Protective Characteristics of Human Breast Milk on Early Childhood Otitis Media: A Narrative Review

Abstract

Introduction:

Human breast milk (HBM) contains a complex and dynamically changing variety of factors that contribute to the infant's developing immune system's ability to fight upper respiratory tract infections, including otitis media (OM). We sought to summarize the current evidence on the protective characteristics of HBM, through direct or donated feeding, toward early childhood OM.

Methods:

For this narrative review, we performed a literature search on OM in the context of HBM feeding in the PubMed, Embase, and Google Scholar databases, between January 1, 2008, and July 1, 2023.

Results:

Immunoglobulin A (IgA) provides a short-term immunity of 2–3 days against otopathogens causing OM. IgA-mediated immunity is effective against OM up to 7 months of age if breastfeeding continues. The role of transferred IgM and IgG in HBM is unclear. Although there is a potential protective value of microRNA, hormones, oligosaccharides, stem cells, and interleukins present in HBM, their role is unclear. Any duration of breastfeeding is superior to no breastfeeding in OM risk reduction, with a big variability among studies (odds ratio 0.23–0.81, depending on the duration). Duration of breastfeeding ≥6 months was found to be the most effective in OM risk reduction, but there was no evidence of continued benefits after 2 years of age. Expressed breastfeeding was not shown to be more beneficial. The protective values of donor HBM against OM are still undetermined.

Conclusion:

HBM has numerous components that contribute to protection against early childhood OM.

Impact statement

Summarize the recent changes and developments regarding the protective characteristics of human milk feeding and its ability to reduce otitis media in early childhood, with key information on human milk's various components and their effect on the growing immune system.

Address the use of donated human milk in settings with common infections.

Give pediatric health care providers the information they need to be able to educate parents on the positive effect that human milk has against common infections of early childhood, especially otitis media.

Introduction

Otitis media (OM) is a common early childhood infection. During acute OM (AOM), the inflammatory process is caused by an interaction of viral and bacterial pathogens that ascend into the middle ear through the Eustachian tube from the nasopharynx. AOM manifests with symptoms and signs of severe inflammation. AOM can eventually cause a variety of complications, ranging from tympanic membrane perforation to facial nerve palsy, meningitis, labyrinthitis, and mastoiditis.¹ In cases of recurrent AOM (rAOM) episodes or its chronic form as otitis media with effusion (OME), there is an accumulation of fluid in the middle ear cavity, which may negatively impact hearing thresholds.²

Among the factors that predispose to early infancy, OM are male gender genetic predisposition, craniofacial abnormalities, ciliary dysfunction, allergies, passive smoke exposure, daycare attendance, lower socioeconomic status, family history of recurrent AOM in parents or siblings, and lack of breastfeeding.

OM burden is high in many countries and mainly affects young children, as about 22% of 1-year-old infants would experience at least one episode of AOM, and by the end of the third year, the rate is much higher, roughly estimated at 80%.¹ Risk factors for rAOM episodes include preterm birth, male sex, cigarette smoke exposure, low socioeconomic status, and pacifier use.^1,3 In addition, a shorter, wider, and more horizontal Eustachian tube is found in young children when compared with adults, which helps facilitate viral-bacterial transmission into the middle ear.^1,2 Among the known protective factors are immunization with pneumococcal conjugate vaccines (PCVs) and breastfeeding, while the use of probiotics for OM prevention lacks sufficient evidence.^1,3

The predominant middle ear pathogens (otopathogens) in infants suffering from AOM during the pre-PCV era were Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In our post-PCV era, nontypeable H. influenzae prevalence has reportedly increased in middle ear fluid samples in immunized children presenting with AOM,^1,4 with S. pneumoniae being now the second most common. H. influenzae is also the most common bacteria in children with OME or rAOM.⁵ Protection against otopathogens is primarily mediated by ototpathogen-specific antibodies that are transferred from the mother to the infant through breastfeeding, specifically with immunoglobulin A (IgA), and to a lesser extent, also by IgG and IgM.^6,7

