Probiotics and the Neurodevelopment in the Premature Infant <32 Weeks Gestational Age and <1500g

Infant Development Clinical Trial

Official title:

Probiotics and the Neurodevelopment in the Premature Infant <32 Weeks Gestational Age and <1500g

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05945017
• Other study ID #: HCB/2021/0454
• Status: Active, not recruiting
• Phase: N/A
• Start date: January 1, 2014
• Est. completion date: December 31, 2027

Study information

• Verified date: August 2023
• Source: Fundacion Clinic per a la Recerca Biomédica
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Unicentric, quasi-experimental, cohort study to evaluate the effect of combining two probiotics (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748) in the neurodevelopment of preterm neonates below 32 weeks' gestation and a birthweight under 1,500 g. This probiotic combination has shown to be safe and beneficial in premature neonates in the prevention of NEC. The investigators hypothesised that this mixture would contribute to better neurodevelopmental outcomes of preterm neonates when assessed at 24 months corrected age. Additionally, neurodevelopment improved would be more relevant at 6 years of age, together with a better pattern of neuronal plasticity biomarkers.

Secondarily, this mixture of probiotics could reduce NEC, LOS, intraventricular haemorrhage and neonatal mortality in accordance with previous studies.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 233
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 32 Weeks

Eligibility

Inclusion Criteria:

• Premature infants under 32 weeks gestational age and less than 1500g birthweight.

• Born at BCNatal Hospital Clínic between years 2014-2019.

Exclusion Criteria:

• All neonates presenting with suspected congenital anomalies, inborn errors of metabolism, or genetic defects were excluded.

• Infants with a suspected syndrome, or who have suffered events beyond the neonatal period, not related to prematurity, that could entail impairment in neurodevelopment (severe cranioencephalic trauma, oncological process, meningitis, or exposure to toxic substances)

Related Conditions & MeSH terms

• Infant Development
• Infant, Newborn, Diseases

Intervention

Dietary Supplement:
• Infloran® -Berne, Switzerland- (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748

Locations

Country	Name	City	State
Spain	Neonataology Service, BCNatal Hospital Clinic Seu Maternitat	Barcelona

Sponsors (2)

Lead Sponsor	Collaborator
Fundacion Clinic per a la Recerca Biomédica	Hospital Clinic of Barcelona

Country where clinical trial is conducted

Spain, 

References & Publications (24)

Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD005496. doi: 10.1002/14651858.CD005496.pub3. — View Citation

Baucells BJ, Mercadal Hally M, Alvarez Sanchez AT, Figueras Aloy J. [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]. — View Citation

Bi LW, Yan BL, Yang QY, Li MM, Cui HL. Which is the best probiotic treatment strategy to prevent the necrotizing enterocolitis in premature infants: A network meta-analysis revealing the efficacy and safety. Medicine (Baltimore). 2019 Oct;98(41):e17521. d — View Citation

Chou IC, Kuo HT, Chang JS, Wu SF, Chiu HY, Su BH, Lin HC. Lack of effects of oral probiotics on growth and neurodevelopmental outcomes in preterm very low birth weight infants. J Pediatr. 2010 Mar;156(3):393-6. doi: 10.1016/j.jpeds.2009.09.051. Epub 2009 — View Citation

Cryan JF, O'Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 2011 Mar;23(3):187-92. doi: 10.1111/j.1365-2982.2010.01664.x. — View Citation

Food and Agricultural Organization of the United Nations and World Health Organization. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. World Health Organization, (2001).

Hortensius LM, van Elburg RM, Nijboer CH, Benders MJNL, de Theije CGM. Postnatal Nutrition to Improve Brain Development in the Preterm Infant: A Systematic Review From Bench to Bedside. Front Physiol. 2019 Jul 26;10:961. doi: 10.3389/fphys.2019.00961. eCo — View Citation

Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736. doi: 10.1146/annurev.neuro.24.1.677. — View Citation

Jacobs SE, Hickey L, Donath S, Opie GF, Anderson PJ, Garland SM, Cheong JLY; ProPremsStudy Groups. Probiotics, prematurity and neurodevelopment: follow-up of a randomised trial. BMJ Paediatr Open. 2017 Nov 25;1(1):e000176. doi: 10.1136/bmjpo-2017-000176. — View Citation

Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry. 2010 May;49(5):453-63.e1. — View Citation

Liu DY, Shen XM, Yuan FF, Guo OY, Zhong Y, Chen JG, Zhu LQ, Wu J. The Physiology of BDNF and Its Relationship with ADHD. Mol Neurobiol. 2015 Dec;52(3):1467-1476. doi: 10.1007/s12035-014-8956-6. Epub 2014 Oct 30. — View Citation

Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M, Neu J. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One. 2011;6(6):e20647. doi: 10.1371/journal.pone.0020647. Epub 2011 Jun 6. — View Citation

Navarro-Tapia E, Sebastiani G, Sailer S, Toledano LA, Serra-Delgado M, Garcia-Algar O, Andreu-Fernandez V. Probiotic Supplementation During the Perinatal and Infant Period: Effects on Gut Dysbiosis and Disease. Nutrients. 2020 Jul 27;12(8):2243. doi: 10.3 — View Citation

Nikolaou KE, Malamitsi-Puchner A, Boutsikou T, Economou E, Boutsikou M, Puchner KP, Baka S, Hassiakos D. The varying patterns of neurotrophin changes in the perinatal period. Ann N Y Acad Sci. 2006 Dec;1092:426-33. doi: 10.1196/annals.1365.041. — View Citation

