Colostrum and Preterm Babies: A Systematic Review

Colostrum from mothers is rich in immunomodulating bio-factors such as immunoglobulins (IgA), lactoferrin, and oligosaccharides and supports gut microbial and inflammatory processes. The support in these processes may provide some relief for infants who are born pre-term. Pre-term infants are more likely to develop necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and ventilator-acquired/associated pneumonia (VAP). Due to the components of colostrum, there may be incentives towards early administration for preterm infants. An extensive literature review was done using ProQuest, ScienceDirect, and PubMed. Only meta-analyses and experimental studies were used. The search included the keywords ‘colostrum and preterm’ and ‘colostrum and necrotizing enterocolitis’. The initial search generated 13,543 articles and was narrowed to 25 articles through comprehensive inclusion and exclusion criteria. There were significantly higher levels of Lactobacillus and Bifidobacterium in pre-term infants given colostrum and a decrease in Moraxellaceae and Staphylococcaceae. Salivary secretory IgA increased following oral colostrum administration in pre-term infants along with downregulation of interleukin (IL)-1b and IL-8. It was also observed that tumor necrosis factor (TNF)-a, and interferon-gamma (IFN-g) were significantly higher in the control group. There was no significant difference in the incidence of LOS, NEC, or VAP between pre-term infants receiving colostrum and those who did not. Secondary outcomes such as time to full enteral feeding were improved in pre-term infants receiving oral colostrum in addition to reduced hospital stays. Lastly, there was no difference in mortality between pre-term infants that received colostrum compared to those who did not.

Both NEC and LOS are common complications and major risk factors of mortality in preterm infants, particularly in those born before 32 weeks of gestational age and weighing <1000 g [6,7]. The mechanisms of these complications have been determined to be multifactorial in nature, but largely due to the immature immune system of premature infants, which increases susceptibility to triggers resulting in dysbiosis of the intestinal bacterial microbiome [8]. In NEC, preterm infants deal with a prolonged period during which they cannot feed enterally, resulting in intestinal atrophy and an increased risk of inflammation [9]. Immune factors protective against NEC and LOS are found in high concentrations within colostrum; therefore, a reduction in the risk of these complications in premature infants may be seen with OAC [10,11].
VAP VAP is another common and severe complication in premature infants receiving mechanical ventilation [12]. An increased incidence of VAP is seen in very low birth weight preterm infants, suggesting that the incidence of VAP is associated with the reduced immune development and lung maturity seen in this population [13,14]. OAC provides immune factors that stimulate an immune response, mitigate oral contamination, and likely reduce the incidence of VAP in preterm infants [15]. The burden of mortality among preterm infants is high, predominantly due to complications of inflammation manifesting as NEC and LOS [16][17][18]. OAC provides immune factors which are beneficial in reducing the incidence of prematurity-related conditions and, therefore, could reduce mortality from these complications in premature infants [19].
The aim of this article is to determine the effects of OAC to pre-term infants and investigate whether there's a reduction in LOS, NEC, VAP, and mortality.

Review Methods
An extensive and exhaustive literature search was done from January 1, 2002, to December 31, 2022, using ProQuest, PubMed, and ScienceDirect databases. Keywords included 'colostrum and preterm' and 'colostrum and necrotizing enterocolitis' to name a few. The electronic exploration focused on peer-reviewed experimental publications that fell into the scope of this paper. Publications not written in English, and duplicates were excluded from the screening process. A total of 13,543 publications (573 from PubMed, 3112 from ScienceDirect, and 9858 from ProQuest) were found in the initial search. Inclusion criteria comprised studies conducted on humans, published between 2002 and 2022, written in English, focused on using human colostrum for pre-term infants, peer-reviewed, full-text availability including subscription and nonsubscription articles, observational, cohort, case-control studies, and meta-analyses. Exclusion criteria included case reports/series, systematic reviews, and review articles. All duplicates (929 articles) and publications before 2002 (325 articles) were excluded before screening.
During the manual screening process, a total of 12,235 were excluded by three co-authors who independently analyzed them based on their abstracts, full-text accessibility, title, and study type. Of the 54 articles remaining, 29 were excluded based on context, keyword specifics, and abstracts, ultimately resulting in a total of 25 eligible publications.
The screening for this literature review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20] (Figure 1).

