Effect of brewers’ yeast or beta-glucan on breast milk supply following preterm birth: The BLOOM Study – protocol for a multicentre randomised controlled trial

Effect of brewers’ yeast or beta-glucan on breast milk supply following preterm birth: The BLOOM Study – protocol for a multicentre randomised controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Effect of brewers’ yeast or beta-glucan on breast milk supply following preterm birth: The BLOOM Study – protocol for a multicentre randomised controlled trial Luke E. Grzeskowiak, Alice R. Rumbold, Lauren Williams, Renee L. Kam, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4252206/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Many individuals who experience preterm birth struggle with early breast milk supply, which can translate into suboptimal longer-term breastfeeding outcomes. Further investigations into the potential role of early non-pharmacological and pharmacological interventions in improving breast milk production soon after birth is growing. While natural galactagogues, such as brewers’ yeast, are widely perceived by women to be safer than pharmaceutical galactagogues and are taken by many women, evidence to support their efficacy is largely absent. The BLOOM study has been designed to determine the efficacy and safety of brewers’ yeast and beta-glucans, derived from Saccharomyces cerevisiae , when administered soon after birth for increasing early breast milk supply in mothers who have delivered preterm. Methods The BLOOM study is a multicentre, double-blinded, randomised controlled trial that will assess if brewers’ yeast or beta-glucan can increase early breast milk production following preterm birth. Target population are mothers of preterm infants born at less than 34 weeks’ gestation who intend to provide breast milk for their infant, are less than 72 hours following birth and able to give informed consent. Participants will be randomly allocated into three parallel groups at 1:1:1 ratio (n = 33 per group) to receive either brewers’ yeast, beta-glucan or placebo capsules for seven days. The primary outcome is total expressed breast milk volume over a 24-hour period on day 7 of intervention. Participants and their infants will be followed until the infant reaches term corrected age or is discharged home from the neonatal unit (whichever occurs first). Discussion The use of brewers’ yeast as a galactagogue to enhance milk production is extremely common amongst breastfeeding mothers, however, there are no trials evaluating its efficacy and safety. This will be the first randomised controlled trial to evaluate the efficacy and safety of two commonly used galactagogues, brewers’ yeast and beta-glucan, compared with placebo in improving maternal breast milk supply following preterm birth. The trial will also evaluate whether early intervention with galactagogues soon after a preterm birth improves longer-term breastfeeding outcomes. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12622000968774 (registered on 8 July 2022) and UTN U1111-1278-8827 Lactation Breastfeeding Breast milk expression Breast milk production Breast milk supply Preterm birth Galactagogue Brewers’ yeast Figures Figure 1 Figure 2 Background Breast milk is considered the optimal form of enteral nutrition for preterm infants [ 1 , 2 ]. There is a compelling body of evidence demonstrating that the provision of mothers’ own breast milk significantly reduces neonatal morbidity and mortality [ 3 , 4 ]. Specifically, use of mothers’ own breast milk during hospitalisation reduces the incidence and severity of certain morbidities, including necrotizing enterocolitis (NEC), late onset sepsis, chronic lung disease, retinopathy of prematurity, rehospitalisation after discharge, and neurodevelopmental problems in infancy and childhood [ 3 ]. A recent Cochrane review showed preterm infants receiving infant formula are three times more likely to develop NEC, which has a mortality rate of 20–40% [ 5 ]. Further, the ability for a mother to provide her own breast milk represents an important tangible contribution in a situation where mothers are separated from their infant during the neonatal hospitalisation and may have limited opportunities to directly participate in infant care in the first few weeks of life [ 6 – 8 ]. The resultant psychological benefits can include greater feelings of attachment, empowerment, and confidence [ 9 ]. Despite the noted benefits, mothers of preterm infants face many challenges in establishing and maintaining an adequate supply of breast milk during their infant’s prolonged hospitalisation. This is driven by multiple factors including physiological immaturity of the breast associated with preterm birth, inability for the preterm infant to breastfeed directly from the breast, and the stress of having an infant admitted to a Neonatal Intensive Care Unit (NICU). Each of these factors has the ability to interfere with establishment of normal milk supply; one previous study demonstrated 82% of women birthing preterm experienced delayed secretory activation [ 10 ]. While longer-term breastfeeding outcomes were not collected for this cohort, other studies in mothers of term infants have demonstrated that delayed secretory activation is associated with increased risk of early cessation of breastfeeding [ 11 ]. Some mothers may respond well to non-pharmacological lactation support strategies (i.e. correct use of breast milk pump, increasing expressing frequency) for increasing breast milk supply, but for a large number of preterm mothers, their breast milk supply continues to be insufficient to meet their infant’s needs. Insufficient volume of mothers’ own breast milk has been partly addressed through the introduction of human milk banks, however donor milk is not universally available. Further, mothers’ own milk has been demonstrated to be superior to donor human milk with respect to composition and bioactivity, highlighting that focusing on supporting mothers to provide their own breast milk to their infants is key to optimising neonatal outcomes [ 3 ]. Given the challenges mothers of preterm infants face in initiating and sustaining lactation, attention has shifted towards the potential role of early non- pharmacological and pharmacological interventions in improving breast milk production soon after birth. A recent survey of 1876 Australian women found that 60% reported taking galactagogues, known as substances thought to aid in initiating and maintaining adequate milk production, during breastfeeding [ 12 ]. In 2023, galactagogues were also reported as being used in over half of the participants in an online survey of breastfeeding mothers in the United States [ 13 ]. This is despite a lack of clear evidence to guide their use[ 14 , 15 ]. The most commonly reported galactagogues in recent surveys include lactation cookies, oats, and brewers’ yeast [ 12 ]. While lactation cookies may vary in composition, they typically consist of ingredients such as oats, brewers’ yeast and flaxseed. The active ingredient of oats or brewers’ yeast is thought to be beta-glucan, which is a glucose polymer present in the cell walls of cereals as well as yeast (i.e. brewers’ yeast) and fungi [ 16 ]. While natural galactagogues, such as brewers’ yeast, are widely perceived by women to be safer than pharmaceutical galactagogues and are taken by many women [ 12 ], evidence to support their efficacy in increasing breast milk production is largely absent. Furthermore, natural galactagogues have been used to treat lactation insufficiency but appear to be increasingly used prophylactically. Evidence to support their use either in the treatment or prevention of low milk supply following preterm birth is lacking. In the survey conducted by Ryan et al , Brewers’ yeast was the galactagogue participants felt had the greatest impact on increasing breast milk supply [ 13 ]. With respect to brewers’ yeast derived from Saccharomyces cerevisiae , the likely mechanism of action remains unknown. Some have postulated that it could relate to the high concentration of B vitamins, or the presence of beta-glucan isolated from the cell wall [ 17 ]. Further, a number of studies have demonstrated that oral consumption of beta-glucans may have immunomodulatory effects [ 16 ]. As immune dysregulation is a common feature of preterm birth [ 18 ] and has been associated with impaired lactation in animal models [ 19 ], this represents an alternative potential mechanism of action in which brewers’ yeast/ beta-glucans could influence breast milk production. Data in lactating women, however, remains scant. A recent clinical trial by Wesolowska et al. , evaluated the efficacy of a barley malt-based galactagogue (containing a proprietary blend of barley malt and beta-glucan) compared with placebo in mothers of preterm infants [ 20 ]. Compared with placebo, those who took the barley malt preparation reported expressing a greater total volume of breastmilk over the 14-day intervention period (6036 ± 498 vs 4209 ± 335; p = 0.003). Differences in daily expressed breast milk volume between groups were evident by day seven of the intervention. No participants reported experiencing any side effects during the study. However, the study can only be considered to provide low quality evidence due to a substantial loss to follow-up of 32% across both treatment groups. The beta-glucans found in cereals are also noted to be structurally different and exert different physiological effects to those founds in yeast, therefore the generalisability of these findings to brewers’ yeast are uncertain. Given the scant literature, it remains unknown whether natural galactagogues such as brewers’ yeast or beta glucan are effective in improving breast milk production following preterm birth. The BLOOM Study (Can B rewers’ yeast or beta-g L ucan increase m O ther’s O wn M ilk supply following preterm birth?) will evaluate if routine administration, commenced within the first week postpartum, of brewers’ yeast or beta-glucan, both derived from Saccharomyces cerevisiae , increases early breast milk production following preterm birth. Objectives The main objective of this study is to assess if administration of brewers’ yeast or beta-glucan within the first week postpartum can increase daily expressed breast milk volume following preterm birth. Methods Study design and setting The BLOOM study is a randomised, controlled, clinician, researcher and participant/family blinded, multicentre trial with three parallel groups with a 1:1:1 allocation ratio. The sponsoring institution and trial coordinating centre is the South Australian Health and Medical Research Institute (SAHMRI) based at the Women’s and Children’s Hospital. The study will take place in three locations within Australia (Women’s and Children’s Hospital and Flinders Medical Centre, South Australia and The Royal Women’s Hospital, Victoria). Participant screening, enrolment, randomisation, and study visits will be undertaken locally at each study site. A trial steering committee consisting of LEG, LHA and LW and will oversee all clinical trial activities. The study protocol was prepared following the SPIRIT guideline and checklist [ 21 ]. Study population Mothers of preterm infants born at less than 34 weeks’ gestation who intend to provide breast milk for their infant, and are within 72 hours of giving birth. The inclusion criteria will include women, 18 years or older, who have delivered a preterm infant born at less than 34 weeks’ gestation (up to 33 + 6), are between 0 to 72 hours of birth, intend to provide breast milk to their preterm infant for any desired duration, and able to give informed consent. Women with a contraindication to breastfeeding such as infection with human immunodeficiency virus (HIV), as well as those with higher order pregnancies (triplet or more) will be excluded from the study. Information on the study will be provided to eligible participants by their nurse or midwife who will ask them to complete a Consent to Contact form, and following this consent will be contacted by a study researcher (Fig. 1 ). After confirmation of eligibility and receipt of voluntary informed consent, women will be assigned randomly to one of three groups: brewers’ yeast, beta-glucan, or placebo in a 1:1:1 ratio