Probiotics for Preterm Infants

In Australia, more than 26,000 babies are born preterm each year. The World Health Organization (WHO) classifies preterm as babies born alive before 37 weeks of pregnancy are completed. This can be further categorised as moderate to late preterm (32-37 weeks), very preterm (28-32 weeks), or extremely preterm (<28 weeks).

In the developed world, preterm birth is the leading cause of death and disability in children up to five years of age. It is associated with a wide range of complications, including long-term neurological disability, prolonged hospital stay after birth, readmission to hospital in the first 12 months of life, and chronic lung disease. For this reason, the care of preterm and low-birth-weight infants is a global priority.

On World Prematurity Day (17 November 2022), the WHO launched its recommendations for the care of preterm or low-birth-weight infants. The WHO recommendations for care of the preterm or low-birth-weight infant (henceforth referred to as ‘WHO recommendations’) cover preventive care, management of complications, and family involvement and support.

One of the new recommendations applies to the use of probiotics. This recommendation, based on moderate certainty evidence, states that “probiotics may be considered for human-milk-fed very preterm infants (< 32 weeks’ gestation).”

Infant microbiome

The human gastrointestinal tract is normally colonised by many microorganisms. This complex and diverse ecosystem is established through vertical transmission (i.e. from mother to infant) and environmental exposure. However, the intestinal microbiota of a preterm infant is typically quite different to that of a healthy full-term infant. A preterm infant is more likely to be colonised by potentially pathogenic facultative anaerobes, such as Enterobacter, Escherichia, and Klebsiella. In addition, levels of commensal strictly anaerobic microbes, such as Bifidobacterium, Bacteroides, and Clostridium, are reduced. These differences are largely related to gestational age, but may also be affected by the mode of delivery, exposure to antibiotics, and feeding practices.

The gut microbiome appears to play an important role in the development of many diseases in preterm infants, including serious conditions such as necrotising enterocolitis (NEC). Necrotising enterocolitis is a gastrointestinal condition that affects around 5% of very preterm or very low birth weight infants. It has a mortality rate of around 20-40%, although this may be closer to 50% in infants that require surgery. In addition, infants who develop NEC have a higher risk of other infections, slower growth, and longer hospital stays compared to gestation-comparable infants who do not develop NEC.

While the exact pathogenesis of NEC is not completely understood, studies demonstrate that feeding with human milk reduces the risk compared to feeding with cow’s milk formula. The apparent protective effect of human milk is postulated to be related to the prebiotic and probiotic substances it contains.

Probiotics are live microorganisms that provide beneficial health effects when administered in adequate amounts. Prebiotics, on the other hand, are substances that feed intestinal microbes to selectively promote the growth of non-pathogenic microorganisms. In particular, prebiotics in human milk may promote the growth of lactobacilli and bifidobacteria that play a role in maintaining mucosal barrier functions.

Infant probiotics

Due to the serious nature of conditions associated with microbial imbalances, strategies to address this have been investigated. Supplemental probiotics are one such measure.

There is currently a range of commercially available probiotics. These products typically contain one or more bacterial strains but may also contain fungi (e.g. Saccharomyces boulardii). They may be formulated as drops, powders, or capsules.

Infloran® is one example of an infant probiotic. This product contains Bifidobacterium bifidum and Lactobacillus acidophilus in a capsule presentation. Capsules can be opened, and the contents added to a small amount of liquid (e.g. expressed breast milk or formula).

Efficacy

A systematic review of 56 trials (totalling 10,812 infants) provided evidence on the efficacy of probiotics. This study looked at the potential for probiotics to reduce the risk of NEC in infants who were very preterm or very low birth weight (<1.5kg). This review included studies that investigated the enteral administration of probiotics (single or multi-strain) for at least one week using a comparator of placebo or no treatment.

This study suggested the following outcomes:

• Reduced all-cause mortality by hospital discharge (moderate-certainty evidence from 51 trials totalling 10,170 participants [RR 0.76, 95% CI 0.65 to 0.89]);
• Decrease in NEC by hospital discharge (low-certainty evidence from 54 trials totalling 10,604 participants [RR 0.54, 95% CI 0.45 to 0.65]);
• Decrease in invasive infection by hospital discharge (moderate certainty evidence from 47 trials totalling 9,762 participants [RR 0.89, 95% CI 0.82 to 0.97]);
• Decreased length of hospital stay (from 22 trials totalling 5,458 infants [mean difference -1.93 days, 95% CI -3.78 to -0.08]); and
• Little or no effect on neurodevelopment between 18 months and 3 years (low-certainty evidence from five trials totalling 1,518 participants assessing severe neurodevelopmental impairment using a validated test [RR.1.03, 95% CI 0.84 to 1.26]).

The type of probiotics used in these trials varied. Single‐genus probiotics were used in 33 trials (most commonly Bifidobacterium spp. or Lactobacillus spp.), while multi‐genus products were used in 23 trials (most commonly Bifidobacterium spp. plus Lactobacillus spp.).

There was no evidence of subgroup differences depending on probiotic genus for the outcomes of mortality, invasive infection, length of hospital stay after birth, visual impairment, or hearing impairment. However, there was some evidence of subgroup differences for the incidence of NEC.

For NEC, the largest effect size was seen for probiotics that contain:

• Lactobacillus spp.;
• Bifidobacterium spp. plus Lactobacillus spp.;
• Bifidobacterium spp. plus Streptococcus spp.; or
• Bifidobacterium spp. plus Lactobacillus spp. plus Streptococcus spp.

Only five trials (totalling 254 subjects) included formula-fed infants exclusively. Therefore, the WHO recommendations have not been applied to these infants. However, the authors of the systematic review conclude that the findings are likely to be broadly applicable to infants fed enterally with human milk, formula, or a mixture of the two. The risk-benefit equation may differ as the risk of NEC is higher in formula-fed infants.

Safety

The WHO recommendations advise that there is little evidence of harm associated with the use of probiotics in preterm infants. However, there are case reports of probiotic-derived bacteraemia and fungaemia occurring in preterm infants.

Summary

The WHO recommends that only probiotics specifically formulated for preterm or low birth-weight infants should be used in this population. In addition, products should conform to the relevant regulatory standards. In Australia, this would be indicated by the inclusion of the product on the Australian Register of Therapeutic Goods (ARTG).

The WHO recommendations concede that there is currently insufficient evidence to advise on the most appropriate probiotic type (i.e. genera, species or strain), formulation type, dose, or duration of administration. Parents should be involved in the decision-making and be adequately informed of the potential benefits and risks as well as the need for further research.