Probiotics for prevention of necrotizing enterocolitis in preterm infants

Khalid AlFaleh; Jasim Anabrees

doi:10.1002/14651858.CD005496.pub4

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Analysis 1.1

Comparison 1 Probiotics versus control (all infants), Outcome 1 Severe necrotising enterocolitis (stage II‐III).

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Analysis 1.2

Comparison 1 Probiotics versus control (all infants), Outcome 2 Culture proven sepsis.

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Analysis 1.3

Comparison 1 Probiotics versus control (all infants), Outcome 3 Mortality.

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Analysis 1.4

Comparison 1 Probiotics versus control (all infants), Outcome 4 Parenteral nutrition duration (days).

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Analysis 1.5

Comparison 1 Probiotics versus control (all infants), Outcome 5 Hospitalization duration (days).

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Analysis 1.6

Comparison 1 Probiotics versus control (all infants), Outcome 6 Weight gain.

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Analysis 1.7

Comparison 1 Probiotics versus control (all infants), Outcome 7 Time to full enteral feeds.

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Analysis 1.8

Comparison 1 Probiotics versus control (all infants), Outcome 8 Death or severe NEC or sepsis.

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Analysis 1.9

Comparison 1 Probiotics versus control (all infants), Outcome 9 Long‐term outcomes.

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Analysis 2.1

Comparison 2 Probiotics versus control (infants < 1500 g), Outcome 1 Severe necrotising enterocolitis (stage II‐III).

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Analysis 2.2

Comparison 2 Probiotics versus control (infants < 1500 g), Outcome 2 Culture proven sepsis.

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Analysis 2.3

Comparison 2 Probiotics versus control (infants < 1500 g), Outcome 3 Mortality.

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Analysis 3.1

Comparison 3 Probiotics versus control (infants < 1000 g), Outcome 1 Severe necrotising enterocolitis (stage II‐III).

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Analysis 3.2

Comparison 3 Probiotics versus control (infants < 1000 g), Outcome 2 Culture proven sepsis.

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Analysis 3.3

Comparison 3 Probiotics versus control (infants < 1000 g), Outcome 3 Mortality.

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Analysis 4.1

Comparison 4 Probiotics versus control (species of probiotic), Outcome 1 Severe NEC‐ Species of probiotics.

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Analysis 4.2

Comparison 4 Probiotics versus control (species of probiotic), Outcome 2 Culture proven sepsis.

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Analysis 4.3

Comparison 4 Probiotics versus control (species of probiotic), Outcome 3 Mortality.

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Analysis 5.1

Comparison 5 Probiotics versus control (time of initiation), Outcome 1 Severe NEC‐ Time of initiation.

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Analysis 5.2

Comparison 5 Probiotics versus control (time of initiation), Outcome 2 Culture proven sepsis.

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Analysis 5.3

Comparison 5 Probiotics versus control (time of initiation), Outcome 3 Mortality.

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Analysis 6.1

Comparison 6 Probiotics versus control (duration of probiotics administration), Outcome 1 Severe NEC‐ The duration of probiotics administration.

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Analysis 6.2

Comparison 6 Probiotics versus control (duration of probiotics administration), Outcome 2 Culture proven sepsis.

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Analysis 6.3

Comparison 6 Probiotics versus control (duration of probiotics administration), Outcome 3 Mortality.

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Analysis 7.1

Comparison 7 Probiotics versus control (high quality studies), Outcome 1 Severe necrotising enterocolitis (stage II‐III).

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Analysis 7.2

Comparison 7 Probiotics versus control (high quality studies), Outcome 2 Culture proven sepsis.

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Analysis 7.3

Comparison 7 Probiotics versus control (high quality studies), Outcome 3 Mortality.

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Comparison 1. Probiotics versus control (all infants)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe necrotising enterocolitis (stage II‐III) Show forest plot	20	5529	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.33, 0.56]

2 Culture proven sepsis Show forest plot	19		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Any sepsis	19	5338	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.80, 1.03]
2.2 Any Bacterial sepsis	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.36, 1.36]
2.3 Any Fungal sepsis	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	5.10 [0.25, 103.60]
3 Mortality Show forest plot	18		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 All causes of neonatal mortality	17	5112	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.52, 0.81]
3.2 NEC related mortality	7	2755	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.18, 0.82]
4 Parenteral nutrition duration (days) Show forest plot	7	2804	Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐0.52, 0.03]

5 Hospitalization duration (days) Show forest plot	11	3713	Mean Difference (IV, Fixed, 95% CI)	‐3.71 [‐4.32, ‐3.11]

6 Weight gain Show forest plot	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 g/week	1	87	Mean Difference (IV, Fixed, 95% CI)	7.20 [‐0.06, 14.46]
6.2 g/day	2	131	Mean Difference (IV, Fixed, 95% CI)	2.14 [0.01, 4.27]
6.3 g/kg/day	2	241	Mean Difference (IV, Fixed, 95% CI)	0.28 [‐0.93, 1.49]
7 Time to full enteral feeds Show forest plot	8	2657	Mean Difference (IV, Fixed, 95% CI)	‐1.32 [‐1.48, ‐1.17]

