During my neonatal fellowship, when I was not doing my rabbit lung injury experiments or transporting sick infants, I became interested in a lot of clinical issues, including the fact that our preemies were developing rickets and fractures.
It seemed that with every advance in the early ’80s with stabilization and survival of extremely low birth weight infants (ELBW), new clinical problems arose. This was the time when clinicians took the advice of our wise mentors and learned that mimicking what was happening in utero, in any way we could, often lead to the best solution. In addition, nutritional studies demonstrated that breast milk calcium and phosphorus content seemed to be different at earlier stages of pregnancy—and better when compared to breast milk composition at term (1)(2).
Figure. Schematic of NEC pathomechanism. (3)At that time, the observation included feeding either breast milk or formula by tube, even in our ELBW infants, but we were a little nervous about starting enteral feedings when the babies were “sick.” Further, there was this gastrointestinal malady we were seeing, especially in preemies, called necrotizing enterocolitis (NEC). We were taught that the pathophysiology of NEC involved infection, gastrointestinal ischemia, and the presence of substrate (e.g., enteral feedings); it was observed that NEC was quite uncommon in infants who had not been fed. (3)(4)
For optimal bone mineralization of these infants, we believed (and still do) that following the intrauterine “master plan”—otherwise known as the “mineral standard”—was the best way. Somehow we needed to get lots of calcium and phosphorus (and sufficient vitamin D) into these babies. At that time, we were starting to use total parenteral nutrition (TPN) to attempt to optimize nutritional status when too nervous to provide enteral feedings to some of these infants.
Faced with this challenge, investigators devised refined TPN solutions with higher concentrations of calcium and phosphorus as well as new “preemie” formulas with lots more calcium and phosphorus. Nutritional experts also provided recommendations about how much vitamin D premature infants should be receiving to optimize their bone mineralization status and avoid the development of rickets or osteopenia of prematurity (2).
Today, metabolic bone disease of prematurity is an ongoing challenge, especially as infants born at 22 to 25 weeks’ gestation have greater survival rates without the benefit of intrauterine transfer of calcium and phosphorus—more than 80% of transfer occurs during the third trimester (1)(2). Furthermore, the recent increase in use of elemental formulas in this population has been associated with an increase in bone disease (6).
Frank Greer, who was one of my heroes during my fellowship, states in his recent review in NeoReviews that even with our progress in fortification of human milk (either mother’s breastmilk or donor breastmilk) and our “preemie” formulas, bone mineralization is still not optimal in this group of ELBW infants at the time of discharge (2). There are also no long-term data about bone health in this extremely preterm population (2).
In our NICU, a multidisciplinary committee was convened in 2016; it included our neonatal nutritionist, neonatal pharmacist, our TPN team, an endocrinologist, a gastroenterologist (Dr. Timothy Sentongo, who has a special interest in neonatal nutrition, especially long-term TPN), and our neonatal team. What was the conclusion of this esteemed group?
The group proposed an overarching goal that might sound familiar—to mimic the “intrauterine master plan: the mineral standard,” just as we did in 1982 (1)(2)(5). Let’s hope that our progress toward this goal is more successful in the next 30 years compared to the past 30.
- Ryan S. Bone mineralization in preterm infants. Nutrition, 1998;14:745-747.
- Greer FR. Calcium and phosphorus and the preterm infant. NeoReviews. 2016;17:e195-e202
- Caplan MS, Jilling T. The pathophysiology of necrotizing enterocolitis. NeoReviews. 2001;2:e103-e108
- Chu A, Hageman JR, Caplan M. Necrotizing enterocolitis: Preventive strategies. NeoReviews. 2013;14:e113-e120
- Abrams SA, Schanler RJ, Tsang RC, Garza C. Bone mineralization in former very low birth weight infants fed either human milk or commercial formula: one year follow up observation. J Pediatr. 1989;114:1041-1044
- Ballesteros LF, Ma NS, Gordon RJ et al. Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children. Bone. 2017;97:287-292