Probiotics Supplementation in Reduction of Necrotizing Enterocolitis in Very Low Birth Weight Infants

Abstract

Introduction: Probiotic supplementations have become a recent area of interest among the many treatment options for necrotizing enterocolitis (NEC). Therefore, the systematic review sought to answer the question; in very low birth weight infants (VLBW), how can probiotic supplementation reduce necrotizing enterocolitis?

Methodology: This is a systematic analysis conducted using trials obtained from PubMed, EMBASE, and Cochrane Library. Randomized trials from the last decade were considered for inclusion in the study. A literal, systematic analysis of the included studies was performed to investigate outcomes such as feeding tolerance and resumption to full enteral feeding, weight gain, length of hospitalization, and increase in gut colonization and microbiota count.

Results: A total of 10 studies investigating 2480 VLBW infant participants were randomized as follows; 1217 VLBW infants receiving probiotics and 1263 VLBW infants as control. Four outcome measures were used to indicate a reduction of NEC in the patients; feeding tolerance and resumption to full enteral feeding, weight gain, length of hospitalization, and increase in gut colonization and microbiota count. Each outcome was significantly positive in favour of supplemental probiotics.

Conclusions: There is evidence from a systematic analysis of 10 studies that supplementing the feeds of VLBW infants with probiotics increases their chances of surviving NEC. In the future, randomized trials should concentrate on elucidating this niche by conducting direct comparisons of probiotics to determine the most effective among the available.

Introduction

Necrotizing enterocolitis (NEC) is a critical gastrointestinal (GI) medical complication that affects neonates (Springer & Annibale, 2007). NEC causes inflammations in the GI tissues and has been the reason for most new-born fatalities. In some cases, NEC leads to a perforation (a hole) in the baby’s intestine through which bacteria leak into the gut or the bloodstream (Springer & Annibale, 2007). The condition usually occurs within the first two to six weeks of birth. While it may be severe and life-threatening in most cases, NEC has been observed to only have mild effects on some infected infants. NEC causes serious damages to the intestinal tract, such as initial injuries to the mucosal or full-blow thickness necrosis and intestinal perforations. The image below, the Department of Pathology: Cornel University Medical College, shows two varying sections of the bowel. The image is a side-by-side comparison of a normal bowel section to a necrotized section of the bowel.

The symptoms of NEC are quite diverse. At times they can be confused with other bowel GI complications such as sepsis (Rich & Dolgin, 2017). In a systematic review performed by Neu and Walker (2013), NEC was suspected whenever symptoms such as abdominal distention were noticed. To ascertain NEC, a radiograph is usually recommended for the physician to confirm the presence of portal venous gas, pneumatosis intestinalis, or free intraperitoneal air (Neu & Walker, 2013). The infant might also begin experiencing feeding intolerance. In a case where there is not enough evidence to confirm NEC, the physician might confirm the diagnosis through clinical observation and treat with bowel decompression and a brief halting of feeding. The patient might also be considered for a short course of intravenous antibiotics. If there is definitive medical proof that there is NEC, from the aforementioned signs or other features such as dilated and fixed intestine loops and the lack of pathognomonic ileus patterns, the immediate action is to discontinue feeding enterally for at least a week. The platelet and white cell counts are then monitored closely and the patient's abdominal radiographs. The patient's blood is cultured, and they are placed under antibiotics for seven to ten days. In the worst-case scenario, NEC might require a surgical intervention. To ascertain the need for surgery, the patient's initial signs and symptoms have shown no significant improvement (Bell et al., 1978; Walsh & Kliegman, 1986). The abdominal distention and the ileus patterns have persisted, and their laboratory and clinical values such as platelet and neutrophil counts must have declined (Bell et al., 1978; Walsh & Kliegman, 1986). Here the surgical team could perform a laparotomy with resection (Bell et al., 1978; Walsh & Kliegman, 1986).

This systematic review was developed to look at the preventative and corrective measures of suspected or starting NEC rather than treatment measures. However, to understand the workings of supplementation in reducing NEC, it is necessary to understand the pathophysiology of the disease itself. Neu and Walker (2013) posit that the pathophysiology of NEC is not fully comprehended. However, their study further suggests the causes of NEC to be multifactorial. Starting from the point of genetic predisposition, the study weaves to factors such as immature intestines and an imbalanced microvascular tone (Neu & Walker, 2013). Abnormal microbial colonization in GI and prevalent immunoreactive intestinal mucosa further amalgamate these risk factors that predispose patients to NEC (Neu & Walker, 2013). In a separate and later study, Tanner et al. (2015) indicated that the pathophysiology of NEC is secondary to the infant's immunity responding to GI microbiota by the underdeveloped intestinal tract of the neonate. This, therefore, becomes the precursor to bowel inflammation. According to Kim et al. (2019), NEC's major histologic findings include haemorrhages, mucosal oedema, and bland transmural necrosis. Collection of gas in the ileus, secondary bacterial infections, and severe inflammation causes.