using randomly permuted blocks of varying sizes. Block sizes will not be disclosed to ensure allocation concealment. Participants will be randomised using the REDCap Randomisation Module, and the randomisation schedule will be prepared using ralloc. ado in Stata by an independent statistician that is not involved with trial participants or data. The randomisation schedule will be stratified according to study site. Participants and their care providers, outcome assessors, trial investigators and data analysts will be blinded to randomisation group. Women will be allocated a random, unique, re-identifiable randomisation identification number (ID) and assigned to one of six treatment groups and be issued with study medications identified by colour (i.e. green, yellow, red, blue, purple, orange). Women will be free to withdraw themselves and/or their infant from the study at any time. Participant recruitment for the BLOOM trial began in July 2022 and recruitment is expected to be completed in mid-2024. Intervention Participants will be randomised to one of three treatment arms, consisting of either brewers’ yeast ( Saccharomyces cerevisiae ), beta-glucan (purified from Saccharomyces cerevisiae ) or placebo (microcrystalline cellulose), study medications will be manufactured and supplied by Leiber GmbH (Germany). To maintain study blinding, all study participants will take an oral dose of three capsules twice daily (six capsules a day) according to the treatment schedule indicated in Table 1 for a total of seven days from enrolment. To facilitate treatment blinding and aid medication adherence, the medications will be provided in bottles with instructions according to the dosing regimen (Table 1 ) and all study medications will be identical in appearance. Study treatment will be discontinued if either of the following occur: unacceptable toxicity; treatment continuation is determined not to be in the participants’ best interest; or participant declines taking study medication or withdraws their consent. Table 1 BLOOM Study treatment dosing regimen Treatment Arm Morning Evening Total amount active ingredient per day Brewers’ Yeast 3 x 280 mg capsules 3 x 280 mg capsules 1680 mg Beta-glucan 1 x 250 mg capsule 2 x placebo capsules 3 x placebo capsules 250 mg Placebo (Microcrystalline cellulose) 3 x placebo capsules 3 x placebo capsules - Medication adherence will be monitored, with participants asked to document all doses taken in a provided breast milk diary. Participants will be able to access and receive lactation support as necessary and as per local hospital policies during the trial. Given the absence of any known drug-drug interactions, no restrictions will be placed on the concomitant use of other medications including use of other galactagogues. Patient and public involvement We received input from the SAHMRI Women and Kids consumer group, comprising women with young children, to ensure members of the public were involved at several stages of the trial, including design, management, and conduct. The burden of the trial was carefully assessed. We intend to disseminate the main results to trial participants and will seek patient and public involvement in the development of an appropriate method of dissemination. Outcomes Primary outcome Daily expressed breast milk volume on Day 7 post study intervention. Following randomisation all participants will be asked to maintain a daily breast milk diary throughout each day of the study (Fig. 2 ). The diary will act as a record (self-reported) of each time breast milk was expressed, time spent expressing, whether they expressed one breast at a time or both breasts simultaneously, and the volume of expressed milk. Each individual volume of expressed milk will be summed to generate a total for expressed breast milk over a 24-hour period (midnight to midnight). Secondary outcomes Maternal breastfeeding outcomes Infant intake of supplemental enteral feeds (donor milk or infant formula), proportion of enteral feeds consisting of mother’s own breast milk, total duration and extent of breast milk expression and/or direct breastfeeding up until infant discharge or term corrected age (whichever occurs first), total expressed breast milk volume during study intervention, total expressed breast milk volume up to and on day 21 postnatal. Data on breast health will be assessed using a modified breast health questionnaire, while data on breast milk expression will be assessed using the Breast Milk Expression Experience (BMEE) questionnaire [ 22 ]. Maternal outcomes Maternal mental health and wellbeing will be assessed using three validated instruments: Edinburgh Postnatal Depression Scale (EPDS) [ 23 ], Six-item State-Trait Anxiety Inventory (STAI-6) [ 24 ], and the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) [ 25 ]. Impacts of the intervention on maternal and infant bonding will be assessed using the Maternal Postnatal Attachment Scale (MPAS) [ 26 ]. Infant outcomes Differences in infant anthropometrics (weight, length, head circumference) at discharge from hospital or term corrected age (whichever occurs earlier), trajectories of infant anthropometrics from birth (weight, length, head circumference) to discharge from hospital or term corrected age (whichever occurs earlier). Data on infant morbidity and mortality will be compared based on information obtained from the Australian and New Zealand Neonatal Network (ANZNN) registry. Safety outcomes Safety outcomes including side effects and tolerability of study medications will be assessed through routine data collection by maternal self-report. Serious adverse events will be assessed: maternal mortality; maternal hospitalisation; or other life-threatening events. Biological outcomes A range of biospecimens will be collected as part of the study as outlined in Table 2 and Table 4 . Samples will be stored for future analysis relating to this study which may include investigating changes in breast milk macronutrient composition; differences in the faecal microbiome; differences in cytokines and other proteins in breast milk and/or blood; differences in serum prolactin; differences in urinary metabolome; and differences in interactions of breast milk samples with breast cells in vitro. Table 2 Overview of the BLOOM Study schedule of assessments Day 0 Baseline Day 7 Post enrolment Day 21 Postpartum Infant Discharge to Home or Term Corrected Age Questionnaires General - Maternal demographic & lifestyle questionnaire X - Postnatal health X X X Breastfeeding - Daily breast milk diary X X X - General breast milk expression and breastfeeding questions X X X X - Breast health questionnaire X X X - Breast Milk Expression Experience questionnaire X X Mental health and wellbeing - EPDS X X - STAI-6 X X - PSS:NICU X X - MPAS X Medication side-effects X X Physical assessments Maternal anthropometry X Maternal biospecimens* Blood X Urine X Stool X Buccal swab X Breast milk X Case note audit Pregnancy and birth history X Infant feeding record X X X X Infant anthropometry X X X X Infant morbidity and mortality X Protocol window - Day 7–9 Day 21–23 Within 3 days of event EPDS Edinburgh postnatal depression scale, STAI-6 Six-item State-Trait Anxiety Inventory, PSS:NICU Parental Stressor Scale: Neonatal Intensive Care Unit, MPAS Maternal Postnatal Attachment Scale *All biological samples are collected for research purposes only. Data and sample collection Data will be collected from all participants across four study time-points (Day 0 – Baseline, Day 7 post intervention, Day 21 postpartum, and at infant discharge or at term corrected age) as outlined in Table 2 . Questionnaires and assessments will be completed at study visits as described in Table 3 at the corresponding timepoints indicated in Table 2 . Biological samples will be collected for research purposes only as indicated in Table 2 and Table 4 . Appointments will be conducted within the hospital (either within the neonatal unit, postnatal ward, or designated clinical research area), or by telephone (when required, e.g. if mother is not visiting on the day or illness prevents a face-to-face visit). Table 3 Overview of data collected as part of the BLOOM Study Questionnaire or assessment Description Questionnaires/Assessment General information Contact information, including name, address, phone number, hospital ID number. Maternal demographic and lifestyle information Maternal age, height, pre-pregnancy weight, smoking status, alcohol intake, pre-existing medical conditions, ethnicity, country of birth, income status, education level, marital status, previous pregnancy and breastfeeding history, pregnancy complications, medication use, postnatal contraception use, breast type/shape, breast development since puberty and during pregnancy. Breast milk diary Daily breast milk diary recording the number of times each breast was expressed, the method used to express, the volume of expressed milk, duration and if applicable information pertaining to direct breastfeeding for a total of 21 days. Breast milk expression Intended duration of breastfeeding, breast development previous to and during pregnancy, time of first expressing following birth, perceived onset of lactogenesis, methods and type of breast milk expressing (including type of breast milk pump), duration of breast milk expressing or breastfeeding, and provision of lactation support. Breast Health Questionnaire Questionnaire adapted from Fetherston 2006 to assess general breast health and potential risk for mastitis. Collects information on breast fullness, breast pain and discomfort, duration of pain/discomfort, presence of cracks or grazes on the nipples, fever, as well as any areas of heat, swelling or redness on breasts. Breast Milk Expression Experience (BMEE) Questionnaire BMEE provides a measure of milk expression experience across three dimensions: (1) social support for milk expression; (2) ease of learning how to express milk; and (3) personal experiences of milk expression. Postnatal Health Questionnaire Postnatal health issues during the study (e.g. infections, cold/flu), as well as any medications (prescription or non-prescription), herbal supplements or multivitamins taken. Mental Health and Wellbeing Questionnaires • EPDS • STAI-6 • PSS:NICU • MPAS Assessment of depression and anxiety symptoms will be collected using standardises validated questionnaires (Edinburgh Postnatal Depression Scale [EPDS], Spielberger State-Trait Anxiety Inventory [STAI-6]). Stress related to infant hospitalisation will be assessed using the Parental Stressor Scale: NICU (PSS:NICU). Maternal-infant attachment will be assessed using the Maternal Postnatal Attachment Scale (MPAS). Maternal anthropometry Maternal weight, height, waist circumference, hip circumference, and mid upper-arm circumference will be assessed. Medication side-effects and adverse event Recording any side-effects pertaining to potential adverse events or serious adverse events. Details encouraged to be recorded in breast milk diary too. Case Note Data Extraction Pregnancy and birth history Gravida, parity, length of gestation, infant birthweight, infant sex, plurality, onset of labour, method of birth, estimated blood loss, pregnancy complications (i.e. gestational diabetes, gestational hypertension, pre-eclampsia), antenatal interventions (i.e. receipt of antenatal corticosteroids of magnesium sulphate), medication use, antenatal haematology (i.e. haemoglobin, iron studies). Infant feeding record Daily record of total enteral intake, volume of expressed breast milk, donor milk, or infant formula, as well as proportion of enteral feeds consisting of mothers’ own breast milk. Infant anthropometry Weight, length, head circumference. Infant morbidity/mortality Infant morbidity and mortality data will be obtained from the Australian and New Zealand Neonatal Network (ANZNN)[ 28 ] registry. Data include, number of days in hospital (to first discharge home), intraventricular haemorrhage (IVH), confirmed sepsis, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), surgical procedures and death during initial hospitalisation. Table 4 Biospecimen sample collection at Visit 2 (Day 7 following intervention) Sample type Description Maternal blood • 30 mL blood (Serum tube 10 mL, K2 EDTA 10 mL and 5 mL, and Trace Elements 