Exclusive human milk (EHM) diets using either mother’s own milk or donor milk plus a human based human milk fortifier have been the subject of many papers over the last few years. Such papers have demonstrated reductions is such outcomes as NEC, length of stay, days of TPN and number of times feedings are held due to feeding intolerance to name just a few outcomes. There is little argument that a diet for a human child composed of human milk makes a great deal of sense. Although we have come to rely on bovine sources of both milk and fortifier when human milk is unavailable I am often reminded that bovine or cow’s milk is for baby cows.
Challenges with using an exclusive human milk diet.
While it makes intuitive sense to strive for an exclusive human milk diet, there are barriers to the same. Low rates of maternal breastfeeding coupled with limited or no exposure to donor breast milk programs are a clear impediment. Even if you have those first two issues minimized through excellent rates of breast milk provision, there remains the issue of whether one has access to a human based fortifier to achieve the “exclusive” human milk diet.
The “exclusive” approach is one that in the perfect world we would all strive for but in times of fiscal constraint there is no question that any and all programs will be questioned from a cost-benefit standpoint. The issue of cost has been addressed previously by Ganapathy et al in their paper Costs of Necrotizing Enterocolitis and Cost-Effectiveness of Exclusively Human Milk-Based Products in Feeding Extremely Premature Infants. The authors were able to demonstrate that choosing an exclusive human milk diet is cost effective in addition to the benefits observed clinically from such a diet. In Canada where direct costs are more difficult to visualize and a reduction in nursing staff per shift brings about the most direct savings, such an argument becomes more difficult to achieve.
Detractors from the EHM diet argue that we have been using bovine fortification from many years and the vast majority of infants regardless of gestational age have little challenge with it. Growth rates of 15-20 g/kg/d are achievable using such fortification so why would you need to treat all patients with an EHM diet?
A Rescue Approach
In our own centre we were faced with these exact questions and developed a rescue approach. The rescue was designed to identify those infants who seemed to have a clear intolerance to bovine fortifier as all of the patients we care for under 1250g receive either mother’s own or donor milk. The approach used was as follows:
A. < 27 weeks 0 days or < 1250 g
i. 2 episode of intolerance to HMF
ii. Continue for 2 weeks
This month we published our results from using this targeted rescue approach in Winnipeg, Human Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine Based Human Milk Fortifier with Dr. Sandhu being the primary author (who wrote this as a medical student with myself and others. We are thrilled to share our experience and describe the cases we have experienced in detail in the paper. Suffice to say though that we have identified value in such an approach and have now modified our current approach based on this experience to the following protocol for using human derived human milk fortifier in our centre to the current:
A. < 27 weeks 0 days or < 1250 g
i. 1 episode of intolerance to HMF
ii. Continue for 4 weeks
B. ≥ 27 week 0 days or ≥ 750g
i. 2 episodes of intolerance to HMF
ii. Continue for 4 weeks or to 32 weeks 0 days whichever comes sooner
We believe given our current contraints, this approach will reduce the risk of NEC, feeding intolerance and ultimately length of stay while being fiscally prudent in these challenging times. Given the interest at least in Canada with what we have been doing here in Winnipeg and with the publication of our results it seemed like the right time to share this with you. Whether this approach or one that is based on providing human based human milk fortifier to all infants <1250g is a matter of choice for each institution that chooses to use a product such as Prolacta. In no way is this meant to be a promotional piece but rather to provide an option for those centres that would like to use such products to offer an EHM diet but for a variety of reasons have opted not to provide it to all.
A strange title perhaps but not when you consider that both are in much need of increasing muscle mass. Muscle takes protein to build and a global market exists in the adult world to achieve this goal. For the preterm infant human milk fortifiers provide added protein and when the amounts remain suboptimal there are either powdered or liquid protein fortifiers that can be added to the strategy to achieve growth. When it comes to the preterm infant we rely on nutritional science to guide us. How much is enough? The European Society For Pediatric Gastroenterology, Hepatology and Nutrition published recommendations in 2010 based on consensus and concluded:
“We therefore recommend aiming at 4.0 to 4.5 g/kg/day protein intake for infants up to 1000 g, and 3.5 to 4.0 g/kg/day for infants from 1000 to 1800 g that will meet the needs of most preterm infants. Protein intake can be reduced towards discharge if the infant’s growth pattern allows for this. The recommended range of protein intake is therefore 3.5 to 4.5 g/kg/day.”