8 Death or severe NEC or sepsis Show forest plot	1	367	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.37, 0.79]

9 Long‐term outcomes Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 Mental retardation and Cerebral palsy	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.15, 6.94]

Comparison 1. Probiotics versus control (all infants)

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Comparison 2. Probiotics versus control (infants < 1500 g)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe necrotising enterocolitis (stage II‐III) Show forest plot	17	4914	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.31, 0.56]

2 Culture proven sepsis Show forest plot	16		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Any sepsis	16	5154	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.04]
2.2 Any Bacterial sepsis	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.36, 1.36]
2.3 Any Fungal sepsis	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	5.10 [0.25, 103.60]
3 Mortality Show forest plot	17		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 All causes of neonatal mortality	17	5303	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.53, 0.82]
3.2 NEC related mortality	7	2755	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.18, 0.82]

Comparison 2. Probiotics versus control (infants < 1500 g)

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Comparison 3. Probiotics versus control (infants < 1000 g)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe necrotising enterocolitis (stage II‐III) Show forest plot	2	575	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.37, 1.58]

2 Culture proven sepsis Show forest plot	2	1200	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.63, 1.06]

3 Mortality Show forest plot	2	1199	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.58, 1.53]

Comparison 3. Probiotics versus control (infants < 1000 g)

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Comparison 4. Probiotics versus control (species of probiotic)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe NEC‐ Species of probiotics Show forest plot	20		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Lactobacillus	5	1955	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.27, 0.75]
1.2 Bifidobacterium	4	409	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.16, 1.47]
1.3 Saccharomyces boulardii	2	357	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.34, 1.55]
1.4 A mixture of two to three species of probiotics	9	2807	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.25, 0.54]
2 Culture proven sepsis Show forest plot	19		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Lactobacillus	5	1955	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.71, 1.16]
2.2 Bifidobacterium	3	348	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.58, 1.34]
2.3 Saccharomyces boulardii	2	358	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.54, 1.57]
2.4 A mixture of two to three species of probiotics	9	2677	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.06]
3 Mortality Show forest plot	16		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Lactobacillus	4	1734	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.47, 1.10]
3.2 Bifidobacterium	2	271	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.14, 3.60]
3.3 Saccharomyces boulardii	1	271	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.30, 3.40]
3.4 A mixture of two to three species of probiotics	9	2806	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.47, 0.81]

Comparison 4. Probiotics versus control (species of probiotic)

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Comparison 5. Probiotics versus control (time of initiation)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe NEC‐ Time of initiation Show forest plot	16		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Less than 48 hours of age	3	1072	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.23, 1.05]
1.2 More than 48 hours of age	1	319	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.00, 0.90]
1.3 At the time of the first feed	9	2318	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.30, 0.65]
1.4 During the first week when enteral feeds were tolerated	3	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.26, 1.55]
2 Culture proven sepsis Show forest plot	16	4017	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.79, 1.05]

2.1 Less than 48 hours of age	3	1072	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.79, 1.44]
2.2 More than 48 hours of age	1	319	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.12, 0.60]
2.3 At the time of the first feed	10	2459	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.81, 1.14]
2.4 During the first week when enteral feeds were tolerated	2	167	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.58, 1.34]
3 Mortality Show forest plot	14	3838	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.47, 0.79]

3.1 Less than 48 hours of age	3	1072	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.58, 1.17]
3.2 More than 48 hours of age	1	319	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.21, 1.45]
3.3 At the time of the first feed	9	2367	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.26, 0.63]
3.4 During the first week when enteral feeds were tolerated	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.29, 2.64]

Comparison 5. Probiotics versus control (time of initiation)

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Comparison 6. Probiotics versus control (duration of probiotics administration)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe NEC‐ The duration of probiotics administration Show forest plot	16		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Four to six weeks	5	1162	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.13, 0.52]
1.2 More than six weeks or until discharged from NICU	11	2985	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.37, 0.75]
2 Culture proven sepsis Show forest plot	14	3247	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.77, 1.02]

2.1 Four to six weeks	5	1162	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.71, 1.18]
2.2 More than six weeks or until discharged from NICU	9	2085	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.73, 1.04]
3 Mortality Show forest plot	14		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Four to six weeks	4	1075	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.45, 1.00]
3.2 More than six weeks or until discharged from NICU	10	3591	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.49, 0.87]

Comparison 6. Probiotics versus control (duration of probiotics administration)

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Comparison 7. Probiotics versus control (high quality studies)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe necrotising enterocolitis (stage II‐III) Show forest plot	11	4473	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.31, 0.59]

2 Culture proven sepsis Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Any sepsis	10	4323	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.77, 1.04]
3 Mortality Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 All causes of neonatal mortality	10	4386	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.55, 0.91]
3.2 NEC related mortality	4	2298	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.20, 1.09]

Comparison 7. Probiotics versus control (high quality studies)

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