5 mL) • Cryopreservation of plasma trace element, serum, plasma, buffy coat, red blood cells aliquots Breast milk • Expressed milk (3–8 mL) from a single breast expression episode • Cryopreserved aliquots of whole milk Maternal urine • 25 mL urine • Cryopreserved aliquots Maternal stool • 1x Collection pot (Norgen Biotek) • Cryopreserved sample pot Maternal buccal swab • FloqSwab (Copan Diagnostics) • Air-dried swab cryopreserved • Researcher collected Sample size calculation A sample of 99 women (33 per arm) yields 90% power, 0.025 alpha to show a difference in the mean daily breast milk volume of 150 mL/day (200 mL/day standard deviation) between each of the intervention arms and control arm, allowing for 10% loss to follow-up. This includes adjustment for a 0.6 correlation between breast milk volume at study entry and breast milk volume on Day 7 at the end of the intervention phase. Data management Data entry and study management will be using a purpose-built REDCap database and hosted on secure servers at SAHMRI. Electronic case report forms will be used and stored directly in REDCap, and any paper-based case report forms will be stored in a locked office at the study site. Data are collected by trained researchers and entered directly into REDCap, no confidential data are stored on data entry machines. REDCap uses a MySQL database via a secure web interface and includes a complete suite of features to support the Health Insurance Portability and Accountability Act of 1996 compliance, including a full audit trail, user-based privileges and integration with the institutional Lightweight Directory Access Protocol server [ 27 ]. In order to adhere to international best research practice and to ensure eligibility of our study for publication in scientific journals, we plan to archive the fully deidentified sequencing datafiles in the Gene Expression Omnibus (GEO or equivalent database). The sequencing data files prepared for GEO will be free of all identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of the identity of individual subjects, in accordance with the NIH Statement on Sharing Research Data (2003). Statistical analysis methods The primary analysis will be performed according to the treatment group to which participants were randomised (intention-to-treat principle). A secondary per-protocol analysis will also be performed for each of the primary and secondary outcomes. The primary outcome of daily expressed breast milk volume on Day 7 post intervention will be compared between treatment groups using a linear regression. The results will be expressed as a difference in means with a 95% confidence interval and two-sided p-value. Adjustment will be made for baseline daily expressed breast milk volume and the randomisation strata (study centre). A p-value of less than 0.05 will be considered to indicate statistical significance. Analysis of secondary outcomes will use log-binomial regression models for binary outcomes and linear regression models for continuous outcomes with adjustment for stratification variables and other pre- specified prognostic baseline variables. Results will be presented as relative risks and differences in means respectively, along with 95% confidence intervals. Missing data will be addressed using multiple imputation. Sensitivity analyses will also be performed using the original unimputed data. Planned sub-group analyses of the primary and secondary breastfeeding outcomes include: (i) Plurality (singleton vs. twins); (ii) Parity (primiparous vs. multiparous); (iii) Infant gestation at birth (categorical: 23 + 0 –29 + 6 vs. 30 + 0 –31 + 6 vs 32 + 0 -33 + 6 weeks’ gestation and continuous); (iv) Maternal body mass index (categorical: underweight/normal weight [BMI < 25 kg/m 2 ] vs. overweight/obese [BMI ≥ 25 kg/m 2 ] and continuous). Effect modification by each of these factors will be assessed separately by including interaction effects with treatment group in the statistical models. Data monitoring and safety The trial coordinating centre (SAHMRI) will perform ongoing monitoring via weekly reports of participants screened/enrolled/randomised, visits due/overdue/missed, adverse and serious adverse events, product inventory and dispense records, sample collection logs, and participant communication logs. The weekly reports will be reviewed at weekly trial management meetings. No interim analyses are planned. An individual participant may only be unblinded in emergency situations, where the Investigator decides a participant cannot be adequately treated without knowing the identity of their treatment allocation. To break the randomisation code the Principal Investigator must contact the randomisation facility/personnel. The time, date, participant study ID and reason for unblinding will be documented. Events leading to the emergency breaking will be recorded in the serious adverse event (SAE) report form. Ethical issues and dissemination The BLOOM study will be conducted in accordance with the approved version of the Study Protocol and in compliance with the Australian National Statement on Ethical Conduct in Research Involving Humans which builds on the ethical codes of the Declaration of Helsinki and the Principles of International Conference on Harmonisation Good Clinical Practice (as adopted in Australia). All study materials and study protocol (current version 1.1) have been reviewed and approved by the Women’s and Children’s Health Network Human Research Ethics Committee (HREC), South Australia (HREC/22/WCHN/00001), as well as the research governance officers at each of the study sites. Any change to the protocol or Informed Consent Form that affects the scientific intent, study design, patient safety or may affect a participant’s willingness to continue participation in the study is considered an amendment, and therefore, will be written and filed as an amendment to this protocol and/ or informed consent form. All such amendments will be submitted to the HREC, for approval prior to becoming effective. The primary and key secondary breastfeeding objectives will be analysed and reported first. Study findings will be submitted for peer-reviewed publication and for presentation at appropriate local and international conferences. In addition, study findings will be disseminated to participants through a brief lay summary. No participants will be identified in the dissemination of study results and data collected will be treated with confidence. Access to data and study documentation De-identified individual participant data will be made available upon reasonable request. Requests to access data must be reviewed and approved by both the BLOOM trial steering committee and the Women’s and Children’s HREC, and will be assessed for scientific and methodological rigour. Individuals requesting data will be required to sign a data access agreement. Requests for data or study documentation should be directed to the Chair of the BLOOM Steering Committee, LEG via email ( [email protected] ). Discussion This study seeks to monitor the effectiveness and safety of consuming of galactagogues on breast milk production following preterm birth. Galactagogues in the form of brewers’ yeast or beta-glucan will be provided to participants and compared with a placebo group for a 7-day period. Recruitment commenced in July 2022 and will aim to be completed within two years. Strengths and limitations The planned study has a number of strengths, notably the rigorous experimental design and comprehensive assessment across a range of maternal and infant outcomes up until the point of infant discharge home from hospital (or until term corrected age, whichever occurs first) However, the study also has some limitations. Firstly, estimation of total daily breast milk volume is based solely on expressed volumes. In the case that infants fed directly from the breast, pre- and post- feed weighing of the infant was not included due to the added burden and stress, and expected negligible overall impact on the primary study outcome given noted difficulties in establishing direct breastfeeding following preterm birth before 34 weeks’ gestation. Further, the use of infant test-weighing is not an established practice within any of the study trial sites. List of abbreviations ANZNN Australian and New Zealand Neonatal Network BLOOM Can B rewers’ yeast or beta-g L ucan increase m O ther’s O wn M ilk supply following preterm birth? BMEE Breast Milk Expression Experience questionnaire EPDS Edinburgh Postnatal Depression Scale HREC Human Research Ethics Committee MPAS Maternal Postnatal Attachment Scale NEC Necrotizing enterocolitis NICU Neonatal Intensive Care Unit PSS:NICU Parental Stressor Scale: Neonatal Intensive Care Unit SAHMRI South Australian Health and Medical Research Institute STAI-6 Six-item State-Trait Anxiety Inventory Declarations Ethics approval and consent to participate This study obtained ethics approval from the Women's and Children's Health Network Human Research Ethics Committee, Women's and Children's Hospital 72 King William Road North Adelaide SA, Australia (HREC/22/WCHN/00001). Informed consent is obtained from all individual participants included in the study. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: At the time of submission, LHA is the Editor-in-Chief of the International Breastfeeding Journal, while LEG is an Associate Editor. Funding This study is funded by a Channel 7 Children’s Research Foundation Fellowship, Australia awarded to LEG (CRF-210323), as well as a Flinders Innovation Seed Partnership Grant awarded to LEG, LHA, AK, AR in collaboration between Leiber GmbH, Germany and Flinders University, Australia. Study medications are donated by Leiber GmbH, Bramsche, Germany, who also provided financial support. The funder/s have no role in the study design; collection, management, analysis and interpretation of data; writing of the report; and the decision to submit the report for publication and have no authority over any of these activities. Acknowledgements The authors wish to acknowledge support provided by the National Health and Medical Research Council Centre of Research Excellence in Optimising human milk nutrition to improve the long-term health of preterm infants (GNT 2024589). The authors also wish to acknowledge Dr Amanda Brass for their assistance in drafting the study protocol manuscript and Dr Emma Knight for their assistance in providing statistical support with respect to sample size calculation, randomisation, and statistical analysis methods. Authors’ contributions Drafted the manuscript: LEG. Revised the manuscript: AR, WVI, LW, RLK, AK, KM, LHA. Conceptualised and designed the study: LEG and LHA. Obtained grant funding to conduct the study: LEG, LHA, AK, and AR. All authors read and approved the final manuscript. References Rollins NC, Bhandari N, Hajeebhoy N, Horton S, Lutter CK, Martines JC, et al. Lancet Breastfeeding Series G. Why invest, and what it will take to improve breastfeeding practices? Lancet. 2016; 387(10017):491-504. Victora CG, Rollins NC, Murch S, Krasevec J, Bahl R. Breastfeeding in the 21st century. Lancet. 2016; 387(10017):475-490. Meier P, Patel A, Esquerra-Zwiers A. Donor Human Milk Update: Evidence, Mechanisms, and Priorities for Research and Practice. J Pediatr. 2017; 180:15-21. World Health Organisation. WHO recommendations for care of the preterm or low-birth-weight infant. Geneva: World Health Organization; 2022. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2018; 6(6):CD002971. Sweet L. Expressed breast milk as 'connection' and its influence on the construction of 'motherhood' for mothers of preterm infants: a qualitative study. Int Breastfeed J. 2008; 3:30. Li X, Li Y, Qian L, Han P, Feng H, Jiang H. Mothers' experiences of breast milk expression during separation from their hospitalized infants: a systematic review of qualitative evidence. BMC Pregnancy Childbirth. 2024; 24(1):124. Bujold M, Feeley N, Axelin A, Cinquino C. Expressing Human Milk in the NICU: Coping Mechanisms and Challenges Shape the Complex Experience of Closeness and Separation. Adv Neonatal Care. 2018; 18(1):38-48. Bell EH, Geyer J, Jones L. A structured intervention improves breastfeeding success for ill or preterm infants. MCN Am J Matern Child Nurs. 1995; 20(6):309-314. Cregan MD, De Mello TR, Kershaw D, McDougall K, Hartmann PE. Initiation of lactation in women after preterm delivery. Acta Obstet Gynecol Scand. 