DOnor Milk to REpair the Full-term Infant MIcrobiome in Infants Born Via Cesarean Section.

Microbial Colonization Clinical Trial

— DO-RE-MI C-S  

Official title:

DOnor Milk to REpair the Full-term Infant MIcrobiome in Infants Born Via Caesarean Section

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06177184
• Other study ID #: REB23-1356
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2024
• Est. completion date: December 31, 2025

Study information

• Verified date: January 2024
• Source: University of Calgary
• Contact: Meredith Brockway, PhD
• Phone: 403-689-0970
• Email: mbrockwa[@]ucalgary.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 90
• Est. completion date: December 31, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 37 Weeks and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Microbial Colonization

Intervention

Other:
• Donor Human Milk - Nutritional Replacement
All DHM in North America is pasteurized and provided through certified milk banks regulated by the Human Milk Banking Association of North America. DHM for this study will be obtained from the NorthernStar Mothers Milk Bank (NMMB). The milk is pasteurized and rigorously tested according to Human Milk Banking Association of North America guidelines. In Canada, DHM is categorized as food or nutritional therapy and the milk bank is monitored and certified by the Canadian Food Inspection Agency. The product used for this study will be the same product that is provided to other hospital units (mainly the neonatal intensive care units) in Alberta and around Canada. The product will not be modified or tampered with in any way.

Locations

Country	Name	City	State
Canada	Rockeyview General Hospital	Calgary	Alberta

Sponsors (4)

Lead Sponsor	Collaborator
University of Calgary	NorthernStar Mothers Milk Bank, University of British Columbia, University of Victoria

Country where clinical trial is conducted

Canada, 

References & Publications (21)

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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. — View 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 antibioti — View 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. As — View 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 p — View 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 microbi — View 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. — View 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. — View 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. — View 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. — View 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. — View 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 — View 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/nu808047 — View 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. do — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Infant gut microbiome - shallow shotgun metagenomics (RA)	Relative abundance	one week postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (RA)	Relative abundance	three months postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (RA)	Relative abundance	six months postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)	alpha diversity of microbiome	one week postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)	alpha diversity of microbiome	3 months postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (alpha diversity)	alpha diversity of microbiome	six months postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (beta diversity)	beta diversity of microbiome	one week postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (beta diversity)	beta diversity of microbiome	three months postpartum
Primary	Infant gut microbiome - shallow shotgun metagenomics (beta diversity)	beta diversity of microbiome	six months postpartum
Secondary	Infant Sleep	Brief Infant Sleep Questionnaire - Revised Short Form - Scores on each subscale and the total score are scaled from 0 to 100, with higher scores denoting better sleep quality, more positive perception of infant sleep, and parent behaviors that promote healthy and independent sleep.	three months postpartum
Secondary	Infant Sleep	Brief Infant Sleep Questionnaire - Scores on each subscale and the total score are scaled from 0 to 100, with higher scores denoting better sleep quality, more positive perception of infant sleep, and parent behaviors that promote healthy and independent sleep.	six months postpartum
Secondary	Infant Growth - weight	Weight - in grams; weight and height will be combined to report BMI in kg/m^2	one week postpartum
Secondary	Infant Growth - length	Length - in centimeters; weight and height will be combined to report BMI in kg/m^2	one week postpartum
Secondary	Infant Growth - BMI	Body mass index - weight and height will be combined to report BMI in kg/m^2	one week postpartum
Secondary	Infant Growth - BMI	Body mass index - weight and height will be combined to report BMI in kg/m^2	three months postpartum
Secondary	Infant Growth - BMI	Body mass index - weight and height will be combined to report BMI in kg/m^2	six months postpartum
Secondary	Infant Growth - head	Head circumference - in centimeters	one week postpartum
Secondary	Infant Growth - weight	Weight - in grams; weight and height will be combined to report BMI in kg/m^2	three months postpartum
Secondary	Infant Growth - length	Length - in centimeters; weight and height will be combined to report BMI in kg/m^2	three months postpartum
Secondary	Infant Growth - head	Head circumference - in centimeters	three months postpartum
Secondary	Infant Growth - weight	Weight - in grams; weight and height will be combined to report BMI in kg/m^2	six months postpartum
Secondary	Infant Growth - length	Length - in centimeters; weight and height will be combined to report BMI in kg/m^2	six months postpartum
Secondary	Infant Growth - head	Head circumference - in centimeters	six months postpartum
Secondary	Infant feeding	breastfeeding exclusively - measured by 7-day infant feeding journal. Number of participants who consume only breastmilk.	one week postpartum
Secondary	Infant feeding	breastfeeding exclusively - measured by 7-day maternal recall. Number of participants who consume only breastmilk.	three months postpartum
Secondary	Infant feeding	breastfeeding exclusively - measured by 7-day maternal recall. Number of participants who consume only breastmilk.	six months postpartum
Secondary	Maternal Depression	Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes	one week postpartum
Secondary	Maternal Depression	Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes	three months postpartum
Secondary	Maternal Depression	Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes	six months postpartum
Secondary	Maternal Anger	LEVEL 2 - ANGER - Adult (PROMIS Emotional Distress - Anger - Short Form): Range in score from 5 to 25 with higher scores indicating greater severity of anger.	one week postpartum
Secondary	Maternal Anger	LEVEL 2 - ANGER - Adult (PROMIS Emotional Distress - Anger - Short Form): Range in score from 5 to 25 with higher scores indicating greater severity of anger.	three months postpartum
Secondary	Maternal Anger	LEVEL 2 - ANGER - Adult (PROMIS Emotional Distress - Anger - Short Form): Range in score from 5 to 25 with higher scores indicating greater severity of anger.	six months postpartum
Secondary	Maternal Breastfeeding Self-efficacy	Breastfeeding self-efficacy scale - short form: Total scores range from 14 to 70, with higher scores reflecting more significant levels of breastfeeding self-efficacy.	one week postpartum
Secondary	Maternal Breastfeeding Self-efficacy	Breastfeeding self-efficacy scale - short form: Total scores range from 14 to 70, with higher scores reflecting more significant levels of breastfeeding self-efficacy.	three months postpartum
Secondary	Maternal Breastfeeding Self-efficacy	Breastfeeding self-efficacy scale - short form: Total scores range from 14 to 70, with higher scores reflecting more significant levels of breastfeeding self-efficacy.	six months postpartum
Secondary	Maternal Anxiety	State-trait Anxiety inventory: Total scores range from 20 to 80 (each for state and trait), with higher scores indicating worse outcomes (higher anxiety).	Baseline - (birth/enrolment)
Secondary	Maternal Anxiety	State-trait Anxiety inventory: Total scores range from 20 to 80 (each for state and trait), with higher scores indicating worse outcomes (higher anxiety).	three months postpartum
Secondary	Maternal Anxiety	State-trait Anxiety inventory: Total scores range from 20 to 80 (each for state and trait), with higher scores indicating worse outcomes (higher anxiety).	six months postpartum