PEDIATRICS Vol. 122 No. 3 September 2008, pp. 686-687 (doi:10.1542/peds.2008-0675)
LETTER TO THE EDITOR |
Human Milk Intake and Retinopathy of Prematurity in Extremely Low Birth Weight Infants
Talkad S. Raghuveer, MDJohn M. Belmont, PhD
Department of Pediatrics,
University of Kansas Medical Center,
Kansas City, KS 66160
To the Editor.—
We congratulate Heller et al on their recent article.1 We would like to comment regarding their conclusion that human milk (HM) does not decrease the risk of severe retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) infants. We also would like to propose an alternative approach to studying this question.
ROP is a multifactorial disease of ELBW infants that is strongly associated with prolonged exposure to high levels of supplemental oxygen.2,3 Reduced oxygen saturation in ELBW infants is significantly associated with reduced need for laser surgery for severe ROP.4,5 Heller et al did not report details of the oxygen concentration used for resuscitation of their ELBW infants, the oxygen saturation limits while the infants were supplemented with oxygen, or the type of pulse oximeter used in the study's participating centers. If the upper limit for oxygen saturation was set at >95% when the ELBW infants were exposed to oxygen supplements, reactive oxygen species so generated could potentially overwhelm the radical scavenging provided by antioxidants in breast milk. In addition, because the volume of HM that ELBW infants received in the Heller et al study was very low (<80% of the total intake), the amount of antioxidants from HM may have been too low to affect oxidant load.
The primary aim of the Poindexter et al study,6 whose subjects provided the data for the secondary analysis by Heller et al, was to determine if parenteral glutamine supplementation would reduce death of or late-onset sepsis in ELBW infants. Poindexter et al reported a number of secondary outcomes, but ROP was not among them. Nevertheless, after additional analysis, Heller et al concluded that HM intake is not associated with decreased ROP. Considering the limitations of this observational analysis, including those discussed by Heller et al, the conclusion would seem to be premature and possibly incorrect.
A satisfactory study of potential associations between HM intake and ROP as the primary outcome would not be observational regardless of sample size but, rather, would be designed as a randomized prospective study. Heller et al contended that such a study would be "difficult"; we believe that it is essential, considering its potential practical implications. The study would emphasize potential confounders and potential moderating variables that were evidently unavailable to Heller et al, including those with potentially strong influences on ROP, such as oxygen alarm limits and iron supplementation. These would at least be well documented to permit later statistical control but preferably would be controlled directly within the protocol. ELBW infants would be randomly assigned to receive HM to meet >80% of their nutritional needs, from their docosahexaenoic acid (DHA)-supplemented mothers, or to receive formula to meet 100% of their nutritional needs. Aiming for at least 50% relative reduction in severe ROP requiring surgery, the number of subjects per group (to yield 80% power with 
= 5% and Fisher's exact test) would depend on the anticipated incidence in the no-HM control group, which might be as high as 40% or as low as 15% (requiring 73 or 240 per group, respectively).
Glutamine deprivation increases vascular endothelial growth factor (VEGF) in retinal pigment epithelial cells in vitro.7 Elevated VEGF levels lead to retinal neovascularization.8 In addition, a dipeptide of arginine and glutamine has been shown to decrease neovascularization in a mouse model of oxygen-induced retinopathy.9 Heller et al included all the infants from the Poindexter et al study in 1 analysis, yet there were actually 2 groups: 1 treated with parenteral glutamine, and the other not. Considering glutamine's potential role in reducing ROP, it would be of theoretical and possibly practical interest to know whether Poindexter et al's glutamine-treated group had a reduced incidence of ROP requiring laser surgery.
We and others have shown that subnormal amounts of DHA in the diet predisposes newborn rat pups to oxidative retinopathy compared with rat pups who receive diets with normal or increased amounts of DHA.10,11 In addition, the combination of perinatal DHA deficiency, postnatal iron supplementation, and cycling oxygen (hyperoxia and hypoxia) results in the most severe oxidative retinopathy in weanling rat pups.10 The majority of ELBW infants in the Heller et al study were fed infant formula, which would not have been fortified with DHA at the time the study was conducted. Therefore, it is likely that many, if not all, of the ELBW infants were DHA deficient. In addition, the authors did not detail the use, timing, or dosage of iron supplements. Iron supplements may potentially add to the oxidative stress in these ELBW infants.12 If iron supplementation in DHA-deficient ELBW infants exacerbates ROP, as seen in our animal studies, it would be a potential confounder in future ROP studies.
In the Heller et al study, 75% of the infants received some HM, ranging from 6 to 83 mL/kg per day. Their overall intake of HM was 
15% of their total nutrition throughout their hospitalization. The major proportion of the nutrition for the ELBW infants was from infant formula. A recent report by Okamoto et al13 showed that ELBW infants who received 67% to 83% of their total nutritional needs from HM were at a significantly lower risk of retinal detachment compared with infants who received 24% to 38% of their nutritional intake from HM. Thus, Heller et al's conclusion that HM does not protect these infants from severe ROP at least requires additional investigation. In the meantime, the question that seems to arise from the data of Heller et al and Okamoto et al is: Does infant formula increase the risk for severe ROP?
REFERENCES
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[Abstract/Free Full Text] - Raghuveer T, Radel J. Do dietary omega-3 fatty acids and iron influence severity of oxygen-induced retinopathy in neonatal rat pups? E-PAS2006:59:3602.475A. doi:10.1016/j.freeradbiomed.2005.10.027
- Connor KM, San Giovanni JP, Lofqvist C, et al. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007;13 (7):868 –873[CrossRef][Medline]
- Raghuveer TS, McGuire EM, Martin SM, et al. Lactoferrin in the preterm infants' diet attenuates iron-induced oxidation products. Pediatr Res. 2002;52 (6):964 –972[Web of Science][Medline]
- Okamoto T, Shirai M, Kokubo M, et al. Human milk reduces the risk of retinal detachment in extremely low-birth weight infants. Pediatr Int. 2007;49 (6):894 –897[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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