2002; 81(9):870-877. Brownell E, Howard CR, Lawrence RA, Dozier AM. Delayed onset lactogenesis II predicts the cessation of any or exclusive breastfeeding. J Pediatr. 2012; 161(4):608-614. McBride GM, Stevenson R, Zizzo G, Rumbold AR, Amir LH, Keir AK, Grzeskowiak LE. Use and experiences of galactagogues while breastfeeding among Australian women. PLoS One. 2021; 16(7):e0254049. Ryan RA, Hepworth AD, Lyndon A, Bihuniak JD. Use of Galactagogues to Increase Milk Production Among Breastfeeding Mothers in the United States: A Descriptive Study. J Acad Nutr Diet. 2023; 123(9):1329-1339. Forinash AB, Yancey AM, Barnes KN, Myles TD. The use of galactogogues in the breastfeeding mother. Ann Pharmacother. 2012; 46(10):1392-1404. Gabay MP. Galactogogues: medications that induce lactation. J Hum Lact. 2002; 18(3):274-279. Jayachandran M, Chen J, Chung SSM, Xu B. A critical review on the impacts of beta-glucans on gut microbiota and human health. J Nutr Biochem. 2018; 61:101-110. Jia LL, Brough L, Weber JL. Saccharomyces cerevisiae Yeast-Based Supplementation as a Galactagogue in Breastfeeding Women? A Review of Evidence from Animal and Human Studies. Nutrients. 2021; 13(3). Keelan JA. Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. J Reprod Immunol. 2011; 88(2):176-184. Glynn DJ, Hutchinson MR, Ingman WV. Toll-like receptor 4 regulates lipopolysaccharide-induced inflammation and lactation insufficiency in a mouse model of mastitis. Biol Reprod. 2014; 90(5):91. Wesolowska A, Pietrzak B, Kociszewska-Najman B, Wielgos M, Czajkowski K, Wietrak E, et al. Barley malt-based composition as a galactagogue - a randomized, controlled trial in preterm mothers. Ginekol Pol. 2021; 92(2):118-125. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013; 158(3):200-207. Flaherman VJ, Gay B, Scott C, Aby J, Stewart AL, Lee KA. Development of the breast milk expression experience measure. Matern Child Nutr. 2013; 9(3):425-430. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987; 150:782-786. Ferreira R, Murray J. Spielberger's State-Trait Anxiety Inventory: Measuring anxiety with and without an audience during performance on a stabilometer. Percept Mot Skills. 1983; 57(1):15-18. Miles MS, Funk SG, Carlson J. Parental Stressor Scale: neonatal intensive care unit. Nurs Res. 1993; 42(3):148-152. Condon JT, Corkindale CJ. The assessment of parent-to-infant attachment: Development of a self-report questionnaire instrument. Journal of reproductive and infant psychology. 1998; 16(1):57-76. TGA: Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) annotated with Therapeutic Goods Administration (TGA) comments. In. Therapeutic Goods Administration; 2000. Australian & New Zealand Neonatal Network. https://www.anznn.net/. Accessed 03 May 2023. Additional Declarations Competing interest reported. The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: At the time of submission, LHA is the Editor-in-Chief of the International Breastfeeding Journal, while LEG is an Associate Editor of the International Breastfeeding Journal. The authors declare no other conflicts of interest. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 03 Jun, 2024 Reviews received at journal 01 Jun, 2024 Reviews received at journal 02 May, 2024 Reviewers agreed at journal 01 May, 2024 Reviewers agreed at journal 01 May, 2024 Reviewers invited by journal 29 Apr, 2024 Editor assigned by journal 25 Apr, 2024 Submission checks completed at journal 12 Apr, 2024 First submitted to journal 11 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4252206","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":290583093,"identity":"3fa0af2c-d0f0-4ca3-abdf-07576bb19e6c","order_by":0,"name":"Luke E. Grzeskowiak","email":"data:image/png;base64,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","orcid":"","institution":"Flinders University of South Australia","correspondingAuthor":true,"prefix":"","firstName":"Luke","middleName":"E.","lastName":"Grzeskowiak","suffix":""},{"id":290583096,"identity":"cb5f3e3a-c92c-44b8-b6a5-6cdb40f5cc75","order_by":1,"name":"Alice R. Rumbold","email":"","orcid":"","institution":"SAHMRI Women and Kids, South Australian Health and Medical Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Alice","middleName":"R.","lastName":"Rumbold","suffix":""},{"id":290583099,"identity":"7b62000d-262b-4650-b8f2-a978bb2ff35b","order_by":2,"name":"Lauren Williams","email":"","orcid":"","institution":"SAHMRI Women and Kids, South Australian Health and Medical Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Lauren","middleName":"","lastName":"Williams","suffix":""},{"id":290583102,"identity":"e125ecb9-02db-41b5-9494-db02a047ba6b","order_by":3,"name":"Renee L. Kam","email":"","orcid":"","institution":"La Trobe University","correspondingAuthor":false,"prefix":"","firstName":"Renee","middleName":"L.","lastName":"Kam","suffix":""},{"id":290583105,"identity":"21099014-b27f-41eb-9fe0-34d91c3f662b","order_by":4,"name":"Wendy V. Ingman","email":"","orcid":"","institution":"University of Adelaide, The Queen Elizabeth Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wendy","middleName":"V.","lastName":"Ingman","suffix":""},{"id":290583108,"identity":"b59b4e04-7d53-4b82-912c-1f2b1ac36171","order_by":5,"name":"Amy Kier","email":"","orcid":"","institution":"Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Amy","middleName":"","lastName":"Kier","suffix":""},{"id":290583111,"identity":"2ef65fbe-6729-4a08-9f8d-561aac5e0c45","order_by":6,"name":"Kathryn A. Martinello","email":"","orcid":"","institution":"Flinders University of South Australia","correspondingAuthor":false,"prefix":"","firstName":"Kathryn","middleName":"A.","lastName":"Martinello","suffix":""},{"id":290583113,"identity":"cc170ee6-dbe2-4c22-b23f-40060a4b541a","order_by":7,"name":"Lisa H. Amir","email":"","orcid":"","institution":"La Trobe University","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"H.","lastName":"Amir","suffix":""}],"badges":[],"createdAt":"2024-04-11 11:43:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4252206/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4252206/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55004227,"identity":"401b43cf-6530-4532-a4d8-ad8078ac4120","added_by":"auto","created_at":"2024-04-19 18:45:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91667,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBLOOM Study participant flow throughout the study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4252206/v1/cf212861e7e131bc5f01a6f7.png"},{"id":55004228,"identity":"1a1201b3-e499-4491-a3dc-ab124616d1ca","added_by":"auto","created_at":"2024-04-19 18:45:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":189713,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExcerpt of BLOOM Study Breast Milk Diary\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4252206/v1/0bf01a31a36730ad258360fb.jpg"},{"id":55005873,"identity":"0b29c8e0-910f-48eb-bac2-7efd7f62db72","added_by":"auto","created_at":"2024-04-19 18:53:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":822322,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4252206/v1/4e441c73-1d08-4beb-872b-baa24972fd63.pdf"}],"financialInterests":"Competing interest reported. The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: At the time of submission, LHA is the Editor-in-Chief of the International Breastfeeding Journal, while LEG is an Associate Editor of the International Breastfeeding Journal. The authors declare no other conflicts of interest.","formattedTitle":"Effect of brewers’ yeast or beta-glucan on breast milk supply following preterm birth: The BLOOM Study – protocol for a multicentre randomised controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eBreast milk is considered the optimal form of enteral nutrition for preterm infants [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There is a compelling body of evidence demonstrating that the provision of mothers\u0026rsquo; own breast milk significantly reduces neonatal morbidity and mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Specifically, use of mothers\u0026rsquo; own breast milk during hospitalisation reduces the incidence and severity of certain morbidities, including necrotizing enterocolitis (NEC), late onset sepsis, chronic lung disease, retinopathy of prematurity, rehospitalisation after discharge, and neurodevelopmental problems in infancy and childhood [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A recent Cochrane review showed preterm infants receiving infant formula are three times more likely to develop NEC, which has a mortality rate of 20\u0026ndash;40% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Further, the ability for a mother to provide her own breast milk represents an important tangible contribution in a situation where mothers are separated from their infant during the neonatal hospitalisation and may have limited opportunities to directly participate in infant care in the first few weeks of life [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The resultant psychological benefits can include greater feelings of attachment, empowerment, and confidence [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the noted benefits, mothers of preterm infants face many challenges in establishing and maintaining an adequate supply of breast milk during their infant\u0026rsquo;s prolonged hospitalisation. This is driven by multiple factors including physiological immaturity of the breast associated with preterm birth, inability for the preterm infant to breastfeed directly from the breast, and the stress of having an infant admitted to a Neonatal Intensive Care Unit (NICU). Each of these factors has the ability to interfere with establishment of normal milk supply; one previous study demonstrated 82% of women birthing preterm experienced delayed secretory activation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While longer-term breastfeeding outcomes were not collected for this cohort, other studies in mothers of term infants have demonstrated that delayed secretory activation is associated with increased risk of early cessation of breastfeeding [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome mothers may respond well to non-pharmacological lactation support strategies (i.e. correct use of breast milk pump, increasing expressing frequency) for increasing breast milk supply, but for a large number of preterm mothers, their breast milk supply continues to be insufficient to meet their infant\u0026rsquo;s needs. Insufficient volume of mothers\u0026rsquo; own breast milk has been partly addressed through the introduction of human milk banks, however donor milk is not universally available. Further, mothers\u0026rsquo; own milk has been demonstrated to be superior to donor human milk with respect to composition and bioactivity, highlighting that focusing on supporting mothers to provide their own breast milk to their infants is key to optimising neonatal outcomes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the challenges mothers of preterm infants face in initiating and sustaining lactation, attention has shifted towards the potential role of early non- pharmacological and pharmacological interventions in improving breast milk production soon after birth. A recent survey of 1876 Australian women found that 60% reported taking galactagogues, known as substances thought to aid in initiating and maintaining adequate milk production, during breastfeeding [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In 2023, galactagogues were also reported as being used in over half of the participants in an online survey of breastfeeding mothers in the United States [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This is despite a lack of clear evidence to guide their use[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The most commonly reported galactagogues in recent surveys include lactation cookies, oats, and brewers\u0026rsquo; yeast [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. While lactation cookies may vary in composition, they typically consist of ingredients such as oats, brewers\u0026rsquo; yeast and flaxseed. The active ingredient of