Human breast milk (HBM) is known as the ideal nutrition for infants, supplying energy, modulating the infant's growing immune system, and plays a positive role in neural development and the maturation of the gastrointestinal tract.^8,9 Secretory IgA constitutes about 80–90% of the total secreted Igs in HBM. Approximately 0.5 to 1.0 g/day of this protein is ingested by infants fed exclusively with HBM.¹⁰ Breastfeeding for ≥2 months reduces the risk of infant death from causes such as necrotizing enterocolitis and sudden infant death syndrome.^11,12 Breastfeeding is acknowledged by the World Health Organization and the United Nations International Children's Emergency Fund as the baby's “first vaccine.”¹³

In addition to direct breastfeeding, a solution for infants whose mothers cannot breastfeed them was introduced more than a century ago, when the first human milk bank was founded in 1909 in Vienna, Austria.¹¹ Donor mothers usually nurse their child and have a large enough volume of milk that exceeds their child's feeding needs, and thus can contribute to others. Thus, it allows infants who were otherwise not fed with HBM to benefit from its advantages. Preterm infants are the largest and most important group of donated milk recipients because their mothers tend to have insufficient HBM.¹¹

Breastfeeding is known to reduce infectious diseases in early infancy, including OM, in both low- and high-income countries, thus decreasing overall infancy morbidity and mortality.¹⁴ Therefore, early breastfeeding is encouraged in pediatric hospital care guidelines.^14,15

Traditionally, the protection of HBM against OM is thought to be mediated by the transfer of Igs to the infant, but little is known about the other factors that may contribute too. Notably, as many studies in the field of breastfeeding medicine are based on parental reports and questionnaires, the evidence of the reviewed components is still shadowed by the presence of strong confounding factors that cannot be completely controlled in observational studies.

To date, there is no consensus regarding the minimal or ideal time needed to achieve sufficient protection against single and rAOM episodes, and only scarce data are published regarding other factors in the HBM that participate in OM prevention. In the absence of sufficient randomized or high-quality case–control studies aiming to determine the benefits of HBM against early childhood OM, we performed a narrative review that summarizes the current knowledge on this subject. To the best of our knowledge, the last review was published over a decade ago.¹⁶

Methods

We performed a narrative literature search on OM in the context of HBM feeding in the following databases: PubMed, Embase, and Google Scholar, between January 1, 2008, and July 1, 2023, for relevant articles in the English language only. Early childhood was defined as the age of 0–8 years.¹⁷ We reviewed HBM feeding in the forms of expressed milk bottle feeding, donated milk bottle feeding, and breastfeeding, and their effects on pediatric OM in regard to AOM, rAOM episodes, and OME. We used the following MeSH terms: [“breastfeeding”] AND [all forms of OM] and [‘‘exclusive”] and [‘‘breast milk’’] and [‘‘human milk”] and [“milk bank”] and [all forms of URTI]. We included both randomized controlled and observational studies, after ensuring the study design and outcomes fell into the scope of our review.

Results

Change in composition of breast milk over time

HBM has a dynamically changing and highly complex composition of fats, proteins, whey (alpha-lactalbumin, lactoferrin, lipases, lysozyme, secretory immunoglobulins, mucins), hormones (the most abundant are prolactin, progesterone, and estrogen), and carbohydrates (human milk oligosaccharides [HMOs]).^8,18 The colostrum is the milk produced in the first few days postpartum. HMO levels are highest in colostrum milk and are reduced by almost half until around 120 days postpartum, and as lactation continues, the protein level in the produced milk is gradually reduced between the second to seventh months of lactation, while lactose and fat concentrations increase.^8,18

Immunoglobulins

The main type of Ig found in HBM is secretory IgA, the highest concentration of which is found in the colostrum. IgA can be traced in secretions of breastfed infants much earlier than in formula-fed infants (2 days postpartum versus 1 month postpartum).¹⁸ Like other Igs present in HBM, and with a short half-time of 3–4 days, IgA helps block pathogens from entering the respiratory tract mucosa, including S. pneumoniae and H. influenzae, which are major OM pathogens, as it has both immobilization and toxin-neutralization abilities.¹⁹

Although antigen-specific IgA titers against S. pneumoniae or H. influenzae antigens in HBM were similar between infants with and without an OM diagnosis at a study visit in Australian Aboriginal and Torres Strait Islander mother-infant pairs, it was shown that in breastfed infants, higher levels of IgA at 7 months of age were associated with lower colonization rate with H. influenzae and rAOM episodes.²⁰

