Clinical trial NCT06177184: DOnor Milk to REpair the Full-term Infant MIcrobiome in Infants Born Via Cesarean Section.
Official title: DOnor Milk to REpair the Full-term Infant MIcrobiome in Infants Born Via Caesarean Section
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Microbial Colonization
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: University of British Columbia
name: University of Victoria
name: NorthernStar Mothers Milk Bank
First posted: 2023-12-20
Enrollment: 90
Sex: ALL
Minimum age (years): 37
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An experimental study design in which each participant will be randomized to one of two groups (intervention \[DHM\] or standard care/control \[formula\]).
Primary purpose: TREATMENT

Brief summary: The objective of this novel study is to establish proof of concept using a pilot randomized controlled trial to determine the effect of DHM compared to formula supplementation on the microbiome in full-term infants who are born via caesarean section and require supplementation. Secondarily, this study aims to compare the infant health outcomes of sleep and growth between groups to assess if these outcomes are mediated by infant feeding type or potential differences in microbial signatures. Finally, this study will compare maternal outcomes of depression, anger, breastfeeding self-efficacy and breastfeeding rates between groups.

The infant gut microbiome plays a critical role in the developing immune, neurologic, and endocrine systems. Yet, most infants experience early life disruptions (ELDs) to their microbiome that have potential long-term health and development impacts. A major source of disruption is caesarean section (c-section) delivery because the infant is born surgically and is not exposed to important commensal bacteria required to establish the infant microbiome. Currently in Canada, over 28% of infants are born via c-section.

Exclusive breastfeeding can improve gut microbiota composition in infants who are born via c-section. However, approximately 60% of infants born via c-section require formula supplementation in their first week of life. Evidence indicates that even one bottle of formula can further disrupt the gut microbiome.

Donor human milk (DHM) is a superior alternative to formula when supplementation is required as its biotic properties minimize perturbations to the infant gut microbiome and may help to repair the microbiome in infants who experience ELDs. Yet, while DHM is well researched in preterm populations, evidence on the impact of DHM as a therapeutic intervention on the full-term infant gut microbiome is lacking.

The hypothesis of this study is: that replacing formula with DHM supplementation will minimize gut microbiome dysbiosis and foster homeostasis following supplementation. In addition, it is hypothesized that improved homeostasis will promote improved sleep and growth outcomes in participant infants. Finally, mothers whose infants receive DHM will have lower depression and anger scores and higher breastfeeding self-efficacy and exclusive breastfeeding rates compared to mothers whose infants receive formula.

Detailed description: Investigators propose to conduct a pilot clinical RCT in the postpartum hospital setting examining DHM as an intervention provided to full-term infants delivered via caesarean section. Randomization of participant infants is currently an ethical practice because DHM supplementation is not standard practice in this population; infants receive formula if supplementation of mother's own milk (MOM) is required. Additionally, randomization will allow investigators to determine causal relationships between DHM supplementation compared to formula supplementation on the infant gut microbiome. Finally, conducting research in the clinical setting will allow for pragmatic assessment of DHM as an intervention, enhancing external validity and increasing the likelihood of its implementation into healthcare systems to improve healthcare quality.

Population: The population of interest is caesarean section born, full-term infants whose mothers are planning on breastfeeding.

Recruitment: Mothers greater than 37 weeks' gestation in the labour and delivery or postpartum unit who deliver via caesarean section will be screened for participation in the study by nurses on the postpartum and labour and delivery units. Upon recruitment and completion of informed consent, infants requiring supplementation of MOM will be randomized to the control or intervention group. Investigators will randomize 90 mother-infant dyads, providing adequate power to detect overall microbiome differences (\~45 in each group).

Intervention - Donor Human Milk (DHM) - Infants randomized to the intervention group will receive DHM each time supplementation is required for the first 7 days of life. The exposure time of 7 days was selected due to feasibility of DHM cost, and this is the period when breastfeeding is being established and most formula supplementation occurs. Infants in the control group will receive formula when supplementation is required (standard care). All DHM in North America is pasteurized and provided through certified milk banks regulated by the Human Milk Banking Association of North America and DHM for this study will be obtained from the NorthernStar Mothers Milk Bank (NMMB).

Data Collection, Analysis, and Outcomes: The primary outcome for this pilot study will result from comparisons of DHM to formula supplementation groups for differences in microbiome signatures, such as diversity, proportions of Bifidobacteria, and proportions of pathogenic organisms. Infant stool samples will be collected from soiled diapers at one week, 3 months and 6 months postpartum.

Secondary outcomes include infant growth, sleep, and breastfeeding outcomes that will be collected at one week, 3 months and 6 months postpartum.

Eligibility criteria: Inclusion Criteria:

* Gestation greater than 37 weeks gestation (full-term)
* Caesarean Section delivery
* Intending to breastfeed
* Consent for infant to receive DHM
* Working understanding (proficient in reading and understanding) of English
* Mother has provided signed and dated informed consent and authorization to use protected health information, as required by national and local regulations.
* In the investigator's opinion, the subject mother understands and can comply with protocol requirements, instructions, and protocol-stated restrictions, and is likely to complete the study as planned.

