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Am J Clin Nutr 89: 210-215, 2009. First published December 3, 2008; doi:10.3945/ajcn.2008.26845
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26845
Vol. 89, No. 1, 210-215, January 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Human milk enhances antioxidant defenses against hydroxyl radical aggression in preterm infants1,2,3

Ana Ledo, Alessandro Arduini, Miguel A Asensi, Juan Sastre, Raquel Escrig, María Brugada, Marta Aguar, Pilar Saenz and Maximo Vento

1 From the Division of Neonatology, Hospital Universitario Materno Infantil La Fe, Valencia, Spain (AL, RE, MB, MA, PS, and MV), and the Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain (AA, MAA, and JS).

2 Supported by a research grant from the Foundation for Research Hospital La Fe (Valencia, Spain) (to RE, MB, MA, and MV) and by a Consolider Research Grant (CSD-2007-00020) from the Spanish Ministry of Health (to JS, AA, and MV).

3 Reprints not available. Address correspondence to M Vento, Neonatal Research Unit, Division of Neonatology, University Children's Hospital La Fe, Avenida de Campanar, 21, E46009 Valencia, Spain. E-mail: maximo.vento{at}uv.es.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Preterm infants endowed with an immature antioxidant defense system are prone to oxidative stress. Hydroxyl radicals are very aggressive reactive oxygen species that lack specific antioxidants. These radicals cannot be measured directly, but oxidation byproducts of DNA or phenylalanine in urine are reliable markers of their activity. Human milk has a higher antioxidant capacity than formula.

Objective: We hypothesized that oxidative stress associated with prematurity could be diminished by feeding human milk.

Design: We recruited a cohort of stable preterm infants who lacked perinatal conditions associated with oxidative stress; were not receiving prooxidant or antioxidant drugs, vitamins, or minerals before recruitment; and were fed exclusively human milk (HM group) or preterm formula (PTF group). Collected urine was analyzed for oxidative bases of DNA [8-hydroxy-2'-deoxyguanosine (8-oxodG)/2'-deoxyguanosine (2dG) ratio] and oxidative derivatives of phenylalanine [ortho-tyrosine (o-Tyr)/Phe ratio] by HPLC coupled to tandem mass spectrometry. Healthy term newborn infants served as control subjects.

Results: Both preterm groups eliminated greater amounts of metabolites than did the control group. However, the PTF group eliminated significantly (P < 0.02) higher amounts of 8-oxodG (8-oxodG/2dG ratio: 10.46 ± 3.26) than did the HM group (8-oxodG/2dG ratio: 9.05 ± 2.19) and significantly (P < 0.01) higher amounts of o-Tyr (o-Tyr/Phe ratio: 14.90 ± 3.75) than did the HM group (o-Tyr/Phe ratio: 12.53 ± 3.49). When data were lumped together independently of the type of feeding received, a significant correlation was established between the 8-oxodG/2dG and o-Tyr/Phe ratios in urine, dependent on gestational age and birth weight.

Conclusion: Prematurity is associated with protracted oxidative stress, and human milk is partially protective.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fetal life is sustained under low oxygen tension; however, as breathing begins immediately after birth, a rapid increase in tissue oxygenation takes place (1, 2). The antioxidant defense system matures during gestation and term newly born infants are perfectly adapted to face this physiologic situation (3–9). Hence, it has been shown that postnatal oxidative stress up-regulates expression of specific genes whose end products are beneficial in postnatal adaptation (10–13). Premature neonates, however, are endowed with an immature antioxidant defense system and therefore are highly susceptible to the deleterious effects of reactive oxygen species (ROS) generated in the fetal to neonatal transition (5, 6, 10–13). In addition, requirement of supplemental oxygen to treat respiratory immaturity worsens oxidative stress (14). Under hyperoxia or during reoxygenation, mitochondrial superoxide anion and hydrogen peroxide production is enhanced. These ROS, in the presence of ferrous iron, result in hydroxyl radicals capable of causing damage to nearby molecules, such as phospholipids, proteins, and nucleic acids (15, 16). Accumulation of this damage is implicated in the causes of conditions, such as diabetes, hypertension, obesity, neurodegenerative diseases, and aging (17).