IgM antibodies, which presumably take part in protecting the mucosal surfaces against pathogens, and IgGs, whose anti-inflammatory effect is achieved by direct binding, opsonization, and agglutination of pathogens, are also important proteins of mucosal immunity.^9,13 As for IgM, we could not find any good-quality study showing any association between maternal IgM transfer in milk and OM occurrence in their infants. The evidence regarding IgG is conflicting: While specific IgG levels against the outer membrane of H. influenzae protein P6 were higher in exclusively breastfed infants when compared to breasted/formula and formula-fed children at 2 and 6 months,²¹ it was shown that maternal IgGs do not add further protection against the infant's OM episodes.²⁰ In another work, there was a general concern about whether NTHi antigen IgG can be transferred maternally and protect against OM.²² Figure 1 shows the composition of human breast milk in the different stages of its production.

FIG. 1.

Variability of nutritional components in: (a) Colostrum, (b) Transitional HBM, and (c) Mature/Term HBM. Adapted with permission from: Shende and Khanolkar.¹⁴ EGF, epidermal growth factor; HBM, human breast milk; IGF, insulin like growth factor; sIgA, serum immunoglobulin A; VEGF, vascular endothelial growth factor.

Conferring protection against bacteria and viruses

HBM also contains a variety of hormones that have a proven effect on the newborn's developing immune system: Among its many physiological roles, prolactin advances the proliferation and activation of lymphocytes and macrophages. Progesterone and estrogen have a proven effect on the newborn's T cell and B cell differentiation process. This way, the breast milk hormone composition affects the breastfed infants' ability to fight infections.²³ There is no evidence that these hormones protect against OM.

HBM is enriched with microRNA, which plays an important role in the infant's growing immune system through its effect on gene expression. Human milk microRNA regulates genes that are responsible for anti-inflammatory activity and immune development and maturation. This way it presumably improves the growing immune systems' ability to fight respiratory infections, such as OM.²³ Although evidence for microRNA in OM pathogenesis widely exists, especially in the more chronic OM forms, it remained unclear in HBM.²⁴

HBM contains >200 different kinds of HMOs, whose prebiotic effect helps the infants' growing flora inhabit more beneficial bacteria and helps their immune system in fighting the pathogenic bacteria owing to their antiadhesive properties, and their production of bacteriocins and organic acids that help fight bacterial pathogen growth in the gastrointestinal tract. As the third most abundant component of human milk, they inhibit the binding of pathogens to the intestinal mucosa, stimulate the growth of prebiotic microbes in the gut, and modulate signaling and inflammation in the intestinal mucosa.²⁵

The infant's microbiota can stimulate virus-specific CD4⁺ and CD8⁺ T lymphocytes and virus-specific antibodies to help fight respiratory viral infections.^9,13 Nevertheless, data regarding the efficacy of HMOs in preventing OM in breastfed infants are scarce. In their cohort study of some 1,000 German newborns, Siziba et al.²⁶ found no statistically significant association between the HMO levels in the HBM and the risk of OM in the first or second year of their lives (p = 0.53 in the first year and 0.79 in the second year).

Stem cells present in HBM may also aid in cellular immunity against infections, but their role in OM protection has not been demonstrated so far.²⁷

Finally, to have the ability to enhance and reduce its inflammatory response as needed, the infant's immature immune system depends on the breast milk-rich supply of a variety of cytokines, such as interleukin (IL)-1b, IL-2, IL-6, IL-8, IL-10, IL-12, IL-18, IFN-γ, TNF α, TGF-b, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.¹³ These are all key players in the development of neonatal organs, the regulation of inflammatory responses against pathogens, and the development of mucosal resistance to pathogens, including upper respiratory mucosa.¹⁶ Although shown in animal models of eosinophilic OM, levels of relevant ILs have not been measured or detected in HBM in OM cases.^28,29 Figure 2 shows the variety of cells present in human breast milk.

FIG. 2.

Different types of cells present in HBM. Adapted with permission from: Shende and Khanolkar.¹⁴ HBM, human breast milk.

