Introduction

The aim of this scoping review is to locate and examine existing evidence regarding the consumption of probiotics for the prevention and treatment of human lactational mastitis. The use of probiotics as an intervention for prevention and treatment of human lactational mastitis has not yet been extensively researched, and new and varied evidence continues to arise from a variety of sources. As scoping reviews are useful in mapping diverse evidence, this approach has been selected as the most appropriate.1,2

Lactational mastitis is a debilitating illness caused by blocked milk ducts leading to inflammation of the breast tissue, which may or may not be associated with infection.3 One in seven lactating women are affected by lactational mastitis, and will experience localized pain, erythema, and flu-like symptoms, such as fever, rigor, nausea, and vomiting.4,5 Lactational mastitis can lead to painful breast abscesses requiring further intervention, and can also lead to early breastfeeding cessation.4,6

The complexity of breastmilk and its benefits to the mother and baby dyad is well researched.7,8 Breastfeeding reduces infant mortality and morbidity rates, and reduces the incidence of sudden infant death syndrome, necrotizing enterocolitis, diarrhea, respiratory infections, otitis media, type 1 and 2 diabetes, childhood leukemia, and obesity in childhood.7,8 Benefits to the mother include reducing rates of ovarian cancer, depression, and breast cancer.7 Breastfeeding is also environmentally friendly, using no resources and producing no waste, while contributing to substantial decreases in health care costs by reducing the burden of disease.9 The World Health Organization (WHO) recommends exclusively breastfeeding for the first six months of a baby's life and then to continue, with supplementary foods, until age two and above.8

Despite well-known benefits and recommendations, there are factors in a woman's breastfeeding experience that can lead to cessation of breastfeeding earlier than intended or recommended. This can interfere with potential benefits to the mother and baby. Alarmingly, the rates of exclusive breastfeeding of infants are below 50% in most countries, with short-duration breastfeeding being especially common in high-resource countries.10 Lactational mastitis affects a mother and baby's breastfeeding experience, leads to undesired weaning, and contributes to diminishing breastfeeding rates, resulting in women and babies losing the benefits from breastfeeding.6

In addition to adversely affecting breastfeeding length, another concerning factor is that bacterial lactational mastitis is often treated with antibiotics.6,11 The use of antibiotics can be associated with risks including gastrointestinal disturbances, urogenital and oral infections, the formation of biofilms, and higher health care costs, while also potentially adding to ongoing antibiotic overuse and resistance, which, according to the WHO, is one of the biggest threats to global health.11-13 The human microbiome refers to over 100 trillion living microorganisms or microbes within human bodies and the influence they have on our health.14 Antibiotics are known to affect the maternal microbiome during pregnancy or breastfeeding and can adversely affect the infant's gastrointestinal microbiome.12 While research into this area is evolving, studies have shown that the resulting effect on a baby's gastrointestinal system increases the risk of gastrointestinal disturbances and allergies, lowers the amounts of good bacteria in the stools of infants with colic, and increases the risk of recurrent wheeze in the first two years of life.12

Adding to the concerning risks and side effects of antibiotic use is uncertainty among clinicians and a lack of evidence on the most effective antibiotic to treat lactational mastitis.11 There is also inconclusive evidence that antibiotic therapy is beneficial in treating lactational mastitis.11 However, with severe symptoms, such as breast abscesses, antibiotics and even hospitalization may be required.3 For women with infective lactational mastitis, the most common underlying pathogen is Staphylococcus aureus, which is treated with antibiotics.3 Flucloxacillin has been reported to be the most common antibiotic used in Australia for treating lactational mastitis.11 Although flucloxacillin is compatible with breastfeeding, some women and health professionals are cautious about using medications during lactation due to potential exposure to the infant.11,15 With uncertainty and lack of clarity in treatment of lactational mastitis, the development of alternative strategies, such as probiotic interventions, has been explored and studied.

Probiotics have been used for thousands of years, occurring naturally in foods including yoghurt, cheese, and fermented foods.16 Probiotics include many species and strains, and may potentially benefit certain aspects of a consumer's health, if administered correctly.14 As organisms of the human digestive system, probiotics appear to be generally safe, while some minor side effects have been reported in the literature, including constipation, bloating, increased thirst, flatulence, nausea, and vomiting.14 Yet, probiotics may benefit human health and have a high healing potential in conditions such as obesity, insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease.16 Probiotics have been found to reduce the incidence of necrotizing enterocolitis in preterm babies born between 1000 and 1500 g, resulting in the introduction of probiotics in many neonatal intensive care units.17 While research is ongoing, clinical trials have demonstrated that probiotics may assist in the treatment of inflammatory bowel conditions, such as the remission of ulcerative colitis and Crohn's disease.18 In recent years, interest in the human microbiome has soared, with a large amount of research into the use of probiotics and their potential health benefits to the human microbiome.