O'Reilly H, Johnson S, Ni Y, Wolke D, Marlow N. Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm Birth. Pediatrics. 2020 Feb;145(2):e20192087. doi: 10.1542/peds.2019-2087. Epub 2020 Jan 10. — View Citation

Ranuh R, Athiyyah AF, Darma A, Risky VP, Riawan W, Surono IS, Sudarmo SM. Effect of the probiotic Lactobacillus plantarum IS-10506 on BDNF and 5HT stimulation: role of intestinal microbiota on the gut-brain axis. Iran J Microbiol. 2019 Apr;11(2):145-150. — View Citation

Romeo MG, Romeo DM, Trovato L, Oliveri S, Palermo F, Cota F, Betta P. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. J Perinatol. 2011 Jan;31(1):63- — View Citation

Sari FN, Eras Z, Dizdar EA, Erdeve O, Oguz SS, Uras N, Dilmen U. Do oral probiotics affect growth and neurodevelopmental outcomes in very low-birth-weight preterm infants? Am J Perinatol. 2012 Sep;29(8):579-86. doi: 10.1055/s-0032-1311981. Epub 2012 May 7 — View Citation

Sjogren YM, Jenmalm MC, Bottcher MF, Bjorksten B, Sverremark-Ekstrom E. Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy. 2009 Apr;39(4):518-26. doi: 10.1111/j.1365-2222.2008.03156.x. Epub 2009 Feb 9. — View Citation

Thomas JP, Raine T, Reddy S, Belteki G. Probiotics for the prevention of necrotising enterocolitis in very low-birth-weight infants: a meta-analysis and systematic review. Acta Paediatr. 2017 Nov;106(11):1729-1741. doi: 10.1111/apa.13902. Epub 2017 Jun 9. — View Citation

Underwood MA, Sohn K. The Microbiota of the Extremely Preterm Infant. Clin Perinatol. 2017 Jun;44(2):407-427. doi: 10.1016/j.clp.2017.01.005. Epub 2017 Mar 22. — View Citation

van den Akker CHP, van Goudoever JB, Shamir R, Domellof M, Embleton ND, Hojsak I, Lapillonne A, Mihatsch WA, Berni Canani R, Bronsky J, Campoy C, Fewtrell MS, Fidler Mis N, Guarino A, Hulst JM, Indrio F, Kolacek S, Orel R, Vandenplas Y, Weizman Z, Szajews — View Citation

Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med. 2000 Aug 10;343(6):378-84. doi: 10.1056/NEJM200008103430601. — View Citation

Yang I, Corwin EJ, Brennan PA, Jordan S, Murphy JR, Dunlop A. The Infant Microbiome: Implications for Infant Health and Neurocognitive Development. Nurs Res. 2016 Jan-Feb;65(1):76-88. doi: 10.1097/NNR.0000000000000133. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Degree of neurodevelopment at 24 months corrected age	Normal neurodevelopment will be considered when no muscle tone changes, no impaired fine or gross motor coordination, Bayley scale score between above 84, no behaviour disorders or visual disability.	24 months
Primary	Degree of neurodevelopment at 24 months corrected age	Mild impairment will be considered if any of the following: muscle tone changes, impaired fine or gross motor coordination, Bayley scale score between 71-84, moderate behaviour disorders or mild visual disability.	24 months
Primary	Degree of neurodevelopment at 24 months corrected age	Moderate impairment will be diagnosed when suffering from any of the following: spastic diplegia, hemiplegia, seizures (non-febrile), Bayley scores between 50-70, severe behaviour disorders, moderate visual disability or mild-moderate hypoacusis.	24 months
Primary	Degree of neurodevelopment at 24 months corrected age	Severe impairment will be attributed to subjects with any of the following: spastic quadriplegia, choreoathetosis, ataxia, Bayley score <50, blindness or severe hypoacusis	24 months
Primary	Degree of neurodevelopment at 6 years of age	Wechsler Intelligence Scale for Children - Fifth edition. Ranges from below 69 to above 130. Scores from 90-109 indicate average, above it indicates above average and below, below average performance.	6 years
Primary	Degree of neurodevelopment at 6 years of age	Child behaviour checklist 6-18 years of age. 113 items about behaviour and social competence scored from 0 "absent" to 2 "occurs often"	6 years
Primary	Degree of neurodevelopment at 6 years of age	Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2). Parent/teacher self reporting form.	6 years
Primary	Neuroplasticity biomarkers and intestinal permeability	NeuN, Doublecortin, GFAP, GDNF, Ki67, Nrf2, BDNF, NGF, neurotrophin-1 (NT-1), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), DYRK1A, HIF1a, S100B i GSK3B. IL1B, IL6, IL8, IL10, IL12, TNF- a	6 years
Secondary	Incidence of necrotising enterocolitis	cases fulfilling the stage II or above of the modified Bell's Criteria	40 weeks
Secondary	Mortality	Proportion of dead participants before discharge	40 weeks
Secondary	Incidence of late onset sepsis	positive blood culture beyond 72 hours of life	40 weeks
Secondary	Incidence of Intraventricular haemorrhage	Grade I-IV	40 weeks
Secondary	Intensive care length of stay	Days of intensive care	40 weeks