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Meta-Analysis
. 2020 Oct 15;10(10):CD005496.
doi: 10.1002/14651858.CD005496.pub5.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants

Sahar Sharif  1 , Nicholas Meader  1 , Sam J Oddie  1   2 , Maria Ximena Rojas-Reyes  3 , William McGuire  1
Affiliations
Meta-Analysis

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants

Sahar Sharif et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity. OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants.

Search methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.

Selection criteria: We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants.

Data collection and analysis: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment.

Main results: We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence).

Authors' conclusions: Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.

Trial registration: ClinicalTrials.gov NCT01315821 NCT00977912 NCT01181791 NCT01375309 NCT02552706.

PubMed Disclaimer

Conflict of interest statement

SS is funded by the UK National Institute of Health Research (NIHR) for the review.

NM: the UK NIHR pays a grant to NM's institution.

MXRR has no interest to declare.

SO: the UK NIHR pays a grant to SO's institution. (SR‐PG 13/89/12).

WM: the UK NIHR pays a grant to WM's institution. WM is co‐coordinating editor of Cochrane Neonatal.

Figures

1
1
Study flow diagram: review update 2020
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Probiotics versus control, outcome: 1.1 Necrotising enterocolitis.
4
4
Funnel plot of comparison: 1 Probiotics versus control, outcome: 1.1 Necrotising enterocolitis.
5
5
Forest plot of comparison: 1 Probiotics versus control, outcome: 1.2 Mortality.
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6
Funnel plot of comparison: 1 Probiotics versus control, outcome: 1.2 Mortality.
1.1
1.1. Analysis
Comparison 1: Probiotics versus control, Outcome 1: Necrotising enterocolitis
1.2
1.2. Analysis
Comparison 1: Probiotics versus control, Outcome 2: Mortality
1.3
1.3. Analysis
Comparison 1: Probiotics versus control, Outcome 3: Invasive infection
1.4
1.4. Analysis
Comparison 1: Probiotics versus control, Outcome 4: Duration of birth hospitalisation (days)
1.5
1.5. Analysis
Comparison 1: Probiotics versus control, Outcome 5: Severe neurodevelopmental impairment
1.6
1.6. Analysis
Comparison 1: Probiotics versus control, Outcome 6: Cerebral palsy
1.7
1.7. Analysis
Comparison 1: Probiotics versus control, Outcome 7: Visual impairment
1.8
1.8. Analysis
Comparison 1: Probiotics versus control, Outcome 8: Hearing impairment
1.9
1.9. Analysis
Comparison 1: Probiotics versus control, Outcome 9: Continuous early learning composite measure
2.1
2.1. Analysis
Comparison 2: Probiotics versus control (extremely preterm or ELBW), Outcome 1: Necrotising enterocolitis
2.2
2.2. Analysis
Comparison 2: Probiotics versus control (extremely preterm or ELBW), Outcome 2: Mortality
2.3
2.3. Analysis
Comparison 2: Probiotics versus control (extremely preterm or ELBW), Outcome 3: Invasive infection
2.4
2.4. Analysis
Comparison 2: Probiotics versus control (extremely preterm or ELBW), Outcome 4: Duration of birth hospitalisation (days)
3.1
3.1. Analysis
Comparison 3: Subgroup analysis by type of feeding, Outcome 1: Necrotising enterocolitis
3.2
3.2. Analysis
Comparison 3: Subgroup analysis by type of feeding, Outcome 2: Mortality
3.3
3.3. Analysis
Comparison 3: Subgroup analysis by type of feeding, Outcome 3: Invasive infection
3.4
3.4. Analysis
Comparison 3: Subgroup analysis by type of feeding, Outcome 4: Duration of birth hospitalisation (days)
4.1
4.1. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 1: Necrotising enterocolitis
4.2
4.2. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 2: Mortality
4.3
4.3. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 3: Invasive infection
4.4
4.4. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 4: Duration of birth hospitalisation (days)
4.5
4.5. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 5: Severe neurodevelopmental impairment
4.6
4.6. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 6: Cerebral palsy
4.7
4.7. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 7: Visual impairment
4.8
4.8. Analysis
Comparison 4: Sensitivity analyses: Risk of bias, Outcome 8: Hearing impairment
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Samanta 2009 {published data only}
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Sari 2011 {published data only}