The link between probiotic consumption and its effect on human lactational mastitis is emerging, following mixed results from research in dairy cows.15 Researchers have investigated the entero-mammary pathway, which allows the transfer of bacteria from the maternal gastrointestinal system to the mammary glands via a process involving gut monocytes.15,19 From this physiological process, evolving research into probiotics and the effect on human lactational mastitis is continuing to be investigated, both for prevention and treatment. The probiotic species and strain the research explores is vital to consider, as probiotic use is not a one-size-fits-all approach; the particular type of the probiotic is significant in regards to its effect on a condition.14 From the several hundred species of bacteria in human milk, researchers have discovered the probiotic bacteria lactobacilli, and there is emerging evidence that these bacteria may have a role in protecting women against lactational mastitis.15

A search of Embase and the Cochrane Library showed there have been no systematic reviews or scoping reviews on probiotics and human lactational mastitis. The first evidence from human participants emerged from a pilot study by Jimenez et al.20 who investigated two lactobacilli probiotic strains as treatment for women experiencing lactational mastitis, following unsuccessful antibiotic treatment.20 Following this, Arroyo et al.21 conducted a randomized controlled trial using two lactobacilli strains isolated from breast milk to treat mastitis compared to traditional antibiotic therapy.21 Fernandez et al.22 then explored probiotic use as a preventive intervention for lactational mastitis.22 These few studies appear to indicate heterogeneity in the available evidence and provide inconclusive evidence to support the effectiveness of probiotics as interventions for lactational mastitis, despite increasing commercial interest and marketing of probiotics to pregnant and breastfeeding women who may be eager to avoid the risks of antibiotic use.23,24

Because evidence regarding probiotics and lactational mastitis is limited, the authors agreed to not restrict the review to high-quality evidence or particular study designs. As such, the scoping review will map any existing evidence to guide future primary research and determine the value of a subsequent systematic review.2 Where systematic reviews typically answer questions of effectiveness and safety, a scoping review may be more appropriate when a topic or concept is new or has not been extensively researched and where specific analytical questions cannot yet be asked of the evidence.2 Scoping reviews address broader topics and take an exploratory approach.1,2

In 2005, Arksey and O'Malley25 described a six-staged framework for scoping studies. Approaches for undertaking and reporting scoping reviews have evolved since this first framework. In 2015, JBI developed an updated scoping review methodology, which draws on the work of Arksey and O'Malley and that of Tricco et al.26-28 The JBI methodology27 received minor updates in 2017 and, most recently, formed the basis of a reporting guideline and checklist: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR).26

Review question

What is the evidence regarding probiotic consumption and human lactational mastitis?

Inclusion criteria

Population

Eligible studies will include women of any age who are planning a pregnancy, pregnant, breastfeeding, or expressing post-childbirth. As a scoping review aims to capture a wide range of evidence, there will be no exclusion based on co-morbidity, previous history, or current diagnosis or treatment of lactational mastitis.

Concept

The concept of interest is the use of oral probiotics to prevent, treat, or in association with lactational mastitis. As the use of probiotics in relation to lactational mastitis is a relatively new concept and there is not an extensive amount of research available, the scoping review will include all types of probiotics, but will make note of the specific probiotic used, including species, strain, and dosage. All dosages, preparations, and timing/scheduling of probiotic administration will be included. Probiotics administered with or without antibiotics or other supplements are eligible for inclusion.

Context

There will be no geographical limitation applied in relation to this scoping review. Evidence presented from any cultural or geographic context will be eligible.

Types of studies

All research methodologies, qualitative reviews, quantitative reviews, literature reviews, and unpublished (gray) literature will be included.

Methods

This scoping review will follow the JBI approach and will utilize the PRISMA-ScR reporting guideline and checklist.26-28

Search strategy

Sources of evidence published in English from the year 2000 to the present will be considered. This time frame has been chosen to allow as much evidence as possible to be captured, as this topic has not been extensively researched. However, based upon preliminary reading, the authors expect that most of the research found will have been published within the previous 10 years, due to the innovative and developing nature of the topic. The search strategy aims to locate any published and gray literature involving human lactational mastitis and the use of probiotics. The first step of the search strategy will involve the examination of MEDLINE (Ovid) for relevant sources using an initial search strategy (Appendix I). The search strategy will then be adapted and refined for use in the Cochrane Library, Scopus, Embase, and Emcare. These databases have been selected as they are the most extensive nursing/midwifery databases.

The gray literature will be examined for any relevant protocols, policy documents, or supplementary literature. This will involve searching Google, Google Scholar, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and ProQuest Dissertations and Theses. Hand searching of relevant breastfeeding associations and journals will occur including: the International Breastfeeding Journal, Breastfeeding Medicine, Breastfeeding Report Card-United States, and Breastfeeding Review-professional publication of the Nursing Mothers Association of Australia, and the Australian Breastfeeding Association. Following study selection, the reference lists of the selected studies will be searched for any additional studies not previously identified.