Up to this point, the consensus is that premature neonates have underdeveloped intestines just as other organs like the lungs. This immaturity means that they are weaker compared to full-term infants. As a result, premature babies do not have blood circulation or digestion of their food as properly as they should. Similar unfortunate characteristics might be experienced with very-low-birth-weight babies. When the birth weight is very low, their growth restriction and compromised development predispose them to NEC risks (Patel & Shah, 2012). Patel and Shah (2012) identify various risk factors that make premature and very low birth weight infants more susceptible to NEC. Their study outlines mechanical factors that lead to barrier integrity, such as decreased peristalsis, mucus layer deficiency, and composition of lipids which makes the premature bowel more permeable. Additionally, bacterial factors such as paucity of anaerobic bacteria and compromised colonization of bacteria suscept these very low birth weight infants to NEC (Patel & Shah, 2012). Other factors such as decreased levels of lactase, decreased production of gastric acid, and decreased bile acids all contribute to NEC in very low birth weight infants (Patel & Shah, 2012).

The incidence of NEC is not uncommon; thus, it is one to take note of. In the United States, the rate of NEC ranges from 1 per 1000 live births to 3 per 1000 live births (Kim et al., 2019). According to a systematic review and meta-analysis by Alsaied et al. (2020), 7 out of 100 of all very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU) are likely to develop NEC. These numbers add to the necessity of finding more, better, and improved therapeutic measures that give very low birth weight infants a fighting chance in the neonatal intensive care unit. Until recently, probiotic supplementation in reducing NEC has not been a common application. Probiotics are living microorganisms that confer health benefits to a host when administered in certain amounts (Patel & Shah, 2012). Probiotics add to the population of good bacteria in the digestive system. They have been presented in various therapeutic deliberations as an alternative for antibiotics, a statement that Patel and Shah (2012) posit in reference to reducing NEC as well. Sharif et al. (2020) conducted a meta-analysis to investigate the effect of supplemental probiotics on NEC risk factors in this same target population, but the trial designs of the included studies became a limiting factor. The review looked at 56 trials totalling 10,812, including infants. The findings of this meta-analysis did not include conclusive results regarding the effects of supplemental probiotics on NEC, death, and infection. However, from the ana analysis of 56 studies (10,812 infants involved), Sharif et al. (2020) still reported a risk ratio (RR) of 0.76, at a 95% Confidence Interval (CI) [0.65 to 0.89] for the reduction in mortality from NEC. Probiotics were also found to moderately reduce NEC risk: 0.54, 95% CI 0.45 to 0.65 (Sharif et al., 2020). The results of Sharif et al. (2020) did not cover the area aimed by this systematic review: how do supplemental probiotics reduce NEC?

Early agitations to the composition of gut microbiota heighten the risk of NEC. Modulating this microbiota has been an area of interest by various specialists. In a trial to investigate whether probiotic supplementation improves the growth and development of very-low-birth-weight infants, Al-Hosni et al. (2012) discovered that the velocity of growth in very-low-birth-weight infants increases with probiotic supplementation. Al-Hosni et al. (2012) tested 101 infants randomized into two groups probiotics-supplementation group (50) and the control group (51). After 34 weeks of observation, the probiotics-supplementation group had a growth velocity of 14.9g per day versus 12.6g per day in the control group (P = 0.05) (Al-Hosni et al., 2012). The study provided a further rationale for using probiotic supplementation in very-low-birth-weight infants to counter the effects of slowed growth and compromised development, but it also indicated the reliable safety levels of the intervention. In vitro tests conducted on human cell cultures and in vivo tests in mice revealed the reconstructive activities of probiotics in repairing inflamed guts. Strains of Lactobacillus acidophilus bacterium have been cited as necessary for the integrity restoration in an inflamed gut (Beghetti et al., 2021). All this evidence presents strong evidence that supports probiotics in preventing NEC in these low-birth-weight infants. Besides Lactobacillus acidophilus, Beghetti et al. (2021) state that Bifidobacterium lactis Bb-12/B94 had the ability to reduce the risk of NEC. In comparison, Lactobacillus acidophilus had better therapeutic results with an odds ratio of 0.03 at 95% credible intervals (CrIs) 0.00-0.21 (Bechetti et al., 2021). Evidence of effective results being achieved when treating with probiotics has been demonstrated in various other systematic reviews and metanalysis such as Patel & Underwood (2018), Underwood (2019), Neu (2014), among others.

