|Year : 2019 | Volume
| Issue : 1 | Page : 1-5
Supplementation of Lactobacillus acidophilus in prevention of necrotizing enterocolitis in preterm newborns
Sonia G Al Sharkawy, Amany M El-Kelany, Mohamed A Al Said
Department of Pediatrics, Faculty of Medicine, Suez Canal University, Ismilia, Egypt
|Date of Submission||16-Feb-2019|
|Date of Acceptance||01-Apr-2019|
|Date of Web Publication||9-Sep-2019|
Amany M El-Kelany
Pediatrics Department, Faculty of Medicine, Suez Canal University, 4.5 Km the Ring Road, Ismailia, 41522
Source of Support: None, Conflict of Interest: None
Background Necrotizing enterocolitis (NEC) is a serious worldwide health problem in preterm neonates, especially those with very low birth weight. Probiotics may play a role in prevention of NEC and NEC-related mortality.
Aim The aim of this study was to evaluate the possible role of Lactobacillus acidophilus in reducing the incidence of NEC (Bell’s stage≥2) and NEC-related mortality.
Patients and methods A prospective, blinded, randomized controlled trial was conducted at NICU of Suez Canal University Hospital, Egypt. We studied 100 preterm (≤34 weeks of gestational age) neonates who survived to feed, and they were assigned randomly into two equal groups. The intervention group received L. acidophilus at the first feeding twice daily for 6 weeks or discharge from NICU and the control group did not. Clinicians responsible for the neonates were blinded to the group assignment.
Results Probiotic supplementation was associated with significant reduction in incidence of NEC (P<0.05) but did not reduce NEC-related mortality (P=1). Infants in the probiotic group had less gastrointestinal intolerance manifestations than the control group (P=0.027).
Conclusion Oral L. acidophilus can reduce the occurrence of NEC (Bell’s stage≥2) and gastrointestinal intolerance manifestations in preterm neonates.
Keywords: necrotizing enterocolitis, preterm, probiotics
|How to cite this article:|
Al Sharkawy SG, El-Kelany AM, Al Said MA. Supplementation of Lactobacillus acidophilus in prevention of necrotizing enterocolitis in preterm newborns. Alex J Pediatr 2019;32:1-5
|How to cite this URL:|
Al Sharkawy SG, El-Kelany AM, Al Said MA. Supplementation of Lactobacillus acidophilus in prevention of necrotizing enterocolitis in preterm newborns. Alex J Pediatr [serial online] 2019 [cited 2020 Jan 20];32:1-5. Available from: http://www.ajp.eg.net/text.asp?2019/32/1/1/266412
| Introduction|| |
The main goal of enteral nutrition given to preterm neonates is to achieve growth similar to fetal growth with satisfactory functional development . Preterm neonates have incomplete ability to digest and absorb nutrients owing to the physiological intestinal immaturity, which may contribute to the occurrence of necrotizing enterocolitis (NEC) . NEC is the most serious gastrointestinal problem of preterm infants that can rapidly progress from gastrointestinal dysfunction to bowel perforation, causing significant risk of morbidity and mortality plus high economic costs needed for short-term and long-term care of survivors .
Suspicion of NEC can be triggered by many nonspecific signs such as abdominal tenderness or distention, feeding intolerance, bloody stools, and apnea. The definite signs of NEC include pneumatosis intestinalis and portal venous gas, which are revealed by radiographs . Early-onset NEC occurs at a mean of 7 days compared with 32 days for late-onset NEC . Bell’s staging criteria were developed to better classify and diagnose NEC using nonspecific and definite signs and symptoms of NEC: suspected NEC is stage 1, proven NEC as stage 2, and severe cases as stage 3 ,.
Probiotics were first described in the literature by Lilly and Stillwell  as growth-promoting factors produced by certain microorganisms. Probiotic bacteria are live microbial supplements delivered enterally. They colonize the gastrointestinal tract and can improve its mucosal defenses and potentially provide benefit to the host . Recently, probiotics have been used throughout the world for many indications; one of these indications is to reduce the risk of NEC and death in preterm infants .