oats or brewers\u0026rsquo; yeast is thought to be beta-glucan, which is a glucose polymer present in the cell walls of cereals as well as yeast (i.e. brewers\u0026rsquo; yeast) and fungi [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile natural galactagogues, such as brewers\u0026rsquo; yeast, are widely perceived by women to be safer than pharmaceutical galactagogues and are taken by many women [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], evidence to support their efficacy in increasing breast milk production is largely absent. Furthermore, natural galactagogues have been used to treat lactation insufficiency but appear to be increasingly used prophylactically. Evidence to support their use either in the treatment or prevention of low milk supply following preterm birth is lacking. In the survey conducted by Ryan \u003cem\u003eet al\u003c/em\u003e, Brewers\u0026rsquo; yeast was the galactagogue participants felt had the greatest impact on increasing breast milk supply [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. With respect to brewers\u0026rsquo; yeast derived from \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e, the likely mechanism of action remains unknown. Some have postulated that it could relate to the high concentration of B vitamins, or the presence of beta-glucan isolated from the cell wall [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Further, a number of studies have demonstrated that oral consumption of beta-glucans may have immunomodulatory effects [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. As immune dysregulation is a common feature of preterm birth [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and has been associated with impaired lactation in animal models [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], this represents an alternative potential mechanism of action in which brewers\u0026rsquo; yeast/ beta-glucans could influence breast milk production. Data in lactating women, however, remains scant.\u003c/p\u003e \u003cp\u003eA recent clinical trial by Wesolowska \u003cem\u003eet al.\u003c/em\u003e, evaluated the efficacy of a barley malt-based galactagogue (containing a proprietary blend of barley malt and beta-glucan) compared with placebo in mothers of preterm infants [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Compared with placebo, those who took the barley malt preparation reported expressing a greater total volume of breastmilk over the 14-day intervention period (6036\u0026thinsp;\u0026plusmn;\u0026thinsp;498 vs 4209\u0026thinsp;\u0026plusmn;\u0026thinsp;335; p\u0026thinsp;=\u0026thinsp;0.003). Differences in daily expressed breast milk volume between groups were evident by day seven of the intervention. No participants reported experiencing any side effects during the study. However, the study can only be considered to provide low quality evidence due to a substantial loss to follow-up of 32% across both treatment groups. The beta-glucans found in cereals are also noted to be structurally different and exert different physiological effects to those founds in yeast, therefore the generalisability of these findings to brewers\u0026rsquo; yeast are uncertain. Given the scant literature, it remains unknown whether natural galactagogues such as brewers\u0026rsquo; yeast or beta glucan are effective in improving breast milk production following preterm birth.\u003c/p\u003e \u003cp\u003eThe BLOOM Study (Can \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eB\u003c/span\u003erewers\u0026rsquo; yeast or beta-g\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eL\u003c/span\u003eucan increase m\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eO\u003c/span\u003ether\u0026rsquo;s \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eO\u003c/span\u003ewn \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eM\u003c/span\u003eilk supply following preterm birth?) will evaluate if routine administration, commenced within the first week postpartum, of brewers\u0026rsquo; yeast or beta-glucan, both derived from \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e, increases early breast milk production following preterm birth.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe main objective of this study is to assess if administration of brewers\u0026rsquo; yeast or beta-glucan within the first week postpartum can increase daily expressed breast milk volume following preterm birth.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design and setting\u003c/h2\u003e\n\u003cp\u003eThe BLOOM study is a randomised, controlled, clinician, researcher and participant/family blinded, multicentre trial with three parallel groups with a 1:1:1 allocation ratio. The sponsoring institution and trial coordinating centre is the South Australian Health and Medical Research Institute (SAHMRI) based at the Women\u0026rsquo;s and Children\u0026rsquo;s Hospital. The study will take place in three locations within Australia (Women\u0026rsquo;s and Children\u0026rsquo;s Hospital and Flinders Medical Centre, South Australia and The Royal Women\u0026rsquo;s Hospital, Victoria). Participant screening, enrolment, randomisation, and study visits will be undertaken locally at each study site. A trial steering committee consisting of LEG, LHA and LW and will oversee all clinical trial activities. The study protocol was prepared following the SPIRIT guideline and checklist [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy population\u003c/h2\u003e\n\u003cp\u003eMothers of preterm infants born at less than 34 weeks\u0026rsquo; gestation who intend to provide breast milk for their infant, and are within 72 hours of giving birth.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria will include women, 18 years or older, who have delivered a preterm infant born at less than 34 weeks\u0026rsquo; gestation (up to 33\u0026thinsp;+\u0026thinsp;6), are between 0 to 72 hours of birth, intend to provide breast milk to their preterm infant for any desired duration, and able to give informed consent. Women with a contraindication to breastfeeding such as infection with human immunodeficiency virus (HIV), as well as those with higher order pregnancies (triplet or more) will be excluded from the study.\u003c/p\u003e\n\u003cp\u003eInformation on the study will be provided to eligible participants by their nurse or midwife who will ask them to complete a Consent to Contact form, and following this consent will be contacted by a study researcher (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). After confirmation of eligibility and receipt of voluntary informed consent, women will be assigned randomly to one of three groups: brewers\u0026rsquo; yeast, beta-glucan, or placebo in a 1:1:1 ratio using randomly permuted blocks of varying sizes. Block sizes will not be disclosed to ensure allocation concealment. Participants will be randomised using the REDCap Randomisation Module, and the randomisation schedule will be prepared using ralloc. ado in Stata by an independent statistician that is not involved with trial participants or data. The randomisation schedule will be stratified according to study site. Participants and their care providers, outcome assessors, trial investigators and data analysts will be blinded to randomisation group. Women will be allocated a random, unique, re-identifiable randomisation identification number (ID) and assigned to one of six treatment groups and be issued with study medications identified by colour (i.e. green, yellow, red, blue, purple, orange).\u003c/p\u003e\n\u003cp\u003eWomen will be free to withdraw themselves and/or their infant from the study at any time.\u003c/p\u003e\n\u003cp\u003eParticipant recruitment for the BLOOM trial began in July 2022 and recruitment is expected to be completed in mid-2024.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eIntervention\u003c/h2\u003e\n\u003cp\u003eParticipants will be randomised to one of three treatment arms, consisting of either brewers\u0026rsquo; yeast (\u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e), beta-glucan (purified from \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e) or placebo (microcrystalline cellulose), study medications will be manufactured and supplied by Leiber GmbH (Germany). To maintain study blinding, all study participants will take an oral dose of three capsules twice daily (six capsules a day) according to the treatment schedule indicated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e for a total of seven days from enrolment. To facilitate treatment blinding and aid medication adherence, the medications will be provided in bottles with instructions according to the dosing regimen (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) and all study medications will be identical in appearance. Study treatment will be discontinued if either of the following occur: unacceptable toxicity; treatment continuation is determined not to be in the participants\u0026rsquo; best interest; or participant declines taking study medication or withdraws their consent.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBLOOM Study treatment dosing regimen\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTreatment Arm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMorning\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEvening\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal amount active ingredient\u003c/p\u003e\n\u003cp\u003eper day\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrewers\u0026rsquo; Yeast\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 x 280 mg capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 x 280 mg capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1680 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBeta-glucan\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 x 250 mg capsule\u003c/p\u003e\n\u003cp\u003e2 x placebo capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 x placebo capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e250 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003cp\u003e(Microcrystalline cellulose)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 x placebo capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 x placebo capsules\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMedication adherence will be monitored, with participants asked to document all doses taken in a provided breast milk diary. Participants will be able to access and receive lactation support as necessary and as per local hospital policies during the trial. Given the absence of any known drug-drug interactions, no restrictions will be placed on the concomitant use of other medications including use of other galactagogues.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient and public involvement\u003c/h2\u003e\n\u003cp\u003eWe received input from the SAHMRI Women and Kids consumer group, comprising women with young children, to ensure members of the public were involved at several stages of the trial, including design, management, and conduct. The burden of the trial was carefully assessed. We intend to disseminate the main results to trial participants and will seek patient and public involvement in the development of an appropriate method of dissemination.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes\u003c/h2\u003e\n\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n\u003ch2\u003ePrimary outcome\u003c/h2\u003e\n\u003cp\u003eDaily expressed breast milk volume on Day 7 post study intervention. Following randomisation all participants will be asked to maintain a daily breast milk diary throughout each day of the study (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The diary will act as a record (self-reported) of each time breast milk was expressed, time spent expressing, whether they expressed one breast at a time or both breasts simultaneously, and the volume of expressed milk. Each individual volume of expressed milk will be summed to generate a total for expressed breast milk over a 24-hour period (midnight to midnight).