Bias
All studies were assessed for bias, and the results varied greatly between studies due to limited sample size and lack of exact methods in some. A medium risk of bias overall was concluded. To assess the individual risk of bias, the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool was used, which evaluates flaws like inconsistency, indirectness, and imprecision.

Results
OAC may have positive effects on preterm infants. Research shows that alterations to the gut microbiota may prevent NEC and LOS. One such alteration is an increase in Lactobacillus and Bifidobacterium. There are also immunomodulating changes, such as an increase in sIgA and lactoferrin, promoting symbiosis of the gut microbiota. Despite noted positive benefits, overall, there are no significant differences in the incidence of NEC, LOS, VAP, and mortality rate. However, there is a split between whether OAC reduces the time to full enteral feeding or not.

Gut Microbiota
Neonates have vastly different gut microbiota compared to adults because they start with a sterile environment, but it grows quickly soon after birth. Increased phylum levels of Proteobacteria and Actinomycetota (or Actinobacteria) were observed at OAC together with increased Firmicutes levels at 96 hours in the study by Sohn et al. [21]. At 48 hours, the OAC group had a significantly lower percentage of Moraxellaceae (p = 0.03). Subsequently, at 96 hours, they had a lower rate of Staphylococcaceae (p = 0.01) and an increased share of Planococcaceae (p = 0.09). Compared to the OAC group at 96 hours, five infants in the control group had an increased percentage of Staphylococcaceae [21]. However, Cortez et al. observed a nonsignificant increase in Staphylococcus, Escherichia, and Shigella in preterm infants receiving OAC compared to the standard care group [22]. Abd-Elgawad et al. found that the presence of Klebsiella species was significantly lower in pre-term infants in the oropharyngeal administration of mother's milk (OPAMM) group [23]. There were also significantly higher levels of Lactobacillus and Bifidobacterium species in followup stool cultures in pre-term infants and OPAMM groups compared to initial cultures [22,23].

Immunomodulating Changes
There was a significant increase in salivary sIgA on the seventh day of life in pre-term infants who received colostrum compared to those in the control group [24,25]. At week one, there was another significant increase in urinary sIgA in the pre-term infants receiving OAC compared to placebo, and this trend continued into the second week and up to one month [26][27][28]. However, no statistically significant difference was found between baseline levels of sIgA and that on the seventh day of OAC [29,30]. It was also found that in the OAC group, IgM was significantly higher compared to the control group on the 15th and 30th day of life [28]. Additionally, in the OAC group, lactoferrin was higher compared to the control group from day seven until day 30 [26][27][28]31]. Moreno-Fernandez et al. also looked at resistin levels and found it was significantly higher in pre-term infants given OAC [28].
OAC was responsible for down-regulating IL-1b and, consequently, IL-8 production with decreased salivary levels of TGF-b1 [27]. In another study by Martín-Álvarez et al., when compared to the control group, proinflammatory ILs such as IL-6, IL-8, and IL-10 were significantly decreased, with IL-1ra increasing dramatically in the first month of life in the OAC group (p<0.05). Compared to the OAC group, on the 15th postnatal day, TNF-a and IFN-g were significantly higher in the control group (p = 0.024 and p = 0.039, respectively) [32]. It was observed that worse prognoses are associated with a high Il-6/IL-10 ratio; therefore, the results of the study with high IL-10 concentration and decreased IL-6 concentration in the OAC group of pre-term infants are likely beneficial [32].

LOS
Most research agrees with the analysis that OAC does not significantly decrease the chance of developing sepsis. Only one article analyzed the incidence of early-onset sepsis and found that the incidence was comparable between the OAC group and the control group (p = 0.49) [33]. There was no significant difference in LOS between the OAC and control groups [23,25,29,31,[33][34][35][36][37]. While there is no significant decrease in the incidence of LOS, it is noted that there may be positive effects of OAC [36]. Ma et al. observed a downward trend and postulated that more extensive studies might prove significant [38]. This is in line with several other studies that found a significant decrease in the incidence of LOS [27,30,[39][40][41]. Salve et al. observed that neonates receiving OAC within 48 hours of birth had a lower incidence of LOS at 3.7% compared to those in the control group, where 46.3% developed LOS [41].