Duration of breastfeeding

Table 1 summarizes the recent evidence regarding the duration of breastfeeding and the associated protection against OM in early childhood. Due to the large heterogeneity of study designs, we could not draw a concrete conclusion on the best duration for breastfeeding for OM prevention. Any duration of breastfeeding is superior to no breastfeeding in acute OM risk reduction. The early introduction of formula (before 6 months of age) at the expense of exclusive breastfeeding was shown to increase the risk for AOM.³⁰ Overall, no evidence of continued benefits of breastfeeding after 2 years of age was found regarding further OM protection.³¹ Not shown in the table, there were a few more studies that were based on mothers' reports on OM episodes of their infants and thus suffered from a recall bias.

Table 1.

Duration of Breastfeeding and OM Risk, by Study

Author	Year of publication	Study type (country)	Risk for OM	Statistical significance
McNiel et al. (30)	2010	Review of 4 studies included in the U.S. Agency for Healthcare Research and Quality (AHRQ)-breastfeeding and maternal and infant health outcomes in the developed world	OM if any formula is introduced at the age of 3 to 6 months, OR 2.00	95% CI 1.40–2.78
Bowatte et al. (31)	2015	Meta-analysis of 22 studies (US, Europe)	Exclusively BF for the first 6 months, for AOM, by 24m: OR 0.57 Ever vs. never BF, by 24m, OR 0.67 More vs. less BF at 2–8 years: OR 1.03	95% CI 0.44–0.75 95% CI 0.56–0.80 95% CI 0.59–1.79
Kørvel-Hanquist et al. (32)	2018	Prospective cohort study (Denmark)	BF <6 months and risk of >3 OM episodes: Age 0–18 months: OR 1.36 Age 0–7 years: OR 1.15	95% CI 1.24–1.49 95% CI 1.05–1.27
AL-Nawaiseh et al. (36)	2022	retrospective case-control study, age <2 years (Jordan)	Non-exclusively BF, OR for AOM 0.234 Exclusively breastfed for 3 months, OR 0.182 Exclusively breastfed for 6 months, OR 0.245	p < 0.05
Usonis et al. (37)	2016	Epidemiological, prospective, observational, multi-center cohort study, AOM in children aged <6 years (Estonia, Lithuania, Poland, Romania and Slovenia)	BF vs. not BF: OR 0.19	95% CI 0.08–0.44
Frank et al. (38)	2019	The Environmental Determinants of Diabetes in the Young (TEDDY)—A prospective cohort study. Children included those carrying high-risk genes for Type 1 Diabetes Mellitus. (USA, Finland, Germany, Sweden)	Non-exclusive vs. no BF, risk for OM, OR 0.81 Exclusive vs. no BF, OR = 0.64	95% CI 0.66–1.00 95% CI 0.49–0.84
Ardiç et al. (39)	2019	5-year prospective birth cohort study (Turkey)	Mean number of AOM events: Exclusive BF ≥6 months: 1.57 ± 1.016 , vs exclusive BF <6 months: 2.78 ± 1.969 In duration of total BF ≥12 months: 1.31 ± 0.717 vs total BF <12 months: 2.71 ± 1.729 In every BF: 1.45 ± 0.569 vs never BF: 2.89 ± 1.632	p = 0.01 p = 0.03 p = 0.01
Davisse-Paturet et al. (40)	2020	Prospective cohort, recruited from pregnancy (France)	Ever BF vs. never, OR 0.81 For the lagged occurrence category, OR 0.87 for the infrequent occurrence category, OR 0.7 for increasing events throughout the infancy category	p = 0.03 Lagged occurrence = a 1^st AOM event at age >12 months
van Ingen et al. (41)	2021	Prospective cohort (The Netherlands)	BF at 6 months: OR 0.78 for early AOM (in the first 3 years of life) OR 0.77 for persistent AOM (children who remained otitis- prone after the age of 3 years)	95% CI 0.66–0.91 95% CI 0.66–0.90
Mattar et al. (42)	2019	Retrospective and cross-sectional study (Lebanon)	The longer total duration of BF and OM occurrence, OR 0.956	95% CI 0.93–0.99
Størdal et al. (43)	2017	Large Cohort and Sibling Analysis (Norway)	BF 9–11 months: 1.01 (0.98, 1.05) BF 6–8 months: 1.06 (1.02, 1.10) BF 4–6 months: 1.04 (0.99, 1.10) BF <4 months: 1.11 (1.07, 1.16) No breast-feeding: 1.10 (0.96, 1.25)	95% CI

AOM, acute otitis media; BF, breastfeeding; CI, confidence interval; OM, otitis media, OR, odds ratio.

