Possible Benefits and Risks of Using Probiotics in Neonates

KEY POINTS

• 1.

  Probiotics are live microorganisms that, when consumed in adequate amounts by an adult host, are believed to and in many instances have been shown to confer health benefits.

• 2.

  The best-known probiotics belong to the genera Bifidobacteria , Lactobacillus , and Saccharomyces .

• 3.

  Extensive clinical evidence indicates that probiotics can reduce the risk of necrotizing enterocolitis (NEC) and late-onset sepsis in term and very low birth weight infants. Further work is needed to ensure safety in extremely low birth weight infants.

• 4.

  The baseline incidence of conditions such as NEC and other inflammatory conditions is an important consideration in deciding whether to initiate the administration of probiotics in a neonatal intensive care unit.

• 5.

  Several probiotics dampen inflammation by inhibiting TLR4 and TLR2 and by stimulating expression of antiinflammatory mediators. Several probiotics improve intestinal barrier function by strengthening the mucus layer and tight junctions between enterocytes. Many probiotics increase energy harvest by producing short-chain fatty acids, amino acids, vitamins, and secondary bile acids.

• 6.

  Many probiotics alter the intestinal microbiota by selectively competing for human milk oligosaccharides and by producing bacteriocins.

Probiotics are live microorganisms that, when consumed in adequate amounts, are believed to and in many instances have been shown to confer health benefits in adult hosts. In older children, the gut microbiome is relatively stable and the addition of probiotics can potentiate intestinal homeostasis, nutrition, and mucosa immunity. However, in neonates, particularly in the extremely low birth weight (ELBW) ones, early introduction of probiotics evokes debate. The proponents who advocate for the administration of probiotics emphasize that these agents could neutralize the dysbiosis associated with the acquisition of hospital-acquired gram-negative flora. Probiotics may not be natural, but neither are the nosocomial gram-negative bacilli. The opponents argue that the sequential appearance of gram-positive and gram-negative bacteria and anaerobes in the neonatal intestine at specific stages of development might have a natural rationale that we might not quite understand yet. They emphasize that the intention might be to promote health, but the safety of administering live bacteria in ELBW infants is not assured; recall that these bacteria may have caused sepsis-like illness in some infants. The opponents question that the administration of live bacteria, even if apparently advantageous in mature adults and in many premature infants, could still be an underappreciated mistake in some that might not necessarily fix an earlier mistake that enabled the overgrowth of potentially harmful bacteria.

In neonatal intensive care units (NICUs), families now increasingly ask clinicians whether they should be adding probiotics to the feedings of their premature or critically ill infants, and if so, for help in choosing products. These questions create a dilemma, given that none of the currently available probiotic preparations are recognized as therapeutic agents. These are perceived as dietary supplements, and there is indeed some room for criticism of the scientific rigor and the “number needed to treat.” Our neonatologists, pediatricians, and allied personnel long for guidance for these questions.

In this chapter, we have summarized the current information on the types of probiotics, available pharmaceutical preparations, effects, likely mechanism(s) of action, and evidence that favors and negates the impact of probiotics. Wherever possible, we provide evidence-based information to guide both clinicians and parents about the potentially protective effects of probiotics against necrotizing enterocolitis, sepsis, and other inflammatory conditions. In areas where sufficient evidence is available, we have tried to include information on the individual probiotic strains or combinations that may be effective and the clinical contexts that warrant further research. We have included a brief section on prebiotics and synbiotics, because those are perceived by many as potentially safer. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence.

Types of Probiotics

The International Scientific Association for Probiotics and Prebiotics defines probiotics as live microorganisms that confer a health benefit to the recipient when administered in adequate amounts. This definition does not include transplant of fecal microbiota or dead organisms. Many probiotic species are known and are commercially available ( Table 18.1 ). Many probiotics have been accorded the GRAS (generally recognized as safe) status by the Food and Drug Administration (FDA) in the United States and have been safely used in food based either on a history of use before 1958 or on published scientific evidence, and they need not be approved by the FDA before being used. Probiotics listed with GRAS status in the United States are listed in Table 18.1 ( https://www.fda.gov/food/generally-recognized-safe-gras/microorganisms-microbial-derived-ingredients-used-food-partial-list ).

The best studied probiotic species are Bifidobacteria and Lactobacilli ( Fig. 18.1 ). A list of commercially available probiotic products can be easily found with a Google search using the search phrases “infant probiotics,” “probiotics for infants,” “commercially available infant probiotics,” and “commercially available probiotics infant.” The availability of specific products may differ by geographic region and the variety used in trials and observational studies to date, and no product(s) can be specifically recommended yet ( https://clinicaltrials.gov/ct2/show/NCT02472769 ; http://ibtherapeutics.com/the-phase-3-study-protocol-is-modified-after-ibts-meeting-with-the-fda/ ). Clinicians need to evaluate specific products for safety and efficacy.

