Article Original

Introduction

Prematurity is a public health issue due to its high morbidity and mortality <sup>1 ➤
1. Guevara Ríos E. La prematuridad: Un problema de salud pública. Rev Peru Investig Matern Perinat 2022; 12(1): 7-8DOI https://doi.org/10.33421/inmp.2022334</sup> ; its main causes are necrotizing enterocolitis and late-onset sepsis <sup>2 ➤
2. Panchal, H., G. Athalye-Jape, and S. Patole, Oropharyngeal Colostrum for Preterm Infants: A Systematic Review and Meta-Analysis. Adv Nutr, 2019. 10(6): p. 1152-1162. DOI: 10.1093/advances/nmz033</sup> .Globally, 15 million preterm infants are born annually, of which approximately one million die <sup>3 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> . In Peru, the number of births in 2020 was 461,735, and in 2023, 410,442, with 6.4% and 7.5% being preterm, and 0.83% and 0.95% being very low birth weight (VLBW) preterm infants, respectively <sup>4 ➤
4. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> . The neonatal mortality rate for 2021 was 8.8 per 1000 live births (lb), with an average of 5000 neonatal deaths <sup>4 ➤
4. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> ;of the total neonatal deaths in 2023, 70% were preterm infants, and 46.5% were VLBW <sup>5 ➤
5. MINSA. Centro nacional de Epidemiología, prevención y control de enfermedades CDC (Consulta 29 de marzo 2024). Sala virtual de muerte fetal y neonatal. https://www.dge.gob.pe/dashmnp/</sup> . At the INMP, 13,555 live births were recorded in 2021, while 12,314 were attended in 2023, with a mortality rate of 14.9 per 1000 lb and 16.5 per 1000 lb, respectively, with 16% being preterm infants and 2.4% VLBW. Of the latter group, 60% of the deaths were neonatal <sup>6 ➤
6. Oficina de epidemiología y Salud ambiental - INMP. (2023). Boletin Epidemiologico semana 01al 52. Boletin Epidemiologico. (Consulta 29 de marzo 2024) https://www.inmp.gob.pe/institucional/boletin-epidemiologico/1421335605</sup> .

Transitory immune deficiency in preterm infants is reported; functions such as phagocytosis, cell-mediated immunity, humoral immunity, and complement system development are incomplete. When a preterm infant is born, the transplacental transfer of bioactive elements, such as maternal IgG, as well as naïve and memory T cells, B cells, NK cells, and monocytes, abruptly halts <sup>7 ➤
7. Garofoli, F.; Civardi, E.; Pisoni, C.; Angelini, M.; Ghirardello, S. Anti-Inflammatory and Anti-Allergic Properties of Colostrum from Mothers of Full-Term and Preterm Babies: The Importance of Maternal Lactation in the First Days. Nutrients 2023, 15, 4249. https:// doi.org/10.3390/nu15194249</sup> . Morbidity and mortality are inversely related to gestational age, with the most common pathologies in preterm infants being hyaline membrane disease, hypoglycemia, intraventricular hemorrhage, neonatal sepsis, necrotizing enterocolitis, anemia, jaundice, patent ductus arteriosus, coagulation disorders, retinopathy, hearing loss, and bronchopulmonary dysplasia; infectious events are most associated with mortality. Additionally, they require assisted ventilation and longer hospitalizations compared to term neonates.

