Postnatal Oxidative Stress and the Role of Enteral and Parenteral Nutrition

Abstract

Premature infants are vulnerable to the effects of early childbirth, which includes immature defenses against the early novel adaptation to oxygen. Developmental progress initiated early in the life cycle pushes the normal programming sequence in ways we only partially understand. In addition to antioxidant capabilities that are pushed possibly too soon, the exposure to excess oxygen is almost routine for the smaller younger infant. What role nutrition plays in the mosaic of prematurity is not certain, but we do know that what the infant is fed is clinically important perhaps more so than at any other time in the life cycle. Every attempt is made to introduce human milk as early as possible, the only food made by humans for humans. It is clear human milk can be tailored for the premature and perhaps for each and every infant. When the premature is too young for suckling, parenteral nutrition is needed which unexpectedly may increase the oxidative load of the premature infant. Technology while extending the life of many premature infants brings its own problems in need of resolution. The unfortunate creation of free radicals in solution while unintended and in fact only recently recognized creates iatrogenic issues. We describe nutritional advances in feeding the premature infant and the important role of nutrition as medicine has on outcome.

Childbirth is accompanied by an increase in oxidative stress, as birth is a hyperoxic challenge. The fetus is born from an intrauterine hypoxic environment (pO₂ of 20–25 mmHg) to an extrauterine normoxic yet relatively hyperoxic environment with a pO₂ of 100 mmHg (Muller, Proc Nutr Soc 46(1):69–75, 1987). Increased exposure to oxygen at high concentrations compared with the womb can be accommodated by neonatal animals of many species because of the newborn lungs’ ability to increase its normal battery of protective antioxidant enzymes during O₂ exposure (Frank, Fed Proc 44(7):2328–2334, 1985). The evolutionary adaptation to extrauterine aerobic existence necessitated the development of efficient cellular electron transport systems to produce energy. Along with this challenge of energy-producing oxidative metabolism, biochemical defenses including antioxidant enzymes, evolved to protect against oxidation of cellular constituents by oxygen radicals (Frank and Sosenko, J Pediatr 110(1):9–14, 1987).

Antioxidant enzymes mature during late gestation (Robles et al. Early Hum Dev 65 Suppl 2(0):S75–S81, 2001) accompanied by an increased transfer of antioxidants across the placenta, including vitamins E and C, betacarotenes, and ubiquinone during the latter stage of gestation (Friel et al., Pediatr Res 51(5):612–618, 2002, Friel et al., Nutr Res 22(1):55–64, 2002; Ripalda et al. Pediatr Res 26(4):366–369, 1989). While disease in newborns has been extensively studied, particularly in the premature infant (Allen, Proc Soc Exp Biol Med 196(2):117–129, 1991), little is known about neonatal adaptation to physiologic stress of delivery and early postnatal life in normal full-term healthy infants.

Not all free radicals are “bad.” ROS play a major and important role in signal transduction and are required for development. How the newborn infant can cope with possible excess exposure to ROS is not yet clear. Developing antioxidant defense mechanisms may be overcome by the generation of excessive ROS during the neonatal period. We and others have shown that human milk provides antioxidant protection in early life with the ability to scavenge free radicals, a function not seen in artificial infant feeds (Buescher and McIlheran, Pediatr Res 24(1):14–19, 1988; Friel et al., Pediatr Res 51(5):612–618, 2002, Friel et al., Nutr Res 22(1):55–64, 2002). Indeed, van Zoeren-Grobben reported that infants fed human milk had higher resistance to oxidative stress, than did control infants who were formula fed (Van Zoeren-Grobben et al., Am J Clin Nutr 60(6):900–906, 1994). This may be due to the presence of antioxidant enzymes glutathione peroxidase (GPx), catalase (Cat), and superoxide dismutase (SOD) present in human milk, but not in formula (L’Abbé and Friel, Pediatr Res 32(2):183–188, 1992). Further, in addition to their antioxidant effect in the gut, these enzymes may pass intact through the porous neonatal intestine early in infancy (Friel et al., Pediatr Res 51(5):612–618, 2002, Friel et al., Nutr Res 22(1):55–64, 2002).