In the neonatal period, accessibility to biological samples is difficult. Therefore, availability of noninvasive markers of hydroxyl radical–derived damage is relevant. In this regard, urinary detection of reliable markers of amino acid (representing proteins) and guanidine bases (representing DNA) oxidation is of special interest. ortho-Tyrosine (o-Tyr) is formed exclusively on reaction of hydroxyl radicals with phenylalanine and eliminated entirely by urine and therefore is detectable (18). Guanine is prone to oxidation by hydroxyl radicals, and its lesion product, 8-hydroxyguanine, along with its 2'-deoxynucleoside equivalent, 8-hydroxy-2'-deoxyguanosine (8-oxodG), are highly mutagenic; its urinary elimination perfectly reflects nuclear attack by hydroxyl radicals (19–21).

Mother's milk is the gold standard of human nutrition and its advantages in physical and neurodevelopmental aspects clearly recognized (22). In addition, breast milk from term and preterm infants has important antioxidant properties compared with formula milk (23, 24). The presence of an oxidative stress in the neonatal period has been detected in acute situations, such as respiratory distress or asphyxia (14, 25); however, increasing evidence indicates that conditions appearing in the adulthood, such as type 2 diabetes, hypertension, obesity, and others, may have their origin in the fetal or neonatal period of life by alteration of gene expression through epigenetic mechanisms triggered by ROS (26–28).

We hypothesized that preterm infants fed artificial formula are at higher risk of oxidative stress than premature infants fed preterm human milk. To prove this hypothesis urinary elimination of 2 specific markers of hydroxyl radical activity, o-Tyr and 8-oxodG, were compared in a cohort of healthy preterm infants fed exclusively preterm formula or human milk.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Design
This is a prospective clinical study performed in a tertiary referral center (Division of Neonatology, University Hospital La Fe, Valencia, Spain) during a 6-mo period enrolling stable preterm infants fed exclusively human milk or special preterm formula. Initial date of enrollment was 2 January 2007, and re-cruitment ended 2 July 2007. Biological samples were blinded for the research laboratory (Physiology Department, Faculty of Pharmacy, Valencia, Spain). The study was approved by the ethical and scientific committees of the hospital. Parental informed consent was obtained for every enrolled patient.

Population
Infants included in the study were premature (<37 wk gestation) and fulfilled the following enrollment criteria of clinical stability and nutrition: 1) absence of acute perinatal or chronic postnatal disease, including asphyxia, sepsis, chronic lung disease, intraperiventricular hemorrhage, retinopathy of prematurity, or necrotizing enterocolitis; 2) full enteral feeding exclusively with human milk (own mother's milk or donor) or preterm formula from initiation of weight gain; 3) not on supplemental oxygen or receiving drugs, mineral, or vitamin supplementation; 4) consistent and adequate weight gain the week before enrollment; and 5) no transfusions 2 wk before enrollment. The recruited patients did not receive oxygen or mechanical ventilation after birth and did not receive surfactant replacement for respiratory distress syndrome or indomethacin for ductus closure (Table 1 ). Infants not fulfilling the enrollment criteria or having severe congenital malformations or chromosomopathies, who were submitted to gastrointestinal surgery, or who had parenteral nutrition were not admitted in the study. Control infants were 15 healthy term newborn infants aged 1 mo who were exclusively fed mother's milk. The most relevant confounders of the population and the characteristics of weight, amount of intake, and days of postnatal life at recruitment are shown in Table 1.


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  		TABLE 1. General characteristics of the population enrolled in the study at birth and at recruitment1

 
Infants were classified in 2 groups according to the type of nutrition. Thus, the HM group (n = 29) was fed exclusively human milk from their mothers or donors, and the PTF group (n = 34) was fed exclusively preterm formula. Infants received fresh nonpasteurized human milk from their own mothers or frozen milk from donors ad libitum. All infants fed preterm formula received the same commercial brand to avoid inadvertent bias. Researchers were blinded for the brand of the formula. It contained 80 kcal and 2.1 g/100 mL of protein after dilution.

Methods
Clinical assessment
The clinical information retrieved from the patients' records was stored in an ad hoc database and is shown in Table 1. Patients were weighed (precision electronic weight scale with ±5 g precision) and length (precision: ±0.1 cm) and head circumference (precision: ±0.1 cm) were measured at birth, when admitted to the study, and weekly thereafter until discharge following a precise methodology described elsewhere (29). Daily intake was registered in bottle-fed infants. Breastfed infants were weighed before and after intake and difference expressed in grams was notated. Clinical laboratory tests were performed as routine in the neonatal division.