The use of probiotics as preventive therapy in preterm newborns was recommended by meta-analyses , but evidence to suggest the use of specific type of probiotics and optimum dose to prevent NEC is still at level 2a (Evidence-Based on systematic reviews with homogeneity of cohort studies) .
| Aim|| |
The primary objective of this study was to evaluate the role of supplementation with probiotic Lactobacillus acidophilus in the prevention of NEC and NEC-related mortality. The secondary objective is to assess the effect of probiotics on time needed to reach full feeding (130–150 ml/kg/day).
| Patients and methods|| |
A prospective, single-blinded, simple, randomized controlled clinical trial was conducted in NICU at Suez Canal University Hospital, Ismailia, Egypt, from May 2015 to May 2017. The calculated sample size with a 10% dropout was 110 preterm newborn infants, who were assigned into two equal groups: 55 were allocated to the probiotics group and 55 to the control group. During the study, five patients dropped out from each group, so the total sample actually studied was 100 infants.
The study included preterm neonate (≤34 weeks of gestation) who had an Apgar score at 5 min more than 7, negative CRP at admission, survived to start enteral feeding.
Congenital anomalies, metabolic acidosis in first 48 h, and inborn error of metabolism were the exclusion criteria.
The study protocol was approved by the Medical Ethics Committee of Faculty of Medicine, Suez Canal University. Written informed parental consent consistent with the ethical principles of the International Conference of Harmonization guidelines, Good Clinical Practice, was obtained.
All neonates in the study were given enteral feeding, according to enteral feeding protocol of Manual of Neonatal Care 2008 . Freshly expressed mother’s breast milk is the feed of choice, followed by mixed feeding (breast milk and preterm formula). Formula is used only when breast milk is unavailable or insufficient.
Infants in the study group were given L. acidophilus, 1×109 CFU/day, added to milk twice daily for 6 weeks or till discharge from NICU. Lactobacillus GG was prepared by Rameda Company (Giza, Egypt). The capsules were opened and contents dispersed in 2-ml distilled water before administration. For the control group, sterile distilled water (placebo) was given twice daily until discharged.
All patients in the study were followed closely for signs and symptoms of NEC (NEC was classified in accordance with Bell’s criteria , modified by Walsh and Kliegman ) and were carefully examined with each feed for gastrointestinal symptoms and signs, such as vomiting, regurgitation, abdominal distension, characteristics of the feces, and gastric residual vomiting.
Statistical analysis was performed using SPSS software version 21 (IBM Crop, Armonk, NY). Categorical variables are stated as frequencies and percent, and comparison between studied groups was done using χ2.
Continuous variables were expressed as mean and SD, and according to the normality of data, comparison between groups was done using either t-test or Mann–Whitney test. P value less than or equal 0.05 was considered statistically significant.
| Results|| |
The baseline characteristics of preterm infants are reported in [Table 1]. Both groups were comparable regarding weight, gestational age, sex, type of feeding, and mode of delivery.
|Table 1 Baseline characteristics of studied preterm infants in the experimental and control group|
Click here to view
Enteral feeding was initiated at a similar postnatal age in both the probiotic (3.3±0.95 days) and control (3.0±0.79 days) groups. The time to reach full enteral feeding was not significantly different between the two groups. There was no statistically significant difference between both groups regarding cause of admission. The most common presenting complaint was respiratory distress followed by jaundice ([Table 1]).
