Effect of probiotics on necrotizing enterocolitis in preterm infants: a network meta-analysis of randomized controlled trials

Dai, Yu; Yu, Qinlei; Zhang, Fan; Ma, Ke; Yan, Xiangyun; Chen, Wenjuan; Chen, Xiaohui; Li, Shushu; Han, Shuping

doi:10.1186/s12887-025-05469-z

Table 1 Characteristics of the included studies

From: Effect of probiotics on necrotizing enterocolitis in preterm infants: a network meta-analysis of randomized controlled trials

Study	Country	Sample size	Control	Intervention (Daily dosage)	Length of intervention(from/to)		Outcomes
Taciana D 2011	USA	231	blank	B.breve + L.casei (3.5 × 10⁷ to 3.5 × 10⁹ CFU)	2 days	29 days	1	2		4
Lingfen X 2016	China	125	blank	S.boulardii CNCM I-745 (10⁹ CFU twice daily)	< 7 days	> 7 days or discharge	1	2	3		5
ALONA 2005	Israel	145	blank	B.infantis + S.thermophilus + B.bifidus (each 0.35 × 10⁹ CFU)	feeding starts	36 weeks postconceptual age	1	2		4	5
Dilek D 2015	Turkey	400	placebo	B.lactis (5 × 10⁹ CFU)	2–3 days	discharge	1	2	3	4	5
				prebiotic (inulin, 900 mg)
				B.lactis (5 × 109 CFU) + prebiotic (inulin, 900 mg)
Kate C 2016	UK	1315	placebo	B.breve BBG-001 (8.2 to 9.2 log₁₀ CFU)	as soon as possible	36 weeks postmenstrual age or discharge	1	2	3	4	5
Stephane H 2015	France	199	placebo	B.lactis (1 × 10⁹ CFU)	1 week	4/6 weeks		2
				B.longum (1 × 10⁹ CFU)
				B.lactis + B.longum (1 × 10⁹ CFU)
Costalos 2003	Greece	87	placebo	S.boulardii (10⁹ CFU twice daily)	3.2 days	30 days				4	5
Manzoni 2006	Italy	80	blank	L.rhamnosus (6 × 10⁹ CFU)	3 days	6 weeks or discharge		2	3	4	5
Shashidhar 2017	India	104	blank	L.acidophilus + L.rhamnosus + B.longum + S.boulardii (1.25 × 10⁹ CFU)	2 days	mean 26.3 days	1	2	3	4
Elaheh A 2017	Iran	60	blank	S.thermophilus + L.rhamnosus + L.acidophilus + L.bulgaricus + B.infantis + L.casei. (1 × 10⁹ CFU)		13.2 days		2
Carlo D 2002	Italy	585	placebo	L.rhamnosus GG (6 × 10⁹ CFU)	feeding starts	discharge		2			5
W.A.M 2010	Germany	183	placebo	B.lactis 12 × 10⁹ CFU/kg/day	feeding starts	7–35 days	1	2		4
M.A.H 2012	USA	101	blank	L.rhamnosus GG + B.infantis (each species 500 million CFU)	the first enteral feeding	34 weeks postmenstrual age or discharge	1	2			5
G.A.J 2022	Australia	173	REF group(PANTS)	B.breve M-16 V (3 × 10⁹ CFU)	mean 3 days	discharge	1	2			5
G.A.J 2022	Australia	173	REF group(PANTS)	B.breve M-16 V + B.longum subsp. infantis M-63 + B.longum subsp. longum BB536 (each species 1 × 10⁹ CFU)	mean 3 days	discharge	1	2			5
O.S.P 2020	Turkey	248	placebo	820 million L.rhamnosus + 410 million L.plantarum + 410 million L.casei + 410 million B.lactis + 383 mg fructooligosaccharide + 100 mg galactooligosaccharide + 2 mg bovine lactoferrin + 25 mg vitamin C + 8 mg vitamin E + 0.5 mg vitamin B1, B2 and B6	feeding starts	discharge	1	2	3		5
Chowdhury 2016	Bangladesh	120	blank	Bifidobacterium spp. + Lactobacillus (each species 3 × 10⁹ CFU)	feeding starts	discharge, at least 10 days		2	3	4