We hypothesize that early infancy would be a time of oxidative stress due to the major shift in oxygen exposure and the difficulty of adapting to ambient oxygen. Therefore, we assessed lipid peroxidation, the activity of antioxidant enzymes, and the ability to resist oxidative stress in full-term healthy breast-fed infants during the 1st year of life. As a measure of lipid peroxidation, we measured F2-isoprostanes, which are prostaglandin F2-like compounds produced by free radical-catalyzed peroxidation of arachidonic acid (Morrow and Roberts, Methods Enzymol 300:3–12, 1999).

We found markedly elevated levels of F2-isoprostanes in plasma in early infancy and a decreasing ability to resist oxidative stress (Friel et al., Pediatr Res 56(6):878–882, 2004). The rapid decline in F2-isoprostanes between 1 and 3 and 3 and 6 months to normal adult levels (Morrow and Roberts, Methods Enzymol 300:3–12, 1999) suggests that these infants adjusted to oxidative stress due to birth itself over time. In support of these findings, both SOD and CAT in red blood cells increased between 1 and 3 months and then declined, suggesting a response to oxidative stress that appears to normalize with age. Another interpretation might be that metabolites of arachidonic acid or F2-isoprostanes themselves are required for cell signaling or other processes in the rapidly growing child. Growth rate is the greatest at that time of life.

The most likely candidates for early stress are the transition from a hypoxic environment in the womb to a relatively hyperoxic extrauterine environment and a high metabolic rate requiring a high level of mitochondrial respiration and subsequent increased mitochondrial superoxide formation (McCord, Am J Med 108(8):652–659, 2000). High levels of inspired oxygen are required to maintain arterial oxygen tension necessary for postnatal life and are substantially higher than those normally present during fetal existence. Therefore, newborns are exposed to more reactive oxygen species (ROS) than they would be had they remained in utero. The transition from fetus to newborn can be stressful as seen from supportive evidence concerning the mortality rate in the first 28 days of life compared with the remainder of infancy (MacDorman et al., Pediatrics 110(6):1037–1052, 2002). In North America, 67 % of all deaths during the 1st year occur in the 1st month of life. This data suggests that the transition from the womb to the extrauterine environment may be an oxidative challenge that may overwhelm the antioxidant capacity of the organism and be one possible reason that not all infants can survive this event. That this challenge involves an oxidative stress in coping with ambient oxygen pressure has been shown in several studies (Berger et al., J Biol Chem 272(25):15656–15660, 1997; Buonocore et al., Free Radic Biol Med 25(7):766–770, 1998; Rogers et al., Br J Obstet Gynaecol 105(7):739–744, 1998; Wispe et al., Pediatr Res 19(4):374–379, 1985).

There are numerous reports in the literature of oxidative stress associated with birth. Higher lipid peroxidation reflected by increased malondialdehyde levels (MDA) in cord blood, compared to the neonatal period, suggests oxidative stress during the birth process (Rogers et al., Br J Obstet Gynaecol 105(7):739–744, 1998; Wispe et al., Pediatr Res 19(4):374–379, 1985). Other studies report increased lipid peroxidation in newborn infants; however, these results are difficult to interpret as the methods are not universally accepted.

Collectively these data suggest that newborn infants are experiencing oxidative stress that resolves only with age. Possible mechanisms may include the degradation of fetal erythrocytes that are present in early infancy. In vitro, fetal erythrocytes produce more superoxide and hydrogen peroxide than do adult red blood cells (Jain, Semin Hematol 26(4):286–300, 1989). It is known that during the fetal–neonatal transition period, dramatic changes are occurring in the pO₂ in lung and blood cells with a more gradual change in the liver and brain. These changes may result in increased oxidative stress to cells.