NEC
NEC is a critical factor in neonatal mortality for pre-term babies. Evidence showed a reduced incidence of NEC in the OAC group, but no statistically significant difference existed between the OAC and control groups [33,42]. Most research has concluded that there is no significant difference in the incidence of NEC in preterm neonates receiving OAC [25,29,30,31,[34][35][36][37]43]. While there was no significant difference in the NEC rate, there is evidence of positive effects on pre-term infants [36]. One article found a statistically significant difference in the incidence of NEC between groups; however, the study population warrants caution in these interpretations [39]. On the other hand, one meta-analysis observed a significant difference in the incidence of NEC, where the OC group had an incidence of 3.6% compared to those in the control group, which had 6.9% [40].

VAP
Pre-term neonates suffer from pulmonary complications such as bronchopulmonary dysplasia (BD) and VAP. Huo et al. observed that the incidence of BD was 14.2% vs. 18.4% in the colostrum and control groups; however, their meta-analysis indicated this was not statistically significant [40]. The remainder of the articles discussing BD also collectively described no significant difference in the incidence of BD [30,38]. The incidence of VAP was inconclusive between the OAC groups and the control. Ma et al. found that the reduction in ventilator-associated pneumonia in low-birth-weight infants given OAC was statistically significant (p=0.02) [38]. Huo et al. concurred with these results in their meta-analysis, which found that VAP was reduced significantly in the OAC group (p = 0.03) [40]. Two articles found a borderline significantly reduced incidence of VAP in the OAC group compared to the control group [21,23]. The remaining two articles observed no significant difference in the incidence of VAP between the two groups [25,33]. Abd-Elgawad et al. noticed that while continuous positive airway pressure (CPAP) and mechanical ventilation did not statistically differ between OPAMM and regular gavage, oxygen therapy duration was significantly shorter in OPAMM [23].

Time to Full Enteral Feeding and Hospital Duration
Infants receiving OAC had a significantly decreased incidence of feeding intolerance and increased feeding discontinuation orders [23]. The time to reach full feeding was reduced in pre-term infants of the OAC group compared to regular gavage [23]. Infants receiving colostrum reached full enteral feeding earlier, around 7.2 days, compared to 9.1 for the control group (p < 0.05) [28]. Numerous other studies have concluded that the effective full enteral feeding time was significantly reduced in pre-term infants receiving OAC compared to those in the control group [32,34,36,[38][39][40]44,45]. Reaching full enteral nutrition sooner may improve the development of the digestive system of pre-term infants and reduces cytokine release. Therefore, OPAMM is likely to influence clinical outcomes positively [32]. Earlier full enteral feeding may also contribute to the statistically significant difference in the weight gain between OC and control groups [40]. Some studies, however, have concluded that there is a comparable number of days to reach full enteral feeding between the OAC and control groups [29,31,35,37,43]. All but one article concluded that OAC significantly reduced the duration of hospital stay in pre-term infants [33,36,40,43]. However, Panchal et al. observed no statistically significant difference in the duration of hospital stay [35].

Mortality
There was some discrepancy in the observed mortality rate of pre-term infants receiving OAC compared to the control groups. A couple of studies found that the mortality rate was significantly decreased in infants receiving OAC [41,42]. Fallahi et al. observed that in neonates weighing < 1500g, OAC significantly lowered mortality rates compared to the control group (p = 0.2), but this was not seen in neonates who weighed 1500-1800 g (p = 0.92) [42]. Contrary to this, Huo et al. saw that the death rate before discharge was 10.4% in the colostrum group, compared to 12.6% in the control group; however, their meta-analysis showed that the difference between groups was not clinically significant [40]. Most studies found to agree with the finding that there was no significant difference in the mortality rate for those receiving OAC [29,30,33,35,36,40,43]. It is important to note that there were found to be low-to-no adverse effects following OAC [30,33]. A summary of the discussion/reviewed findings is presented in Table 1. There were no significant differences in the incidence of common neonatal outcomes; however, the mother's milk group showed quicker time to reach full enteral feeding, decreased IL-6, IL-8, TNF-a, and INF-g, and increased IL-1ra and IL-10.