Gamze D 2013	Turkey	271	blank	S.boulardii (5 billion CFU)	feeding starts	discharge	1	2	3	4	5
S Dongol Singh S 2017	Nepal	72	blank	L.rhamnosus 35 (0.8 mg in infants > 1500 g and 0.4 mg in infants < 1500 g in 2 ml of expressed breast milk two times daily)	3 days	30 days	1	2
Fernández 2013	Mexico	150	blank	L.acidophilus (1.0 × 10⁹ CFU/g) + L.rhamnosus (4.4 × 10⁸ CFU/g) + L.casei (1.0 × 10⁹ CFU/g) + L.plantarum (1.76 × 10⁸ CFU/g) + B.infantis (2.76 × 10⁷ CFU/g) + S.thermophillus (6.6 × 10⁵ CFU/g)	median 5 days	median 38 days	1	2	3	4
Moumita S 2009	India	186	blank	B.infantis + Bifidobacteria bifidum + B.longum + L.acidophilus (2.5 billion CFU twice daily)	mean 5.97 days	discharge	1	2	3	4	5
E.V.N 2015	South Africa	184	HIV-unexposed placebo	HIV-unexposed L.rhamnosus + B.infantis (each species 0.35 × 10⁹ CFU)	feeding starts	28 days		2		4	5
				HIV-exposed Placebo
				HIV-exposed L.rhamnosus GG + B.infantis (each species 0.35 × 10⁹ CFU)
V.V.T 2015	India	244	Very preterm placebo	Very preterm Bacillus clausii (2.4 × 10⁹ CFU)	day 5 in asymptomatic and day 10 in symptomatic neonates	6 weeks or discharge	1	2			5
				Extreme preterm placebo
				Extreme preterm Bacillus clausii (2.4 × 10⁹ CFU)
Havranek 2013	USA	31	placebo	L.rhamnosus + B.infantis (each species 500 million CFU)	mean 9.4 days	34 weeks or discharge				4
M Strus 2018	Poland	181	placebo	L.rhamnosus KL53A + B.breve PB04 (1 × 10⁶ CFU)		6 weeks or discharge	1	2			5
Susan E 2013	Australia	1099	placebo	B.infantis + S.thermophilus + B.lactis (1 × 10⁹ CFU)	mean 5 days	40 weeks or discharge	1	2	3	4	5
Risma K 2019	Indonesia	94	placebo	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	feeding starts	discharge, at least 7 days	1	2	3	4	5
H.C.L 2005	China	367	blank	L.acidophilus + B.infantis (each species 1 × 10⁹ CFU, twice daily)	mean 7.7 days	discharge		2			5
H.C.L 2008	China	443	blank	L.acidophilus + B.infantis (each species 10⁹ CFU, twice daily)	mean 4.5 days	6 weeks	1	2	3	4	5
Erik W 2018	Sweden	134	placebo	L.reuteri DSM 17,938 (1.25 × 10⁸ CFU)	< 3 days	gestational week 36 + 0	1	2		4	5
Mazyar V 2020	Iran	106	placebo	B.infantis + Lactobacillus rhamnosus + L.reuteri + fructooligosaccharide (2.5 × 10⁸ CFU)	1.83 ± 0.580 days	discharge			3	4
Belal A 2022	Canada	62	blank	B.breve HA-129 + B.bifidum HA-132 + B.longum subsp + infantis HA-116 + B.longum subsp + longum HA-135 + L.rhamnosus HA-111 (4 billion CFU)		37 weeks corrected gestational age/discharge			3	4	5
L.P.N 2015	India	220	blank	L.acidophilus (700 million CFU) + B.longum (400 million CFU) + L.rhamnosus (400 million CFU) + L.plantaris (300 million CFU) + L.casei (300 million CFU) + L.bulgaricus (300 million CFU) + B.infantis (300 million CFU) + B.breve (300 million CFU) + 100 mg fructooligosaccharide	feeding starts			2	3	4	5
Satsuki T 2014	Japan	283	placebo	B.bifidum OLB6378 (2.5 × 10⁹ CFU)	< 21 days		1	2	3	4	5
Flavia I 2017	Italy	60	placebo	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	48 h	30 days			3	4