Urinary sampling
Urine was collected using a Hollister U-bag (Hollister Inc, Kirksville, MO) under sterile conditions. Aliquots of 2 ml were poured into Eppendorf tubes and frozen at -–80°C until processed.

HPLC coupled to mass spectrometry
Markers studied in the urine were o-Tyr, Phe, 8-oxodG, and 2'-deoxyguanosine (dG). Determinations were performed using HPLC coupled to tandem mass spectrometry (MS/MS) as described previously (30, 31). A Quattro Micro triple-quadruple mass spectrometer (Micromass, Manchester, United Kingdom) equipped with a Shimadzu LC-10ADvp pump and an SLC-10Avp Controller system with a SIL-10ADvp auto injector (Shimadzu, Kyoto, Japan) was used. Samples were analyzed by reversed-phase HPLC with a Phenomenex Prodigy (Phenomenex, Torrance, CA) ODS column (100 x 2 mm) with 3-µm particle size. In all cases, 30 µL was injected onto the column. The temperature of the column was fixed at 25°C. The following gradient system, pumped through the column at 0.2 mL/min, was used (min/%A/%B) (A, 0.1% formic acid; B, methanol): 0/95/5, 10/95/5, 15/95/5, 15.1/95/5, and 30/95/5. Positive ion electrospray tandem mass spectra were recorded with the electrospray capillary set at 3.5 kV and a source block temperature of 120°C. Nitrogen was used as the drying and nebulizing gas at flow rates of 300 and 30 L/h, respectively. Argon at 1.5 x 10–3 mbar was used as the collision gas for collision-induced dissociation. An assay using HPLC-MS/MS with multiple reaction monitoring was developed using the transitions m/z 182->136 for o-Tyr, 166->120 for Phe, 284->168 for 8-oxodG, and 268->152 for dG, all of which represent favorable fragmentation pathways for these protonated molecules. Calibration curves were obtained using a standard (0.001–10 µmol/L) and in each case were found linear with correlation coefficients >0.99. The limits of detection and quantitation for the method were 0.001 µmol/L.

Statistics
Baseline characteristics for all parameters were determined by using SPSS 13 (SPSS Inc, Chicago, IL) for Windows. Initially, we performed a one-factor analysis of variance (ANOVA) and when the overall comparison of groups was significant, differences between individual groups were investigated by the Tukey test. Differences were considered significant at P < 0.05. In addition, we used nonparametric statistics (Mann-Whitney U test) for comparison of nonpaired samples when data did not show a normal distribution as for the HPLC-MS/MS results (32).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 74 premature infants were eligible for the study; however, 21 were not admitted for not fulfilling all the study requirements. Hence, 7 infants of the HM group inadvertently received preterm formula, 5 infants of the PTF group received vitamin or fortifier supplementation, and in 9 cases parents refused to complete the study. A total of 53 premature infants completed the study and were available for analytic and clinical determinations. Information regarding the principal confounders of the recruited population studies is shown in Table 1. No differences regarding gestational age, sex, type of delivery and Apgar scores were found. Infants enrolled in the PTF group were heavier (P < 0.05), however, than those of the HM group. As shown in Table 1, there also were no differences in mean intake and weight gain expressed in grams per day between both groups. In addition, no differences regarding lifestyle (tobacco smoking, alcohol use, or drug intake) during pregnancy and thereafter were found in mothers from the PTF and HM groups.

The o-Tyr/Phe quotient in the control group was 6.43 ± 1.82 in the HM group 12.53 ± 3.49, and 14.90 ± 3.75 in the PTF group. As shown in Figure 1, the o-Tyr/Phe quotient was significantly higher in both groups of premature infants than in the control group; however, the group fed exclusively human milk (HM group) had a significantly lower (P < 0.01) o-Tyr/Phe ratio (12.53 ± 3.49) than did the PTF group fed exclusively preterm formula (14.78 ± 3.76).


Figure 1
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  		FIGURE 1. Comparison of the o-Tyr/Phe ratio measured by HPLC coupled to mass spectrometry as a reliable marker of oxidation of circulating Phe between infants fed exclusively human milk (HM group; n = 29) and infants fed exclusively preterm formula (PTF group; n = 34). Healthy breastfed neonates aged 1 mo acted as control subjects (n = 15). Black horizontal bars reflect the median value of the data. Comparisons were performed by using Student's t test with Bonferroni correction: **P ≤ 0.01 compared with control group; ##P < 0.01 compared with HM group.

