Microbiome-targeting therapies in the neonatal intensive care unit: safety and efficacy

Figures & data

Table 1. Probiotic interventions with efficacy against selected outcomes as supported by moderate to high certainty evidence and statistically significant differences between the treatment and at least one other treatment and placebo in pooled analyses (from Figure 2 in Morgan et al.³¹

Intervention	Outcome	References
Combination of Lactobacillus spp. and Bifidobacterium spp.	All-cause mortality	Lin et al.^Citation126 Lin et al.^Citation127 Samanta et al.^Citation128 Rougé et al.^Citation129 Braga et al.^Citation130 Al-Hosni et al.^Citation49 Roy et al.^Citation131 Saengtawesin et al.^Citation132 Van Niekerk et al.^Citation133
Bifidobacterium animalis subsp. lactis	NEC occurrence	Mihatsch et al.^Citation134 Stratiki et al.^Citation135 Hays et al.^Citation136 Dilli et al.^Citation114
Combination of Lactobacillus spp. and Bifidobacterium spp.		Lin et al.^Citation126 Lin et al.^Citation127 Samanta et al.^Citation128 Rougé et al.^Citation129 Braga et al.^Citation130 Al-Hosni et al.^Citation49 Roy et al.^Citation131 Saengtawesin et al.^Citation132 Van Niekerk et al.^Citation133
Combination of Lactobacillus spp., Bifidobacterium spp., and Saccharomyces boulardii	Days to reach full feeds	Shashidhar et al.^Citation137 Hariharan et al.^Citation138 Arora et al.^Citation139
Bifidobacterium animalis subsp. lactis	Duration of hospitalization	Mihatsch et al.^Citation134 Stratiki et al.^Citation135 Hays et al.^Citation136 Dilli et al.^Citation114
Lactobacillus reuteri		Romeo et al.^Citation140 Rojas et al.^Citation141 Indrio et al.^Citation142 Oncel et al.^Citation143 Hernández-Enríquez et al.^Citation144

Table 2. Effects of Bifidobacterium animalis subsp. lactis on NEC risk and/or duration of hospitalization (DOH).

Study	Country	NEC (Bell stage ≥ II) frequency (no. with event divided by no. in treatment arm)		Average duration of hospitalization (days)		Registered	Sequence generation & Allocation concealment	Data collectors/outcome assessors blinded	Year last enrolled participant	Primary Outcome(s)	Comments^1
		Treatment	Control	Treatment	Control
Stratiki et al.^Citation135	Greece	0/41	3/36	NA	NA	No	Low risk	Clinical staff were blinded as to treatment status, but blinding of outcome assessors not specified in text.	2005	Intestinal permeability	NEC stated as secondary outcome
Mihatsch et al.^Citation134	Germany	2/91	4/89	31.1	30.8	No	Low risk	Blinding of caregivers and investigators not specified in text.	2003	Nosocomial infections	NEC stated as secondary outcome
Dilli et al.^Citation114	Turkey	2/100*	18/100*	37*	50*	Yes (NCT01807858)^‡	Low risk	The study is described as double blind in the methods, and the authors provide assurance that the staff and families were not aware of the treatment or control status of the infants. However, they also state that “ … the only personnel who knew of the infants’ group assignments were the investigators,” but do not provide specific assurance that the treatment assignment was concealed to the outcome assessors.	2014	NEC	DOH stated as secondary outcome
Hays et al.^Citation136	France	2/50	3/52	“The mean duration of hospitalization was 50.4 ± 17.4 days, which was similar for both treatment groups.”		Yes (NCT01379417)^‡	Low risk	The investigators knew infants’ group assignments.	2010	Short-term postnatal growth and body composition	Outcome category unclear but not primary; secondary outcome was safety of probiotic administration

NA = not available.

*Difference in outcome between treatment and control arms was significant.

Table 3. Effects of Lactobacillus reuteri on duration of hospitalization (DOH).

Study	Country	Sample size		Average duration of hospitalization (days)		Registered	Sequence generation & Allocation concealment	Data collectors/outcome assessors blinded	Year last enrolled participant	Primary Outcome(s)	Comments
		Treatment	Control	Treatment	Control
Romeo et al.^Citation140	Italy	83	83	17.8	31.3	No	The three arms had different dosing regimens and were, therefore, not concealed to the staff or families.	UTD	2007	Incidence of enteric fungal colonization and fungal and bacterial infections	Outcome category unclear but not primary
Rojas et al.^Citation141	Colombia	372	378	20.0	20.0	Yes (NCT00727363)^‡	Low risk	UTD	2011	Death or nosocomial infection	DOH stated as secondary outcome. Subgroup analysis demonstrated that this outcome was significant for infants with birth weight <1500 g.
Oncel et al.^Citation143	Turkey	200	200	38*	46*	Yes (NCT01531179)^‡	Low risk	Low risk	2013	NEC or death	DOH stated as secondary outcome
Hernández-Enríquez et al.^Citation144	Mexico	24	20	39.3	50.6	No	Low risk	The neonatologists who diagnosed and classified necrotizing enterocolitis knew the group allocation.	2013	NEC	Outcome category unclear but not primary
Indrio et al.^Citation142	Italy	30	30	13.4*	22.4*	Yes (NCT00985816)^‡	Low risk	Low risk	2012	Feeding tolerance	DOH stated as secondary outcome

NA = not available.

UTD = unable to be determined based on information provided.

*Difference in outcome between treatment and control arms was significant.

Table 4. Effects of a combination of Lactobacillus spp., Bifidobacterium spp., and Saccharomyces boulardii on days to reach full feed.