Among the strategies proposed to improve outcomes in preterm infants is colostrum therapy, also known as immune therapy, which involves the administration of colostrum to the oropharyngeal mucosa of the newborn <sup>3-10 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> Colostrum contains oligosaccharides that protect the mucosal barrier and stimulate the growth of beneficial bacteria in the mucosa, extracellular vesicles, secretory IgA, lactoferrin, lysozyme, cytokines, leukocytes, stem cells, and microRNA (miRNA), transferring active immune compounds with immediate effectiveness compared to transitional or mature milk, with higher concentrations <sup>3 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> , <sup>7 ➤
7. Garofoli, F.; Civardi, E.; Pisoni, C.; Angelini, M.; Ghirardello, S. Anti-Inflammatory and Anti-Allergic Properties of Colostrum from Mothers of Full-Term and Preterm Babies: The Importance of Maternal Lactation in the First Days. Nutrients 2023, 15, 4249. https:// doi.org/10.3390/nu15194249</sup> , <sup>11 ➤
11. 11. Moreno J, Sanchez B, Serrano L, Martin E, Diaz J, Pena M, et al. Mejora de la respuesta inmunitaria a través de la administración de calostro por vía orofaringea en recién nacidos prematuros; 2019, Mar. 30(2): 234-241. Doi: 10.1111/pai.13008. Epub 2018 Dec 13. PMID: 30444546.eal%20colostrum.</sup> , <sup>12 ➤
12. 12. Meier PP, Engstrom JL, Patel AL, Jegier BJ, Bruns NE. Improving the Use of Human Milk During and After the NICU Stay. Clin Perinatol 2010;37:217-45.</sup> . Sudeep et al. found a protective effect against late-onset sepsis with the use of colostrum therapy compared to placebo (22.7% vs. 43.3%, RR: 0.73; 95% CI: 0.57-0.9) <sup>8 ➤
8. 8 ➤
8. Sudeep, K.C., Kumar, J., Ray, S. et al. Oral Aplicación oral de calostro y leche materna a lactantes prematuros: un ensayo aleatorizado y 21 controlado. Indian 89, 579–586 (2022). https://doi.org/10.1007/s12098- 021-03982-4</sup> Ou Yang et al. determined a protective effect of this intervention against necrotizing enterocolitis (2.36% vs. 10.4%, RRa: 0.23; 95% CI: 0.06-0.84) and late-onset sepsis (4.72% vs. 13.6%, RRa: 0.36; 95% CI: 0.14-0.95) <sup>13 ➤
13. OuYang X, Yang CY, Xiu WL, Hu YH, Mei SS, Lin Q. Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial. Int Breastfeed J [Internet]. 21 de agosto de 2021 [citado 25 de mayo de 2023];16:59. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379587/</sup>

This study aims to determine the protective effect of colostrum therapy in very low birth weight preterm infants for late-onset sepsis, necrotizing enterocolitis, days on mechanical ventilation, and achievement of full enteral feeding using three statistical models, thus supporting its use as a cost-effective measure to reduce morbidity and mortality in this specific population.

MATERIALS AND METHODS

Study design: This is an analytical observational longitudinal cohort study, with a retrospective cohort design, conducted in the Neonatology Department of INMP.

Population and sample: The population consisted of very low birth weight preterm infants hospitalized in the Intensive Care, Intermediate Neonatal Care, and Immediate Attention services of the Neonatology Department at INMP, a Level III institution, between 2018 and 2021, with the following inclusion criteria: Exposed group: very low birth weight preterm infants who received colostrum during the study period; Unexposed group: very low birth weight preterm infants who did not receive colostrum during the same period. Patients with incomplete clinical records or missing data on study variables, or those born outside the hospital, with diaphragmatic hernia, asphyxia, esophageal atresia, or major congenital malformations were excluded.

For sample size calculation, the GRANMO V.7.12 sample size calculator was used, accepting an alpha risk of 0.05 and a beta risk of 0.2 in a bilateral contrast. A total of 231 very low birth weight preterm infants were included in both the exposed and unexposed groups, aiming to detect a minimum relative risk of 0.3, with a disease rate in the unexposed group of 0.1. The POISSON approximation was used. For cohort selection, simple random sampling was performed using an Excel 2016 random number generator for the clinical records of both groups.

Variables and instrument: To meet the study's objectives, variables were grouped into three segments: obstetric history (number of pregnancies, preeclampsia and/or hypertensive disorders of pregnancy, premature rupture of membranes, chorioamnionitis, urinary tract infection, vulvovaginitis, and third-trimester bleeding), neonatal characteristics (sex, weight, gestational age, minimal enteral nutrition within the first 5 days of life, and administration of colostrum therapy), and neonatal pathologies (early sepsis, late-onset sepsis, necrotizing enterocolitis, mechanical ventilation requirement, days on mechanical ventilation, congenital malformations, days of hospital stay, and discharge condition). Quantitative data on colostrum therapy administration included the age at treatment initiation, number of doses on the first, second, and third days, and the average dose volume each day. Data was collected using a data sheet from selected clinical records based on the sample.

Procedures: The data recorded in the instrument were entered into a database structured in Excel 2016 to ensure no errors. The database was then exported to SPSS-22 for univariate and bivariate analysis. For multivariate analysis, data was entered into STATA16.

Statistical analysis: Descriptive analysis was performed on qualitative and quantitative variables. For quantitative variables, central tendency measures (mean) were calculated. For qualitative variables, frequencies and percentages were determined. Bivariate analysis assessed the association between these variables and the administration of colostrum therapy. Inferential analysis was conducted to demonstrate associations between quantitative variables using the parametric Student’s t-test for normally distributed data or the non-parametric Mann-Whitney U test otherwise. For qualitative variables, the Chi-square test was used, with p-values < 0.05 considered significant.