Exclusion Criteria:

* Diagnosed with clinically significant major congenital malformation that will interfere with breastfeeding or growth
* No intention to breastfeed

Primary outcomes:
measure: Infant gut microbiome - shallow shotgun metagenomics (RA)
timeFrame: one week postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (RA)
timeFrame: three months postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (RA)
timeFrame: six months postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)
timeFrame: one week postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)
timeFrame: 3 months postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)
timeFrame: six months postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (beta diversity)
timeFrame: one week postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (beta diversity)
timeFrame: three months postpartum
measure: Infant gut microbiome - shallow shotgun metagenomics (beta diversity)
timeFrame: six months postpartum
Secondary outcomes:
measure: Infant Sleep
timeFrame: three months postpartum
measure: Infant Sleep
timeFrame: six months postpartum
measure: Infant Growth - weight
timeFrame: one week postpartum
measure: Infant Growth - length
timeFrame: one week postpartum
measure: Infant Growth - BMI
timeFrame: one week postpartum
measure: Infant Growth - BMI
timeFrame: three months postpartum
measure: Infant Growth - BMI
timeFrame: six months postpartum
measure: Infant Growth - head
timeFrame: one week postpartum
measure: Infant Growth - weight
timeFrame: three months postpartum
measure: Infant Growth - length
timeFrame: three months postpartum
measure: Infant Growth - head
timeFrame: three months postpartum
measure: Infant Growth - weight
timeFrame: six months postpartum
measure: Infant Growth - length
timeFrame: six months postpartum
measure: Infant Growth - head
timeFrame: six months postpartum
measure: Infant feeding
timeFrame: one week postpartum
measure: Infant feeding
timeFrame: three months postpartum
measure: Infant feeding
timeFrame: six months postpartum
measure: Maternal Depression
timeFrame: one week postpartum
measure: Maternal Depression
timeFrame: three months postpartum
measure: Maternal Depression
timeFrame: six months postpartum
measure: Maternal Anger
timeFrame: one week postpartum
measure: Maternal Anger
timeFrame: three months postpartum
measure: Maternal Anger
timeFrame: six months postpartum
measure: Maternal Breastfeeding Self-efficacy
timeFrame: one week postpartum
measure: Maternal Breastfeeding Self-efficacy
timeFrame: three months postpartum
measure: Maternal Breastfeeding Self-efficacy
timeFrame: six months postpartum
measure: Maternal Anxiety
timeFrame: Baseline - (birth/enrolment)
measure: Maternal Anxiety
timeFrame: three months postpartum
measure: Maternal Anxiety
timeFrame: six months postpartum
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Rockeyview General Hospital
state: Alberta
Study officials:
affiliation: University of Calgary
name: Meredith Brockway, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The Human Microbiome and Child Growth - First 1000 Days and Beyond. Trends Microbiol. 2019 Feb;27(2):131-147. doi: 10.1016/j.tim.2018.09.008. Epub 2018 Oct 24.
citation: Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020 Oct;53:101340. doi: 10.1016/j.smrv.2020.101340. Epub 2020 May 13.
citation: Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for health outcomes. Nat Med. 2016 Jul 7;22(7):713-22. doi: 10.1038/nm.4142.
citation: Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Front Immunol. 2014 Sep 5;5:427. doi: 10.3389/fimmu.2014.00427. eCollection 2014.
citation: Korpela K, de Vos WM. Infant gut microbiota restoration: state of the art. Gut Microbes. 2022 Jan-Dec;14(1):2118811. doi: 10.1080/19490976.2022.2118811.
citation: Persaud RR, Azad MB, Chari RS, Sears MR, Becker AB, Kozyrskyj AL; CHILD Study Investigators. Perinatal antibiotic exposure of neonates in Canada and associated risk factors: a population-based study. J Matern Fetal Neonatal Med. 2015 Jul;28(10):1190-5. doi: 10.3109/14767058.2014.947578. Epub 2014 Aug 14.
citation: Zimmermann P, Curtis N. Effect of intrapartum antibiotics on the intestinal microbiota of infants: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2020 Mar;105(2):201-208. doi: 10.1136/archdischild-2018-316659. Epub 2019 Jul 11.