Study	Country	Treatment	Sample size		Average days to reach full feed		Registered	Sequence generation & Allocation concealment	Data collectors/outcome assessors blinded	Year last enrolled participant	Primary Outcome(s)	Comments
			Treatment	Control	Treatment	Control
Hariharan et al.^Citation138	India	L. acidophilus, B. bifidum, S. boulardii	93	103	23.6*	32.4*	No	UTD randomization method	UTD	UTD	Time to achieve oral feeds	Abstract only
Arora et al.^Citation139	India	L. rhamnosus, L. acidophilus, B. longum, S. boulardii	75	75	8.53	10.7	No	UTD randomization method	UTD	2016	NEC	Days to reach full feed stated as secondary outcome
Shashidhar et al.^Citation137	India	L. rhamnosus, L. acidophilus, B. longum, S. boulardii	48	48	11.2	12.7	Yes (CTRI/2012/08/002853)^¶	Low risk	Low risk	2013	Time to full enteral feeding

NA = not available.

UTD = unable to be determined based on information provided.

*Difference in outcome between treatment and control arms was significant.

Table 5. Effects of a combination of Lactobacillus spp. and Bifidobacterium spp. on NEC occurrence and/or all-cause mortality.

Study	Country	Treatment	Mortality (no. with event divided by no. in treatment arm)		NEC (Bell stage ≥ II) frequency (no. with event divided by no. in treatment arm)		Registered	Sequence generation & Allocation concealment	Data collectors/outcome (NEC) assessors blinded	Year last enrolled participant	Primary Outcome(s)	Comments
			Treatment	Control	Treatment	Control
Lin et al.^Citation126	Taiwan	L. acidophilus, B. infantis	7/180*	20/187*	2/180*	10/187*	No	Low risk	The investigators knew the infants’ group assignments, but NEC was diagnosed by individuals who were not aware of the allocation of the participants.	2003	NEC or death	Efficacy not reported by birthweight of participants
Lin et al.^Citation127	Taiwan	L. acidophilus, B. bifidum	2/217^†	9/217^†	4/217	14/217	Yes (NCT00540033)^‡	Low risk	The investigators knew the infants’ group assignments, but NEC was diagnosed by individuals who were not aware of the allocation of the participants.	2007	NEC or death	Protective effect not apparent in children whose birth weights were ≤ 1,000 g
Samanta et al.^Citation128	India	B. infantis, B. bifidum, B. longum, B. acidophilus	4/91*	15/95*	5/91*	15/95*	No	Low risk	UTD	2008	NEC, sepsis, death, days to reach full feed, DOH were co-primary outcomes	P-values not corrected for multiple comparisons
Rougé et al.^Citation129	France	B. longum BB536, L. rhamnosus GG	2/45	4/49	1/45	2/49	Yes (NCT00290576)^‡	Low risk	UTD	2007	Percent of infants receiving more than half of their nutritional needs enterally	Mortality but not NEC stated as secondary outcome
Braga et al.^Citation130	Brazil	L. casei, B. breve	26/119	27/112	0/119	4/112	Yes (67165178)^§	Low risk	Low risk	2008	NEC	P-value for efficacy in preventing NEC was 0.054
Al-Hosni et al.^Citation49	United States	L. rhamnosus GG, B. infantis	3/50	4/51	3/50	4/51	Yes (NCT01164124)^‡	UTD randomization method	UTD	2009	Growth velocity, weight gain, volume of feeding	Outcome category unclear but not primary
Roy et al.^Citation131	India	L. acidophilus, B. longum, B. bifidum, B. lactis	7/56	8/56	2/56	2/56	Yes (CTRI REF/2012/12/004378)^¶	Low risk	UTD	2013	Incidence of enteric fungal colonization	NEC stated as secondary outcome
Saengtawesin et al.^Citation132	Thailand	L. acidophilus, B. bifidum	0/31	0/29	1/31	1/29	No	Low risk	UTD	2013	NEC
Van Niekerk et al.^Citation133	South Africa	L. rhamnosus GG, B. infantis	2/54 (HIV-unexposed)	5/56 (HIV-unexposed)	0/54 (HIV-unexposed)	2/56 (HIV-unexposed)	Yes (NCT01868737)^‡	Low risk	Low risk	2012	NEC
			3/37 (HIV-exposed)	1/37 (HIV-exposed)	0/37 (HIV-exposed)	2/37 (HIV-exposed)

UTD = unable to be determined based on information provided.

* Difference in outcome between treatment and control arms was significant.

† Difference in incidence of death not attributable to NEC was significant.

Table 6. Year at which the last participant of the study was enrolled.

Intervention	Outcome	Year last participant enrolled
Bifidobacterium animalis subsp. lactis	NEC, duration of hospitalization	2014, 2010, 2005, 2003
Lactobacillus reuteri	Duration of hospitalization	2013, 2013, 2012, 2011, 2007
Lactobacillus spp., Bifidobacterium spp., and Saccharomyces boulardii	Days to reach full feed	2016, 2013
Lactobacillus spp. and Bifidobacterium spp.	NEC, all-cause mortality	2013, 2013, 2012, 2009, 2008, 2008, 2007, 2007, 2003
All studies		Median: 201.5 (11.5 years ago), IQR: 9–15 years; Mean: 2009.85 (12.15 years ago), SDL 3.73 years

**If the outcome cited in Morgan et al.³¹ was categorized as primary or secondary in the original paper, we noted it as such. If the outcome was not specifically designated as secondary in a paper in which another outcome was primary, we described it as outcome category unclear, but not primary.

^‡https://clinicaltrials.gov/. There should not be a “.” after this url as it causes problems when pasting it into a browser.

^¶ctri.nic.in. There should not be a “.” after this url as it causes problems when pasting it into a browser.

^§isrctn.com. There should not be a “.” after this url as it causes problems when pasting it into a browser.

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