    1. 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. European Journal of Clinical Nutrition 2011;65(4):434-9. [DOI: 10.1038/ejcn.2010.278] [PMID: ] - DOI - PubMed
    1. Sari FN, Eras Z, Dizdar EA, Erdeve O, Oguz SS, Uras N, et al. Do oral probiotics affect growth and neurodevelopmental outcomes in very low-birth-weight preterm infants? American Journal of Perinatology 2012;29(8):579-86. [DOI: 10.1055/s-0032-1311981] [DOI: 10.1055/s-0032-1311981] [PMID: ] - DOI - DOI - PubMed
Serce 2013 {published data only}
    1. Serce O, Benzer D, Gursoy T, Karatekin G, Ovali F. Efficacy of saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: a randomised controlled trial. Early Human Development 2013;89(12):1033–6. [DOI: 10.1016/j.earlhumdev.2013.08.013] [PMID: ] - DOI - PubMed
    1. Serce O, Gursoy T, Ovali F, Karatekin G. Effects of Saccharomyces boulardii on neonatal hyperbilirubinemia: a randomized controlled trial. American Journal of Perinatology 2015;30(2):137-42. [DOI: 10.1055/s-0034-1376390] [PMID: ] - DOI - PubMed
Shadkam 2015 {published data only}
    1. Shadkam MN, Jalalizadeh F, Nasiriani K. Effects of probiotic lactobacillus reuteri (DSM 17938) on the incidence of necrotizing enterocolitis in very low birth weight premature infants. Iranian Journal of Neonatology 2015;6(4):15-20. [DOI: 10.22038/IJN.2015.6143] - DOI
Shashidhar 2017 {published data only}
    1. Shashidhar A, Suman Rao PN, Nesargi S, Bhat S, Chandrakala BS. Probiotics for promoting feed tolerance in very low birth weight neonates - a randomized controlled trial. Indian Pediatrics 2017;54(5):363-7. [DOI: 10.1007/s13312-017-1106-2] [PMID: ] - DOI - PubMed
Stratiki 2007 {published data only}
    1. Stratiki Z, Costalos C, Sevastiadou S, Kastanidou O, Skouroliakou M, Giakoumatou A, et al. The effect of a bifidobacteria supplemented bovine milk on intestinal permeability of preterm infants. Early Human Development 2007;83(9):575–9. [DOI: 10.1016/j.earlhumdev.2006.12.002] [PMID: ] - DOI - PubMed
Strus 2018 {published data only}
    1. Strus M, Helwich E, Lauterbach R, Rzepecka-Węglarz B, Nowicka K, Wilińska M, et al. Effects of oral probiotic supplementation on gut Lactobacillus and Bifidobacterium populations and the clinical status of low-birth-weight preterm neonates: a multicenter randomized, double-blind,placebo-controlled trial. Infection and Drug Resistance 2018;11:1557-71. [DOI: 10.2147/IDR.S166348] [PMID: ] - DOI - PMC - PubMed
Tewari 2015 {published data only}
    1. Tewari VV, Dubey SK, Gupta G. Bacillus clausii for prevention of late-onset sepsis in preterm infants: a randomized controlled trial. Journal of Tropical Pediatrics 2015;61:377–85. [DOI: 10.1093/tropej/fmv050] [PMID: ] - DOI - PubMed
Totsu 2014 {published data only}
    1. Totsu S, Terahara M, Kusuda S. Probiotics and the development of very low birthweight infants: follow-up study of a randomised trial. BMJ Paediatrics Open 2018;2(1):e000256. [DOI: 10.1136/bmjpo-2018-000256] [PMID: ] - DOI - PMC - PubMed
    1. Totsu S, Yamasaki C, Terahara M, Uchiyama A, Kusuda S, Probiotics Study Group in Japan. Bifidobacterium and enteral feeding in preterm infants: cluster-randomized trial. Pediatrics International 2014;56(5):714-9. [DOI: 10.1111/ped.12330] [PMID: ] - DOI - PMC - PubMed
Van Niekerk 2014 {published data only}
    1. Van Niekerk E, Kirsten GF, Nel DG, Blaauw R. Probiotics, feeding tolerance, and growth: a comparison between HIV-exposed and unexposed very low birth weight infants. Nutrition 2014;30(6):645-53. [DOI: 10.1016/j.nut.2013.10.024] [PMID: ] - DOI - PubMed
Wang 2007 {published data only}
    1. Wang C, Shoji H, Sato H, Nagata S, Ohtsuka Y, Shimizu T, et al. Effects of oral administration of bifidobacterium breve on fecal lactic acid and short-chain fatty acids in low birth weight infants. Journal of Pediatric Gastroenterology and Nutrition 2007;44(2):252-7. [DOI: 10.1097/01.mpg.0000252184.89922.5f] [PMID: ] - DOI - PubMed
Wejryd 2019 {published data only}
    1. Wejryd E, Marchini G, Frimmel V, Jonsson B, Abrahamsson T. Probiotics promoted head growth in extremely low birthweight infants in a double-blind placebo-controlled trial. Acta Paediatrica 2019;108(1):62-9. [DOI: 10.1111/apa.14497] [PMID: ] - DOI - PubMed
Zeber‐Lubecka 2016 {published data only}
    1. Zeber-Lubecka N, Kulecka M, Ambrozkiewicz F, Paziewska A, Lechowicz M, Konopka E, et al. Effect of Saccharomyces boulardii and mode of delivery on the early development of the gut microbial community in preterm infants. PLOS One 2016;11(2):e0150306. [DOI: 10.1371/journal.pone.0150306] [PMID: ] - DOI - PMC - PubMed

