Can We Feed Our Way Out of BPD?

 

Our culture heavily emphasizes eating as a response to many situations in our life. If we exercise, we are told to drink lots of water, or even better, consume fancy sports drinks. With prolonged exercising, we are told to eat power fuel foods to keep going.

We are told to have the most important meal of the day when we wake up (breakfast). Eat something nutritious, they say. But what exactly is that? Dairy or no dairy, gluten or gluten free, unprocessed fruits and vegetables or pulverized smoothies. Fast forward to now, and it’s become, “Absolutely don’t do breakfast, just fast!”

We are all subject to shift work in neonatology, which adds to our hunger even more. When I am feeling tired or sleepy post-call, it takes no effort to quickly justify the consumption of any amount of comfort food to really hit the spot (literally the spot around my mid-abdomen). And when we are sad or depressed, it’s no holds barred!

But what about our patients and their nutrition needs?

Nutrition and our BPD NICU patients

Thinking about these confusing dietary directives, I started thinking about one of our biggest nutrition nightmares in the NICU: babies with bronchopulmonary dysplasia (BPD).

Years ago, we managed BPD infants with loads of additional nutrition modules, adding carbohydrate and fats to boost energy while neglecting protein. That led to unbalanced growth, with infants who were gaining weight excessively with no proportional length growth. That produced many adorable pictures of very chubby babies who were simply too obese.

The last summary of our neonatology community’s progress in tackling our acronymic challenges in the NICU; IVH, NEC, BPD, ROP, LOS, etc. was quite reassuring.1 Over the period of 2005 to 2014, we have seen a steady decline in all but one of these conditions – the sobering outlier, BPD.

Our understanding of the pathophysiology of BPD centers on the area of developmental arrest in alveolar and vascular growth. There is a strong relationship between growth and BPD. Preterm fetuses that are born small that have suffered from restricted growth in utero are at high risk for BPD. Poor fetal growth prevents the normal development of the lung and its blood vessels. Furthermore, infants with BPD are often the worst growers. They work harder than their peers to breathe and expend much more energy, often even 20-30% more, to grow in the same manner. No surprise then that they are generally the most stunted growers in the crowd.

How big a deal is poor growth? The most sobering statistic is the relationship between poor growth in the NICU and poor developmental outcomes in the future.2 Being stunted as a baby has huge consequences to the future. It is not unexpected then that infants with BPD find themselves as one of the highest risks for poor brain development.

We are working on a statewide collaborative in California called Grow, Babies, Grow. What participating teams are finding is that the path to better growth for their babies involves meeting weekly and standardizing feeding practices to eliminate outliers and feed infants more consistently. Teams are finding out there are many parts of the feeding journey that can go wrong. Tracing out your own NICU’s needs is very unique. Paying particular attention to standardized approaches that address the highest risk infants such as those at risk for BPD is key.

BPD babies and human milk

There is some interesting data that supports the relationship between the use of human milk, both mothers’ milk and donor human milk, and the incidence of BPD.3,4 A human diet could have several possible mechanisms, but are not proven.

The most obvious is the anti-inflammatory mechanism of many of the components in mothers’ milk. We see this positive effect of mothers’ milk with necrotizing enterocolitis (NEC) too. It is a fascinating observation, since both conditions involve two very serious degrees of inflammation.

How might mothers’ milk work in these cases? With the gut, I can see a more direct influence of mothers’ milk on antimicrobial and anti-inflammatory effects in the lumen, where microbes live in abundance. How could mothers’ milk work for the lung and inflammation? One way is to modify the immune state of the whole infant through the gut since it is the largest immune system in the body. Could the ingestion of mothers’ milk lead to a more balanced immune response to inflammation?

In NEC the bigger issue is not just the development of inflammation, but rather the inability to properly downregulate inflammation once it gets going. BPD has a period of several weeks where lung inflammation is rampant. Having a systemwide modifier of inflammation sounds very helpful, and may be part of the answer on the action of mothers’ milk reducing BPD.

Can better growth using mothers’ milk result in less BPD? The argument against that is mothers’ milk use in preemies has been increasing steadily for more than a decade, and infants have been growing better over the same period. If the effect was very strong, why haven’t we seen an overall reduction of BPD rates?  I think we need to be cautious in accepting this argument when looking at the population level, rather than the individual patient level.

As a whole during the past two decades, we are surviving and managing many more micropreemies than ever before. The immaturity of all their organs is impressive, but the risk of early oxygen exposure of the lungs, much more than the fetal environment, may lead to a disproportionate amount of alveolar and vascular developmental derangement compared to problems of other organs. Those lung-specific effects may have counteracted any trends to reduce BPD.

There have been many research attempts that have tried to find the missing nutrient ingredient that could solve our BPD problem. Many were in the area of antioxidants, given the early oxygen exposure, while others were focused on improving lung development and vascular growth. There were numerous nutrient studies on vitamins A, C, E, N-acetylcysteine, glutamine, and long chain fats such as DHA. The only real winner was early high dose vitamin A – but delivered through intramuscular shots. We went through this with many of our babies, painfully for them, but when we had critical shortages nationally for vitamin A our NICU and many others simply stopped this practice. Some people have argued that since the BPD rate did not rebound after the few years of vitamin A shortages we no longer needed it. I would caution again that this is a population observation, and one that needs adjusting for individual variables. We need an alternative to injecting our babies if we want to continue with vitamin A.

What about lactoengineering? We know now that giving good amounts of fat soluble vitamin D can alter levels of vitamin D in mothers’ milk. Could we do the same with vitamin A? The needle on earlier fortification of mothers’ milk keeps moving to even as low as 40 mL/kg/day, which will deliver earlier vitamin A too. Maybe these will put a small dent into BPD. Stay tuned though, on future enteral vitamin A and fish oil (DHA) trials as these may be promising.

For now, at the very least, we can be tasked to correct what is correctable. Keeping our infants with BPD on a better and balanced growth trajectory for weight, length, and head circumference is a worthy goal. Insisting on mothers’ milk with earlier fortification is another simple target. The potential to impact their neurodevelopment is the mighty enough endpoint.

Let’s continue to focus on an aggressive approach to keeping these infants from falling off their curves in the meantime. Grow, babies, grow!!

 

Resources:

1. Horbar JD, Edwards EM, Greenberg LT, Morrow KA, Soll RF, Buus-Frank ME, Buzas JS. Variation in Performance of Neonatal Intensive Care Units in the United States. JAMA Pediatr. 2017 Mar 6;171(3):e164396. doi: 10.1001/jamapediatrics.2016.4396. Epub 2017 Mar 6. Erratum in: JAMA Pediatr. 2017 Mar 1;171(3):306. PubMed PMID: 28068438.
2. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006 Apr;117(4):1253-61. PubMed PMID: 16585322.
3. Huang J, Zhang L, Tang J, Shi J, Qu Y, Xiong T, Mu D. Human milk as a protective factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2019 Mar;104(2):F128-F136. doi: 10.1136/archdischild-2017-314205. Epub 2018 Jun 15. PubMed PMID: 29907614.
4. Villamor-Martínez E, Pierro M, Cavallaro G, Mosca F, Kramer BW, Villamor E.Donor Human Milk Protects against Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis. Nutrients. 2018 Feb 20;10(2). pii: E238. doi:10.3390/nu10020238. Review. PubMed PMID: 29461479; PubMed Central PMCID:PMC5852814.