[Table 2] shows that there was no significant association between the type of feeding and the incidence of NEC among studied preterm neonates, with P value more than 0.05. However, the incidence of NEC was significantly higher among neonates with a birth weight less than 1500 g, with P value less than 0.05.
|Table 2 Comparison between necrotizing enterocolitis and non-necrotizing enterocolitis cases according to weight and type of feeding|
Click here to view
The incidence of definite NEC (stage II–III) was significantly lower in the probiotic group compared with the control group. Newborns supplemented with probiotics had fewer gastrointestinal symptoms (such as vomiting, regurgitation, and abdominal distension), with P=0.029. There was no reduction in the incidence of death related to NEC in the probiotic group (100%) compared with the control group (100%), with P=1. All preterm with severe NEC in both groups died. There was no significant difference between the probiotic group and control group in mortality not related to NEC. The incidence of death not related to NEC was seen in 6/50 (12%) infants in the case group versus 8/50 (16%) infants in the control group ([Table 3]).
| Discussion|| |
Definite NEC (stage 2 and stage 3) is a potentially disastrous illness in preterm neonates, with significant mortality (≥20–25%) and morbidity, including surgical intervention and resultant short bowel syndrome with its consequences such as recurrent sepsis and dependence on total parenteral nutrition .
Probiotics are now used throughout the world for many indications. It has been suggested that probiotics could become an effective tool to prevent severe NEC (Bell stage≥2) and decrease mortality in preterm infants .
This study showed efficacy of probiotics containing L. acidophilus in reducing the incidence of NEC and NEC-related mortality and improving gastrointestinal tolerance, with significant reduction in time to reach full oral feeding, among preterm infants less than 34 weeks of gestation.
Regarding reduction in the incidence of NEC and its related mortality, the significant reduction in incidence of NEC and NEC-related mortality in the probiotic group was proved in this study. Moreover, Lin et al.  reported in a multicenter study in Taiwan that the incidence of NEC stage 2 was significantly lower in infants weighing 1001–1500 g (P<0.02) in the probiotic group than control group, but they found that the incidence of death not attributable to NEC was significantly lower in probiotics-treated group in comparison with the placebo group (P<0.04) . Review of meta-analysis and systematic review who studied the efficacy of oral probiotics in the prevention of NEC and subsequent mortality revealed that enteral supplementation of probiotics prevents severe NEC and NEC-related mortality ,,.
Probiotics may prevent NEC by prevention of gut colonization by pathogenic organisms , acceleration of the maturity and function of gut mucosal barrier, and modulating the immune system to the advantage of the host such as IgA production and control of the balance of proinflammatory and anti-inflammatory cytokines . These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection . Moreover, probiotics have a beneficial effect through protection of intestinal epithelial cells from oxidative stress . Its effect on innate intestinal host defenses by strengthening tight junctions, increasing mucous secretion, enhancing intestinal motility, and reducing the proinflammatory mediators is responsible for the reduction of intestinal tissue damage .
Regarding the reduction in time needed to reach full feeding, our results were in agreement with Rouge et al.  who found the time to reach full enteral feeding in preterm infants more than 1000 g who received oral supplementation with probiotics supplementation was significantly shortened (P=0.04), with improvement in gastrointestinal tolerance than control group.
Shortening the time to reach full enteral feeding plus better gastrointestinal tolerance is a desirable and important objective that accelerates feeding schedules for all preterm infants and decreases the need for parenteral nutrition, with its possible well-known complications.
Decreased manifestations of gastrointestinal intolerance reported in the present study is consistent with the results of three earlier studies using different types of probiotics (Lactobacillus reuteri and Lactobacillus sporogenes). They compared feeding intolerance episodes between preterm infants (weight≤1500 g) who received probiotic and placebo. Feeding intolerance episodes were significantly lower in probiotics group ,,.
Improved gastrointestinal tolerance in probiotics-supplemented preterms may be owing to significant increased gastric emptying rate, reduced fasting antral area, its effect on mucus production, and improving intestinal motility ,.
This study showed that the incidence of NEC is not significantly reduced by type of milk used. Despite in other studies, human milk feeding (mothers’ own milk and pasteurized donor human milk) had been shown to reduce the incidence of NEC but cannot eradicate it ,.