While all these studies have been thorough in covering the effect of probiotics in effectively preventing the risk factors leading to NEC occurrence, there is enough emphasis placed on the general risks and benefits of using probiotics as a treatment option when dealing with NEC. In preparation for this systematic review, there are three target effects that were identified as barely reviewed. The effects of probiotics in preventing death, infection, and reducing NEC damage needed a more focused approach. This systematic review was carried out in the position that more support could be provided to warrant physicians using probiotics as treatment options in the place of antibiotics. The systematic review, therefore, sought to answer the PICO question; in very low birth weight infants (P), how can probiotic supplementation (I) reduce necrotizing enterocolitis (O)?

Methods

Results

Studies were searched from three separate databases and supplemented by a hand search through various systematic reviews and meta-analyses' reference lists. A total of 279 useful studies were discovered. This number was trimmed down to 186 by the Covidence software, which automatically removed duplicates and other ineligible studies. The titles and abstracts of the 186 studies were screened, and 107 studies were eliminated. The full-text screening was done on the remaining 79 studies, and 12 qualified for inclusion. However, several methodological incongruences were considered during data extraction, and two studies (Li et al., 2013; Kanic et al., 2015) got eliminated. This systematic review utilized the ten remaining studies (Shashidhar et al., 2017; Oshiro et al., 2019; Chowdhury et al., 2016; Que et al., 2021; Saengtawesin et al., 2014; Sari et al., 2011; Serce et al., 2013; Oncel et al., 2014; Repa et al., 2015; Strus et al., 2018). The selection process has been summarised in the PRISMA diagram below.

Discussion

The primary target of this systematic review was to identify the action of probiotics reducing the progression of NEC. Incidences of NEC were direct indicators of non-reducing illness. Mortality was the worst outcome possible after treating NEC. Reduced NEC had five observable effects on the participating VLBW infants. These positive outcomes of reduced NEC in VLBW infants were the resumption of full enteral feeding, revitalization of feeding tolerance, increased gut colonization and increased microbiota count, weight gain, and shortened length of hospitalization. Shashidhar et al. (2017) observed the feeding patterns of the infants but did not find any significant differences in the resumption to full enteral feeding [probiotics versus control: 11.2 (8.3) Vs. 12.7 (8.9) days (mean, SD) (P = 0.4)] or improvement to the feeding tolerance. Similar resorts of insignificant difference were reported by Oncel et al. (2014), who found an increasing feeding tolerance favouring probiotics group (28% vs 39.5%; p = 0.015). Sari et al. (2011) observed intolerance to feeding and the probiotics groups had decreased intolerance (44.5% (n: 49) vs 63.1% (n: 70); P = 0.006). On the contrary, Chowdhury et al. (2016) saw significant changes to their feeding tolerance when the infants were treated with probiotics as opposed to none (14.88 ± 3.15 and 18.80 ± 4.32 days; p < 0.001). These findings were supported by Saengtawesin et al. (2014) [12.03 ± 5.49 days vs. 13.76 ± 8.25 days (p = 0.31)], and Serce et al. (2013) (11.9 ± 7 vs 12.6 ± 7 days, p = 0.37).

Strus et al. (2018) explained that episode of feeding intolerance leads to episodes of gastric residuals, regurgitation of food, vomiting, abdominal rigidity, gut motility and abdominal distention, and other disorders of the gut. These disorders are a result of distortion in eh gut microbiota. The introduction of supplemental probiotics improves the gut’s microbiota count and increases gut colonization. Strus et al. 92018) found that 90% of the infants under probiotics has successful gut colonization by the probiotics. The increase in these microbiotas was also observed by Oshiro et al. (2019), who reported raised microbiota counts, which increase the count of beneficial microbiota to 109 cells/g faeces. When Bifidobacterium dominates among the faecal bacteria, they begin to aid the correction of most of these abdominal disorders through breaking down the food, nutrients absorption, and defence against bad disease-causing organisms (Oshiro et al., 2019). These are some crucial abdominal functions of VLBW infants since they are trying to develop faster before they fall victim to their susceptibility to various diseases. By starving off disease-causing bacteria and enabling optimal absorption of nutrients, the growth of these infants increases. Oshiro et al. (2019) observed earlier weight gain within the probiotics group as opposed to the control group.

