Table 1.
Characteristics of randomized controlled trials evaluating probiotics, prebiotics, and synbiotics for NEC.
| Author | Year | Country of origin | Sample size | Participant details | Details of intervention, probiotic species, and strains | Main finding |
|---|---|---|---|---|---|---|
| Probiotic interventions | ||||||
| Al-Hosni et al. (52) | 2012 | USA | 101 | ELBW | LGG, B. infantis | No significant difference in incidence of NEC |
| Arora et al. (53) | 2017 | India | 150 | GA ≤ 34 wk | S. boulardii, L. rhamnosus, L. acidophilus, B. longum | Reduced incidence and severity of NEC |
| Awad et al. (54) | 2010 | Egypt | 150 | PT admitted to NICU | L. acidophilus, Living and Killed | Reduced incidence of NEC Killed retained similar benefits to live bacteria |
| Benor et al. (55) | 2014 | Israel | 49 | Mothers of VLBW infants | L. acidophilus and B. lactis | Reduced incidence of NEC and in stage 2 NEC |
| Bin-Nun et al. (56) | 2005 | Israel | 145 | BW ≤ 1,500 g | B. infantis, S. thermophilus, and B. bifidus | Reduced both incidence and severity of NEC |
| Braga et al. (57) | 2011 | Brazil | 231 | VLBW, BW 750–1,500 g | L. casei, B. breve | Reduced incidence of NEC (stage ≥2) |
| Chandrashekar et al. (58) | 2018 | India | 145 | GA <34 wk | L. acidophilus, L. rhamnosus, B. longum, and S. boulardii | Reduced incidence and severity of NEC |
| Chowdhury et al. (59) | 2016 | Bangladesh | 119 | VLBW, GA 28–33 wk | LGG, L. paracasei, L. casei, L. acidophilus, L. lactis, B. bifidum, B. longum, B. infantis | Reduced incidence of NEC |
| Costeloe et al. (60) | 2016 | UK | 1310 | GA 23–30 wk | B. breve BBG-001 | No evidence of benefit |
| Dani et al. (61) | 2002 | Italy | 585 | GA <33 wk or BW <1,500 g | LGG | Non-significant reduction in incidence of NEC |
| Dashti et al. (62) | 2014 | Iran | 136 | BW 700–1,800 g | L. acidophilus, L. rhamnosus, L. bulgaricus, L. casei, S. thermophilus, B. longum, B. breve | No evidence of benefit |
| Demirel et al. (63) | 2013 | Turkey | 271 | BW ≤ 1,500 g GA ≤ 32 wk | S. boulardii | No significant difference in incidence of NEC |
| Dongol-Singh et al. (64) | 2017 | Nepal | 72 | Hospitalized PT | L. rhamnosus LCR35 | Trend toward reduction in incidence of NEC |
| Fernández-Carrocera et al. (65) | 2013 | Mexico | 150 | BW <1,500 g | L. rhamnosus, L. casei, L. plantarum, L acidophilus, B. infantis, S. thermophilus | Trend toward reduction in incidence of NEC |
| Gomez-Rodriguez et al. (66) | 2019 | USA | 90 | ELBW and VLBW (700–1,500 g) | L. acidophilus boucardii versus mix of L. acidophilus, L. rhamnosus, L. casei, L. plantarum, B. infantis, and S. thermophilus | No difference between use of single strain or multispecies probiotics on NEC incidence |
| Hays et al. (67) | 2015 | France | 199 | GA 25–31 wk, BW 700–1,600 g | B. lactis or B. longum or both | Incidence rates of NEC similar in the two groups |
| Hernández-Enríquez et al. (68) | 2016 | Mexico | 44 | GA <34 wk or BW ≤1,550 g | L. reuteri DSM 17938 | Reduced incidence of NEC |
| Hoyos et al. (69) | 1999 | Colombia | 1237 | NICU | L. acidophilus and B. infantis | Reduced incidence of NEC and NEC-associated fatalities |
| Jacobs et al. (70) | 2013 | Australia and New Zealand | 1099 | GA <32 wk, BW <1,500 g | B. infantis, S. thermophilus, B. lactis | Reduced incidence of NEC of stage 2 or more |
| Janvier et al. (71) | 2014 | USA | 611 | GA <32 wk, NICU | B. breve, B. bifidum, B. infantis, B. longum, L. rhamnosus HA-111 | Reduced incidence of NEC |
| Kaban et al. (72) | 2019 | Indonesia | 94 | GA 28–34 wk, BW 1,000–1,800 g | L. reuteri DSM 17938 | Trend to reduction in incidence of NEC |
| Lin et al. (73) | 2005 | Taiwan | 367 | VLBW | L. acidophilus, B. infantis (Infloran®) | Reduced incidence and severity of NEC |
| Lin et al. (74) | 2008 | Taiwan | 434 | VLBW | B. bifidum, L. acidophilus | Reduced incidence of NEC |