 
The mean (±SD) quotient 8-oxodG/2dG ratio was 4.57 ± 1.39 in the control term infants. The 8-oxodG/2dG ratios for the control and both experimental groups are shown in Figure 2. The 8-oxodG/2dG ratio was significantly lower (P < 0.02) in the control group; however, the HM group had significantly lower values (9.05 ± 2.19) than did the PTF group (10.46 ± 3.26).


Figure 2
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  		FIGURE 2. Comparison of the ratio of 8-hydroxy-2'-deoxyguanosine to 2'-deoxyguanosine measured by HPLC coupled to mass spectrometry as a reliable marker of guanosine bases of DNA oxidation between infants fed exclusively human milk (HM group; n = 29) and infants fed exclusively preterm formula (PTF group; n = 34). Healthy breastfed neonates aged 1 mo acted as control subjects (n = 15). Black horizontal bars reflect the median value of the data. Comparisons were performed by using Student's t test with Bonferroni correction: **P ≤ 0.01 compared with control group; ##P ≤ 0.02 compared with HM group.

 
Postconceptional age at the time of recruitment and the antioxidant capacity independent of the type of nutrition received were correlated. For this purpose, all data from recruited infants were lumped together and correlation coefficient for o-Tyr/Phe and 8-oxodG/2dG quotients and postconceptional age at the moment of recruitment was established. As shown in Figure 3, both coefficients were statistically significant (o-Tyr/Phe/postconceptional age: R2 = 0.383, P < 0.01; 8-oxodG/2dG/postcon-ceptional age: R2 = 0.197, P < 0.05), which established a positive correlation between postconceptional age and antioxidant capacity. There also was a statistically significant correlation between birth weight (taken together all infants recruited in the study) and oxidative stress markers (o-Tyr/ Phe/birth weight: R2 = 0.346, P < 0.01; 8-oxodG/2dG/postconceptional age: R2 = 0.213, P < 0.05).


Figure 3
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  		FIGURE 3. Correlation and linear regression coefficient between the gestational (postconceptional) age of premature infants and the o-Tyr/Phe ratio (A) and the ratio of 8-hydroxy-2'-deoxyguanosine to 2'-deoxyguanosine (B) independent of the type of feeding received. A: R2 = 0.3833, P < 0.01; B: R2 = 0.1976, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Preterm delivery, defined as birth before completion of 37 wk of gestation, has increased in the past decade (33). Spontaneous preterm birth as a consequence of spontaneous preterm labor or rupture of fetal membranes commonly results from pathologic processes, such as intrauterine infection or inflammation or decidual hemorrhages, all with common downstream molecular mechanisms (34–36). Very recent work has linked acute pre- and postnatal infection and inflammation in preterm infants born <32 wk gestation with alterations in neurodevelopmental outcome at later ages (37, 38). In addition, subtle perinatal changes in the form of slow growth in utero have been associated with alterations in weight gain and increased risk of coronary heart disease, hypertension, and type 2 diabetes (39). Moreover, prematurity independent of the size at birth is associated with insulin resistance and glucose intolerance in prepubertal children and elevated blood pressure as adults (40). The use of oxygen during resuscitation causes prolonged oxidative stress in the form of altered reduced to oxidized glutathione ratio (GSH/GSSG) (41) and is associated with increased incidence of childhood leukemia (42, 43).