These recommendations are from six years ago though and are based on evidence that preceded their working group so one would hope that the evidence still supports such practice. It may not be as concrete though as one would hope.
Let’s Jump To 2012
Miller et al published an RCT on the subject entitled Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial. This trial is quite relevant in that it involved 92 infants (mean GA 27-28 weeks and about 1000g on average at the start), 43 of whom received a standard amount of protein 3.6 g/kg/day vs 4.2 g/kg/d in the high protein group. This was commenced once fortification was started and carried through till discharge with energy intakes and volume of feeds being the same in both groups. The authors used a milk analyzer to ensure consistency in the total content of nutrition given the known variability in human milk nutritional content. The results didn’t show much to write home about. There were no differences in weight gain or any measurements but the weight at discharge was a little higher in the high protein group. The length of stay trended towards a higher number of days in the high protein group so that may account for some of the difference. All in all though 3.6 or 4.2 g/kg/d of protein didn’t seem to do much to enhance growth.
Now let’s jump to 2016
This past month Maas C et al published an interesting trial on protein supplementation entitled Effect of Increased Enteral Protein Intake on Growth in Human Milk-Fed Preterm Infants: A Randomized Clinical Trial. This modern day study had an interesting question to answer. How would growth compare if infants who were fed human milk were supplemented with one of three protein contents based on current recommendations. The first group of 30 infants all < 32 weeks received standard protein intake of 3.5 g/kg/d while the second group of 30 were given an average intake of 4.1 g/kg/d. The second group of 30 were divided though into an empiric group in which the protein content of maternal or donor milk was assumed to be a standard amount while the second 15 had their protein additive customized based on an analysis of the human milk being provided. Whether the higher intake group was estimated or customized resulted in no difference in protein intake on average although variability between infants in actual intake was reduced. Importantly, energy intake was no different between the high and low groups so if any difference in growth was found it would presumably be related to the added protein.
Does it make a difference?
The results of this study failed to show any benefit to head circumference, length or weight between the two groups. The authors in their discussion postulate that there is a ceiling effect when it comes to protein and I would tend to agree. There is no question that if one removes protein from the diet an infant cannot grow as they would begin to break down muscle to survive. At some point the minimum threshold is met and as one increases protein and energy intake desired growth rates ensue. What this study suggests though is that there comes a point where more protein does not equal more growth. It is possible to increase energy intakes further as well but then we run the risk of increasing adiposity in these patients.
I suppose it would be a good time to express what I am not saying! Protein is needed for the growing preterm infant so I am not jumping on the bandwagon of suggesting that we should question the use of protein fortification. I believe though that the “ceiling” for protein use lies somewhere between 3.5 – 4 g/kg/d of protein intake. We don’t really know if it is at 3.5, 3.7, 3.8 or 3.9 but it likely is sitting somewhere in those numbers. It seems reasonable to me to aim for this range but follow urea (something outside of renal failure I have personally not paid much attention to). If the urea begins rising at a higher protein intake approaching 4 g/kg/d perhaps that is the bodies way of saying enough!
Lastly this study also raises a question in my mind about the utility of milk analyzers. At least for protein content knowing precisely how much is in breastmilk may not be that important in the end. Then again that raises the whole question of the accuracy of such devices but I imagine that could be the source of a post for another day.