Among them was the Danish National Birth Cohort, which reported that infants being breastfed <6 months had an increased odds ratio (OR) of 1.42 (confidence interval [95% CI] 1.28–1.58) for OM when compared to children being breastfed >6 months.³² In another prospective longitudinal, question-based study from Western Australia, there was a significant, independent association between predominant breastfeeding and OM (OR = 1.33 [1.04–1.69]; p = 0.02), and breastfeeding duration (OR = 1.35 [1.08–1.68]; p = 0.01) with OM at 3 years of age.

However, at 6 years of age, this relationship was no longer statistically significant (predominant breastfeeding; OR = 0.78 [0.48–1.06]; p = 0.09; and duration of breastfeeding, OR = 1.34 [0.81–2.23]; p = 0.25).³³ By using advanced data analysis techniques, such as the Monte Carlo simulation, it was estimated that compared with the non-Hispanic white population in the United States, a non-Hispanic black population had 1.7 times the number of excess cases of OM, attributable to suboptimal and insufficient breastfeeding (95%CI 1.7–1.7).³⁴

Mode of feeding

Boone et al.³⁵ showed a 17% reduced risk for AOM in infants fed with HBM during their first 6 months of life versus those who were exclusively formula fed. However, within the no-formula feeding group, bottle feeding of expressed HBM was not as effective as breastfeeding in AOM risk reduction, with the odds of AOM increased by ∼14% for a month of expressed HBM feeding and by 115% for 6 months.

Donated human milk

Premature infants are the main consumers of donated human milk when their mother's milk is often insufficient or unavailable.¹¹ The popularity of human milk banks increased during the recent COVID-19 pandemic.¹² The pasteurization process of donated human milk damages, but does not destroy its anti-infective and cellular components, growth factors, fat, protein, and vitamins.

Igs are reduced by up to 100% during the pasteurization, yet some imperative components like HMOs, glycosaminoglycan, and some ILs are thought not to be reduced during the “Holder Pasteurization.” Nevertheless, some authors concluded that the immunological effects of donated milk remain significant and donor milk is still highly preferable in comparison to formula.^11,44 Others, such as Verd et al.,⁴⁵ have detected no statistically significant difference in the risk for infection in infants fed with donor milk versus formula feeding; however, they did show a correlation between human milk feeding and reduced respiratory support requirements. To date, there is no study regarding OM prevalence in infants fed with donated HBM.

Conclusion

HBM nutrition has a proven protective effect against OM in early childhood. Breastfeeding should be encouraged as a safe and sustainable method to improve their children's health outcomes. Much of the evidence on the protective characteristics of HBM against early infancy OM comes from longitudinal population-based birth cohort studies that span across several decades. Although these studies include a large number of mothers and infants, it is important to comment on a potential confounder—the use of subjective reporting: On one hand, the recall bias of maternal reports on the duration of HBM feeding and on the exclusive breastfeeding period, and on the other hand, the parental reports on their child's OM episodes. Parental recollection may lead to an overestimation of the number of OM episodes, and that should be taken into account while interpreting these findings.

Also, one needs to consider drop-off and loss to follow-up rates. Like in many other reports on breastfeeding medicine, the evidence of the reviewed components is still shadowed by the presence of strong confounding factors that can never be completely controlled in observational studies. In the case of OM, multiple risk factors have been identified and studied, and thus, the sole role of HBM feeding cannot be isolated. Health education campaigns should highlight the important role of breastfeeding against OM, one of the most common early childhood infections. The benefits of donated human milk against OM are that it is processed and loses almost all its immunoglobulin contents.

Footnotes

Authors' Contributions

Y.T.W. collected the data, wrote the article, critically reviewed the article, and approved the final article as submitted; S.O.T. and O.G. critically reviewed the article, and approved the final article as submitted; T.M. conceptualized and designed the study, critically reviewed the article, and approved the final article as submitted.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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