Patients recruited in the study (HM and PTF groups) were in healthy condition. Thus, they had no clinical or biochemical signs of asphyxia, did not present with respiratory distress, did not need ventilatory support or oxygen supplementation, did not have infections,and did not have abnormalities in head ultrasound. In addition, they had not received any medication or vitamin-mineral supplementation susceptible of increasing free radical production. Both groups, when compared with normal term newborns, however, eliminated significantly higher amounts of urinary markers of hydroxyl radical oxidation of DNA (8-oxodG/2dG) or Phe (o-Tyr). Do these findings have clinical relevance (18)? Previous studies have confirmed the correlation between elimination of both urinary peroxides and nitrate/nitrite and the degree of oxidative stress in premature infants (44). Measurement of 8-oxodG in urine has been used to assess whole-body oxidative DNA damage (19, 20). This can be achieved by HPLC and MS techniques (30, 31). However, 8-oxodG can arise from degradation of oxidized D-guanosine triphosphate in the DNA precursor pool, not only from removal of oxidized guanine residues from DNA by repair processes. Furthermore, there are many other products of oxidative DNA damage (45). Hence, urinary 8-oxodG is a partial measure of damage to guanine residues in DNA and its nucleotide precursor pool, and 8-oxodG concentrations may not reflect rates of oxidative damage to DNA (45). Nevertheless, the recently completed Biomarkers of Oxidative Stress Study (BOSS), which involved the acute carbon tetrachloride poisoning of rodents as a model for oxidative stress, showed that 8-hydroxy-2'-deoxyguanosine in urine is a potential candidate general biomarker of oxidative stress, whereas neither leukocyte DNA-malondialdehyde (MDA) adducts nor DNA-strand breaks resulted from CCl4 treatment (46). o-Tyr has been identified as a highly reliable marker of oxidative stress under different clinical and experimental situations (47, 48). A recent study demonstrated that 8-oxodG/2dG and o-Tyr/Phe ratios reflected oxidative stress in a piglet model of asphyxia reoxygenation and that their concentration in urine correlated significantly with oxygen concentration given during resuscitation (49).

The antioxidant properties of human milk are reported widely in the literature (23, 24). Friel et al (23) in a recent study confirmed that human milk of term and of preterm mothers provided better antioxidant protection. They found that human milk produced less ascorbate whether or not oxidative stress was present. Elevated concentrations of ascorbate are prooxidant in the extracellular milieu (23). Moreover, the antioxidant enzyme activity of catalase, superoxide dismutase, and glutathione peroxidase increased with time in human milk (23). Additional studies have shown that human milk–fed neonates had a higher plasma total antioxidant and vitamin C content. Biomarkers of oxidative status, such as total peroxide and oxidative stress index, were higher in formula-fed neonates at 3 to 6 mo postnatal age (24). Human milk of preterm mothers at 35–36 wk postconceptional age also seemed to have a positive effect on the oxidant status of their infants. The preterm infants fed preterm human milk had significantly lower elimination of markers of hydroxyl radical aggression meaning they produced fewer amounts of free radicals or they had a more efficient antioxidant defense system. Because there were no clinical conditions or pharmacologic interventions causing prooxidation, it seems plausible that reduced elimination of oxidative stress markers in the urine of the HM group was the result of the beneficial effects of human milk. In addition, the infants were consuming fresh nonpasteurized human milk, which increases the antioxidant power (50).

Premature infants have a tendency toward oxidative stress even under "normal" circumstances (shown previously) (51). Thus, although healthy and stable preterm infants were selected for the study who had no inflammatory or prooxidant conditions or who did not receive drugs or mineral/vitamin/fortifier supplementation that could induce free radical production, significantly increased elimination of markers of hydroxyl radical activity was detected as compared with that of term newborns. The consequences of this protracted proinflammatory status are beyond the scope of the current study. Cancer (43, 44), diabetes, hypertension, and osteopenia (26–28) are associated with prolonged oxidative stress. In this regard, epigenetic changes induced by oxidative stress on DNA, such as methylation and histone modification, could be responsible (second-hit theory) for triggering the pathophysiologic cascades, leading to the appearance of the conditions described previously (26). In this scenario, the beneficial effects of human milk in preterm infants on buffering oxidative stress during the neonatal period possibly could attenuate deleterious consequences in later life. To categorically ascertain this positive influence of human milk, however, sufficiently powered prospective studies, including long-term follow-up, are needed.


   ACKNOWLEDGMENTS
 
The authors' responsibilities were as follows—MV: designed the study, supervised the recruitment of patients and sample collection, and wrote the manuscript; AL, MB, MA, RE, and PS: recruited infants, collected clinical data and biological samples, and performed statistical analysis; and AA, MAA, and JS: contributed to the design and performed the analysis of the samples by HPLC-MS/MS. None of the authors declared any potential conflicts of interest related to this study.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 15, 2008. Accepted for publication September 23, 2008.




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M. Vento, M. Moro, R. Escrig, L. Arruza, G. Villar, I. Izquierdo, L. J. Roberts II, A. Arduini, J. J. Escobar, J. Sastre, et al.
Preterm Resuscitation With Low Oxygen Causes Less Oxidative Stress, Inflammation, and Chronic Lung Disease
Pediatrics, September 1, 2009; 124(3): e439 - e449.
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