Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants

Review question
Do probiotics given to pregnant women prior to delivery and/or probiotics given to mothers of premature babies after birth compared with administration of placebo, no intervention or postnatal administration of probiotics to premature babies themselves reduce the risk of morbidity and mortality in premature babies?

Background
Inflammation may contribute to premature birth and to morbidity of premature babies. Premature babies are at risk for alterations in the growth of normal "good" bacteria in their intestinal tract. Probiotics are supplements of "good bacteria." Giving these bacteria directly to premature babies may decrease inflammation and decrease the risk for severe gastrointestinal disease (necrotizing enterocolitis) as well as the risk of death. However, there are safety concerns about administration of probiotics directly to premature babies.

Study characteristics
Twelve eligible trials with a total of 1450 mothers and 1204 known infants were included from searches, up to date as of March 2017. Eleven trials gave probiotics to mothers during pregnancy and one trial gave probiotics to mothers after the birth of their preterm infants. No studies compared maternal probiotic administration directly versus neonatal administration.The studies of pregnant women focused on various aspects of the studies with different probiotics given at different times. The pregnant women included in these trials were overall at low risk for preterm birth. The one trial with mothers given probiotics after birth was to mothers of infants who weighed less than 1500 g at birth.

Key results
There is insufficient evidence to conclude whether there is appreciable benefit or harm to neonates of either oral supplementation of probiotics administered to pregnant women at low risk for preterm birth or oral supplementation of probiotics to mothers of preterm infants after birth. There were no trials that gave mothers at high risk for having a premature infant probiotics, so the effects of probiotics given to those mothers is unknown. More studies are needed to know if probiotics given to mothers of preterm infants decreases death, necrotizing enterocolitis, or other problems related to prematurity.

Quality of evidence
In general, the evidence was of low to very low quality due to imprecision (small sample sizes) and indirectness (enrolled mothers were not necessarily at high risk for delivering their babies early).

Authors' conclusions: 

There is insufficient evidence to conclude whether there is appreciable benefit or harm to neonates of either oral supplementation of probiotics administered to pregnant women at low risk for preterm birth or oral supplementation of probiotics to mothers of preterm infants after birth. Oral supplementation of probiotics to mothers of preterm infants after birth may decrease time to 50% enteral feeds, however, this estimate is extremely imprecise. More research is needed for post-natal administration of probiotics to mothers of preterm infants, as well as to pregnant mothers at high risk for preterm birth.

Read the full abstract...
Background: 

Inflammation may contribute to preterm birth and to morbidity of preterm infants. Preterm infants are at risk for alterations in the normal protective microbiome. Oral probiotics administered directly to preterm infants have been shown to decrease the risk for severe necrotizing enterocolitis (NEC) as well as the risk of death, but there are safety concerns about administration of probiotics directly to preterm infants. Through decreasing maternal inflammation, probiotics may play a role in preventing preterm birth and/or decreasing the inflammatory milieu surrounding delivery of preterm infants, and may alter the microbiome of the preterm infant when given to mothers during pregnancy. Probiotics given to mothers after birth of preterm infants may effect infant bacterial colonization, which could potentially reduce the incidence of NEC.

Objectives: 

1. To compare the efficacy of maternal probiotic administration versus placebo or no intervention in mothers during pregnancy for the prevention of preterm birth and the prevention of morbidity and mortality of infants born preterm.

2. To compare the efficacy of maternal probiotic administration versus placebo, no intervention, or neonatal probiotic administration in mothers of preterm infants after birth on the prevention of mortality and preterm infant morbidities such as NEC.

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 2), MEDLINE via PubMed (1966 to 21 March 2017), Embase (1980 to 21 March 2017), and CINAHL (1982 to 21 March 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.

Selection criteria: 

We included randomized controlled trials in the review if they administered oral probiotics to pregnant mothers at risk for preterm birth, or to mothers of preterm infants after birth. Quasi-randomized trials were eligible for inclusion, but none were identified. Studies enrolling pregnant women needed to administer probiotics at < 36 weeks' gestation until the trimester of birth. Probiotics considered were of the genera Lactobacillus, Bifidobacterium or Saccharomyces.

Data collection and analysis: 

We used the standard methods of the Cochrane Collaboration and Cochrane Neonatal to determine the methodologic quality of studies, and for data collection and analysis.

Main results: 

We included 12 eligible trials with a total of 1450 mothers and 1204 known infants. Eleven trials administered probiotics to mothers during pregnancy and one trial administered probiotics to mothers after birth of their preterm infants. No studies compared maternal probiotic administration directly with neonatal administration. Included prenatal trials were highly variable in the indication for the trial, the gestational age and duration of administration of probiotics, as well as the dose and formulation of the probiotics. The pregnant women included in these trials were overall at low risk for preterm birth. In a meta-analysis of trial data, oral probiotic administration to pregnant women did not reduce the incidence of preterm birth < 37 weeks (typical risk ratio (RR) 0.92, 95% confidence interval (CI) 0.32 to 2.67; 4 studies, 518 mothers and 506 infants), < 34 weeks (typical risk difference (RD) 0.00, 95% CI -0.02 to 0.02; 2 studies, 287 mothers and infants), the incidence of infant mortality (typical RD 0.00, 95% CI -0.02 to 0.02; 2 studies, 309 mothers and 298 infants), or the gestational age at birth (mean difference (MD) 0.15, 95% CI -0.33 to 0.63; 2 studies, 209 mothers with 207 infants).

One trial studied administration of probiotics to mothers after preterm birth and included 49 mothers and 58 infants. There were no significant differences in the risk of any NEC (RR 0.44, 95% CI 0.13 to 1.46; 1 study, 58 infants), surgery for NEC (RR 0.15, 95% CI 0.01 to 2.58; 1 study, 58 infants), death (RR 0.66, 95% CI 0.06 to 6.88; 1 study, 58 infants), and death or NEC (RR 0.53, 95% CI 0.19 to 1.49; 1 study, 58 infants). There was an improvement in time to reach 50% enteral feeds in infants whose mothers received probiotics, but the estimate is imprecise (MD -9.60 days, 95% CI -19.04 to -0.16 days; 58 infants). No other improvement in any neonatal outcomes were reported. The estimates were imprecise and do not exclude the possibility of meaningful harms or benefits from maternal probiotic administration. There were no cases of culture-proven sepsis with the probiotic organism. The GRADE quality of evidence was judged to be low to very low due to inconsistency and imprecision.

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