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

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.

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.

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.

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.

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.

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.

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.