| Oncel et al. (75) | 2014 | Turkey | 424 | BW ≤ 1,500 g, GA ≤ 32 wk | L. reuteri DSM 17938 | No significant difference in incidence of NEC |
| Rojas et al. (76) | 2012 | Colombia | 750 | PT, BW ≤ 2,000 g | L. reuteri DSM 17938 | Non-significant decrease in incidence of NEC |
| Saengtawesin et al. (77) | 2014 | Thailand | 60 | BW ≤ 1,500 g, GA ≤ 34 wk | L. acidophilus, B. bifidum (Infloran®) | No difference in incidence of NEC stage ≥2 |
| Samanta et al. (78) | 2009 | India | 186 | Very PT or VLBW | B. infantis, B. bifidum, B. longum, L. acidophilus | Reduced morbidity due to NEC |
| Sari et al. (79) | 2011 | Turkey | 221 | BW <1,500 g, GA <33 wk | L. sporogenes | No significant difference in incidence of death or NEC |
| Serce et al. (80) | 2013 | Turkey | 208 | GA ≤ 32 wk, BW ≤ 1,500 g | S. boulardii | Did not decrease the incidence of NEC |
| Shadkam et al. (81) | 2015 | Iran | 60 | GA 28–34 wk, BW 1,000–1,800 g | L. reuteri DSM 17938 | Reduced incidence of NEC |
| Shashidhar et al. (82) | 2017 | India | 104 | BW ≤ 1,500 g | L. acidophilus, L. rhamnosus, B. longum, S. boulardii | Trend toward lower incidence NEC |
| Van Niekerk et al. (83) | 2015 | South Africa | 184 | GA <34 wk and VLBW (<1,250 g) | Pro-B2: LGG and B. infantis | Reduced incidence of NEC in VLBW but not in HIV-exposed infants |
| Wang et al. (84) | 2014 | China | 100 | FT in NICU | L. casei, L. acidophilus, B. subtilis and E. faecalis | No significant difference in the incidence of NEC |
| Zampieri et al. (85) | 2013 | Italy | 32 | BW 600–1,500 g with stage 2 NEC | L. paracasei subsp. paracasei F-19 | Reduced clinical progression of NEC |
| Prebiotic interventions | ||||||
| Armanian et al. (86) | 2014 | Iran | 75 | BW ≤ 1,500 g, GA ≤ 34 wk | scGOS/lcFOS | Reduced incidence of NEC |
| Dasopoulou et al. (87) | 2015 | Greece | 167 | PT admitted to NICU | scGOS/lcFOS | No significant difference in incidence of NEC |
| Dilli et al. (88) | 2015 | Turkey | 400 | VLBW | Inulin | No significant difference in incidence of NEC |
| Manzoni et al. (89) | 2009 | Italy | 743 | VLBW | Lactoferrin | Reduced incidence of ≥stage 2 NEC and of death |
| Riskin et al. (90) | 2010 | Israel | 28 | GA 23–34 wk | Lactulose | Fewer episodes of lower stage NEC |
| Synbiotic interventions | ||||||
| Dilli et al. (88) | 2013 | Turkey | 100 | Infants with cyanotic congenital heart disease | B. lactis plus inulin | Reduced incidence of NEC |
| Dilli et al. (91) | 2015 | Turkey | 400 | VLBW | B. lactis plus inulin | Probiotic alone and synbiotic but not prebiotic alone reduced incidence of NEC |
| Guney-Varal et al. (92) | 2017 | Turkey | 110 | GA ≤ 32 wk and BW ≤ 1,500 g | L. rhamnosus, L. casei, L. plantarum, B. animalis plus FOS and GOS | Reduced the incidence of NEC and mortality rate |
| Manzoni et al. (89) | 2009 | Italy | 743 | VLBW | LGG plus lactoferrin | Reduced incidence of ≥stage 2 NEC and of death |
| Nandhini et al. (93) | 2016 | India | 220 | GA 23–34 wk, BW >1,000 g | PREPRO HS®—L. acidophilus, B. longum, L. rhamnosus, L. plantaris, L. casei, L. bulgaricus, B. infantis, and B. breve plus FOS | Reduced incidence of NEC, did not reduce severity of NEC |
VLBW, very low birth weight; wk, weeks; ELBW, extremely low birth weight; GA, gestational age; BW, birth weight; PT, preterm; FT, full term; GOS, galacto-oligosaccharides; FOS, fructo-oligosaccharides; scGOS, short-chain galacto-oligosaccharides; lcFOS, long-chain fructo-oligosaccharides. Search Strategy: We searched PubMed and CENTRAL in May 2021 with the search terms “premature” or “prematurity” and “probiotic” or “prebiotic” or “synbiotic” and “necrotizing enterocolitis.” Publication type: “clinical trial” and “randomized controlled trial.” The RCT was excluded if only the abstract was available.