Discharging patients was the last indicator of a reduction of NEC infection. To determine whether NEC had declined, the physicians continually monitor the radiographs for reseeding signs such as portal venous gas, pneumatosis intestinalis, or free intraperitoneal air (Neu & Walker, 2013). Three studies compared days spent in the hospital to comment on the action of probiotics in halting the progression of NEC in VLBW infants (Chowdhury et al., 2016; Oncel et al., 2014; Que et al., 2021). In the group receiving probiotic supplements in the Chowdhury et al. (2016) study, there was a significantly shorter hospital stay than the placebo (15.82 ± 2.94 days vs 19.57 ± 4.26 days; p < 0.001). Similar significant effects on hospitalization were demonstrated by Onceal et al. (2014), where the study group spent 38 (10–131) days compared to 46 (10–180) days by the placebo group (P = 0.022). In the Que et al. (2021), hospital stay was not significantly different between the two study groups. The probiotic group had a slightly shorter hospital stay than the control group (58 [20–98] days Vs. 52.5 [22–92.25] days (P = 0.42). Observing the P-values of the three studies, Chowdhury et al. (2016) demonstrated the highest significance (P < 0.001). Granted, the treatment modality of the study utilized a variety of probiotics; Lactobacillus rhamnosus GG, L. paracasei, L. casei, L. acidophilus, Lactococcus latis, Bifidobacterium bifidum, B. longum, B. infantis (Chowdhury et al., 2016). These probiotics were packed in the Cap TS6 capsule and administered until the day of discharge.

Besides the disparity in the probiotic’s profiles applied by the three studies, the element of using breast milk in place of formula milk remained constant. Repa et al. (2015) conducted a subgroup analysis and compared the action of probiotics when supplementing breast milk or formula milk. Better therapeutic results were obtained in the breast milk-fed group; VLBW infants receiving probiotic supplements in breast milk experienced an 11.2% (20/179) reduction in NEC incidence. In comparison, the formula milk-fed VLBW infants had a 7.4% (4/54) reduction. The preventive effects of Lactobacillus acidophilus and Bifidobacterium bifidum seem to be dependent on the composition of breast milk (Repa et al., 2015). Human breast milk contains oligosaccharides (carbohydrates with 3 and 10 single sugar residues) that enhance the growth of Lactobacillus acidophilus and Bifidobacterium bifidum. Therefore, the effect of these probiotics in their preventive action against NEC gets enhanced when they are supplementing human breast milk. Formula milk has not only been linked to poorer functioning probiotics, but there are highlights from studies such as Shulhan et al. (2017), listing formula milk as a risk factor for NEC infection.

Conclusion

The benefits of supplemental probiotics in reducing NEC cannot be dismissed. There is evidence from a systematic analysis of 10 studies that supplementing the feeds of VLBW infants with probiotics increases their chances of surviving NEC. Probiotics have demonstrated reliable effectiveness with minimal to no side effects. Using probiotics helps VLBW infants gain increased colonization of microbiota in their guts. This colonization boosts gut health and fosters the healing of the damaged intestines. Once the patient begins to experience a decline in feeding intolerance and manages to resume full enteral feeding, the intervention is considered successful and can be discharged. Almost every study included used a single dosage of probiotic supplementation per day. The findings of this systematic review can therefore be applied to a wide spectrum of VLBW. The major recommendation is to increase breast milk feeding in place of formula milk so as to optimize the treatment outcome. This study is not able to make recommendations regarding the type of probiotics to use in treatment interventions. A very broad set of applicable probiotics has been demonstrated to work efficiently by the included studies. As direct comparisons of individual probiotics do not exist, the recommendation of what probiotic to recommend remains in the hands of the physicians attending to the patients. In the future, randomized trials should concentrate on elucidating this niche by conducting direct comparisons of probiotics to determine the most effective among the available.

Declarations

•       List of abbreviations: Mentioned at first instance. 

•        Ethics approval and consent to participate: Not Applicable

•        Consent for publication: Provided. 

•        Availability of data and materials: Not applicable.

•        Competing interests: None.

•        Funding: None.

•        Authors' contributions: Solo author article.

•        Acknowledgements: None.

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Image 1

Image 1 is available in the Supplementary Files section.