Design & Study
The study provides support that 15-day OAC decreases the pro-inflammatory state and improves the immune system of pre-term infants, ultimately improving their developmental outcomes. There were no significant differences in primary outcomes between the OAC group and control group. The effect was largely uncertain because the studies analyzed had small sample sizes and therefore a low quality of evidence.
The quality of studies included was low, so larger, well-designed trials are necessary to provide more precise and reliable results about the benefits of OAC on clinically important outcomes for preterm infants. 13 Silva et al., 202, [45].

Brazil
Retrospective study (n = 42) Significant differences in hospitalization length, birth weight recovery, and time to achieve full enteral feeding in newborns who received enteral nutritional therapy soon after birth.
Significant reduction in time to full enteral feeding and to recover birth weight in very-low-birth-weight infants that were administered colostrum. Infants in the treatment group had lower incidence rates of adverse health outcomes although no significant differences were observed. Changes in sIgA levels also showed no statistically significant findings when reviewing baseline and concluding data.
Incidence of LOS in pre-term neonates decreased when infants received an OMOM and administration to infants were notably safe. 16 Tao et al., 2020, [36]. China Meta-analysis (n = 689) No statistically significant finding in reducing adverse effects NEC, LOS, and mortality but there was a significant difference in time to achieve full enteral feeding and hospitalization in pre-term infants. Concentration of salivary sIgA were significantly higher seven days after birth in preterm infants given OPAMM compared to control (p < 0.05), but this did not hold 14 days after.

Brazil
Observational study (n = 20) In pre-terms receiving OAC, there was an increase in colonization of oral microbiota with a higher abundance of Staphylococcus. There was also an increase in abundance of Bifidobacterium and Bacteroides in infants in the OAC group In infants receiving OAC, there was an increase in oral microbiota, but timing is a key factor in both groups. 22 Fallahi et al., 2021, [42].

Iran
Experiment study (n = 156) Incidence of NEC was comparable between the intervention and control group. In-hospital mortality was significantly decreased in the intervention group compared to the control group. There were no observable differences in complications such as retinopathy or bronchopulmonary dysplasia of prematurity between the intervention and control groups.
There is significantly lower mortality rate in low-birth-weight neonates who received breast milk cell fraction. 23 Ferreira et al., 2019, [29].

Brazil
Experimental study (n = 113) There was no significant difference in the incidence of LOS and proven sepsis between colostrum and placebo groups. IgA concentrations were similar before and after administration of colostrum and placebo. There was no difference seen in IgA in urine as well.
There is no confirmation of the beneficial effects of OAC for pre-term infants such as reducing LOS or increasing IgA levels. In infants receiving OAC, there were significantly higher concentrations of salivary sIgA compared to the controls on day seven but didn't withstand at day 14.
SsIgA is increased on the seventh day of life, but this impact still needs to be studied. OAC: oropharyngeal administration of colostrum; NEC: necrotizing enterocolitis; LOS: late-onset sepsis; VAP: ventilator-associated pneumonia; TGF-b: transforming growth factor-beta; RCT: randomized control trial; NICU: neonatal intensive care unit; INF-g: interferon gamma; IL: interleukin; sIgA: secretory IgA; OMOM: oral application of mother's own milk; OPAMM; oropharyngeal administration of mother's milk There are some limitations to this article. Experiments on neonates are limited due to ethical issues that can easily arise; this also means there are usually small sample sizes, as noted in most of the cited articles. The reduced sample sizes limit the power of most studies, so these results should be carefully interpreted. There was also a limited number of studies to be analyzed to account for the reduced sample size. The metaanalyses used in this study had their own conclusions but the conclusions themselves also varies between each meta-analysis. Again, information from this article should be interpreted carefully, recognizing that the information warrants further research.

Conclusions
Overall, the pooled analysis shows that the administration of oral colostrum in preterm infants is safe and feasible and does not result in any adverse events such as NEC, LOS, VAP, and mortality. The seeming reduction in the observed adverse events was due to beneficial alterations to the gut microbiota, although it was not significantly different. Additionally, based on data analysis, oral colostrum can serve as an immunological protective agent as it demonstrated an increase in sIgA and lactoferrin, which promoted symbiosis of the gut microbiota.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.