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n\u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n\u003cdiv id=\"Sec11\" class=\"Section4\"\u003e\n\u003ch2\u003eMaternal breastfeeding outcomes\u003c/h2\u003e\n\u003cp\u003eInfant intake of supplemental enteral feeds (donor milk or infant formula), proportion of enteral feeds consisting of mother\u0026rsquo;s own breast milk, total duration and extent of breast milk expression and/or direct breastfeeding up until infant discharge or term corrected age (whichever occurs first), total expressed breast milk volume during study intervention, total expressed breast milk volume up to and on day 21 postnatal. Data on breast health will be assessed using a modified breast health questionnaire, while data on breast milk expression will be assessed using the Breast Milk Expression Experience (BMEE) questionnaire [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eMaternal outcomes\u003c/h2\u003e\n\u003cp\u003eMaternal mental health and wellbeing will be assessed using three validated instruments: Edinburgh Postnatal Depression Scale (EPDS) [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], Six-item State-Trait Anxiety Inventory (STAI-6) [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], and the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Impacts of the intervention on maternal and infant bonding will be assessed using the Maternal Postnatal Attachment Scale (MPAS) [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eInfant outcomes\u003c/h2\u003e\n\u003cp\u003eDifferences in infant anthropometrics (weight, length, head circumference) at discharge from hospital or term corrected age (whichever occurs earlier), trajectories of infant anthropometrics from birth (weight, length, head circumference) to discharge from hospital or term corrected age (whichever occurs earlier). Data on infant morbidity and mortality will be compared based on information obtained from the Australian and New Zealand Neonatal Network (ANZNN) registry.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eSafety outcomes\u003c/h2\u003e\n\u003cp\u003eSafety outcomes including side effects and tolerability of study medications will be assessed through routine data collection by maternal self-report. Serious adverse events will be assessed: maternal mortality; maternal hospitalisation; or other life-threatening events.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eBiological outcomes\u003c/h2\u003e\n\u003cp\u003eA range of biospecimens will be collected as part of the study as outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Samples will be stored for future analysis relating to this study which may include investigating changes in breast milk macronutrient composition; differences in the faecal microbiome; differences in cytokines and other proteins in breast milk and/or blood; differences in serum prolactin; differences in urinary metabolome; and differences in interactions of breast milk samples with breast cells in vitro.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOverview of the BLOOM Study schedule of assessments\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDay 0\u003c/p\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDay 7\u003c/p\u003e\n\u003cp\u003ePost enrolment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDay 21\u003c/p\u003e\n\u003cp\u003ePostpartum\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eInfant Discharge to Home or Term Corrected Age\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eQuestionnaires\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGeneral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Maternal demographic \u0026amp; lifestyle questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Postnatal health\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreastfeeding\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Daily breast milk diary\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- General breast milk expression and breastfeeding questions\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Breast health questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Breast Milk Expression Experience questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMental health and wellbeing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- EPDS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- STAI-6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- PSS:NICU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- MPAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedication side-effects\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical assessments\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal anthropometry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal biospecimens*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBlood\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStool\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBuccal swab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast milk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCase note audit\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePregnancy and birth history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant feeding record\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant anthropometry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant morbidity and mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eX\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eProtocol window\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eDay 7\u0026ndash;9\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eDay 21\u0026ndash;23\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eWithin 3 days of event\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003cem\u003eEPDS\u003c/em\u003e Edinburgh postnatal depression scale, \u003cem\u003eSTAI-6\u003c/em\u003e Six-item State-Trait Anxiety Inventory, \u003cem\u003ePSS:NICU\u003c/em\u003e Parental Stressor Scale: Neonatal Intensive Care Unit, \u003cem\u003eMPAS\u003c/em\u003e Maternal Postnatal Attachment Scale\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e*All biological samples are collected for research purposes only.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eData and sample collection\u003c/h2\u003e\n\u003cp\u003eData will be collected from all participants across four study time-points (Day 0 \u0026ndash; Baseline, Day 7 post intervention, Day 21 postpartum, and at infant discharge or at term corrected age) as outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eQuestionnaires and assessments will be completed at study visits as described in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e at the corresponding timepoints indicated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Biological samples will be collected for research purposes only as indicated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Appointments will be conducted within the hospital (either within the neonatal unit, postnatal ward, or designated clinical research area), or by telephone (when required, e.g. if mother is not visiting on the day or illness prevents a face-to-face visit).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOverview of data collected as part of the BLOOM Study\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eQuestionnaire or assessment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDescription\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQuestionnaires/Assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGeneral information\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eContact information, including name, address, phone number, hospital ID number.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal demographic and lifestyle information\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal age, height, pre-pregnancy weight, smoking status, alcohol intake, pre-existing medical conditions, ethnicity, country of birth, income status, education level, marital status, previous pregnancy and breastfeeding history, pregnancy complications, medication use, postnatal contraception use, breast type/shape, breast development since puberty and during pregnancy.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast milk diary\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDaily breast milk diary recording the number of times each breast was expressed, the method used to express, the volume of expressed milk, duration and if applicable information pertaining to direct breastfeeding for a total of 21 days.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast milk expression\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntended duration of breastfeeding, breast development previous to and during pregnancy, time of first expressing following birth, perceived onset of lactogenesis, methods and type of breast milk expressing (including type of breast milk pump), duration of breast milk expressing or breastfeeding, and provision of lactation support.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast Health Questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQuestionnaire adapted from Fetherston 2006 to assess general breast health and potential risk for mastitis. Collects information on breast fullness, breast pain and discomfort, duration of pain/discomfort, presence of cracks or grazes on the nipples, fever, as well as any areas of heat, swelling or redness on breasts.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast Milk Expression Experience (BMEE) Questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMEE provides a measure of milk expression experience across three dimensions: (1) social support for milk expression; (2) ease of learning how to express milk; and (3) personal experiences of milk expression.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePostnatal Health Questionnaire\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePostnatal health issues during the study (e.g. infections, cold/flu), as well as any medications (prescription or non-prescription), herbal supplements or multivitamins taken.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMental Health and Wellbeing Questionnaires\u003c/p\u003e\n\u003cp\u003e\u0026bull; EPDS\u003c/p\u003e\n\u003cp\u003e\u0026bull; STAI-6\u003c/p\u003e\n\u003cp\u003e\u0026bull; PSS:NICU\u003c/p\u003e\n\u003cp\u003e\u0026bull; MPAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAssessment of depression and anxiety symptoms will be collected using standardises validated questionnaires (Edinburgh Postnatal Depression Scale [EPDS], Spielberger State-Trait Anxiety Inventory [STAI-6]). Stress related to infant hospitalisation will be assessed using the Parental Stressor Scale: NICU (PSS:NICU). Maternal-infant attachment will be assessed using the Maternal Postnatal Attachment Scale (MPAS).\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal anthropometry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal weight, height, waist circumference, hip circumference, and mid upper-arm circumference will be assessed.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedication side-effects and adverse event\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRecording any side-effects pertaining to potential adverse events or serious adverse events. Details encouraged to be recorded in breast milk diary too.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCase Note Data Extraction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePregnancy and birth history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGravida, parity, length of gestation, infant birthweight, infant sex, plurality, onset of labour, method of birth, estimated blood loss, pregnancy complications (i.e. gestational diabetes, gestational hypertension, pre-eclampsia), antenatal interventions (i.e. receipt of antenatal corticosteroids of magnesium sulphate), medication use, antenatal haematology (i.e. haemoglobin, iron studies).\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant feeding record\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDaily record of total enteral intake, volume of expressed breast milk, donor milk, or infant formula, as well as proportion of enteral feeds consisting of mothers\u0026rsquo; own breast milk.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant anthropometry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight, length, head circumference.