Study selection

Results from the database and gray literature search will be de-duplicated and transferred to Covidence (Veritas Health Innovation, Melbourne, Australia) for study screening and selection against the predefined inclusion criteria. This will occur by first looking at the key text words included in the title and abstract. Potentially relevant sources will be examined in more detail against the inclusion criteria in full-text form. One reviewer (MB) will lead the process of study screening and selection supported by a second reviewer (MS). Where uncertainty occurs, another reviewer (MP or PA) will be consulted. Reasons for the exclusion of any full-text source will be recorded and reported. The selection process will be mapped showing the inclusion and exclusion process using the PRISMA-ScR flow chart.

Assessment of methodological quality

According to the PRISMA-ScR, it is not mandatory for scoping reviews to include an assessment of the methodological quality of the evidence identified via the literature search.26 It was decided, however, that an assessment of methodological quality would be included as a component of the proposed scoping review as a useful means of supporting informed, evidence-based decision making in maternity care, and to provide a structured and thorough means of critically examining the characteristics of the evidence. Critical appraisals of the methodological quality of all relevant studies will be assessed using standardized tools relevant to the study design, (e.g. the JBI tool for assessing quality of randomized controlled trials).27 The results of the critical appraisal will be presented in the results section of the review along with strengths and limitations of the studies, sources of funding, and any reported relevant conflicts of interest. An overall statement regarding the quality of research in the field will also be provided, as well as recommendations for research and practice.

Data extraction

Data extraction will focus on identifying and charting data regarding probiotic consumption and any effect reported in relation to lactational mastitis. This will include when the probiotic was taken, if it was prophylactic or for treatment, and the effect this had on lactational mastitis. Characteristics of the participant groups, type of probiotic, strain, species, and dosage will be extracted. The source of information (i.e. where and when the study was conducted) and research methodology will be recorded. The extraction process will be carried out by one reviewer (MB), with consultation from a second reviewer, if needed (MP, PA, or MS). If disagreements occur between reviewers, a third and fourth reviewer will be consulted. A data extraction table will be used, which may be refined and updated during the course of the work (Appendix II). Any refinements will be explained in the scoping review report.

Data presentation

A tabular and accompanying narrative summary of the information extracted from the included studies will be provided in relation to the scoping review question. Patterns and trends (if identified) will be illustrated using figures and or diagrams, and summarized narratively. If outcomes are identified in relation to a specific group of participants or probiotic characteristic, for example, this will be presented and explained.

Final conclusions will be drawn from the mapped evidence, as well as recommendations for future research in this field. Provisional recommendations for practice may be developed, as a formal appraisal of the quality of the evidence will have been conducted.

Acknowledgments

Sarah McQuillen at the University of South Australia Library for her assistance with the development of the search strategy; Associate Professor David Evans, Dr Angela Brown, and Dr Megan Cooper for their constructive feedback on early drafts of this protocol.

Appendix I: Search strategy

Search results for MEDLINE (Ovid): 37 studies

Search conducted: 2 Nov 2018

1. Mastitis/

2. mastitis.mp. [mp = title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]

3. 1 or 2

4. prebiotics/

5. probiotics/

6. synbiotics/

7. exp Lactobacillus/

8. exp Bifidobacterium/

9. (lactobacill^* or probiotic? or synbiotic? or prebiotic? or "L. rhamnosus" or "l. crispatus" or "l. delbrueckii" or "l. helveticus" or "l. johnsonii" or "l. leichmannii" or "l. paracasei" or "l. pentosus" or "l. reuteri" or "l. sakei" or "l. salivarius" or "L. acidophilus" or "L. plantarum" or "L. casei" or "L. brevis" or "L. johnsonii" or "L. fermentum" or "L. reuteri" or "B. infantis" or "B. animalis" or "B. bifidum" or "B. longum" or "B. breve" or Bifidobacteri^* or "S. boulardi" or "Saccharomyces boulardi" or "Lactococcus lactis" or "L. lactis" or "b. adolescentis" or "b. pseudocatenulatum" or Enterococcus durans or Enterococcus faecium or "E. durans" or "E. faecium" or Streptococcus thermophilus or "S. thermophilus" or Pediococcus acidilactici or "P. acidilactici" or Leuconostoc mesenteroides or "L. mesenteroides" or Bacillus or "B. coagulans" or "B. subtilis" or "B. cereus" or "Escherichia coli Nissle 1917" or "E. coli Nissle 1917").mp. [mp = title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]

10. 4 or 5 or 6 or 7 or 8 or 9

11. 3 and 10

12. limit 11 to (English language and humans)

Appendix II: Data extraction tool

References