For multivariate analysis, variables that showed a significant association were used. Three study models were proposed (model 1: necrotizing enterocolitis, model 2: mechanical ventilation requirement, and model 3: mortality). To study the degree of association of colostrum's protective factors in each model, relative risk and corresponding 95% confidence intervals (CI) were determined. Variables that were statistically significant in the bivariate analysis were further analyzed using Poisson multiple logistic regression, indicating adjusted relative risk and corresponding 95% CIs.

Ethical Considerations

This study followed the ethical considerations of the Taipei Declaration for health database studies. The results will be used solely for the benefit of society; the protection of privacy and confidentiality of the clinical data collected has been ensured. Data collection, storage, and implementation were conducted exclusively by the study team to verify transparency and ensure academic use only.

Additionally, this research was reviewed and approved by the Institutional Ethics Committee for Research and the Functional Research Unit of INMP.

RESULTS

A total of 462 neonates were included in the study. A descriptive analysis was performed for both the exposed and unexposed groups to characterize them and determine the frequencies of each variable. In the exposed group, 43.1% of primigravidae received colostrum therapy, while in the unexposed group, 56.9% were primigravidae, with no significant difference between the two groups (p = 0.063). The presence of preeclampsia and/or hypertensive disorders of pregnancy showed a significant difference between the groups; 42.1% of newborns with this maternal history received colostrum therapy (p = 0.037).

Los antecedentes maternos de ruptura prematura de membranas, corioamnionitis, infección urinaria y vulvovaginitis no mostraron diferencia significativa entre ambos grupos (p >0.05). El antecedente de hemorragia del tercer trimestre sí mostró una diferencia significativa entre ambos grupos; se evidenció que 13.6 % con este antecedente recibió la terapia a diferencia de 86.4 % en los no expuestos (p<0.01).

Maternal history of premature rupture of membranes, chorioamnionitis, urinary tract infection, and vulvovaginitis did not show significant differences between the groups (p > 0.05). However, third-trimester bleeding showed a significant difference, with 13.6% of those with this history receiving therapy compared to 86.4% in the unexposed group (p < 0.01).

Regarding neonatal characteristics, no significant difference was found between the sexes in both groups (p = 0.226), but there was a significant difference in birth weights (p = 0.037). Colostrum therapy was administered to 39.1% of neonates with a gestational age (GA) of 28 weeks or less, 53.4% between 29 and 32 weeks, and 57.1% with a GA greater than 32 weeks (p-value: 0.008). Concerning enteral nutrition, an association was observed with colostrum therapy administration (p < 0.01), with 60.1% of neonates receiving early enteral nutrition also receiving colostrum therapy.

In terms of neonatal pathologies, early sepsis and late-onset sepsis did not show an association with colostrum therapy (p > 0.05). However, the development of necrotizing enterocolitis and the need for mechanical ventilation were associated with colostrum therapy administration (p = 0.002 and 0.004, respectively).

Neither the number of days on mechanical ventilation nor the presence of congenital malformations showed a significant association with the intervention (p > 0.05). However, the number of days in the hospital and discharge status were significantly associated with colostrum therapy administration (both p < 0.01). In the unexposed group, 76.7% of the neonates died (table 1).

Subsequently, a descriptive analysis of the quantitative variables of the 231 neonates who received colostrum therapy was conducted. The average age at the start of colostrum therapy was 23.85 hours, with a median of 22 hours, a minimum age of 2 hours, and a maximum of 72 hours. A total of 130 (56.3%) neonates started colostrum therapy before 24 hours of life; 85 (36.8%) started between 24 and 48 hours, and 16 (6.9%) between 48 and 72 hours.

On the first day of colostrum therapy, neonates received an average of 2.24 doses, with an average volume of 0.935 ml per dose. The minimum number of doses was 1, and the maximum was 12, with a minimum volume per dose of 0.1 ml and a maximum of 3.8 ml. A total of 66.7% (154 neonates) received between one and two doses on the first day, while 33.3% (77 neonates) received more than two doses.

On the second day, 104 neonates received colostrum therapy, with an average of 2.49 doses and an average volume of 1.06 ml. The number of doses ranged from one to eight, with a minimum volume of 0.2 ml and a maximum of 4 ml. A total of 37 (35.6%) neonates received one dose, while 67 (64.4%) received more than one dose.

