Adding recombinant human (rh) insulin to human milk and formula helped preterm infants reach full enteral feeding faster, the randomized FIT-04 study found.
Among 303 infants with a gestational age of 26 to 32 weeks, those receiving either low-dose rh insulin (400 μIU/mL milk) or high-dose rh insulin (2,000 μIU/mL milk) for 28 days were able to achieve an enteral intake of ≥150 mL/kg per day for 3 consecutive days more quickly than infants on placebo, reported Johannes B. van Goudoever, MD, PhD, of Amsterdam University Medical Centers in the Netherlands, and colleagues in JAMA Pediatrics.
The median time to achieve full enteral feeding -- the study's primary outcome -- was significantly reduced for both groups on insulin versus placebo:
- Low-dose rh insulin: 10.0 days (IQR 7.0-21.8 days, P=0.03)
- High-dose rh insulin: 10.0 days (IQR 6.0-15.0 days, P=0.001)
- Placebo: 14.0 days (IQR 8.0-28.0 days)
Likewise, the proportion of infants who achieved full feeding in the initial days of intervention was significantly higher in both insulin groups versus the placebo group:
- Day 6: low dose 21%, high dose 25%, placebo 9%
- Day 8: low dose 35%, high dose 37%, placebo 22%
- Day 10: low dose 48%, high dose 48%, placebo 32%
However, rates of weight gain did not differ between the groups. Infants across each of the three arms saw a range from a median 17.2 to 17.9 g/kg/d gain.
All study groups also saw similar head circumference gains -- 0.8 cm/week for both insulin groups and 0.7 cm/week for placebo -- as well as similar body length gains, with a median growth of 1 cm/week for all groups.
Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 6% of the low-dose group, 5% of the high-dose group, and 10% of the placebo group.
None of the preterm infants in any of the study groups developed serum insulin antibodies. The rate of hypoglycemic events was also similar between the groups.
"These findings support the use of rh insulin as a supplement to human milk and preterm formula," van Goudoever's group concluded.
When discussing the background behind the study, the researchers highlighted the slew of clinical benefits of preterm infants being fed with their mother's own milk. Some of these benefits include fewer clinical symptoms of feeding intolerance and a lower risk of postnatal complications relative to preterm infants fed with formula.
However, "it has been shown that the natural insulin concentration in human milk peaks in the early postpartum period but declines to a basal level within the first 3 days postpartum," the group pointed out. "To date, insulin is absent in formula."
For this study, van Goudoever's group enrolled preterm infants with a birth weight of 500 g from 46 neonatal intensive care units throughout Europe, Israel, and the U.S. from 2016 to 2018. Exclusion criteria included major congenital malformations, suspected infections, confirmed necrotizing enterocolitis, and maternal diabetes.
The rh insulin supplement came in powdered form for enteral administration. A standard stock solution was prepared each day by either the researcher, physician, or neonatal nurse, including one insulin powder sachet per 1.8-mL solvent (i.e., mother's own milk, donor human milk, or preterm formula). A 0.04-mL dose of stock solution per planned mL of enteral feeding was also prescribed each day for all infants to obtain the target rh insulin concentration (400 μIU/mL milk for the low-dose group and 2,000 μIU/mL milk for the high-dose group).
The minimum of four administrations for each infant was to ensure intestinal rh insulin exposure throughout the day.
Although infants younger than 26 weeks' gestation were intentionally excluded, van Goudoever and colleagues said they "expect that the effect would be even more significant in infants with a lower gestational age given that time to achieve full enteral feeding is inversely related to gestational age."
This should be a topic for future research, they noted.
Disclosures
The study was supported by Nutrinia Ltd.
van Goudoever and some co-authors reported receiving grants and other fees from Nutrinia Ltd during the conduct of the study. van Goudoever also reported being founder and director of the Dutch National Human Milk Bank; being a member of the National Health Council; and serving as chair of the Committee on Nutrition and Pregnancy. One co-author reported being employed with Baxter Healthcare Corporation after the study's completion.