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant morbidity/mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfant morbidity and mortality data will be obtained from the Australian and New Zealand Neonatal Network (ANZNN)[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] registry. Data include, number of days in hospital (to first discharge home), intraventricular haemorrhage (IVH), confirmed sepsis, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), surgical procedures and death during initial hospitalisation.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBiospecimen sample collection at Visit 2 (Day 7 following intervention)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSample type\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDescription\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal blood\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; 30 mL blood (Serum tube 10 mL, K2 EDTA 10 mL and 5 mL, and Trace Elements 5 mL)\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cryopreservation of plasma trace element, serum, plasma, buffy coat, red blood cells aliquots\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBreast milk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Expressed milk (3\u0026ndash;8 mL) from a single breast expression episode\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cryopreserved aliquots of whole milk\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal urine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; 25 mL urine\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cryopreserved aliquots\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal stool\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; 1x Collection pot (Norgen Biotek)\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cryopreserved sample pot\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal buccal swab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; FloqSwab (Copan Diagnostics)\u003c/p\u003e\n\u003cp\u003e\u0026bull; Air-dried swab cryopreserved\u003c/p\u003e\n\u003cp\u003e\u0026bull; Researcher collected\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003ch2\u003eSample size calculation\u003c/h2\u003e\n\u003cp\u003eA sample of 99 women (33 per arm) yields 90% power, 0.025 alpha to show a difference in the mean daily breast milk volume of 150 mL/day (200 mL/day standard deviation) between each of the intervention arms and control arm, allowing for 10% loss to follow-up. This includes adjustment for a 0.6 correlation between breast milk volume at study entry and breast milk volume on Day 7 at the end of the intervention phase.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n\u003ch2\u003eData management\u003c/h2\u003e\n\u003cp\u003eData entry and study management will be using a purpose-built REDCap database and hosted on secure servers at SAHMRI. Electronic case report forms will be used and stored directly in REDCap, and any paper-based case report forms will be stored in a locked office at the study site. Data are collected by trained researchers and entered directly into REDCap, no confidential data are stored on data entry machines. REDCap uses a MySQL database via a secure web interface and includes a complete suite of features to support the Health Insurance Portability and Accountability Act of 1996 compliance, including a full audit trail, user-based privileges and integration with the institutional Lightweight Directory Access Protocol server [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eIn order to adhere to international best research practice and to ensure eligibility of our study for publication in scientific journals, we plan to archive the fully deidentified sequencing datafiles in the Gene Expression Omnibus (GEO or equivalent database). The sequencing data files prepared for GEO will be free of all identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of the identity of individual subjects, in accordance with the NIH Statement on Sharing Research Data (2003).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis methods\u003c/h2\u003e\n\u003cp\u003eThe primary analysis will be performed according to the treatment group to which participants were randomised (intention-to-treat principle). A secondary per-protocol analysis will also be performed for each of the primary and secondary outcomes.\u003c/p\u003e\n\u003cp\u003eThe primary outcome of daily expressed breast milk volume on Day 7 post intervention will be compared between treatment groups using a linear regression. The results will be expressed as a difference in means with a 95% confidence interval and two-sided p-value. Adjustment will be made for baseline daily expressed breast milk volume and the randomisation strata (study centre). A p-value of less than 0.05 will be considered to indicate statistical significance. Analysis of secondary outcomes will use log-binomial regression models for binary outcomes and linear regression models for continuous outcomes with adjustment for stratification variables and other pre- specified prognostic baseline variables. Results will be presented as relative risks and differences in means respectively, along with 95% confidence intervals. Missing data will be addressed using multiple imputation. Sensitivity analyses will also be performed using the original unimputed data.\u003c/p\u003e\n\u003cp\u003ePlanned sub-group analyses of the primary and secondary breastfeeding outcomes include: (i) Plurality (singleton vs. twins); (ii) Parity (primiparous vs. multiparous); (iii) Infant gestation at birth (categorical: 23\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e\u0026ndash;29\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e vs. 30\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e\u0026ndash;31\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e vs 32\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-33\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks\u0026rsquo; gestation and continuous); (iv) Maternal body mass index (categorical: underweight/normal weight [BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e] vs. overweight/obese [BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e] and continuous). Effect modification by each of these factors will be assessed separately by including interaction effects with treatment group in the statistical models.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n\u003ch2\u003eData monitoring and safety\u003c/h2\u003e\n\u003cp\u003eThe trial coordinating centre (SAHMRI) will perform ongoing monitoring via weekly reports of participants screened/enrolled/randomised, visits due/overdue/missed, adverse and serious adverse events, product inventory and dispense records, sample collection logs, and participant communication logs. The weekly reports will be reviewed at weekly trial management meetings. No interim analyses are planned.\u003c/p\u003e\n\u003cp\u003eAn individual participant may only be unblinded in emergency situations, where the Investigator decides a participant cannot be adequately treated without knowing the identity of their treatment allocation. To break the randomisation code the Principal Investigator must contact the randomisation facility/personnel. The time, date, participant study ID and reason for unblinding will be documented. Events leading to the emergency breaking will be recorded in the serious adverse event (SAE) report form.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n\u003ch2\u003eEthical issues and dissemination\u003c/h2\u003e\n\u003cp\u003eThe BLOOM study will be conducted in accordance with the approved version of the Study Protocol and in compliance with the Australian National Statement on Ethical Conduct in Research Involving Humans which builds on the ethical codes of the Declaration of Helsinki and the Principles of International Conference on Harmonisation Good Clinical Practice (as adopted in Australia). All study materials and study protocol (current version 1.1) have been reviewed and approved by the Women\u0026rsquo;s and Children\u0026rsquo;s Health Network Human Research Ethics Committee (HREC), South Australia (HREC/22/WCHN/00001), as well as the research governance officers at each of the study sites. Any change to the protocol or Informed Consent Form that affects the scientific intent, study design, patient safety or may affect a participant\u0026rsquo;s willingness to continue participation in the study is considered an amendment, and therefore, will be written and filed as an amendment to this protocol and/ or informed consent form. All such amendments will be submitted to the HREC, for approval prior to becoming effective.\u003c/p\u003e\n\u003cp\u003eThe primary and key secondary breastfeeding objectives will be analysed and reported first. Study findings will be submitted for peer-reviewed publication and for presentation at appropriate local and international conferences. In addition, study findings will be disseminated to participants through a brief lay summary. No participants will be identified in the dissemination of study results and data collected will be treated with confidence.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n\u003ch2\u003eAccess to data and study documentation\u003c/h2\u003e\n\u003cp\u003eDe-identified individual participant data will be made available upon reasonable request. Requests to access data must be reviewed and approved by both the BLOOM trial steering committee and the Women\u0026rsquo;s and Children\u0026rsquo;s HREC, and will be assessed for scientific and methodological rigour. Individuals requesting data will be required to sign a data access agreement. Requests for data or study documentation should be directed to the Chair of the BLOOM Steering Committee, LEG via email ([email protected]).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study seeks to monitor the effectiveness and safety of consuming of galactagogues on breast milk production following preterm birth. Galactagogues in the form of brewers\u0026rsquo; yeast or beta-glucan will be provided to participants and compared with a placebo group for a 7-day period. Recruitment commenced in July 2022 and will aim to be completed within two years.\u003c/p\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe planned study has a number of strengths, notably the rigorous experimental design and comprehensive assessment across a range of maternal and infant outcomes up until the point of infant discharge home from hospital (or until term corrected age, whichever occurs first) However, the study also has some limitations. Firstly, estimation of total daily breast milk volume is based solely on expressed volumes. In the case that infants fed directly from the breast, pre- and post- feed weighing of the infant was not included due to the added burden and stress, and expected negligible overall impact on the primary study outcome given noted difficulties in establishing direct breastfeeding following preterm birth before 34 weeks\u0026rsquo; gestation. Further, the use of infant test-weighing is not an established practice within any of the study trial sites.\u003c/p\u003e \u003c/div\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eANZNN Australian and New Zealand Neonatal Network\u003c/p\u003e\n\u003cp\u003eBLOOM Can \u003cu\u003eB\u003c/u\u003erewers\u0026rsquo; yeast or beta-g\u003cu\u003eL\u003c/u\u003eucan increase m\u003cu\u003eO\u003c/u\u003ether\u0026rsquo;s \u003cu\u003eO\u003c/u\u003ewn \u003cu\u003eM\u003c/u\u003eilk supply following preterm birth?