Only 17 neonates received colostrum therapy on the third day. The average number of doses was 2.94, and the average volume was 1.1 ml. Nine (52.9%) neonates received between one and two doses, while eight (47.1%) received more than two doses. Five (29.4%) neonates received less than 1 ml, while 12 (70.6%) received 1 ml or more (tabla 2). It is important to note that colostrum intake was not associated with any adverse events in the neonates.

Three regression models were designed: Model 1 focused on necrotizing enterocolitis (NEC); Model 2 examined the requirement for mechanical ventilation (MV); and Model 3 analyzed mortality, aiming to calculate the risk associated with each variable and the model as a whole.

Model 1: Gestational age (< 28 weeks: RR: 2.28, 95% CI: 0.63-8.22 and 29 to 32 weeks: RR: 0.72, 95% CI: 0.02-25.75), the number of colostrum doses on the first day (RR: 0.5, 95% CI: 0.072-3.482), minimal enteral nutrition (RR: 1.15, 95% CI: 0.459-2.871), early sepsis (RR: 1.979, 95% CI: 0.744-5.269), and hospital stay (1 to 21 days: RR: 1.24, 95% CI: 0.13-11.41; 22 to 39 days: RR: 0.27, 95% CI: 0.04-1.62; 40 to 55 days: RR: 0.55, 95% CI: 0.1-3.01) showed no significant association with necrotizing enterocolitis (NEC). Nevertheless, 22.2% of neonates with a maternal history of vulvovaginitis developed NEC, increasing the risk of NEC by 5.03 times (95% CI: 1.378-18.38). Additionally, 22.7% of infants with a third-trimester bleeding history developed NEC, increasing the risk by 5.882 times (95% CI: 2.39-14.476). A birth weight below 750 g significantly increased the risk of NEC (RR: 5.9, 95% CI: 1.7-20.44). Only 1.73% of neonates who received colostrum therapy developed NEC, compared to 7.79% in the unexposed group. Colostrum therapy acts as a protective factor against NEC development (RR: 0.222, 95% CI: 0.076-0.647). Delayed initiation of colostrum therapy (48-72 hours) increased the risk of NEC (RR: 16.23, 95% CI: 1.34-196.57). Among neonatal pathologies, late-onset sepsis (RR: 18.926, 95% CI: 2.56-139.5) and the need for mechanical ventilation (RR: 9.414, 95% CI: 1.279-69.307) significantly increased the risk. Hospital stay was not associated with an increased risk of NEC.

Model 2: The history of third-trimester bleeding (RR: 1.126, 95% CI: 0.89-1.424) and the age of colostrum therapy initiation (24-48 hours: RR: 1.19, 95% CI: 0.96-1.48; 48-72 hours: RR: 0.84, 95% CI: 0.39-1.83) did not show a significant association with the need for mechanical ventilation (MV). Lower birth weight significantly increased the risk of requiring MV (below 750 g: RR: 1.74, 95% CI: 1.34-2.26; 750 to 999 g: RR: 1.91, 95% CI: 1.6-2.27; 1000 to 1249 g: RR: 1.5, 95% CI: 1.24-1.81). Gestational age less than 28 weeks increased the risk of requiring MV (RR: 2.32, 95% CI: 1.89-2.84), as did gestational age between 29 and 32 weeks (RR: 1.88, 95% CI: 1.5-2.34). Colostrum therapy was a protective factor against MV (RR: 0.833, 95% CI: 0.736-0.943), with 62.77% of neonates who received colostrum therapy requiring MV, compared to 75.32% of those unexposed. A higher number of doses on the first day reduced the risk of MV (RR: 0.88, 95% CI: 0.674-0.993). Minimal enteral nutrition within the first five days was also a protective factor (RR: 0.806, 95% CI: 0.718-0.906). Among neonatal pathologies, early sepsis (RR: 1.275, 95% CI: 1.106-1.47), late-onset sepsis (RR: 1.345, 95% CI: 1.181-1.531), and NEC (RR: 1.409, 95% CI: 1.26-1.576) significantly increased the risk of requiring MV. A hospital stay of less than 56 days was a protective factor against the need for MV (1 to 21 days: RR: 0.84, 95% CI: 0.74-0.95; 22 to 39 days: RR: 0.53, 95% CI: 0.4-0.64; 40 to 55 days: RR: 0.67, 95% CI: 0.58-0.78).