Effect of Probiotics on Composite Outcomes Including NEC, LOS, and All-Cause Mortality

In Table 18.3, we show a summary of the studies by Deshmukh and Patole, Chi et al., Morgan et al., Balasubramanian et al., Bi et al., Zhu et al., Deshpande et al., Dermyshi et al., Chang et al., and Olsen et al. A large implementation cohort study in Germany used Infloran, a probiotic preparation of L. acidophilus and Bifidobacterium bifidum , and included more than 5000 infants. Another cohort study of 3093 infants <29 weeks’ gestation in Canada showed prophylactic probiotic supplementation to lower the risk of NEC (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.41–0.99) and death (adjusted OR, 0.41; 95% CI, 0.26–0.63). An earlier single-center cohort study in the United States and Canada had shown these formulations to be efficacious. Other implementation cohort studies from France, Australia, and Switzerland have also reported decreased NEC after routine use of probiotics. Additionally, the pooled treatment effects of probiotics on NEC, death, and LOS in observational studies are similar to those in clinical trials. These findings support the external validity of the pooled estimates of probiotic treatment effects from randomized trials and increase confidence in the findings from meta-analyses of randomized trials.

Effect of Probiotics on the Risk of NEC

Data from the studies by Sharif et al., Liu et al., Jiao et al., Hagen et al., and Lau et al. are summarized in Table 18.4. The table also shows the findings from the Probiotics in Preterm Infants (PiPS) trial, which did not find a difference in the risk of NEC between the probiotic and the placebo group.

Most trials of probiotic supplementation have enrolled very low birth weight (VLBW) infants, but ELBW infants are underrepresented in many studies. A large German cohort study demonstrated beneficial effects of probiotics in ELBW infants. However, the subgroup analyses of the ProPrems trial did not find any significant differences in effects of probiotics on NEC between ELBW and other premature infants. The use of probiotics in more mature populations to prevent NEC may substantially increase the number needed to treat (NNT) to prevent NEC, because the baseline incidence would be lower in this population.

The 2020 Cochrane Database of Systematic Reviews evaluated 56 trials with 10,812 infants. Most trials were small (median sample size, 149), and there were concerns about the possibility of bias in about half of the trials. Trials varied by the formulation of the probiotics; most preparations contained Bifidobacteria , Lactobacilli , Saccharomyces species (spp.), and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: relative risk [RR], 0.54; 95% CI, 0.45–0.65 (54 trials; 10,604 infants; I ² = 17%); risk difference [RD], −0.03; 95% CI, −0.04 to −0.02; NNT for an additional beneficial outcome (NNTB), 33; 95% CI, 25–50. Evidence was assessed as low certainty because of the limitations in trials design and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR, 0.70; 95% CI, 0.55–0.89 (16 trials, 4597 infants; I ² = 25%); RD, −0.02; 95% CI; −0.03 to −0.01; NNTB, 50; 95% CI, 33–100. Meta-analyses showed that probiotics probably reduce mortality (RR, 0.76; 95% CI, 0.65–0.89 [51 trials, 10,170 infants; I ² = 0%]; RD, −0.02; 95% CI, −0.02 to −0.01; NNTB, 50; 95% CI, 50–100), and late-onset invasive infection (RR, 0.89; 95% CI, 0.82–0.97; [47 trials, 9762 infants; I ² = 19%]; RD, −0.02; 95% CI, −0.03 to −0.01; NNTB, 50; 95% CI 33–100). Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR, 1.03; 95% CI, 0.84–1.26 (five trials, 1518 infants; I ² = 0%). The certainty of this evidence is low because of design limitations.

Effect of Probiotics on the Risk of Late-Onset Sepsis and Other Conditions ( Table 18.5 )

Rao et al. examined pooled results from 37 RCTs (N = 9416) of probiotics versus placebo/no probiotics using a fixed effects model. In meta-analysis, probiotics decreased the risk of LOS.

Qamer et al. performed a systematic review of efficacy and safety of probiotics in the management of cow's milk protein allergy (CMPA). Primary outcomes were resolution of hematochezia and acquisition of tolerance to CMP, and the secondary outcomes included effects on allergic symptoms, growth, gut microbiota, and adverse effects. Ten RCTs (N = 845) were analyzed, but no significant benefits were seen. However, in confirmed CMPA, limited low-quality evidence showed that probiotics expedited the acquisition of tolerance to CMP at the end of 3 years.

Colic is defined as periods of inconsolable crying, fussing, or irritability that have no apparent cause and present in otherwise healthy infants. Simonson et al. performed a systematic review and showed that oral administration of probiotics to breastfed infants with colic resulted in at least a 50% reduction in crying time compared with placebo. Ong et al., Sung et al., and Harb et al. also showed benefit.

Probiotics seem to be efficacious in reducing the severity of neonatal hyperbilirubinemia. Deshmukh et al. analyzed 9 RCTs (prophylactic: 6 trials, N = 1761; therapeutic: 3 trials, N = 279). Total serum bilirubin (TSB) was significantly reduced at 96 hours. Chen et al. examined 13 RCTs involving 1067 neonates with jaundice in a meta-analysis and also noted efficacy.

In other gastrointestinal surgical conditions, probiotics may not be so effective. Rao et al. examined two RCTs; the first was conducted in 24 neonates with gastroschisis, the second in 8 with various surgical conditions. Based on these data, the role of probiotics in neonates with gastrointestinal surgical conditions is still unclear and needs further study.

Mechanisms of Probiotic Effects