Can we stop our kids from going blind in the NICU?

Retinopathy of prematurity (ROP) has been a long-time nemesis of neonatology caregivers since uncontrolled oxygen began being delivered to preterm infants more than 50 years ago. Oxygen is a drug and, when given in excess, has a toxicity to the developing, immature eye that can lead to serious vascular changes – and ultimately blindness.

There are few diseases in neonatology or medicine that I can think of where our best treatment involves deliberately damaging a part of the body in order for stop the disease from spreading. Most preterm infants who require critical laser treatment on their eyes are saved from blindness, but suffer collateral loss of a significant portion of their peripheral vision due to broad regions of retinal damage from the laser treatment.

Modern treatment continues to lean on this post-disease strategy to disrupt the aggressive vascular growth at the edge of the developing retina by scarring the tissue beyond the growing retina so that it can no longer support retinal vascular development. Many of us have been patiently waiting for a better treatment for ROP.

Loss of some part of vision to prevent blindness is a worthy tradeoff, but more sophisticated alternatives need to come. Blindness is now much less common than it used to be, but it is not zero. I feel a sense of failure each time one of our infants loses vision even in one eye.

So what causes this disease and what do we have that can prevent, rather than treat, ROP?

It is clear that the role of oxygen and the fluctuations in oxygenation and/or saturation of the body can influence the vascular landscape of the growing retina. Numerous quality improvement strategies to tightly target a lower saturation range (85-89%) has greatly improved the incidence of ROP. However, recent data from several multicenter studies on oxygen saturation targets have conclusively supported the need for a higher saturation target (91-95%) in an effort to reduce overall mortality, yet will carry the risk of generating higher ROP rates. This is greatly concerning, as we have not come up with a suitable alternate, biological strategy to treat ROP.

Does nutrition matter with ROP prevention? The answer to this question is a growing and resounding YES. I want to share several nutrition strategies that may reduce the chances of our preterm babies from getting ROP.

The first important observation is that the rate of growth may be an important correlate with ROP disease.¹ Undernutrition seems to correlate with worse ROP disease. The relationship between growth and the growth factor IGF-1 may be important as IGF-1 is a critical factor in early eye development. We know that compared to term infants, preterm infants are relatively low in IGF-1 levels in their blood. Research studies are underway to see if supplementing IGF-1 early on may prevent ROP. For now though, achieving better growth may be an important global way to prevent ROP. It is also confounded by the fact that the sicker infants tend to grow poorly and also have more ROP.

The type of diet preterm infants have also seems to matter. We are now well aware of the need for important long chain fatty acids in maternal diet to provide an ideal fatty acid supply during pregnancy and lactation that are key for healthy brain and eye development. The change in our preterm and term infant formulas to contain matching amounts of long chain polyunsaturated fatty acids similar to that found in mother’s milk was a major recognition of this. Mounting data also support that providing preterm infants with fish oil based long chain fatty acids such as DHA and EPA may also help reduce the incidence of ROP.² Interestingly, although it is not prime time to start recommending fish oil supplements to all our pregnant mothers, this is already happening with many of our mothers based on the many other health benefits of fish oil and the low risk in taking these supplements.

The final nutrition connection is that human milk appears to be protective for ROP.³ Infants who are provided mother’s milk during their preterm period in hospital have less ROP. The reasons for this effect are less clear. Mother’s milk contains many elements that are positive for eye development or reduction in vascular proliferation in ROP. A slew of growth factors, anti-inflammatory, anti-oxidants, and cytokines carry potential benefits to the growing eye. What these specific responsible elements are will need to be determined in the coming years.

A recent retrospective study also provided further tantalizing evidence that human milk exclusivity with the addition of human milk derived fortifier (or conversely a bovine milk protein-free diet) is associated with reduced ROP.⁴ It is even more complicated to ponder a mechanism here, as it may in fact point to the negative effects of intact bovine protein on other co-morbidities that may cause more inflammation or impair overall growth. Again, large prospective studies are still needed to determine the potential effects of a bovine protein free diet.

While we wait for the most promising biologic treatment to ROP to come (and they are coming, albeit slower than many of us want), I believe we have some real opportunities to support a best nutrition approach in preventing ROP. These include having a strategic program to prevent growth failure in the NICU, advocating for more human milk alongside a reduction in intact bovine protein as long as possible throughout the growing retina stage up to at least adjusted term age when eye development is near completing. The innocuous nature of introducing fish oil supplementation in maternal diet may also be helpful, although timing and dose are much less clear here. So it is becoming very obvious that how and what we feed our preemies does matter in matters of vision and blindness. I hope you will all join me in shining the nutritional light on this important problem!

---

REFERENCES:

1. Cayabyab R, Ramanathan R. Retinopathy of Prematurity: Therapeutic Strategies
   Based on Pathophysiology. Neonatology. 2016;109(4):369-76. doi:
   1159/000444901. PubMed PMID: 27251645.

2. Vayalthrikkovil S, Bashir RA, Rabi Y, Amin H, Spence JM, Robertson HL, Lodha
   Parenteral Fish-Oil Lipid Emulsions in the Prevention of Severe Retinopathy of
   Prematurity: A Systematic Review and Meta-Analysis. Am J Perinatol. 2016 Dec 19.
   [Epub ahead of print] PubMed PMID: 27992937.

3. Bharwani SK, Green BF, Pezzullo JC, Bharwani SS, Bharwani SS, Dhanireddy R.
   Systematic review and meta-analysis of human milk intake and retinopathy of
   prematurity: a significant update. J Perinatol. 2016 Nov;36(11):913-920. doi:
   1038/jp.2016.98. PubMed PMID: 27416321.

4. Hair AB, Peluso AM, Hawthorne KM, Perez J, Smith DP, Khan JY, O’Donnell A,
   Powers RJ, Lee ML, Abrams SA. Beyond Necrotizing Enterocolitis Prevention:
   Improving Outcomes with an Exclusive Human Milk-Based Diet. Breastfeed Med. 2016
   Mar;11(2):70-4. doi: 10.1089/bfm.2015.0134. PubMed PMID: 26789484; PubMed Central
   PMCID: PMC4782036.