Model 3: A history of vulvovaginitis (RR: 1.611, 95% CI: 0.764-3.395), the number of colostrum therapy doses on the first day (RR: 1.643, 95% CI: 0.738-3.658), and late-onset sepsis (RR: 0.834, 95% CI: 0.662-1.118) did not show a significant association with discharge outcomes. 68.2% of neonates with a history of third-trimester bleeding died, increasing the risk of death by 2.437 times (95% CI: 1.899-3.647). Lower birth weight significantly increased the risk of neonatal mortality (below 750 g: RR: 8.66, 95% CI: 5.48-13.7; 750 to 999 g: RR: 6.14, 95% CI: 3.93-9.59; 1000 to 1249 g: RR: 2.45, 95% CI: 1.36-4.43). A total of 56.5% of neonates with a gestational age of less than 28 weeks died, showing a 4.94 times higher risk of death compared to those older than 32 weeks (95% CI: 3.17-7.69). Only 12.98% of neonates who received colostrum therapy died, demonstrating a protective factor for discharge outcomes (RR: 0.303, 95% CI: 0.21-0.44). Late initiation of colostrum therapy (24 to 48 hours: RR: 3.06, 95% CI: 1.43-6.57) increased the risk of death. Minimal enteral nutrition within the first five days was another protective factor (RR: 0.255, 95% CI: 0.19-0.343). Early sepsis (RR: 1.5, 95% CI: 1.08-2.1), NEC (RR: 2.435, 95% CI: 1.71-3.465), and mechanical ventilation (RR: 3.166, 95% CI: 1.949-5.19) significantly increased the risk of death. A hospital stay of 1 to 21 days increased the risk of death by 11.95 times compared to a stay of 56 to 219 days (95% CI: 7.89-18.11)(table 3).

Subsequently, we conducted the multivariate analysis. In the first model, the association between colostrum therapy and the presence of necrotizing enterocolitis (NEC) was measured. It was found that the history of vulvovaginitis, birth weight, and the need for mechanical ventilation did not show a significant association with the presence of NEC. However, colostrum therapy (RRa: 0.304, 95% CI: 0.099-0.91) acted as a protective factor against NEC. On the other hand, a history of third-trimester bleeding (RRa: 3.496, 95% CI: 1.19-10.31) and late-onset sepsis (RRa: 14.416, 95% CI: 1.93-109.07) increased the risk of developing NEC.

In the second model, the association between colostrum therapy and the use of mechanical ventilation (MV) was analyzed. It was demonstrated that receiving colostrum therapy, birth weight, enteral nutrition, early sepsis, late-onset sepsis, and days of hospital stay were not associated with the need for MV. However, gestational age ≤28 weeks and between 29 to 32 weeks increased the risk of requiring MV (RRa: 1.599, 95% CI: 1.03-2.49 and RRa: 1.589, 95% CI: 1.1-2.3, respectively).

The third model aimed to measure the association between receiving colostrum therapy and mortality. It was found that birth weight, gestational age, early sepsis, and the need for mechanical ventilation did not show a significant association with mortality. However, receiving colostrum therapy (RRa: 0.495, 95% CI: 0.32-0.76) and receiving enteral nutrition (RRa: 0.458, 95% CI: 0.31-0.68) acted as protective factors against mortality (tabla 4).

DISCUSSION

Of the 462 neonates weighing less than 1500 grams at birth who participated in the study, 231 received colostrum therapy in their first days of life. Despite the extreme prematurity associated with a high comorbidity rate due to their high vulnerability and the strict inverse relationship between weight and gestational age, which is further exacerbated by associated maternal pathologies ^{14 ➤
14-16. Referencias N14-16} ; colostrum therapy is among the scientifically evidenced protective strategies. The oligosaccharides in colostrum support immunity, particularly intestinal immunity, modulate helper T cells (Th1/Th2), act on pathogen recognition receptors, possess specific bifidogenic activity, and reduce the growth of pathogenic microorganisms. Additionally, colostrum contains many other molecules, live cells, and even microbes that provide protective effects in neonates <sup>7 ➤
7. Garofoli, F.; Civardi, E.; Pisoni, C.; Angelini, M.; Ghirardello, S. Anti-Inflammatory and Anti-Allergic Properties of Colostrum from Mothers of Full-Term and Preterm Babies: The Importance of Maternal Lactation in the First Days. Nutrients 2023, 15, 4249. https:// doi.org/10.3390/nu15194249</sup> .

