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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Microbial Colonization

Intervention / Treatment
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* Other: Donor Human Milk - Nutritional Replacement


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 37 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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]).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donor Human Milk<br>Infants randomized to the intervention group will receive DHM each time supplementation is required for the first 7 days of life. | Other: Donor Human Milk - Nutritional Replacement<br>* 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.<br>|
| No Intervention: Standard Care (Infant Formula)<br>Infants randomized to the standard care group will receive formula each time supplementation is required for the first 7 days of life. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant gut microbiome - shallow shotgun metagenomics (RA) | Relative abundance | one week postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (RA) | Relative abundance | three months postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (RA) | Relative abundance | six months postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (alpha diversity) | alpha diversity of microbiome | one week postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (alpha diversity) | alpha diversity of microbiome | 3 months postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (alpha diversity) | alpha diversity of microbiome | six months postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (beta diversity) | beta diversity of microbiome | one week postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (beta diversity) | beta diversity of microbiome | three months postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (beta diversity) | beta diversity of microbiome | six months postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Infant Growth - weight | Weight - in grams; weight and height will be combined to report BMI in kg/m^2 | one week postpartum | 
| Infant Growth - length | Length - in centimeters; weight and height will be combined to report BMI in kg/m^2 | one week postpartum | 
| Infant Growth - BMI | Body mass index - weight and height will be combined to report BMI in kg/m^2 | one week postpartum | 
| Infant Growth - BMI | Body mass index - weight and height will be combined to report BMI in kg/m^2 | three months postpartum | 
| Infant Growth - BMI | Body mass index - weight and height will be combined to report BMI in kg/m^2 | six months postpartum | 
| Infant Growth - head | Head circumference - in centimeters | one week postpartum | 
| Infant Growth - weight | Weight - in grams; weight and height will be combined to report BMI in kg/m^2 | three months postpartum | 
| Infant Growth - length | Length - in centimeters; weight and height will be combined to report BMI in kg/m^2 | three months postpartum | 
| Infant Growth - head | Head circumference - in centimeters | three months postpartum | 
| Infant Growth - weight | Weight - in grams; weight and height will be combined to report BMI in kg/m^2 | six months postpartum | 
| Infant Growth - length | Length - in centimeters; weight and height will be combined to report BMI in kg/m^2 | six months postpartum | 
| Infant Growth - head | Head circumference - in centimeters | six months postpartum | 
| Infant feeding | breastfeeding exclusively - measured by 7-day infant feeding journal. Number of participants who consume only breastmilk. | one week postpartum | 
| Infant feeding | breastfeeding exclusively - measured by 7-day maternal recall. Number of participants who consume only breastmilk. | three months postpartum | 
| Infant feeding | breastfeeding exclusively - measured by 7-day maternal recall. Number of participants who consume only breastmilk. | six months postpartum | 
| Maternal Depression | Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes | one week postpartum | 
| Maternal Depression | Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes | three months postpartum | 
| Maternal Depression | Edinburgh Postnatal Depression Screen - Range in score from 0 to 30; higher scores indicate worse outcomes | six months postpartum | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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 | 
| 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 |