Preterm (also called premature) babies can face a host of complications including neurological problems due to their underdeveloped physiological systems.
Recent research shows that gut dysbiosis increases the risk of necrotizing enterocolitis (NEC) in premature infants. Specific probiotics have been effective in preventing this dangerous condition, which has led researchers to explore if probiotics may ameliorate neurodevelopment complications as well.
This blog will explore the evidence for the use of probiotics in decreasing the risk of neurodevelopmental problems in preterm infants.
Neurodevelopment in the preterm infant, in brief
Spontaneous preterm labor or medical indications may lead to preterm birth, defined as any birth before 37 completed weeks of pregnancy. If the baby is born before 28 weeks of gestation, known as “extremely preterm,” health problems become considerably more challenging.
Highly contingent on how early the baby is born, immediate complications may impact respiration, cardiovascular systems, temperature control, digestion, metabolism, and immunity. Long-term effects may include cerebral palsy, hearing and vision deficits, and learning delays.
Neonatal care advances have enabled the medical focus to pivot from survival to minimizing long-term disability such as impaired neurodevelopmental effects.
The third trimester of gestation is a time of rapid brain growth and increases in total brain volume. In premature babies, research shows that brains are smaller with slower growth in various brain regions. The authors reported that oxygen fluctuations and systemic inflammation are associated with cerebral white matter injury, hemorrhages, and cerebellar disturbances, which can ultimately lead to reduced neuronal connectivity and brain volume, both key predictors of neurodevelopmental outcomes in the preterm infant.
Moreover, premature birth can affect a child’s developmental milestones, including motor skills, cognitive development, and language development. In addition, children who were born very preterm display greater behavioral difficulties, and are more likely than children born full-term to receive an autism diagnosis.
Preterm birth and the gut-brain axis
Dysbiosis in preterm infants is well-documented. Studies reveal that preterm infants have an immature and less diverse gut microbiota compared to full-term infants. Importantly, the gut microbiome among premature infants with NEC is also different from the microbiome of those without NEC. Microbial dysbiosis preceding NEC in preterm infants is characterized by increased Proteobacteria abundance and decreased abundances of Firmicutes and Bacteroidetes.
Through two-way biochemical signaling, the gut microbiota communicates with the central nervous system along what is called the gut-brain axis. Homeostasis along these complex endocrine, neural, and immune pathways is essential to proper neurodevelopment.
Gut microbiota—capable of producing metabolites, impeding pathogens, and modulating immune response— may impact the gut-brain axis through several mechanisms including:
- Altering gut permeability to pro-inflammatory factors such as lipopolysaccharide (LPS), which may impact fetal neurodevelopment processes.
- Regulating neurotrophins, such as brain-derived neurotrophic factor (BNDF), nerve growth factors, and neurotrophin-3 and 4, involved in neuroinflammation and neurodevelopment.
Probiotics in neurodevelopment
Studies in mice suggest that the developing preterm brain presents a critical window for the correction of dysbiosis with probiotics to provide long-term benefits in neurodevelopment. In one rat study, probiotic treatment (Bifidobacterium bifidum and Ligilactobacillus salivarius) showed a reduction in inflammation and improved brain-related biomarkers, suggesting potential therapeutic benefits for neurodevelopment in neonates affected by prenatal gut microbiota disruption induced by LPS.
Several clinical studies testing the benefits of probiotics in the neurodevelopment of preterm infants have shown disappointing results with various species and strains of lactobacilli, bifidobacteria, andstreptococci. Researchers suggested that numerous factors could have affected results: variations in probiotic strain, dose, and timing as well as gestational age and birth weight.
With that in mind, a 2023 research group opted to use a probiotic combination previously shown to be beneficial in premature neonates in the prevention of NEC and late-onset sepsis along with extensive follow-up and a broader analysis of neurodevelopmental outcomes. In this study, a multistrain probiotic (Bifidobacterium bifidum and Lactobacillus acidophilus) was administeredto 109 neonates born before 32 weeks and weighing less than 1500 grams at birth. The control group had 124 preterm infants not receiving probiotics. Neurodevelopment was assessed at 24 months corrected age. Those receiving probiotics showed a reduction in neurodevelopment impairment at 2 years of age and a reduction in the degree of impairment.
Additionally, there was a significant reduction in late-onset sepsis, noteworthy because infection can alter BDNF expression and resulting exposure to antibiotics which are known to cause dysbiosis.
Furthermore, the probiotic group experienced fewer days in intensive care, lower care level transfers, reduced painful procedures, and overall stress, all potentially leading to improved neurobehavioral development.
The authors thought that perhaps their wider neurodevelopmental evaluation (including mild and moderate impairment) may “have highlighted a more subtle effect of probiotics, and impacted our results, compared to more restrictive criteria of other authors.”
Takeaway
The dysbiosis evident in preterm infants is thought to impact neurodevelopment through mechanisms operating through the gut-brain axis. Probiotics have been suggested as candidates to restore microbial homeostasis and improve outcomes.