The multivariate analysis showed that colostrum therapy acts as a protective factor against the development of NEC (Bell stage 2 or 3) (RR: 0.222, 95% CI: 0.076-0.647), consistent with findings from OuYang et al. In their randomized controlled trial, they found a 2.36% incidence of NEC in the group that received therapy compared to 10.4% in the placebo group (RR: 0.23, 95% CI: 0.06-0.84) <sup>13 ➤
13. 13. OuYang X, Yang CY, Xiu WL, Hu YH, Mei SS, Lin Q. Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial. Int Breastfeed J [Internet]. 21 de agosto de 2021 [citado 25 de mayo de 2023];16:59. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379587/</sup> ; Similarly, Zhen Yan Fu et al., in a meta-analysis of 16 studies including 1736 neonates, found a statistically significant difference favoring the intervention group for NEC incidence [RR = 0.56, 95% CI: 0.38-0.84, Z = 2.86, P = 0.004] <sup>17 ➤
17. 17. Fu ZY, Huang C, Lei L, et al. The effect of oropharyngeal colostrum administration on the clinical outcomes of premature infants: A meta-analysis. Int J Nurs Stud. 2023;144:104527. doi:10.1016/j.ijnurstu.2023.104527</sup> , corroborating the findings of other researchers <sup>18 ➤
18. 18. Sanchez, V., & Cisneros, L. (2020). FACTORES DE RIESGO DE ENTEROCOLITIS NECROTIZANTE EN RECIÉN NACIDOS MUY PREMATUROS, HOSPITAL VÍCTOR LAZARTE ECHEGARAY. Revista peruana de pediatria, 72, 59.</sup> .

However, other authors, like Tao et al., did not find a significant association in their meta-analysis regarding NEC incidence (RR = 0.59, 95% CI: 0.33-1.06, p = 0.08) <sup>19 ➤
19. 19. Tao J, Mao J, Yang J, Su Y. Effects of oropharyngeal administration of colostrum on the incidence of necrotizing enterocolitis, late-onset sepsis, and death in preterm infants: a meta-analysis of RCTs. Eur J Clin Nutr [Internet]. 2020 [citado 25 de mayo de 2023];74(8):1122-31. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222151/</sup> Similarly, Panchal et al., who reviewed five RCTs, found no significant difference in NEC incidence (RR: 0.83, 95% CI: 0.39-1.75, P = 0.62) <sup>3 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> , and this result has been echoed by others <sup>8 ➤
8. Sudeep, K.C., Kumar, J., Ray, S. et al. Oral Aplicación oral de calostro y leche materna a lactantes prematuros: un ensayo aleatorizado y 21 controlado. Indian 89, 579–586 (2022). https://doi.org/10.1007/s12098- 021-03982-4</sup> , <sup>20 ➤
20. 20. Kumar J, Meena J, Ranjan A, Kumar P. Oropharyngeal application of colostrum or mother's own milk in preterm infants: a systematic review and meta-analysis. Nutr Rev. 2023;81(10):1254-1266. doi:10.1093/nutrit/nuad002</sup> , <sup>21 ➤
21. 21. Slouha E, Anderson ZS, Ankrah NMN, Kalloo AE, Gorantla VR. Colostrum and Preterm Babies: A Systematic Review. Cureus. 2023;15(7):e42021. Published 2023 Jul 17. doi:10.7759/cureus.42021</sup> .

The difference in effect could be attributed to variations in the timing of colostrum therapy initiation, the doses administered per day, the total quantity, and the number of days of intervention. Early initiation and higher frequency of administration appear to enhance the protective effect.

Regarding mortality, 13% of neonates who received colostrum therapy died compared to 42.8% of those who did not receive it. In the multivariate analysis, colostrum therapy showed a protective effect (adjusted RR: 0.494, 95% CI: 0.32-0.76). Our results align with those of Bashir et al., who conducted a prospective study and found [OR: 0.11, 95% CI: 0.03-0.40] <sup>22 ➤
22. 22. Bashir T, Reddy KV, Kiran S, Murki S, Kulkarni D, Dinesh P. Effect of colostrum given within the 12 hours after birth on feeding outcome, morbidity and mortality in very low birth weight infants: a prospective cohort study. Sudan J Paediatr [Internet]. 2019 [citado 25 de mayo de 2023];19(1):19-24. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589796/</sup> ; Additionally, Zhen Yan Fu's meta-analysis of 10 studies showed that the intervention group had a lower incidence of death compared to the control group, and the difference was statistically significant [RR = 0.71, 95% CI: 0.53-0.94, Z = 2.38, P = 0.02] <sup>17 ➤
17. 17. Fu ZY, Huang C, Lei L, et al. The effect of oropharyngeal colostrum administration on the clinical outcomes of premature infants: A meta-analysis. Int J Nurs Stud. 2023;144:104527. doi:10.1016/j.ijnurstu.2023.104527</sup> Additionally, Zhen Yan Fu's meta-analysis of 10 studies showed that the intervention group had a lower incidence of death compared to the control group, and the difference was statistically significant [RR = 0.71, 95% CI: 0.53-0.94, Z = 2.38, P = 0.02] <sup>23 ➤
23. 23. Martín E, Diaz J, Peña M, Serrano L, Moreno J, Sánchez-Martínez B, et al. Oropharyngeal Colostrum Positively Modulates the Inflammatory Response in Preterm Neonates. Nutrients [Internet]. 5 de febrero de 2020 [citado 6 de mayo de 2023];12(2):413. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32033312/</sup> .

