Comparing Impacts of Donor Human Milk to Formula Supplementation on the Gut Microbiome of Full-term Infants

Study Overview
=================
Brief Summary
-----------------
The goal of this pilot randomized controlled trial (RCT) is to examine donor human milk (DHM) as a clinical intervention targeted at achieving beneficial microbiome signatures in full-term infants who are exposed to intrapartum antibiotic prophylaxis (IAP) therapy during labour. 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 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 high 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 who are exposed to Group B Streptococcus (GBS) antibiotic prophylaxis during labour. 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 vaginally born, full-term infants who are exposed to antibiotics in labour through IAP and whose mothers are planning on breastfeeding. Recruitment: Mothers greater than 37 weeks' gestation admitted to the postpartum unit who test positive for GBS and deliver vaginally will be screened for participation in the study by nurses on the postpartum unit. Approximately 20% of all pregnant mothers will test positive for GBS and Alberta Health Services protocol indicates that GBS-positive mothers are given intravenous antibiotics during labour. Only mothers who receive the complete Alberta Health Services protocol will qualify for the study. Upon recruitment and completion of informed consent, infants requiring supplementation of MOM will be randomized to the control or intervention group. Investigators will randomize 60 mother-infant dyads, providing adequate power to detect overall microbiome differences ( 30 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, six and 12 weeks postpartum. Secondary outcomes include infant growth, sleep, and breastfeeding outcomes that will be collected at one, six and 12 weeks postpartum.

Official Title
-----------------
Comparing Impacts of Donor Human Milk to Formula Supplementation on the Gut Microbiome of Full-term Infants Exposed to Antibiotics in Labour: A Pilot Randomized Controlled Trial

Conditions
-----------------
Microbial Colonization

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Gestation greater than 37 weeks (full-term) Completion of antibiotic protocol for GBS during labour Vaginal delivery Intending on breastfeeding Consent for infant to receive DHM Working understanding (proficient in reading and understanding) 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 Receiving extended courses of antibiotics (beyond that of the IAP in labour)

Ages Eligible for Study
-----------------
Minimum Age: 37 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An experimental study design in which each participants 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 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?
-----------------
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 | six weeks postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (RA) | Relative abundance | twelve weeks 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 | six weeks postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (alpha diversity) | alpha diversity of microbiome | twelve weeks 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 | six weeks postpartum | 
| Infant gut microbiome - shallow shotgun metagenomics (beta diversity) | beta diversity of microbiome | twelve weeks 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. | Six weeks 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. | Twelve weeks 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 | six weeks postpartum | 
| Infant Growth - BMI | Body mass index - weight and height will be combined to report BMI in kg/m^2 | twelve weeks 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 | six weeks postpartum | 
| Infant Growth- length | Length - in centimeters; weight and height will be combined to report BMI in kg/m^2 | six weeks postpartum | 
| Infant Growth - head | Head circumference - in centimeters | six weeks postpartum | 
| Infant Growth - weight | Weight- in grams; weight and height will be combined to report BMI in kg/m^2 | Twelve weeks postpartum | 
| Infant Growth- length | Length - in centimeters; weight and height will be combined to report BMI in kg/m^2 | Twelve weeks postpartum | 
| Infant Growth - head | Head circumference - in centimeters | Twelve weeks postpartum | 
| Infant feeding | breastfeeding exclusivity - measured by 7-day infant feeding journal. Number of participants whose consume only breastmilk. | one week postpartum | 
| Infant feeding | breastfeeding exclusivity - measured by 7-day maternal recall. Number of participants whose consume only breastmilk. | six weeks postpartum | 
| Infant feeding | breastfeeding exclusivity- measured by 7-day maternal recall. Number of participants whose consume only breastmilk. | twelve weeks 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 | six weeks postpartum | 
| Maternal Depression | Edinburgh Postnatal Depression Screen -- Range in score from 0 to 30; higher scores indicate worse outcomes | twelve weeks 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. | six weeks 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. | twelve weeks 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. | six weeks 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. | twelve weeks 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 Anxiety inventory: Total scores range from 20 to 80, with higher scores indicating worse outcomes (higher anxiety). | six weeks postpartum | 
| Maternal Anxiety | State Anxiety inventory: Total scores range from 20 to 80, with higher scores indicating worse outcomes (higher anxiety). | twelve weeks postpartum | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sleep, Microbiome, Growth, Postpartum depression, Maternal anger, Breastfeeding, Self-efficacy