References to studies excluded from this review

Arora 2017 {published data only}
    1. Arora S, Khurana MS, Saini R. To study the role of probiotics in the prevention of necrotizing enterocolitis in preterm neonates. International Journal of Contempary Pediatrics 2017;4(5):6. [DOI: 10.18203/2349-3291.ijcp20173787] - DOI
Awad 2010 {published data only}
    1. Awad H, Mokhtar H, Imam SS, Gad GI, Hafez H, Aboushady N. Comparison between killed and living probiotic usage versus placebo for the prevention of necrotizing enterocolitis and sepsis in neonates. Pakistan Journal of Biological Sciences 2010;13(6):253-62. [DOI: 10.3923/pjbs.2010.253.262] [PMID: ] - DOI - PubMed
Chi 2019 {published data only}
    1. Chi C, Xue Y, Liu R, Wang Y, Lv N, Zeng H, et al. Effects of a formula with a probiotic Bifidobacterium lactis supplement on the gut microbiota of low birth weight infants. European Journal of Nutrition 2019;59(4):1493–503. [DOI: 10.1007/s00394-019-02006-4] [PMID: ] - DOI - PubMed
Dasopoulou 2015 {published data only}
    1. Dasopoulou M, Briana DD, Boutsikou T, Karakasidou E, Roma E, Costalos C, et al. Motilin and gastrin secretion and lipid profile in preterm neonates following prebiotics supplementation: a double-blind randomized controlled study. Journal of Parenteral and Enteral Nutrition 2015;39(3):359-68. [DOI: 10.1177/0148607113510182] [PMID: ] - DOI - PubMed
Deng 2010 {published data only}
    1. Deng J, Chen K. Early minimal feeding combined with probiotics to prevent necrotizing enterocolitis in preterm infant. Chinese Journal of Modern Drug Application 2010;4(6):13-4.
Denkel 2016 {published data only}
    1. Denkel LA, Schwab F, Garten L, Geffers C, Gastmeier P, Piening B. Protective effect of dual-strain probiotics in preterm infants: a multi-center time series analysis. PLOS One 2016;11(6):e0158136. [DOI: 10.1371/journal.pone.0158136] [PMID: ] - DOI - PMC - PubMed
Di 2010 {published data only}
    1. Di M, Li X. Effects of Bifidobacterium supplementation for prevention of necrotizing enterocolitis in preterm infants: a randomized, controlled trial. Zhong Guo She Qu Yi Shi 2010;231:69.
Dongol‐Singh 2017 {published data only}
    1. Dongol Singh S, Klobassa DS, Resch B, Urlesberger B, Shrestha RP. Placebo controlled introduction of prophylactic supplementation of probiotics to decrease the incidence of necrotizing enterocolitis at Dhulikhel Hospital in Nepal. Kathmandu University Medical Journal 2017;15(60):319-23. [PMID: ] - PubMed
Hua 2014 {published data only}
    1. Hua X-T, Tang J, Mu D-Z. Effect of oral administration of probiotics on intestinal colonization with drug resistant bacteria in preterm infants [口服益生菌对早产儿肠道耐药菌定植的影响]. Chinese Journal of Contempoary Pediatrics 2014;16(6):606-9. [PMID: ] - PubMed
Hussain 2016 {published data only}
    1. Hussain M, Jabeen S, Subhani RU. Role of probiotics in prevention of necrotizing enterocolitis in preterm low birth weight neonates. Pakistan Journal of Medicine and Health Sciences 2016;10:455-9.
Kaban 2019 {published data only}
    1. Kaban RK, Hegar B, Rohsiswatmo R, Handryastuti S, Amelia N, Muktiarti D, et al. Lactobacillus reuteri DSM 17938 improves feeding intolerance in preterm infants. Pediatric Gastroenterology, Hepatology & Nutrition 2019;22(6):545-53. [DOI: 10.5223/pghn.2019.22.6.545] [PMID: ] - DOI - PMC - PubMed
Ke 2008 {published data only}
    1. Ke D, Su Z, Li L. Effects of Bifido supplement for prevention of necrotizing enterocolitis in preterm infants: a randomized controlled trial. Chinese Pediatric Emergency Medicine 2008;12:69-71.
Koksal 2015 {published data only}
    1. Köksal N, Varal İ, Özkan H, Bagcı O, Doğan P. Effect of probiotic support on feeding intolerance and mortality at preterm infants. In: Journal of Perinatal Medicine. Vol. 43. 2015:P-0612.