Breast milk has many benefits and seems to be in the health care news feeds almost daily. As the evidence mounts for long term effects of the infant microbiome, more and more centres are insisting on providing human milk to their smallest infants. Such provision significantly reduces the incidence of NEC, mortality and length of stay. There is a trade-off though in that donor milk after processing loses some of it’s benefits in terms of nutritional density. One such study demonstrated nutritional insufficiencies with 79% having a fat content < 4 g/dL, 56% having protein content< 1.5 g/dL, and 67% having an energy density < 67 kcal/dL (< 20 Kcal/oz). It is for this reason that at least in our unit many infants on donor milk ultimately receive a combination of high fluid volumes, added beneprotein or cow’s milk powders to achieve adequate caloric intake. Without such additions, growth failure ensues. Such growth failure is not without consequence and will be the topic of a future post. One significant concern however is that failure of our VLBW infants to grow will no doubt impact the timing of discharge as at least in our unit, babies less than 1700g are unlikely to be discharged. With the seemingly endless stream of babies banging on the doors of the NICU to occupy a bed, any practice that leads to increasing lengths of stay will no doubt slow discharge and cause a swelling daily patient census.
What if increasing volume was not an option?
Such might be the case with a baby diagnosed with BPD. Medical teams are often reluctant to increase volumes in these patients due to concerns of water retention increasing respiratory support and severity of the condition. While diuretics have not been shown to be of long term benefit to BPD they continue to be used at times perhaps due to old habits or anecdotal experiences by team members of a baby who seemed to benefit. Such use though is not without it’s complications as the need to monitor electrolytes means more needle sticks for these infants subjecting them to painful procedures that they truly don’t need. Alternatively, another approach is to restrict fluids but this may lead to hunger or create little room to add enough nutrition again potentially compromising the long term health of such infants.
Amy Hair and colleagues recently published the following study which takes a different approach to the problem Premature Infants 750–1,250 g Birth Weight Supplemented with a Novel Human Milk-Derived Cream Are Discharged Sooner
This paper is essentially a study within a study. Infants taking part in an RCT of Prolacta cream (Prolacta being the subject of a previous post) were randomized as well to a cream supplement vs no cream. The cream had a caloric density of 2.5 Kcal/mL and was added to donor milk or mother’s own milk when the measured caloric density was less than 19 Kcal/oz. The study was small (75 patients; control 37, cream 38) which should be stated upfront and as it was a secondary analysis of the parent study was not powered to detect a difference in length of stay but that was what was reported here. The results for the groups overall were demonstrated an impact in length of stay and discharge with the results shown below.
|PDA ligation %
|PDA treated medically %
|Length of stay, days
|PMA at discharge, weeks
What about those with sensitivity to fluid?
Before we go into that let me state clearly that this group comparison is REALLY SMALL (control with BPD=12 vs cream with BPD=9). The results though are interesting.
||BPD control (N=12)
||BPD cream N=9
|Length of stay, days
|PMA at discharge, weeks
So they did not reach statistical significance yet one can’t help but wonder what would have happened if the study had been larger or better yet the study was a prospective RCT examining the use of cream as a main outcome. That of course is what no doubt will come with time. I can’t help but think though that the results have biologic plausibility. Providing better nutrition should lead to better growth, enhanced tissue repair and with it earlier readiness for discharge.
One interesting point here is that the method that was used to calculate the caloric density of milk was found to overestimate the density by an average of 1.2 Kcal/oz when the method was compared to a gold standard. Given that fortification with cream was only to be used if the caloric density of the milk fell below 19 Kcal/oz where average milk caloric density is 20 Kcal/oz there is the distinct possibility that the eligible infants for cream were underestimated. Could some of the BPD be attributable to infants being significantly undernourished in the control group as they actually were receiving <19 Kcal/oz but not fortified? Could the added fortification have led to faster recovery from BPD?
Interesting question’s in need of answers. I look forward to seeing where this goes. I suspect that donor milk is not enough, adding a little cream may be needed for some infants especially those who have trouble tolerating cow’s milk fortification.
Will that be q2h, q3h or q4h feeding? When I started my residency in Pediatrics that was the question I needed to ask before writing an order to start oral feeding in a preterm infant. At the time it seemed perfectly reasonable but I have to admit the question for me was “What if they aren’t ready?”. Does a baby who won’t take the breast or bottle at the 3 hour mark clearly show they aren’t able to feed or that they really are just not ready to feed? We commonly say that children are not small adults. Hospitalized adults commonly will utter the words “I’m not hungry” when their food tray is brought to them. This may be a reflection of what has been put before them rather than whether hunger exists or not but they seem to be able to be ready to eat so why not children and by extension preterm infants in the NICU.