Several studies have investigated the relation between NEC and birth weight. They found that the most frequent risk factors associated with NEC were prematurity and low birth weight ,. In this study, very low birth weight played a significant role in susceptibility to NEC.
| Conclusion|| |
The use of probiotics appears to be effective in the prevention of NEC in preterm neonates. L. acidophilus can improve gastrointestinal tolerance to enteral feeding, but it does not decrease time to reach full feeding.
This research was supported by Suez Canal Faculty of Medicine.
Financial support and sponsorship
There are no conflicts of interest.
Conflicts of interest
| References|| |
Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T et al.
Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010; 50:85–91.
Bernardo WM, Aires FT, Carneiro RM, de Sá FP, Rullo VE, Burns DA. Effectiveness of probiotics in the prophylaxis of necrotizing enterocolitis in preterm neonates: a systematic review and meta-analysis. J Pediatr (Rio J) 2013; 89:18–24.
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364:255–264.
Buonomo C. The radiology of necrotizing enterocolitis. Radiol Clin North Am 1999; 37:1187–1198.
Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants; Canadian Neonatal Network. Pediatrics 2012; 129:298.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187:1.
Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33:179–201.
Lilly DM, Stillwell RH. Probiotics: growth-promoting factors produced by microorganisms. Science 1965; 147:747–748.
Millar M, Wilks M, Costeloe K. Probiotics for preterm infants? Arch Dis Child Fetal Neonatal Ed 2003; 88:F354–F358.
Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010; 125:921–930.
Frost BL, Caplan MS. Probiotics and prevention of neonatal necrotizing enterocolitis. Curr Opin Pediatr 2011; 23:151–155.
Murguía-Peniche T, Mihatsch WA, Zegarra J, Supapannachart S, Ding ZY, Neu J. Intestinal mucosal defense system, Part 2.Probiotics and prebiotics. J Pediatr 2013; 162:64–71.
Ellard D, Anderson DM. Nutrition. In: Cloherty JP, Eichenwald EC, Stark AR, editors. Manual of Neonatal Care. 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2008. pp. 114–136.
Papillon S, Castle SL, Gayer CP, Ford HR. Necrotizing enterocolitis: contemporary management and outcomes. Adv Pediatr 2013; 60:263–279.
Lin HC, Hsu CH, Chen HL. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008; 122:693–700.
AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014; 9:584–671.
Kim SY, Woo HK, Kim EK, Jung YH, Koh J, Song IG, Influence of routine probiotic supplementation on the incidence of necrotizing enterocolitis and late onset sepsis. Neonatal Med 2016; 23:88–94.
Martin CR, Walker WA. Probiotics: role in pathophysiology and prevention in necrotizing enterocolitis. Semin Perinatol 2008; 32:127–137.
Tao Y, Drabik KA, Waypa TS. Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells. Am J Physiol Cell Physiol 2006; 290:C1018–C1030.
Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, Hammerman C. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005; 147:192–196.
Rougé C, Piloquet H, Butel MJ. Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2009; 89:1828–1835.
Rojas MA, Lozano JM, Rojas MX, Rodriguez VA, Rondon MA, Bastidas JA et al.
Prophylactic probiotics to prevent death and nosocomial infection in preterm infants. Pediatrics 2012; 130:e1113–e1120.
Sari FN, Dizdar EA, Oguz S, Erdeve O, Uras N, Dilmen U. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr 2011; 65:434.
Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr 2008; 152:801–806.
Commane DM, Shortt CT, Silvi S, Cresci A, Hughes RM, Rowland IR. Effects of fermentation products of pro-and prebiotics on trans-epithelial electrical resistance in an in vitro model of the colon. Nutr Cancer 2005; 51:102–109.
Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2007; 4:CD002971.
Uberos J, Aguilera-Rodríguez E, Jerez-Calero A, Molina-Oya M, Molina-Carballo A, Narbona-López E. Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants. Br J Nutr 2017; 117:994–1000.
[Table 1], [Table 2], [Table 3]