Effect of human milk fortification in exclusively breastfed extremely preterm infants: a randomized controlled trial
Background
Mortality and serious morbidity remain high in extremely preterm infants. Human milk-based nutrient fortifiers can prevent serious complications and death.
The objective was to investigate whether supplementation with a human milk-based fortifier (HMBF), compared to a bovine milk-based fortifier (BMBF), reduced the incidence of the composite outcome of necrotizing enterocolitis (NEC), sepsis and mortality in extremely premature infants fed exclusively on human milk.
Methods
In this multicenter randomized controlled trial in 24 neonatal units in Sweden, extremely preterm infants born between gestation weeks 22 + 0 and 27 + 6 were randomly assigned (1:1) to be exclusively fed human breast milk (own and/or donated ) to receive specific fortification with HMBF or BMBF.
Randomization was performed before enteral feeding reached 100 mL/kg/day and was stratified by enrollment site, gestational age, singleton/twin fetus, and sex. Allocation was concealed before inclusion, but after randomization the study was not blinded to clinical staff.
For the diagnosis of NEC, the study group was masked to an independent radiologist, and final evaluation of NEC and culture-proven sepsis was performed by blinded consensus panel review.
The primary outcome was the composite of stage II-III NEC, culture-proven sepsis, and mortality from enrollment to discharge, no later than postmenstrual week 44 + 0, in the intention-to-treat population (ClinicalTrials.gov, NCT03797157 ).
Results
Between February 21, 2019 and May 21, 2021, 229 newborns (115 HMBF, 114 BMBF) were randomly assigned. After exclusion of one infant due to parental withdrawal of consent, 228 infants were included in the intention-to-treat analysis.
Of 115 infants assigned to HMBF, 41 (35.7%) met criteria for NEC, sepsis, or death, compared with 39 (34.5%) of 113 infants assigned to BMBF (OR 1.05, 95% CI). %: 0.61 to 1.81, p. = 0.86).
Adverse events did not differ significantly between groups.
Interpretation HMBF supplementation, compared with BMBF, did not reduce the incidence of the composite outcome of NEC, sepsis, or death. Our results do not support routine supplementation with human milk-based fortifier (HMBF) as a nutritional strategy to prevent NEC, sepsis, or death in extremely preterm infants exclusively fed human milk. |
Comments
Babies born extremely premature need enrichment in addition to breast milk. But is there a difference in the risk of serious complications in children if the fortification is made with breast milk or cow’s milk? This has been investigated by a large clinical study conducted from Linköping, Sweden.
Babies born between weeks 22 and 27 of pregnancy are among the most vulnerable patients in healthcare. The risk of serious complications is very high. Nearly one in four extremely premature babies dies before their first birthday.
There is strong research support for giving breast milk to these children instead of formula made from cow’s milk. Cow’s milk formula is known to increase the risk of, for example, severe intestinal inflammation and sepsis (serious blood infection).
“In Sweden, all extremely premature babies receive breast milk from their mother or donated breast milk. Despite this, almost one in ten children suffers from a serious inflammation of the intestine called necrotizing enterocolitis . It is a serious illness. “At least three in ten children die and those who survive often have neurological problems afterwards,” says Thomas Abrahamsson, professor at Linköping University and chief physician of the neonatology department at Linköping University Hospital, who led the current study.
Historically, there have been very few studies in extremely premature babies in which treatments have been compared to each other. Therefore, there is a great need for clinical studies that can provide scientific support on how these children should be treated so that they have a better chance of survival and a good life.
In some countries, such as Sweden, babies are fed exclusively with breast milk or donated breast milk. However, for extremely premature babies to grow as well as possible, they need more nutrients than what breast milk contains. For this reason, breast milk is supplemented with additional proteins, called fortification .
The fortification was previously made from cow’s milk. But there have been suspicions that cow’s milk-based fortification increases the risk of serious complications. Today there is fortification that is based on donated breast milk and has begun to be used in healthcare in some places. The big question is whether it can reduce the risk of disease in extremely premature babies.
The current study, called N-Forte (the Nordic study on human milk fortification in extremely premature babies), is the largest ever conducted to seek answers to this question. Pediatricians and others who care for these fragile babies were anxiously awaiting the results.
"We concluded that it does not matter whether extremely premature babies receive enrichment with cow’s milk or with donated breast milk," says Thomas Abrahamsson.
Although the study indicates that there was no difference between the two options, its results may be useful. The breast milk-based product is estimated to cost more than SEK 100,000 per child, which would be equivalent to around SEK 40 million if the product were used in Swedish healthcare.
“On the one hand, we are disappointed that we did not find a positive effect of breast milk-based fortification. On the other hand, it is a large and well-conducted study and we can now say with great certainty that it has no effect on this group of patients. This is also important knowledge not to invest in expensive products that do not have the desired effect,” says Thomas Abrahamsson.
The N-Forte study included 228 extremely premature infants, randomly divided into two groups of equal size that received breast milk and cow’s milk enrichment, respectively. The researchers examined whether the two groups differed in the incidence of necrotizing enterocolitis, sepsis, and death .
Of the children treated with breast milk fortification, 35.7% had these complications, while the corresponding proportion was 34.5% in the group receiving cow’s milk fortification, meaning that no There were differences between the groups.
The study results are in line with a smaller study from Canada published in 2018. In that study, researchers also saw no difference between the two types of fortification in necrotizing enterocolitis and severe sepsis.
The study was carried out in 24 neonatal departments in Sweden, with financial support from the Swedish Research Council, the Swedish Research Council in Southeast Sweden (FORSS), ALF funds and the company Prolacta Bioscience.
Reference : Effect of human milk-based fortification in extremely preterm infants fed exclusively with breast milk: a randomized controlled trial , Georg Bach Jensen, Magnus Domellöf, Fredrik Ahlsson, Anders Elfvin, Lars Navér and Thomas Abrahamsson, (2023), eClinicalMedicine, published online 2 January 2024, doi: 10.1016/j.eclinm.2023.102375