My approach to feeding premature infants was fairly consistent until about 10 years ago when nurses in Edmonton, Alberta (in a level II unit) introduced me to “semi-demand” feeding. What I find interesting about this, is the paucity of evidence that existed on the subject. At the time, the evidence really centred around one paper but the impact of the approach was undeniable. In 2001 McCain et al published the randomized controlled trial involving 81 infants A feeding protocol for healthy preterm infants shortens time to oral feeding. The concept of semi-demand feeding was to assess each infant (once preterms reached 32-34 weeks CGA) before a feed for signs “of feeding readiness”. This was accomplished through offering non-nutritive sucking every three hours before a scheduled feed. If the infant was found to be in a wakeful state, the oral feeding was commenced but otherwise the infant was left for 30 minutes with NNS attempted again. If the infant was still not ready then a gavage would be given. The key here is that the infants were monitored for signs of feeding readiness rather than insisting upon an arbitrary time for their next feed. The study findings were a halving of the time it took to reach full feeds (10 days in control vs. 5 days in semi-demand) with no difference in weight gain observed between groups. The latter point is worth emphasizing, as the concern with semi-demand has been from some that in a worst case scenario where feeds took place every 3.5 hours a baby would miss one feed compared to another infant on a q3h schedule. This fear though does not bear out in the study.
The experience in the centre I currently work at has been so positive that it is hard to find a patient that is not fed in such a way whether a physician orders the approach or not! What is truly fascinating to me is how effective the approach seemingly is and has been adopted again with very little evidence compared to that traditionally needed to change a practice in the neonatal world. Interestingly, although we can’t say for sure we have noticed year over year declines in length of stay for infants born with a birthweight of 1500 – 2000g since the introduction of semi-demand feeding. This could be a coincidence as this has not been the only practice change in our units but it certainly is interesting.
I was delighted to see a paper published this week on the topic by Wellington and Perlman. This was a Quality Improvement project entitled Infant Driven Feeding in Premature Infants: A Quality Improvement Project. This study compared three periods. The first was one in which physicians set the feeding schedule (PDF), the second a training period for a new system and the last the infant driven period (IDP). In the PDF phase, the physicians would order one oral feed a day, then two, three and so on when the full feed was attained at each prescribed level. In the IDF period an assessment sheet for feeding readiness would be completed before each attempt and the decision to offer an oral feed based on the perceived ability to feed at that time.
While this study was not an RCT it is a much larger group of patients than the study by McCain. This comparison was between 153 PDF vs 101 IDF patients. Feeding readiness assessments would start at 32 weeks CGA but feedings would not be offered by either approach until 33 weeks CGA similar to our own approach to feeding for the most part. The use of IDF made no difference to timing of first attempt at nipple feeding. The time to attain full nipple feeding was where significant differences in approach became apparent.
Time to reach full nipple feeding by gestational age at birth:
<28 weeks: IDF versus PDF group reached full NF 17 days sooner (374/7 vs 40 weeks; p=0.03)
28–316/7: IDF versus PDF group reached full NF 11 days sooner (35 4/7 vs 37 1/7 weeks; p<0.001)
≥32 weeks: IDF versus PDF group reached full NF 3 days sooner (354/7 vs 351/7 weeks; p=0.04).
Affect on discharge
<28 weeks GA, no difference between the IDF versus PDF group (41 3/7 vs 39 4/7 weeks; p=0.10).
28–316/7 weeks GA, IDF group were discharged 9 days earlier (366/7 vs 381/7 weeks; p<0.001).
≥32 weeks GA, the IDF group were discharged 3 days earlier (36 weeks vs 363/7 weeks;
Although the findings are clear there does need to be the usual acknowledgement that this is not the gold standard RCT but the practice change in the unit was done pretty carefully. The concept is one that makes a great deal of sense regardless. The lack of difference in discharge for the smallest infants makes some sense as it may well be apnea of prematurity that is the last to resolve. There is no disputing however the benefit in earlier discharge for the 28 – 31 6/7 week group. They achieve feeding earlier and go home faster. From a family centred approach this is the best of both worlds. One should not write off the use of this technique in the smallest infants either as they will have their care normalized much earlier with the NG tube being removed and the parents getting to participate and practice feeding much earlier in their course. Although not measured in this study, it would be intriguing to look at the number of patients who were admitted to hospital post discharge with failure to thrive.