Moles 2015 {published data only}
    1. Moles L, Escribano E, De Andres J, Montes MT, Rodriguez JM, Jimenez E, et al. Administration of Bifidobacterium breve PS12929 and Lactobacillus salivarius PS12934, two strains isolated from human milk, to very low and extremely low birth weight preterm infants: A pilot study. Journal of Immunology Research 2015;2015:538171. [DOI: 10.1155/2015/538171] [PMID: ] - DOI - PMC - PubMed
Partty 2013 {published data only}
    1. Partty A, Luoto R, Kalliomaki M, Salminen S, Isolauri E. Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial. Journal of Pediatrics 2013;163:1272-7. [DOI: 10.1016/j.jpeds.2013.05.035] [PMID: ] - DOI - PubMed
Qiao 2017 {published data only}
    1. Qiao LX, Zhu WY, Zhang HY, Wang H. Effect of early administration of probiotics on gut microflora and feeding in pre-term infants: arandomized controlled trial. Journal of Maternal-Fetal & Neonatal Medicine 2017;30(1):13-6. [DOI: 10.3109/14767058.2016.1163674] [PMID: ] - DOI - PubMed
Rojas 2012 {published data only}
    1. 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 Nov;130(5):e1113-20. [DOI: 10.1542/peds.2011-3584] [PMID: ] - DOI - PubMed
Romeo 2011 {published data only}
    1. Romeo MG, Romeo DM, Trovato L, Oliveri S, Palermo F, Cota F, et al. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. Journal of Perinatology 2011;31(1):63–9. [DOI: 10.1038/jp.2010.57] [PMID: ] - DOI - PMC - PubMed
Shujie 2011 {published data only}
    1. Shujie Y, Haiying Y, Bin G, Shu X, Xianglan D, Jiang W. The clinical application value of endangered preterm infants given earlier amounts of micro feedings and adding probiotics. Journal of Pediatric Pharmacy 2011;17:21-4.
Sinha 2015 {published data only}
    1. Sinha A, Gupta SS, Chellani H, Maliye C, Kumari V, Arya S, et al. Role of probiotics VSL#3 in prevention of suspected sepsis in low birthweight infants in India: a randomised controlled trial. BMJ Open 2015;5(7):e006564. [DOI: 10.1136/bmjopen-2014-006564] [PMID: ] - DOI - PMC - PubMed
Thanhaeuser 2014 {published data only}
    1. Thanhaeuser M, Repa A, Weber M, Endress D, Kreissl A, Binder C, et al. Probiotics (infloran) for NEC prevention: Influence of enteral nutrition. In: Archives of Disease in Childhood. 5th Congress of the European Academy of Paediatric Societies, EAPS 2014, Barcelona, Spain. Vol. 99. 2014:A176-7.
Uhlemann 1999 {published data only}
    1. Uhlemann M, Heine W, Mohr C, Plath C, Pap S. Effects of oral administration of bifidobacteria on intestinal microflora in premature and newborn infants newborn infants. Zeitschrift fur Geburtshilfe und Neonatologie 1999;203(5):213-7. [PMID: ] - PubMed
Underwood 2014 {published data only}
    1. Underwood MA, Kalanetra KM, Bokulich NA, Mirmiran M, Barile D, Tancredi DJ, et al. Prebiotic oligosaccharides in premature infants. Journal of Pediatric Gastroenterology and Nutrition 2014;58(3):352-60. [DOI: 10.1097/MPG.0000000000000211] [PMID: ] - DOI - PubMed
Xu 2016 {published data only}
    1. Xu L, Wang Y, Wang Y, Fu J, Sun M, Mao Z et al. A double-blinded randomized trial on growth and feeding tolerance with Saccharomyces boulardii CNCMI-745 in formula-fed preterm infants. Jornal de Pediatria 2016;92(3):296-301. [DOI: 10.1016/j.jped.2015.08.013] [PMID: ] - DOI - PubMed
Zhou 2012 {published data only}
    1. Zhou N. The observation of effect of probiotics in the prevention of neonatal necrotizing enterocolitis. Chinese Journal of Ethnomedicine and Ethnopharmacy 2012;21:81.
Zhuang 2007 {published data only}
    1. Zhuang X-Y, Li X-Y, Gao X-X, Su L-D. Relative factors of neonatal necrotizing enterocolitis and preventive effect of microeco-preparation. Journal of Applied Clinical Pediatrics 2006;22:1392-3.