Studies in mice suggest that the developing preterm brain presents a critical window for the correction of dysbiosis with probiotics to provide long-term benefits in neurodevelopment. But many clinical studies have not shown benefits in this regard. One recent study, however, reported a reduction in impairment and complications with probiotics when a broader analysis was conducted. Additional clinical trials are required to confirm these findings and elucidate the mechanisms through which reversing dysbiosis could enhance neurological outcomes in preterm infants.
Caution!
Probiotic use in vulnerable populations such as preterm infants must always be approached with great care as rare adverse events have been reported.
On September 29, 2023, the FDA reported that they were investigating the death of a preterm infant with sepsis, who had been administered a probiotic product. The same day, the FDA also issued a warning letter to healthcare providers regarding the use of probiotics in preterm infants. Furthermore, the off-label use of probiotics in hospitalized preterm infants was cautioned by the FDA in October.
IPA issued an extensive internal statement concerning the tragic death of a preterm infant who received a probiotic product.
Image by Arek Socha from Pixabay
Key references
Agrawal, Sachin et al. “Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis.” Pediatrics vol. 142,3 (2018): e20180134. doi:10.1542/peds.2018-0134
Allotey, J et al. “Cognitive, motor, behavioural and academic performances of children born preterm: a meta-analysis and systematic review involving 64 061 children.” BJOG : an international journal of obstetrics and gynaecology vol. 125,1 (2018): 16-25. doi:10.1111/1471-0528.14832
Baucells, Benjamin James et al. “Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant.” Scientific reports vol. 13,1 10344. 26 Jun. 2023, doi:10.1038/s41598-023-37393-6
Baucells, Benjamin James et al. Probiotic associations in the prevention of necrotising enterocolitis and the reduction of late-onset sepsis and neonatal mortality in preterm infants under 1,500g: A systematic review. Anales de pediatria (Barcelona, Spain : 2003) vol. 85,5 (2016): 247-255. doi:10.1016/j.anpedi.2015.07.038
Bouyssi-Kobar, Marine et al. “Third Trimester Brain Growth in Preterm Infants Compared With In Utero Healthy Fetuses.” Pediatrics vol. 138,5 (2016): e20161640. doi:10.1542/peds.2016-1640
Cryan, J F, and S M O’Mahony. “The microbiome-gut-brain axis: from bowel to behavior.” Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society vol. 23,3 (2011): 187-92. doi:10.1111/j.1365-2982.2010.01664.x
Diaz Heijtz, Rochellys et al. “Normal gut microbiota modulates brain development and behavior.” Proceedings of the National Academy of Sciences of the United States of America vol. 108,7 (2011): 3047-52. doi:10.1073/pnas.1010529108
Duess, Johannes W et al. “Necrotizing enterocolitis, gut microbes, and sepsis.” Gut microbes vol. 15,1 (2023): 2221470. doi:10.1080/19490976.2023.2221470
Huang, E J, and L F Reichardt. “Neurotrophins: roles in neuronal development and function.” Annual review of neuroscience vol. 24 (2001): 677-736. doi:10.1146/annurev.neuro.24.1.677
Kar, Fatih et al. “Probiotics ameliorates LPS induced neuroinflammation injury on Aβ 1-42, APP, γ-β secretase and BDNF levels in maternal gut microbiota and fetal neurodevelopment processes.” Metabolic brain disease vol. 37,5 (2022): 1387-1399. doi:10.1007/s11011-022-00964-z
Kulkarni, Tithi et al. “Probiotic sepsis in preterm neonates-a systematic review.” European journal of pediatrics vol. 181,6 (2022): 2249-2262. doi:10.1007/s00431-022-04452-5
Leoni, Marguerite et al. “Exploring cognitive, behavioral and autistic trait network topology in very preterm and term-born children.” Frontiers in psychology vol. 14 1119196. 27 Apr. 2023, doi:10.3389/fpsyg.2023.1119196
McDonnell, Lucy et al. “Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis.” Gut microbes vol. 13,1 (2021): 1-18. doi:10.1080/19490976.2020.1870402
Meyer, Michael P et al. “Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units.” Frontiers in pediatrics vol. 8 119. 7 Apr. 2020, doi:10.3389/fped.2020.00119
Pammi, Mohan et al. “Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.” Microbiome vol. 5,1 31. 9 Mar. 2017, doi:10.1186/s40168-017-0248-8
Twilhaar, E Sabrina et al. “Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk Factors: A Meta-analysis and Meta-regression.” JAMA pediatrics vol. 172,4 (2018): 361-367. doi:10.1001/jamapediatrics.2017.5323
Vinall, Jillian et al. “Invasive procedures in preterm children: brain and cognitive development at school age.” Pediatrics vol. 133,3 (2014): 412-21. doi:10.1542/peds.2013-1863
Yang, Irene et al. “The Infant Microbiome: Implications for Infant Health and Neurocognitive Development.” Nursing research vol. 65,1 (2016): 76-88. doi:10.1097/NNR.0000000000000133