Imagine the impact as well on hospital length of stay data if you multiple the reductions in length of stay by the total number of patients seen in these gestational age categories each year. This almost certainly can represent over a year of patient days for many hospitals.
As I see it the direction is clear. We should not force our premature infants to follow a schedule that works for us. Rather use the cues that only they can provide to tell us when and how much milk they desire. Both the parents, infants and our hospitals will benefit.
The picture looks ridiculous. Why does this seem so unnatural yet we feed babies this same product around the world. Granted they don’t drink it from the source as this man is but the liquid is in essence the same. As the saying goes, “Cow’s milk is for baby cows”. When you put it that way it helps put in context the question posed as the title of this post. Should we be surprised that the consumption of a milk meant for another species might have some side effects at a population level if fed to enough infants; especially those with fragile bowel due to prematurity or other high risk condition compromising blood flow to the gut.
The following piece was written by Kari Bonnar with contributions from Sharla Fast both Registered Dieticians in our NICUs. It has been recognized for some time now that the use of donor milk in our highest risk premature infants is associated with less NEC and based on a previous review of the evidence we have been using DBM for the past several years. What this post explores though is the potential for further benefit by taking the next step. That is to ask the question; what additional benefit may be gained by replacing all sources of Cow’s Milk protein in this population. I am delighted to present their review of the literature here as I am sure you will find it as informative and thought provoking as I have.
The health benefits of human milk for all infants, including those born extremely premature, have been increasingly recognized and published.1 The American Academy of Pediatrics policy statement on breastfeeding and the use of human milk recommends that all preterm infants receive human milk including donor human milk if mother’s own milk is unavailable.2 When compared with a diet of preterm formula, premature infants have improved feeding tolerance and a lower incidence of late onset sepsis and necrotizing enterocolitis (NEC) when fed their mothers’ own milk.3 For mothers of extremely premature infants, providing sufficient milk to meet their infant’s needs is a common challenge. Pasteurized donor human milk has been made available to this population in WRHA since 2011 as it has been found to be well tolerated and is also associated with a significantly lower incidence of NEC.4
However, as the sole nutritive substance, human milk does not meet the macronutrient and micronutrient requirements of preterm infants. Multi-nutrient fortifiers are required to provide additional protein, minerals and vitamins to ensure optimal nutrient intake and neurodevelopmental growth.5 Prolacta Bioscience has recently launched in Canada with their human milk-based fortifiers, which are gaining popularity due to the ongoing research and success with these products in the United States, Austria, and now Canada.6 It is a new and novel approach that is proving to be most beneficial in reducing neonatal morbidity and mortality rates.7
In infants fed an exclusive human milk diet, Sullivan et al. found a reduction in medical NEC of 50% and surgical NEC of almost 90% compared to a diet containing cow’s milk-based products.7 To date, there is no other intervention that has had such a marked effect on the incidence of NEC.8 Abrams et al. found that for every 10% increase in intake of anything other than an exclusive human milk diet, the risk of NEC increases by 11.8% and the risk of surgical NEC increases by 21%, both with a 95% confidence interval.9
Patel et al. found that for every dose increase of 10ml/kg/day of human milk over the first 28 days post birth, the odds of sepsis decreased by 19%.10 Further to this, they found that overall NICU costs were lowest in very low birth weight (VLBW) infants who received the highest daily dose of human milk. Similarly, Abrams et al. reported that for each 10% increase in the intake of other than exclusive human milk diet, there was an 18% increase in risk for sepsis.9 In addition to predisposing the infant to other morbidities in the preterm population, and subsequent neurodevelopmental disability, sepsis significantly increases NICU costs by 31%. This translates into higher societal and educational costs for VLBW infants who survive sepsis with neurodevelopmental disability.10 ,11