citation: Stuivenberg GA, Burton JP, Bron PA, Reid G. Why Are Bifidobacteria Important for Infants? Microorganisms. 2022 Jan 25;10(2):278. doi: 10.3390/microorganisms10020278.
citation: Liu Y, Qin S, Song Y, Feng Y, Lv N, Xue Y, Liu F, Wang S, Zhu B, Ma J, Yang H. The Perturbation of Infant Gut Microbiota Caused by Cesarean Delivery Is Partially Restored by Exclusive Breastfeeding. Front Microbiol. 2019 Mar 26;10:598. doi: 10.3389/fmicb.2019.00598. eCollection 2019.
citation: Korpela K, Salonen A, Virta LJ, Kekkonen RA, de Vos WM. Association of Early-Life Antibiotic Use and Protective Effects of Breastfeeding: Role of the Intestinal Microbiota. JAMA Pediatr. 2016 Aug 1;170(8):750-7. doi: 10.1001/jamapediatrics.2016.0585.
citation: Dai DLY, Petersen C, Hoskinson C, Del Bel KL, Becker AB, Moraes TJ, Mandhane PJ, Finlay BB, Simons E, Kozyrskyj AL, Patrick DM, Subbarao P, Bode L, Azad MB, Turvey SE. Breastfeeding enrichment of B. longum subsp. infantis mitigates the effect of antibiotics on the microbiota and childhood asthma risk. Med. 2023 Feb 10;4(2):92-112.e5. doi: 10.1016/j.medj.2022.12.002. Epub 2023 Jan 4.
citation: Forbes JD, Azad MB, Vehling L, Tun HM, Konya TB, Guttman DS, Field CJ, Lefebvre D, Sears MR, Becker AB, Mandhane PJ, Turvey SE, Moraes TJ, Subbarao P, Scott JA, Kozyrskyj AL; Canadian Healthy Infant Longitudinal Development (CHILD) Study Investigators. Association of Exposure to Formula in the Hospital and Subsequent Infant Feeding Practices With Gut Microbiota and Risk of Overweight in the First Year of Life. JAMA Pediatr. 2018 Jul 2;172(7):e181161. doi: 10.1001/jamapediatrics.2018.1161. Epub 2018 Jul 2.
citation: Francis J, Mildon A, Stewart S, Underhill B, Ismail S, Di Ruggiero E, Tarasuk V, Sellen DW, O'Connor DL. Breastfeeding rates are high in a prenatal community support program targeting vulnerable women and offering enhanced postnatal lactation support: a prospective cohort study. Int J Equity Health. 2021 Mar 3;20(1):71. doi: 10.1186/s12939-021-01386-6.
citation: Ho NT, Li F, Lee-Sarwar KA, Tun HM, Brown BP, Pannaraj PS, Bender JM, Azad MB, Thompson AL, Weiss ST, Azcarate-Peril MA, Litonjua AA, Kozyrskyj AL, Jaspan HB, Aldrovandi GM, Kuhn L. Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations. Nat Commun. 2018 Oct 9;9(1):4169. doi: 10.1038/s41467-018-06473-x.
citation: Chong HY, Tan LT, Law JW, Hong KW, Ratnasingam V, Ab Mutalib NS, Lee LH, Letchumanan V. Exploring the Potential of Human Milk and Formula Milk on Infants' Gut and Health. Nutrients. 2022 Aug 29;14(17):3554. doi: 10.3390/nu14173554.
citation: Peila C, Moro GE, Bertino E, Cavallarin L, Giribaldi M, Giuliani F, Cresi F, Coscia A. The Effect of Holder Pasteurization on Nutrients and Biologically-Active Components in Donor Human Milk: A Review. Nutrients. 2016 Aug 2;8(8):477. doi: 10.3390/nu8080477.
citation: Merjaneh N, Williams P, Inman S, Schumacher M, Ciurte A, Smotherman C, Alissa R, Hudak M. The impact on the exclusive breastfeeding rate at 6 months of life of introducing supplementary donor milk into the level 1 newborn nursery. J Perinatol. 2020 Jul;40(7):1109-1114. doi: 10.1038/s41372-020-0657-6. Epub 2020 Mar 30.
citation: Whipps MDM, Yoshikawa H, Demirci JR, Hill J. Estimating the Impact of In-Hospital Infant Formula Supplementation on Breastfeeding Success. Breastfeed Med. 2021 Jul;16(7):530-538. doi: 10.1089/bfm.2020.0194. Epub 2021 Jun 10.
citation: Wiggins JB, Trotman R, Perks PH, Swanson JR. Enteral Nutrition: The Intricacies of Human Milk from the Immune System to the Microbiome. Clin Perinatol. 2022 Jun;49(2):427-445. doi: 10.1016/j.clp.2022.02.009.
citation: McCune S, Perrin MT. Donor Human Milk Use in Populations Other than the Preterm Infant: A Systematic Scoping Review. Breastfeed Med. 2021 Jan;16(1):8-20. doi: 10.1089/bfm.2020.0286. Epub 2020 Nov 25.
citation: Rao S, Esvaran M, Chen L, Keil AD, Gollow I, Simmer K, Wemheuer B, Conway P, Patole S. Probiotic supplementation in neonates with congenital gastrointestinal surgical conditions: a pilot randomised controlled trial. Pediatr Res. 2022 Oct;92(4):1122-1131. doi: 10.1038/s41390-021-01884-x. Epub 2022 Jan 3.