg per day for those to to postconceptual the to 14 authors enteral zinc of to mcg/kg per to 1 per day when growth (15) The recommendation for parenteral zinc is mcg/kg per day during the and mcg/kg per day for preterm infants. the low absorption of zinc from formulas, the panel from the American Society for Nutritional Sciences in (1) recommended a of kcal and maximum of 1.5 kcal in on iron more on to morbidity in the preterm infant than on is to the prevention and treatment of in such as copper, iodine, manganese, and have been studied in preterm infant nutrition with the of formulas for the preterm baby and for parenteral There are few to VLBW preterm newborns and no of the clinical to neonatal deficiency, which is probably why their characteristics are less reported in is an important element in enzymes such as which from oxidative is stored in the fetal liver to in higher quantities than in However, it is from the liver to by whose concentration is low in newborns in production 6 to 12 weeks after birth. deficiency is in the neonatal period, but when that is to treatment with and difficulties in weight data on preterm infant fed human milk receive parenteral feeding 20 mcg/kg per which is not when there is because is by the that more be undertaken on minerals in preterm infant nutrition so the formulas can have more mineral and be more for the needs of extremely preterm infants who receive long-term parenteral especially vitamin A and E, are among the most studied micronutrients in preterm infants. primarily on such as vitamin A in the prevention of in VLBW preterm infants and vitamin for its antioxidant properties and possible in diseases in which free radicals play an important has been a of studies on vitamin supplements for pregnant aimed not only at reducing and neonatal but also pregnancy complications such as and preterm birth. A and clinical and in studies have these In an important of preterm and reactive oxygen oxidative and vitamins that have antioxidant properties such as vitamin and can prevent oxidative in the and radicals play a role in in and high concentrations of lipid such as are seen in pregnant who studies have a reduced of in receiving vitamin and although results were shown in a randomized, trial in the United of at risk of The pregnant received mg vitamin and vitamin from the of pregnancy. The of was similar between and there was a higher of in the supplemented group. The authors concluded that vitamins and had no on We the results of term vitamin A to a group of by and the most studied of the from foods or is in the organism from metabolism. In the it is to which is through plasma to of is stored in the with the found in such as the and the vitamin A has a role in cell and lung In the VLBW preterm low vitamin A associated with low concentrations lower plasma concentrations than in term newborns. A deficiency is by many authors to be a contributing factor to the development of CLD and BPD, primarily in extremely preterm the first studies that plasma vitamin A concentrations were much lower in preterm newborns who developed BPD, it was that supplements were necessary for VLBW preterm especially those whose were less than who are at high risk of developing of vitamin A supplementation in preterm infants that values higher than 20 vitamin A low-birthweight newborns at risk of vitamin A deficiency present with low concentrations. values of vitamin A with plasma concentrations less than 20 and vitamin A deficiency is by plasma concentrations less than 10 However, the between plasma vitamin A concentration and its is not and many preterm infants have concentrations 20 during their in the neonatal preterm the American of recommends vitamin A corresponding to to mcg/kg per day of of to of less than per day mcg/kg per is associated with an accentuated decline in plasma vitamin A and of more than per day mcg/kg per plasma values. It is whether these values are for extremely low-birthweight preterm infants. to and associates, high of vitamin A with enteral nutrition in VLBW preterm infants can plasma concentrations similar to those from on However, and associates found due to the difficulties in nutrients by the enteral in extremely low-birthweight preterm high vitamin A from birth may not increase plasma concentrations significantly or the clinical still as to the of vitamin A in VLBW preterm vitamin A is when by the parenteral in a and because of and absorption that only of the parenterally is with lipid increases to The American Society for recommends a parenteral dose of mcg/kg per day for preterm newborns. of the importance of vitamin A in lung cell has to the that high vitamin A can prevent in VLBW preterm infants. randomized, were evaluated in a by Darlow and The primary was to the of vitamin A supplementation on mortality and morbidity, BPD, and retinopathy of prematurity. five the resulting in children with vitamin A supplement and not of the meta-analysis showed that high vitamin A did not mortality in the first postnatal but there was a to reduce on oxygen A did affect death and oxygen In vitamin A supplementation did not always maintain concentrations deficiency and associates, in a multicenter, randomized, trial of the of and Human Neonatal evaluated extremely low-birthweight preterm infants who needed respiratory support after birth and were given vitamin A supplement corresponding to three a week for The weight of the infants was in the vitamin A group and in the control group at and gestation, The primary death or CLD at 36 weeks was less in the group Also, the of infants who had serum levels 20 was 25% in the vitamin A group in the control study in extremely low-birthweight preterm infants who received higher of vitamin A three a week or a found no significant differences compared with a standard dose three a in the of or death at 36 weeks The authors recommended the standard by and reported that of vitamin A by the three per week in the first postnatal week had not been used factors were the large number of the results in the respiratory the and the of the They vitamin A by parenteral with lipid to be to oral vitamin A for extremely low-birthweight infants and why there had been no between the parenteral with lipid and the They reported that many neonatal supplements as as enteral nutrition and that the recommended dose is per in Brazil have supplementation by oral supplementation at for VLBW preterm infants after the first week from the time they receive enteral concentrations in VLBW preterm infants to feeding we evaluated plasma by from blood from mothers at the of and from their infants up to 28 days of The infants were two groups to whether they had of the mothers had received We evaluated plasma in the of estimated vitamin A received different in both groups. A for milk fortifier, for preterm per day for vitamin A by parenteral with and for oral vitamin The the concentrations were in the group and in the group. The concentrations in both newborn groups similar to their umbilical