\u003c/p\u003e\n\u003cp\u003eBMEE Breast Milk Expression Experience questionnaire\u003c/p\u003e\n\u003cp\u003eEPDS Edinburgh Postnatal Depression Scale\u003c/p\u003e\n\u003cp\u003eHREC Human Research Ethics Committee\u003c/p\u003e\n\u003cp\u003eMPAS Maternal Postnatal Attachment Scale\u003c/p\u003e\n\u003cp\u003eNEC Necrotizing enterocolitis\u003c/p\u003e\n\u003cp\u003eNICU Neonatal Intensive Care Unit\u003c/p\u003e\n\u003cp\u003ePSS:NICU Parental Stressor Scale: Neonatal Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eSAHMRI South Australian Health and Medical Research Institute\u003c/p\u003e\n\u003cp\u003eSTAI-6 Six-item State-Trait Anxiety Inventory\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study obtained ethics approval from the Women\u0026apos;s and Children\u0026apos;s Health Network Human Research Ethics Committee, Women\u0026apos;s and Children\u0026apos;s Hospital 72 King William Road North Adelaide SA, Australia (HREC/22/WCHN/00001). Informed consent is obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: At the time of submission, LHA is the Editor-in-Chief of the International Breastfeeding Journal, while LEG is an Associate Editor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by a Channel 7 Children\u0026rsquo;s Research Foundation Fellowship, Australia awarded to LEG (CRF-210323), as well as a Flinders Innovation Seed Partnership Grant awarded to LEG, LHA, AK, AR in collaboration between Leiber GmbH, Germany and Flinders University, Australia. Study medications are donated by Leiber GmbH, Bramsche, Germany, who also provided financial support. The funder/s have no role in the study design; collection, management, analysis and interpretation of data; writing of the report; and the decision to submit the report for publication and have no authority over any of these activities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to acknowledge support provided by the National Health and Medical Research Council Centre of Research Excellence in Optimising human milk nutrition to improve the long-term health of preterm infants (GNT 2024589). The authors also wish to acknowledge Dr Amanda Brass for their assistance in drafting the study protocol manuscript and Dr Emma Knight for their assistance in providing statistical support with respect to sample size calculation, randomisation, and statistical analysis methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrafted the manuscript: LEG. Revised the manuscript: AR, WVI, LW, RLK, AK, KM, LHA. Conceptualised and designed the study: LEG and LHA. Obtained grant funding to conduct the study: LEG, LHA, AK, and AR. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRollins NC, Bhandari N, Hajeebhoy N, Horton S, Lutter CK, Martines JC, et al. Lancet Breastfeeding Series G. Why invest, and what it will take to improve breastfeeding practices? Lancet. 2016; 387(10017):491-504.\u003c/li\u003e\n\u003cli\u003eVictora CG, Rollins NC, Murch S, Krasevec J, Bahl R. Breastfeeding in the 21st century. Lancet. 2016; 387(10017):475-490.\u003c/li\u003e\n\u003cli\u003eMeier P, Patel A, Esquerra-Zwiers A. Donor Human Milk Update: Evidence, Mechanisms, and Priorities for Research and Practice. J Pediatr. 2017; 180:15-21.\u003c/li\u003e\n\u003cli\u003eWorld Health Organisation. WHO recommendations for care of the preterm or low-birth-weight infant. Geneva: World Health Organization; 2022.\u003c/li\u003e\n\u003cli\u003eQuigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2018; 6(6):CD002971.\u003c/li\u003e\n\u003cli\u003eSweet L. Expressed breast milk as \u0026apos;connection\u0026apos; and its influence on the construction of \u0026apos;motherhood\u0026apos; for mothers of preterm infants: a qualitative study. Int Breastfeed J. 2008; 3:30.\u003c/li\u003e\n\u003cli\u003eLi X, Li Y, Qian L, Han P, Feng H, Jiang H. Mothers\u0026apos; experiences of breast milk expression during separation from their hospitalized infants: a systematic review of qualitative evidence. BMC Pregnancy Childbirth. 2024; 24(1):124.\u003c/li\u003e\n\u003cli\u003eBujold M, Feeley N, Axelin A, Cinquino C. Expressing Human Milk in the NICU: Coping Mechanisms and Challenges Shape the Complex Experience of Closeness and Separation. Adv Neonatal Care. 2018; 18(1):38-48.\u003c/li\u003e\n\u003cli\u003eBell EH, Geyer J, Jones L. A structured intervention improves breastfeeding success for ill or preterm infants. MCN Am J Matern Child Nurs. 1995; 20(6):309-314.\u003c/li\u003e\n\u003cli\u003eCregan MD, De Mello TR, Kershaw D, McDougall K, Hartmann PE. Initiation of lactation in women after preterm delivery. Acta Obstet Gynecol Scand. 2002; 81(9):870-877.\u003c/li\u003e\n\u003cli\u003eBrownell E, Howard CR, Lawrence RA, Dozier AM. Delayed onset lactogenesis II predicts the cessation of any or exclusive breastfeeding. J Pediatr. 2012; 161(4):608-614.\u003c/li\u003e\n\u003cli\u003eMcBride GM, Stevenson R, Zizzo G, Rumbold AR, Amir LH, Keir AK, Grzeskowiak LE. Use and experiences of galactagogues while breastfeeding among Australian women. PLoS One. 2021; 16(7):e0254049.\u003c/li\u003e\n\u003cli\u003eRyan RA, Hepworth AD, Lyndon A, Bihuniak JD. Use of Galactagogues to Increase Milk Production Among Breastfeeding Mothers in the United States: A Descriptive Study. J Acad Nutr Diet. 2023; 123(9):1329-1339.\u003c/li\u003e\n\u003cli\u003eForinash AB, Yancey AM, Barnes KN, Myles TD. The use of galactogogues in the breastfeeding mother. Ann Pharmacother. 2012; 46(10):1392-1404.\u003c/li\u003e\n\u003cli\u003eGabay MP. Galactogogues: medications that induce lactation. J Hum Lact. 2002; 18(3):274-279.\u003c/li\u003e\n\u003cli\u003eJayachandran M, Chen J, Chung SSM, Xu B. A critical review on the impacts of beta-glucans on gut microbiota and human health. J Nutr Biochem. 2018; 61:101-110.\u003c/li\u003e\n\u003cli\u003eJia LL, Brough L, Weber JL. Saccharomyces cerevisiae Yeast-Based Supplementation as a Galactagogue in Breastfeeding Women? A Review of Evidence from Animal and Human Studies. Nutrients. 2021; 13(3).\u003c/li\u003e\n\u003cli\u003eKeelan JA. Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. J Reprod Immunol. 2011; 88(2):176-184.\u003c/li\u003e\n\u003cli\u003eGlynn DJ, Hutchinson MR, Ingman WV. Toll-like receptor 4 regulates lipopolysaccharide-induced inflammation and lactation insufficiency in a mouse model of mastitis. Biol Reprod. 2014; 90(5):91.\u003c/li\u003e\n\u003cli\u003eWesolowska A, Pietrzak B, Kociszewska-Najman B, Wielgos M, Czajkowski K, Wietrak E, et al. Barley malt-based composition as a galactagogue - a randomized, controlled trial in preterm mothers. Ginekol Pol. 2021; 92(2):118-125.\u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013; 158(3):200-207.\u003c/li\u003e\n\u003cli\u003eFlaherman VJ, Gay B, Scott C, Aby J, Stewart AL, Lee KA. Development of the breast milk expression experience measure. Matern Child Nutr. 2013; 9(3):425-430.\u003c/li\u003e\n\u003cli\u003eCox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987; 150:782-786.\u003c/li\u003e\n\u003cli\u003eFerreira R, Murray J. Spielberger\u0026apos;s State-Trait Anxiety Inventory: Measuring anxiety with and without an audience during performance on a stabilometer. Percept Mot Skills. 1983; 57(1):15-18.\u003c/li\u003e\n\u003cli\u003eMiles MS, Funk SG, Carlson J. Parental Stressor Scale: neonatal intensive care unit. Nurs Res. 1993; 42(3):148-152.\u003c/li\u003e\n\u003cli\u003eCondon JT, Corkindale CJ. The assessment of parent-to-infant attachment: Development of a self-report questionnaire instrument. Journal of reproductive and infant psychology. 1998; 16(1):57-76.\u003c/li\u003e\n\u003cli\u003eTGA: Note for Guidance on Good Clinical Practice (CPMP/GCP/135/95) annotated with Therapeutic Goods Administration (TGA) comments. In. Therapeutic Goods Administration; 2000.\u003c/li\u003e\n\u003cli\u003eAustralian \u0026amp; New Zealand Neonatal Network. https://www.anznn.net/. Accessed 03 May 2023.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-breastfeeding-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ibfj","sideBox":"Learn more about [International Breastfeeding Journal](http://internationalbreastfeedingjournal.biomedcentral.com/)","snPcode":"13006","submissionUrl":"https://submission.nature.com/new-submission/13006/3","title":"International Breastfeeding Journal","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lactation, Breastfeeding, Breast milk expression, Breast milk production, Breast milk supply Preterm birth, Galactagogue, Brewers’ yeast","lastPublishedDoi":"10.21203/rs.3.rs-4252206/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4252206/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMany individuals who experience preterm birth struggle with early breast milk supply, which can translate into suboptimal longer-term breastfeeding outcomes. Further investigations into the potential role of early non-pharmacological and pharmacological interventions in improving breast milk production soon after birth is growing. While natural galactagogues, such as brewers\u0026rsquo; yeast, are widely perceived by women to be safer than pharmaceutical galactagogues and are taken by many women, evidence to support their efficacy is largely absent. The BLOOM study has been designed to determine the efficacy and safety of brewers\u0026rsquo; yeast and beta-glucans, derived from \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e, when administered soon after birth for increasing early breast milk supply in mothers who have delivered preterm.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe BLOOM study is a multicentre, double-blinded, randomised controlled trial that will assess if brewers\u0026rsquo; yeast or beta-glucan can increase early breast milk production following preterm birth. Target population are mothers of preterm infants born at less than 34 weeks\u0026rsquo; gestation who intend to provide breast milk for their infant, are less than 72 hours following birth and able to give informed consent. Participants will be randomly allocated into three parallel groups at 1:1:1 ratio (n\u0026thinsp;=\u0026thinsp;33 per group) to receive either brewers\u0026rsquo; yeast, beta-glucan or placebo capsules for seven days. The primary outcome is total expressed breast milk volume over a 24-hour period on day 7 of intervention. Participants and their infants will be followed until the infant reaches term corrected age or is discharged home from the neonatal unit (whichever occurs first).\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe use of brewers\u0026rsquo; yeast as a galactagogue to enhance milk production is extremely common amongst breastfeeding mothers, however, there are no trials evaluating its efficacy and safety. This will be the first randomised controlled trial to evaluate the efficacy and safety of two commonly used galactagogues, brewers\u0026rsquo; yeast and beta-glucan, compared with placebo in improving maternal breast milk supply following preterm birth. The trial will also evaluate whether early intervention with galactagogues soon after a preterm birth improves longer-term breastfeeding outcomes.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eAustralian and New Zealand Clinical Trials Registry ACTRN12622000968774 (registered on 8 July 2022) and UTN U1111-1278-8827\u003c/p\u003e","manuscriptTitle":"Effect of brewers’ yeast or beta-glucan on breast milk supply following preterm birth: The BLOOM Study – protocol for a multicentre randomised controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:45:07","doi":"10.21203/rs.3.rs-4252206/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-03T15:52:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-01T23:30:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-02T16:15:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153304827676898458202390095311765001402","date":"2024-05-01T18:58:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118087710777438282072501910983956829248","date":"2024-05-01T16:35:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-29T16:17:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-25T09:09:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-12T14:47:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Breastfeeding Journal","date":"2024-04-11T11:42:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-breastfeeding-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ibfj","sideBox":"Learn more about [International Breastfeeding Journal](http://internationalbreastfeedingjournal.biomedcentral.com/)","snPcode":"13006","submissionUrl":"https://submission.nature.com/new-submission/13006/3","title":"International Breastfeeding Journal","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5fd136a9-6dd8-47cc-80a5-1d777f3ee4ea","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T13:53:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 18:45:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4252206","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4252206","identity":"rs-4252206","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}