Conversely, other authors found no such association, particularly in cases where colostrum therapy was initiated later than 48 hours after birth <sup>3 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> , <sup>8 ➤
8. Sudeep, K.C., Kumar, J., Ray, S. et al. Oral Aplicación oral de calostro y leche materna a lactantes prematuros: un ensayo aleatorizado y 21 controlado. Indian 89, 579–586 (2022). https://doi.org/10.1007/s12098- 021-03982-4</sup> , <sup>19 ➤
19. 19. Tao J, Mao J, Yang J, Su Y. Effects of oropharyngeal administration of colostrum on the incidence of necrotizing enterocolitis, late-onset sepsis, and death in preterm infants: a meta-analysis of RCTs. Eur J Clin Nutr [Internet]. 2020 [citado 25 de mayo de 2023];74(8):1122-31. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222151/</sup> .

To achieve the greatest benefit from colostrum, there is ongoing debate about the necessary duration of treatment. In our study, neonates received colostrum therapy for three days, with a median of 2.24 doses per day and an average volume of 0.935 ml per dose. There are reports suggesting treatment durations of 8 to 10 days, but no consensus exists, as most patients are typically on minimal enteral nutrition by the third day.

In our study, we found no significant association between colostrum therapy and neonatal sepsis, whether early or late-onset, which is consistent with the findings of other authors <sup>24 ➤
24. 24. Maraboli Aguilera M, Lavanderos Bustamante G, León Martínez C, Zúñiga Ulloa M, Mena Nannig P. Evaluación de un protocolo de calostro para prematuros de muy bajo peso de nacimiento [Colostrum protocol evaluation for very low birth weight preterm infants]. Andes Pediatr. 2022;93(3):343-350. doi:10.32641/andespediatr.v93l3.3870</sup> , <sup>25 ➤
25. 25. Abd-Elgawad M, Eldegla H, Khashaba M, Nasef N. Oropharyngeal Administration of Mother’s Milk Prior to Gavage Feeding in Preterm Infants: A Pilot Randomized Control Trial. JPEN J Parenter Enteral Nutr [Internet]. enero de 2020 [citado 6 de mayo de 2023];44(1):92-104. Disponible en: https://pubmed.ncbi.nlm.nih.gov/31062377/</sup> , <sup>26 ➤
26. 26. Snyder R, Herdt A, Mejias-Cepeda N, Ladino J, Crowley K, Levy P. Early provision of oropharyngeal colostrum leads to sustained breast milk feedings in preterm infants. Pediatr Neonatol [Internet]. diciembre de 2017 [citado 25 de mayo de 2023];58(6):534-40. Disponible en: https://pubmed.ncbi.nlm.nih.gov/28550982/</sup> ; However, Lee et al. reported that the incidence of sepsis was lower in the colostrum therapy group compared to the control group (50% vs. 92%, p = 0.03) <sup>27 ➤
27. 27. Lee J, Kim HS, Jung YH, Choi KY, Shin SH, Kim EK, et al. Oropharyngeal Colostrum Administration in Extremely Premature Infants: An RCT. Pediatrics [Internet]. 1 de febrero de 2015 [citado 25 de mayo de 2023];135(2):e357-66. Disponible en: https://doi.org/10.1542/peds.2014-2004</sup> . Kumar et al., in a meta-analysis of 17 RCTs, found that colostrum therapy significantly reduced the incidence of sepsis (RR = 0.72, 95% CI: 0.56-0.92) <sup>20 ➤
20. 20. Kumar J, Meena J, Ranjan A, Kumar P. Oropharyngeal application of colostrum or mother's own milk in preterm infants: a systematic review and meta-analysis. Nutr Rev. 2023;81(10):1254-1266. doi:10.1093/nutrit/nuad002</sup> , corroborating findings from other studies <sup>3 ➤
3. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/ S2352-4642(21)00311-4.</sup> , <sup>13 ➤
13. 13. OuYang X, Yang CY, Xiu WL, Hu YH, Mei SS, Lin Q. Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial. Int Breastfeed J [Internet]. 21 de agosto de 2021 [citado 25 de mayo de 2023];16:59. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379587/</sup> , <sup>17 ➤
17. 17. Fu ZY, Huang C, Lei L, et al. The effect of oropharyngeal colostrum administration on the clinical outcomes of premature infants: A meta-analysis. Int J Nurs Stud. 2023;144:104527. doi:10.1016/j.ijnurstu.2023.104527</sup> , <sup>19 ➤
19. 19. Tao J, Mao J, Yang J, Su Y. Effects of oropharyngeal administration of colostrum on the incidence of necrotizing enterocolitis, late-onset sepsis, and death in preterm infants: a meta-analysis of RCTs. Eur J Clin Nutr [Internet]. 2020 [citado 25 de mayo de 2023];74(8):1122-31. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222151/</sup> , <sup>21 ➤
21. 21. Slouha E, Anderson ZS, Ankrah NMN, Kalloo AE, Gorantla VR. Colostrum and Preterm Babies: A Systematic Review. Cureus. 2023;15(7):e42021. Published 2023 Jul 17. doi:10.7759/cureus.42021</sup> , <sup>23 ➤
23. 23. Martín E, Diaz J, Peña M, Serrano L, Moreno J, Sánchez-Martínez B, et al. Oropharyngeal Colostrum Positively Modulates the Inflammatory Response in Preterm Neonates. Nutrients [Internet]. 5 de febrero de 2020 [citado 6 de mayo de 2023];12(2):413. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32033312/</sup> .Researchers who have found this association typically consider five or more consecutive days of colostrum therapy, suggesting that the duration of therapy may influence this protective effect.

