In this randomized controlled trial, we showed a significantly lower mortality rate in neonates with a birth weight of ≤ 1800 grams who received BMCs on the first day of life. In subgroup analysis in neonates with a birth weight of < 1500 grams, the mortality rate was more than 3x times lower in the BMCs group (9.5% vs. 30.2%). In addition, there was a trend for a lower incidence rate of NEC, less positive blood cultures, and shorter intubation period in neonates in the intervention group. However, the difference was not significant in any major complications.
Despite the increased survival rate of premature neonates in recent years, some complications are the most leading cause of death in premature neonates (19). As one of the most severe complications in preterm infants, NEC has a mortality rate ranging from 15–30%, followed by an increased risk of low long-term growth and neurodevelopmental impairment in survived infants (20). In recent decades, many discoveries have been made about BMCs. Breast milk contains a myriad of cell types, including leukocytes, epithelial cells, stem cells, and probiotic bacteria (21)(22). In a study by Indumathi et al. (23), after identifying the cell surface markers in human breast milk, myoepithelial progenitors, immune cells, growth factors, and cell adhesion molecules were demonstrated the major constitutes of BMCs. Some studies presented mesenchymal stem cells as the most multipotent stem cells in breast milk (24)(25). These cells can potentially differentiate into chondrogenic, osteogenic, adipogenic cells and can differentiate into astrocytes and oligodendrocytes as well as neurons (24)(26) (27).
In this controlled trial study, we centrifuged the neonates' own mother breast milk (Fig. 2), and the lower cream-colored watery part at the bottom of the tube extracted and used for pouring into the mouth by using a syringe. A study by Maffei et al. (28) investigated early oral colostrum administration in preterm neonates; Infants who received the oral colostrum by syringe had significantly higher urinary secreted immunoglobulin A and lactoferrin comparing to using a swab. Many studies have suggested early breastfeeding initiation (< 24 h), which leads to a decrease in the mortality rate in the newborn (28)(29). At the same time, there are few controlled trials about the early progressive feeding in preterm infants.
In our study, early use of extracted BMCs during the first 6–12 hours of delivery reduced the risk of in-hospital mortality in neonates with a birth weight of ≤ 1800 grams, while other major complications including NEC, BPD, and positive blood culture were similar between groups. The difference was more significant after sub-group analysis in neonates with a birth weight of less than 1500 grams (9.5% vs. 30.2%; P-value: 0.017). There was no difference regarding gestational age and sex between these groups. In a study by Modi et al. (9), 131 neonates with a birth weight of 750–1250 grams were evaluated for early enteral feeding. All-cause mortality was lower in infants with early aggressive regimes than routine regimes (33.3% vs. 43.1%; P-value: 0.25), but there was no significant difference in mortality or major morbidities. In another study by Salas et al. (11), they investigated early feeding in 60 preterm infants (< 28 weeks). Early progressive feeding reduced the need for parenteral feeding, while in-hospital outcomes, including mortality or NEC, were similar between groups. These differences may be explained by a) we exclusively used their own mothers' breast milk rather than any formula. b) in this new method, we extracted and used precipitated BMCs and 1–2 millimeters of the watery phase. In comparison, other studies used the whole components of breast milk. c) different inclusion criteria regarding gestational age and birth weight can potentially affect these studies' results.
We would like to emphasize that our study has some limitations. First, the low sample size and the lack of double-blinding may have influenced the study results. Second, the prescription of only a single dose of BMCs in the intervention group is another limitation of the study. The repetitive use of BMCs in the first days of life may change this research results, especially in infants who are not allowed to start enteral feeding due to an underlying disease. Third, since it is a single-center study on the Iranian population, future multicenter studies on different ethnicities are needed. Nevertheless, according to our knowledge, this is the first randomized clinical trial that prescribes BMCs to neonates with a birth weight of ≤ 1800 grams. We hope this new method is followed by further research with a larger sample size with repetitive use of BMCs in very low birth weight infants.