Marwyn S 2022	South Africa	200	placebo	L.acidophilus + B.bifidum + B.infantis (each species 0.67 billion CFUs)		28 days				4
M.Y.O 2014	Turkey	424	placebo	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	feeding starts	discharge	1	2	3	4	5
M.Y.O 2015	Turkey	316	nystatin (100,000 U/ml every 8 h)	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	feeding starts	discharge	1	2	3	4	5
İpek Güney V 2017	Turkey	119	blank	L.rhamnosus (4.1 × 10⁸ CFU) + L.casei (8.2 × 10⁸ CFU) + L.plantorum (4.1 × 10⁸ CFU) + B.animalis (4.1 × 10⁸ CFU) + 383 mg ructooligosaccharides + 100 mg galactooligosaccharides	feeding starts	discharge	1	2		4	5
M.A.R 2012	USA	750	blank	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	as early as possible	discharge	1	2	3		5
Sanjay P 2014	Australia	159	placebo	B.breve M-16 V (3 × 10⁹ CFU)	feeding starts	corrected age of 37 weeks	1	2	3	4	5
Sourabh D 2015	India	149	placebo	high dose, long course (10 × 10⁹ CFU)	72 h	long course 21 days, short course 1–14 days	1	2			5
				high dose, short course (10 × 10⁹ CFU)	72 h
				low dose, long course (1 × 10⁹ CFU)	93.5 h
Ghasem B 2021	Iran	76	placebo	B.lactis (1 × 10⁹ CFU)	< 24 h			2	3
Mahtab M 2022	Iran	78	placebo	Probiotic-mothers: L.paracasei (1.5 × 10⁹ CFU/g)		28 days	1		3	4	5
Mahtab M 2022	Iran	78	placebo	Probiotic-infants: L.paracasei (1.5 × 10⁹ CFU/g)		28 days	1		3	4	5
Gamze D 2013	Turkey	181	nystatin (100,000 U/ml every 8 h)	S. boulardii (5 × 10⁹ CFU)	feeding starts	discharge	1	2	3
Zlatka K 2015	Slovenia	80	blank	L.acidophilus + E.faecium + B.infantum (1.5:1:1.5, 0.6 × 10⁷ CFU twice daily)			1	2	3	4	5
Xuewei C 2019	China	114	blank	L.reuteri DSM 17,938 (1 × 10⁸ CFU)	feeding starts	discharge			3	4	5
Varaporn S 2014	Thailand	60	blank	L.acidophilus + B.bifidum (1 × 10⁹ CFU, twice a day)	feeding starts	6 weeks or discharge	1	2	3	4	5
FN Sari 2011	Turkey	221	blank	L.sporogenes (3.5 × 10⁸ CFU)	feeding starts	discharge	1	2		4	5
Ozge S 2013	Turkey	208	placebo	S.boulardii (0.5 × 10⁹ cell/kg, twice daily)	feeding starts	discharge	1	2	3	4	5
M.N.S 2015	Iran	60	blank	L.reuteri DSM 17,938 (20 million/kg every 12 h)	mean 3.2 days	feeding at 120 ml/kg per day	1			4	5
Manish Rasania 2023	India	123	blank	L.rhamnosus GG 6 × 10⁹ CFU	feeding starts	4 weeks or corrected age of 36 weeks	1	2	3	4	5
Manish Rasania 2023	India	123	blank	L.rhamnosus GG 2 × 10⁹ CFU	feeding starts	4 weeks or corrected age of 36 weeks	1	2	3	4	5

The study’s first author, publication date, region, study population, intervention, and primary outcomes are described. Primary outcome 1 was mortality; primary outcome 2 was the incidence of necrotizing enterocolitis (at or beyond Bell Stage II); primary outcome 3 was the length of hospital stay; primary outcome 4 was the time to reach full feeding; primary outcome 5 was the incidence of culture-proven sepsis

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