cord on the when both groups had maximum values of in the group and in the group. values were high in the group on the day. A was similar for both groups per day for the group and per day for in the first A in the group was by enteral at an average of per day from the second to week and in the group was per day for the second week by parenteral and per day in the third and with by the parenteral were for the group and for the group, with gestational ages of and of the infants less than A concentrations 20 were found in only of newborns, most on the third when they were parenteral concluded that in to birthweight newborns, parenterally vitamin A with lipid followed by high by concentrations for the group on the day and for the group on the and cord and third postnatal day concentrations were when supplementation was it is possible that the hepatic of these infants were therefore, supplementation were to the small we not make about the of vitamin A on different result was reported by and associates in a randomized, trial of preterm infants whose were less than and whose mothers received The infants received per day of vitamin A from day 1 by plasma vitamin A values were significantly higher only after but at 12 7 days, and 28 days after they were not different from controls. Also, of the oral vitamin A group had plasma concentrations 20 at 28 days of There were no differences in CLD or other clinical that for extremely preterm infants whose plasma concentrations are low in supplementation by is not the is the or is of a group of eight The most makes up of the vitamin found in human The or are more than The standard for activity is mg of is found in all where it as an antioxidant and free radical It of found in lipid of membranes. when an of hydrogen the of one of the an that is to with an oxygen free The lipid free radical with another a lipid and another free a by the oxygen in the and the hydrogen of the lipid free In is which is in as and of the is in and preterm newborns have less they have less vitamin Also, these are not vitamin concentrations are found in fetal and increase the of gestation with the addition of Plasma concentrations of on the of due to their association with it is to concentration in relation to or total ratio less than a vitamin concentrations in and preterm human milk is two higher than in term milk. the first postnatal week it a vitamin ratio of The to about during the postnatal Preterm babies fed their milk and preterm formulas containing vitamin maintain concentrations. However, authors that enteral nutrition vitamin must be in parenteral nutrition at of to 3.5 per day to maintain plasma concentrations at 1 to 2 Preterm formulas are supplemented with to kcal with a vitamin ratio of to (1) In the of the American Society for Nutritional Sciences recommended that vitamin in preterm formulas be a 2 mg and maximum mg The vitamin ratio total must 1.5 high vitamin have shown that can In addition to the known in which death in preterm infants who received to 100 per day in there are also of increased sepsis and with or oral associated with plasma levels of and associates performed an important of vitamin supplementation in preterm infants and the prevention of morbidity and mortality. It included randomized, clinical from which the most important for VLBW preterm newborns were that vitamin supplementation did not affect mortality, risk of for a small group for and risk of and necrotizing The authors observed an increased risk of sepsis in VLBW newborns in studies and controls. They observed that the risk was higher when the vitamin dose was more than 30 per day and serum concentrations were greater than 3.5 In the of retinopathy of prematurity, vitamin supplementation reduced the risk of a of disease and but only when serum vitamin concentrations were higher than 3.5 The authors for VLBW newborns, the was high of vitamin supplementation by parenteral or supplementation that serum levels 3.5 They that American Society for for extremely low-birthweight preterm infants to 3.5 per should be the standard for preterm infants fed the various vitamin needs of preterm newborns has very as have There are vitamin for parenteral supplementation formulas for preterm and fortifiers for human milk. There are also by specialists from groups of and to the requirements for enteral and parenteral and the maximum and levels for preterm infant formulas. therefore, of the most from which can the neonatologist to to these on vitamin for newborns that preterm infants receiving parenteral nutrition, preterm infant formulas, or human milk fortifiers containing vitamin do not need supplementation. For newborns who are not fed these or who be fed human milk which is very low in vitamin a dose of vitamin may prevent the disease of the In a the postnatal of vitamin reduced clinical at 1 to 7 days and improved of There was no difference between oral and on of at 1 to 7 The recommendation is an dose of mg for infants whose are greater than and mg for those less than of vitamin remains standard for the prevention of disease of the although the is not Some countries an oral of three of to with the first dose after the second after 2 to and the third at the of vitamin few data about the needs and functions of these especially for extremely preterm infants who receive parenteral they are in are by the and maximum with low and can play an important role in extremely preterm infants whose antioxidant are very the of vitamin in the of iron in has been results as to vitamin concentrations in newborns who have In a randomized, controlled, double-blind study of newborns less than Darlow and associates reported no of high vitamin concentrations to 30 per day 10 per day by parenteral only on evaluating oxygen needs at 28 days after birth and 36 weeks as as the of retinopathy of prematurity. The recommended vitamin for extremely preterm infants are between 20 and and between 20 and The of the American Society for Nutritional Sciences recommended that the concentration of vitamin be kcal and the maximum concentration kcal for preterm infant formulas. elements and vitamins are given more importance in the nutrition of pregnant in poorer of developing countries due to their antioxidant and properties. of zinc and vitamin E, and supplements for pregnant mothers have reducing low and neonatal and maternal gestation antioxidant properties of trace elements and vitamins are extremely important in the nutrition of VLBW preterm who are vulnerable to diseases in which free radical an important have shown that VLBW preterm infants need supplements high in vitamin A to reduce the of Selenium is an important supplement in parenteral and enteral nutrition of VLBW infants because it is a component of glutathione an enzyme that the organism from oxidative aggression. supplementation for extremely low-birthweight infants is still a of controlled, randomized studies are needed to the importance and of microelements and vitamins for disease in preterm infants.