A reduction in the number of days on total parenteral nutrition (TPN) was found by Cristofalo at al. with the use of an exclusive human milk based diet, in addition to reduction in sepsis and NEC.12 These same findings have been documented by Ghandehari et al. which reflect that an exclusive human milk diet leads to improved feeding tolerance and therefore, a decrease in total TPN days.13 Given that TPN is often the cause of late onset sepsis, the reduction of TPN days is imperative and almost always translates into decreased length of stay.14 Abrams et al. found that duration of TPN was 8 days less in infants receiving a diet containing <10% cow’s milk-based protein versus ≥ 10%, another recognizable dose related finding.9
It is well documented that increased growth leads to a decreased incidence of cerebral palsy and poor neurodevelopmental scores at 18-22 months corrected age, therefore adequate growth (weight, head circumference and length) is crucial in this population.15 The study by Hair et al. followed a standardized feeding protocol with early and rapid advancement of fortification with donor human milk derived fortifier and found that growth standards were being met and resulted in a marked decrease in extrauterine growth restriction.14 Cristofalo et al. study also compared growth rates, which were found to be slightly slower in the human milk fortified versus cow’s milk fortified arm of this study. However, it was mentioned that the small differences could be prevented with further adjustments in fortifier to improve rates of growth, as shown by Hair et al.12, 14 Abrams et al. confirms in their findings that growth rates were similar among human milk-based and cow’s milk-based fortification.9 This is a popular area of ongoing research with many abstracts also showing adequate growth rates with use of human milk-based fortifiers.
In closing, the review of current evidence clearly indicates that a diet of exclusive human milk is associated with lower mortality and morbidity in extremely premature infants without compromising growth and should be considered as an approach to nutritional care for these infants. Further research is needed to fully capture the extent to which using exclusive human milk diets actually reduce overall healthcare costs via improving the short and long term outcomes of extremely premature infants. Research to date only explores the financial impact for the first few years of life; therefore the true costs of these major morbidities are vastly underestimated and underreported. There are many unpublished trials and abstracts that are currently in process that will only strengthen the shift toward exclusive human milk-based diets, ideally making this common practice among Canadian centres in the very near future.
1 American Academy of Pediatrics. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2005; 115:496-506
2 American Academy of Pediatrics. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012; 129:3;e827-41
3 Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: Beneficial outcomes of feeding fortified human milk vs preterm formula. Pediatrics 1999;103:1150-7
4 Boyd CA, Quigley MA, Brocklehurst P, Donor Breast milk versus infant formula for preterm infants: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2007;92:F169-75
5 Agostini C et al. Enteral nutrition supply for preterm infants: commentary from the European society for pediatric gastroenterology, hepatology, and nutrition committee on nutrition. JPGN 2010;50:1:85-91
6 Prolacta Bioscience, Industry, California: product description. http://www.prolacta.com/human-milk-fortifier
7 Sillivan S, et al. An Exclusively Human Milk-Based Diet is Associated with a Lower Rate of necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products. J Pediatr 2010:156;562-7
8 Bell EF. Preventing necrotizing enterocolitis: what works and how safe? Pediatrics 2005:115;173-4
9 Abrams SA, Schanler RJ, Lee ML, Rechtman DJ. Greater Mortality and Morbidity in Extremely Preterm Infants fed a diet containing cow milk protein products. Breastfeed Med. 2014:9;1-8
10 Patel AL, Johnson TJ, Engstrom JL, Fogg LF, Jegier BJ et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatology 2013:33:514-19
11 Ganapathy V, Hay JW, Kim JH. Cost of necrotizing enterocolitis and cost-effectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed Med. 2012:7;29-37
12 Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013;1-4
13 Ghandehari H, Lee ML, Rechtman DJ. An exclusive human milk based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. BMC. 2012:5;188
14 Hair AB, Hawthorne KM, Chetta KE, Abrams, SA. Human milk feeding supports adequate growth in infants ≤1250 grams birth weight. BMC. 2013:6;459
15 Ehrankranz RA, Dusiuk AM, Vohr BR, Wright LL, Wrage LA, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006.117:4; 1253-61