We also found no significant association between colostrum therapy and the duration of mechanical ventilation, similar to Alvarez et al.'s findings <sup>21 ➤
21. 21. Slouha E, Anderson ZS, Ankrah NMN, Kalloo AE, Gorantla VR. Colostrum and Preterm Babies: A Systematic Review. Cureus. 2023;15(7):e42021. Published 2023 Jul 17. doi:10.7759/cureus.42021</sup> ; Regarding hospital stay, Tao et al. reported that neonates receiving colostrum had shorter hospital stays (mean difference = −10.38, 95% CI = −18.47–2.29, p = 0.01) <sup>19 ➤
19. 19. Tao J, Mao J, Yang J, Su Y. Effects of oropharyngeal administration of colostrum on the incidence of necrotizing enterocolitis, late-onset sepsis, and death in preterm infants: a meta-analysis of RCTs. Eur J Clin Nutr [Internet]. 2020 [citado 25 de mayo de 2023];74(8):1122-31. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222151/</sup> , Other authors have found similar associations favoring the intervention <sup>28 ➤
28. 28. Romano-Keeler J, Azcarate-Peril MA, Weitkamp JH, Slaughter JC, McDonald WH, Meng S, et al. Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu. J Perinatol [Internet]. enero de 2017 [citado 25 de mayo de 2023];37(1):36-41. Disponible en: https://www.nature.com/articles/jp2016161</sup> , while others have reported the opposite <sup>29 ➤
29. 29. Nasuf AWA, Ojha S, Dorling J. Oropharyngeal colostrum in preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev [Internet]. 7 de septiembre de 2018 [citado 25 de mayo de 2023];2018(9):CD011921. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513592/</sup> ; We observed a significant difference in our study, though the longer stays in the exposed group were likely due to the high mortality rate among unexposed neonates.

The main limitations of this study include its execution at a single institution, which may limit the generalizability of the findings, and its retrospective design.

CONCLUSION

Oropharyngeal colostrum administration is a simple and safe procedure. This study demonstrated that it acts as a protective factor against necrotizing enterocolitis and mortality in very low birth weight preterm neonates.

RECOMMENDATIONS

In line with existing scientific evidence and our findings, we recommend that healthcare professionals caring for newborns administer oropharyngeal colostrum from the first hours of life, regardless of the clinical condition of the neonate.