Discussion
This follow-up study of a RCT found that probiotics administered to very preterm infants from soon after birth until discharge home or term CA did not affect neurodevelopmental outcomes or behaviour in early childhood. We previously reported that this probiotic combination administered in the perinatal period halved the rate of NEC ≥Bell Stage 2 in a population with a high breast milk feeding rate.2 This important benefit in very preterm infants without longer-term adverse consequences adds to the safety profile of prophylactic probiotics administration in this vulnerable population.
The three follow-up studies of probiotics administration to preterm infants have smaller sample sizes and were performed in different settings and preterm populations.18–20 Two cohorts from Taiwan (n=301)18 and Turkey (n=221)20 assessed children born weighing <1500 g at 3 years CA and <33 weeks or <1500 g at 18–22 months CA, respectively, using the Bayley Scales of Infant and Toddler Development II; these also found no differences in the incidence of survival without major neurodevelopmental impairment between probiotics and control groups (135/180 (75.0%) vs 138/187 (73.8%), P=0.94)18 and (100/121 (82.6%) vs 98/121 (81.0%), P=0.92).20 Reported rates of CP, visual loss, as well as cognitive and motor impairment were similar to ProPrems.18–20 Another trial enrolled 249 infants weighing <2500 g and <37 weeks’ gestation at birth and reported similar proportions with ‘suboptimal scores’ at 12 months’ CA in probiotic and control groups using the Hammersmith Infant Neurological Assessment (23/166 (13.8%) vs 24/83 (29%), P>0.05).19
In this study, the incidence of sensorineural hearing loss was lower in the probiotics group compared with placebo, although the overall rate for both groups was low. This finding could not be explained by post hoc analysis of ototoxic antibiotic therapy during the primary hospitalisation and has not been reported in other studies. It is unclear if lower rates of hearing loss in probiotics-treated children are real effects or type I errors. One possible explanation for this finding is that probiotics may reduce cochlear injury and therefore sensorineural hearing loss. Although only described until now in adult mice with Lactococcus lactis reducing age-related cochlear degeneration and hearing loss,32 sensorineural hearing loss in preterm infants is also predominantly mediated by cochlear and outer hair cell mediated injury.33 As this is only speculative, until this finding is replicated in other studies, we recommend that it must be interpreted with caution.
While the probiotics combination used in the ProPrems study does not negatively impact on neurodevelopment in early childhood, the rate of NEC ≥Bell stage 2 was low (2.0% vs 4.4%). Emerging evidence suggests that colonisation of the gut with exogenous probiotics can reverse the abnormal psychological effects associated with a dysbiotic intestinal microbiome and malfunctioning brain–gut–microbiome axis. For example, adult human studies have reported beneficial effects of probiotics on depression,34 35 as well as cognitive and neurobehavioural function.36 In these studies, benefits were experienced during probiotics administration. So, although there is a theoretical basis for a primary effect of probiotics on neurodevelopment in very preterm infants, neurobehavioural effects of probiotics may not be seen 2–5 years after probiotics were ceased.
Another possible reason for the lack of effect of this probiotic combination on neurobehaviour is the probiotic strains used. Probiotic effects are known to be strain, dose, condition and site specific37; so it is possible that we did not detect a difference in outcomes between the groups because the most appropriate probiotic strain, or strains, or dose for modulation of the brain–gut–microbiome axis was not used. Further evaluation based on experimental paradigms may be warranted.
The current study, with a sample size of 735 very preterm born children, is the largest follow-up study of probiotic effects in very preterm infants published until now. Assessors and parents were blinded to group allocation throughout the follow-up. We assessed neurodevelopment and socioemotional development.
We acknowledge limitations of this study, particularly that neurodevelopment was not a planned outcome of the ProPrems trial. Neither parents nor participating centres expected further evaluation in early childhood, which may explain the 172 surviving participants lost to follow-up and the 139 families who declined neurodevelopmental assessment (figure 1). The primary outcome was therefore available in only 67% of participants, increasing the risk of type 2 error. However, with 373 intervention and 362 control participants, there was 75% power to detect a difference of 82% versus 74% in survival free of major neurosensory impairment. Also, those who were assessed were at higher risk of adverse neurodevelopmental outcome, being of lower birth weight and gestational age compared with those who were not assessed. Following the sensitivity analyses, it is unlikely that a difference of disability-free survival between probiotics and placebo participants who attended follow-up would be ≥14%. Therefore. we do not believe our conclusions would be altered.
In addition, participants had a wide age range necessitating assessment with different measures, which assess slightly different concepts and which may have impacted on the power of the study to find differences between groups. However, based on the sensitivity analysis, the age range is unlikely to have influenced the study conclusions because numbers were small (n=62) and also because dichotomous outcomes based on SD (2SD below the mean) were used to standardise the different tests. Future trials should plan to assess long-term neurodevelopmental outcome within a narrow age window allowing for a standardised assessment battery.
In conclusion, administration of the probiotics combination Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis to very preterm infants from soon after birth until term CA did not negatively impact on survival free of neurodevelopmental impairment in early childhood. This probiotics mixture reduces NEC in very preterm infants, with apparent safety with respect to early childhood development.