Table 2.

Characteristics, efficacy and safety of clinical trials investigating the role of probiotics in reducing risk of any preterm delivery.

Ref.	Study				Ingredient, Daily Dose	Main Results	Comments
	Objective	Design	Population/Sample Size	Duration
Gille et al. 2016 [145]	To assess whether probiotic supplementation with Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 can improve maternal vaginal microbiota	RCT, DB, PC	Healthy pregnant women (first trimester) from Germany, n = 320, 2010–2012	8 weeks to assess Nugent scores; entire pregnancy for PTB (secondary outcome)	Capsules with 109 CFU, once daily	Compared to placebo, DHA supplementation resulted in No effect on vaginal microbiota (improvement in Nugent scores). No effect on PTB rates.	Low rate of preterm of 4% Very low rate of bacterial vaginosis 3%. Trend increase on miscarriages in treated (7.7% vs. 3.1%, p = 0.08).
Luoto et al. 2010 [146]	To assess whether dietary counselling and probiotic supplementation with (Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12) can improve pregnancy outcomes	RCT, PC 3 groups: (1) Probiotics and dietary counselling vs. (2) Placebo and dietary counselling (DB); (3) Placebo without dietary counselling (SB)	Healthy pregnant women in the first trimester from Finland, n = 256, late 1990s	From the first antenatal visit to the end of pregnancy	Capsules with 1010 CFU, once daily	Compared to placebo, probiotic supplementation resulted in 1. No effect on PTB rate.2. No effect on duration of gestation.	Very low rate of PTB: 1.7%.
Kraus Silva 2011 et al. [143]	To assess whether probiotic supplementation with (L. rhamnosus GR-1 and L. reuteri RC-14) can reduce BV and PTB	RCT, DB, PC	Pregnant women (8 to 20 weeks gestation), With asymptomatic BV: Vaginal pH >4.5, Nugent >4 from Brazil n = 644 randomized, late 1990s	<20 weeks gestation to 24 or 26 weeks	Capsules with 106 colony-forming units each, twice daily	Compared to placebo, probiotics supplementation resulted in no effect on PTB rate. However, the PTB rates were lower with treatment (ITT: 1.6%, 5 in 304; vs. 3.3% 10 in 301)	Low rate of PTB 2.5% Low probiotics dose Exclusion criteria were very broad: previous history of PTB, hypertension, diabetes, asthma, cervical incompetence, atypical vaginal bleeding, atypical vaginal secretion, HPV, gonorrhea, syphilis, dysuria, pruritus, burning, corticotherapy, recent antibiotic therapy (within 8 weeks prior to screening)
Rautava et al. 2012 [148]	The effect of maternal administration of probiotics on atopic disease in infants.	RCT, DB, PC.	Pregnant women with atopic sensitization and either a history of or active allergic disease from Finland n = 241	Probiotics given to the mother 8 weeks before and 8 weeks after delivery.	(1) Dietary food supplement with Lactobacillus rhamnosus LPR + Bifidobacterium longum NCC 3001 (109 CFU/day) (2) Dietary food supplement with Lactobacillus paracasei ST11 + NCC 3001 (19 CFU/day) (3) Placebo	No information on preterm birth rates. Gestational age in all groups was 39 weeks with a similar range (34–41 weeks).	Not possible to draw firm conclusions about effects on preterm delivery. However, papers seems to suggest lack of effect because gestational ages were similar between groups.
Kim et al. 2010 [157]	The effect of maternal and infant administration of probiotics on atopic disease in infants	RCT, DB, PC.	Pregnant women with a family history of allergic diseases day n = 112, and their infants. from Korea	Probiotic was given to mothers from 8 weeks before delivery until 3 months post-delivery, then to infants from 4 months until 6 months	(1) Bifido Inc mix (Bifidobacterium bifidum BGN4, Bifidobacterium lactis AD011, Lactobacillus acidophilus AD030), 1.6 × 109 CFU/day each, in powder (2) Placebo powder (maltodextrin and alpha-corn)	Infants delivered before 36 weeks were excluded. No difference observed in the number of infants removed between the two groups, suggesting no difference in PTB rates. In both groups the gestational ages were around 40 weeks, and birth weights were similar.	Not possible to draw conclusions about effects on PTB. However, papers seems to suggest lack of effect.
Ou et al. 2012 [158]	The effect of maternal administration of probiotics on atopic disease in infants	RCT, DB, PC	Pregnant women with atopic diseases history and Total IgE >100 kU/L from Taiwan n = 191	From 24 weeks gestation until delivery. After delivery, administration was exclusively to breastfeeding mothers	(1) L. rhamnosus GG (Valio, ATCC 53103) 1010 CFU/ day (2) Placebo (microcrystalline cellulose)	PTB rates were not reported. However, gestational age was 39 weeks in both groups (range 31–41 weeks in the L. rhamnosus GG group and 35–41 weeks in placebo group), which suggests lack of efficacy on PTB rates.	The study suggests that L. rhamnosus GG probably has no impact on PTB rates.
Vitali et al. 2012 [159]	The effect of probiotic supplementation during late pregnancy on vaginal microbiota and cytokine secretion	Non-randomized, controlled, pilot	Healthy pregnant women with no symptoms of vaginal or urinary tract infection from Italy n = 27	Probiotic was given during weeks 32–37 of gestation.	(1) Probiotic group: one sachet of VSL #3 (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii ssp. bulgaricus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, S. salivaris ssp. thermophilus) (n = 12) 9 × 1011 total CFU/day (2) Control group: no supplementation (n = 12)	PTB rates were not reported, but the gestational ages were not different between the two groups. This suggests that the probiotic did had no effect on PTB rates. No significant changes were found in the amounts of the principal vaginal bacterial populations in women administered with VSL#3, but qPCR results suggested a potential role of the probiotic product in counteracting the decrease of Bifidobacterium and the increase of Atopobium, that occurred in control women during late pregnancy. Incidence of vaginal infections was not reported.	The study is too small to draw conclusions, but it did not show any effect of VSL3 on gestational age.
Stojanovic et al. 2012 [154]	The effect of probiotics on vaginal microflora, cervical length, cervical consistency, and fetal positioning.	Observational, randomized, prospective	Pregnant women	Probiotic was administered for 12 weeks during pregnancy	(1) untreated arm of the study (n = 30) (2) vaginal application of one tablet containing L. rhamnosus BMX 54 (Normogin™-(n = 30) once a week	No data on PTB rates as women were not followed until delivery. Increase in pathogenic microorganisms in the vaginal and/or cervical swabs of untreated women (p <0.05), also in average pH values (p <0.05), amount (p <0.05) and “whiff test” positivity (p <0.05) of vaginal discharge. Significant trend was also found for decrease in length (p <0.0001) and increase in dilatation (p <0.05) of cervix, as well as for lower position of the fetus (p <0.0001). In the group treated with L. rhamnosus BMX 54, none of these values significantly changed throughout the observation period, with the exception of cervical length that was significantly decreased at T3 (p <0.01).	Cannot conclude on PTB rates. However, it suggests that vaginally administered probiotic had a positive impact on parameters associated with PTB.

CFU: colony forming unit, RCT: randomized controlled trial, DB: double blind, PC: placebo controlled.