References to studies awaiting assessment

Coleta 2013 {published data only}
    1. Coleta E, Gheonea M, Sarbu M. Oral supplementation with probiotics in premature infants-a randomised clinical trial. In: Intensive Care Medicine. 24th Annual Meeting of the European Society of Paediatric and Neonatal Intensive Care edition. Vol. 39. Rotterdam, Netherlands, 2013:S113.
Punnahitananda 2006 {unpublished data only}ISRCTN39142169
    1. Punnahitananda S, Thaithumyanon P, Soongsawang K. Nosocomial infection and necrotizing enterocolitis in preterm neonates treated with Lactobacillus acidophilus and Bifidobacterium infantis in a neonatal intensive care unit: a randomized controlled study. In: 14th Congress of the Federation of Asia Oceania Perinatal Societies. Bangkok, Thailand, 2006.

References to ongoing studies

Marisen 2019 {published data only}
    1. Marisen J, Hais A, Meyer C, Van Rossum T, Bunte LM, Frommhold D, et al. Efficacy of Bifidobacterium longum, B. infantis and Lactobacillus acidophilus probiotics to prevent gut dysbiosis in preterm infants of 28+0-32+6 weeks of gestation: a randomised, placebo-controlled, double-blind, multicentre trial: the PRIMAL Clinical Study protocol. BMJ Open 2019;9(11):e032617. [DOI: 10.1136/bmjopen-2019-032617] [PMID: ] - DOI - PMC - PubMed
NCT00977912 {unpublished data only}
    1. NCT00977912. Necrotizing enterocolitis (Nec) and B. Lactis in premature babies [Prevention of NEC in preterm Infants with B. lactis]. clinicaltrials.gov/ct2/show/NCT00977912 (first received 16 September 2009).
NCT01181791 {unpublished data only}
    1. NCT01181791. Effects of Lactobacillus reuteri in premature infants (reuteri) [Pilot study to evaluate the effects of Lactobacillus reuteri in preterm newborns]. clinicaltrials.gov/ct2/show/NCT01181791 (first received 13 August 2010).
NCT01375309 {unpublished data only}
    1. NCT01375309. Bifidobacterium supplementation for very low birth weight infants (Bifido(RCT)) [Effect of bifidobacterium bifidum supplementation on morbidity of very low birth weight infants]. clinicaltrials.gov/ct2/show/NCT01375309 (first received 17 June 2011).
NCT04541771 {published data only}
    1. NCT04541771. The role of Lactobacillus reuteri in preventing necrotizing enterocolitis (NEC) in pre-term infants (NEC) [The role of Lactobacillus reuteri (L. reuteri) in preventing necrotizing enterocolitis (NEC) in pre-term infants less than 34 weeks of gestation]. clinicaltrials.gov/ct2/show/NCT04541771 (first received 9 September 2020).

Additional references

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