1. Introduction
Breastfeeding is the very means by which humans have thrived and developed as a species.
Indeed, the Developmental Origins of Health and Disease Hypothesis recognises that
the breastfeeding phase, which can continue to 2 years and beyond, plays a major role
in the continuum of optimal programming of the lifelong health and development of
the infant. Early life nutrition therefore presents a window of opportunity where
the infant’s short and long-term health can potentially be improved in the face of
escalating rates of chronic disease that have reached epidemic proportions.
This special issue “Breastfeeding and Human Lactation” is thus timely, in an era of
resurgence of lactation research, and is comprised of 30 manuscripts that cover a
wide range of areas. This research will contribute to a growing scientific knowledge
base that is critical to improving breastfeeding rates and the delivery of human milk
(HM) to all infants, including those that cannot breastfeed, such as the vulnerable
preterm infant. The majority of the papers in this issue address one of two broad
themes; factors influencing milk composition, or relationships between milk composition
and infant development. Findings from these research papers further elucidate the
variability of milk composition and its impact on infant health.
2. Factors Influencing Milk Composition
It is evident that mammalian milk evolved as a protective fluid harbouring antimicrobial
proteins predominantly for the protection of the offspring, with nutrition developing
later. As such, many components of milk have dual roles, working synergistically to
protect and nourish the infant. Indeed, the footprints of evolution are apparent in
the presence of immune cells in HM that increase significantly in response to both
maternal and infant infections. Twigger et al. [1] have identified antimicrobial proteins,
granulysin and perforin along with other granzymes released by leukocytes in HM, that
are elevated in maternal breast infection. Milk immune cells may therefore be beneficial
for protection of both the infant and the breast.
Anti-secretory factor (AF) is involved in the regulation of secretory processes and
inflammation and is expressed in immune cells: B-cells, macrophages and dendritic
cells. AF concentrations in HM are lower than that of maternal plasma, with a positive
relationship between milk AF concentration and maternal body mass index (BMI), which
might be due to a greater level of maternal inflammation associated with obesity [2].
It is increasingly apparent that maternal factors such as body composition, diet,
ethnicity, geography, genetics and lifestyle all contribute to the unique milk signature
of each woman. In this issue, a number of papers have shown differences in milk composition
with respect to geographical location. In particular, concentrations of the immune
active molecules transforming growth factor-β2 (TGF-β2), immunoglobulin A (IgA), and
hepatocyte growth factor (HGF) were higher in African women than in Italian women,
suggesting a stronger response to the environment and thus greater infant protection
against infection [3].
With cutting-edge technologies, it is possible to study metabolites in all bodily
fluids. Variability of the metabolite profile of HM has not been comprehensively explored,
however three papers have attempted this ambitious task. It was shown in two studies
that the milk metabolome differs according to country [4,5] and mode of birth. Further
interactions between the milk metabolites and microbes in the milk were also discovered,
indicating the importance of the milk microbiome [5]. The third paper studied the
endocannabinoid metabolome, for which there are receptors in the infant brain with
evidence of a role in appetite and food intake. The study aimed to determine differences
in endocannabinoids between transitional and mature milk, of which only one was significant
[6]. The impact of these components on infant growth and development is yet to be
studied.
Variability in HM composition would logically depend on maternal diet to some extent,
although few studies have been carried out in this area. Studies that attempted this
difficult task have provided conflicting results, largely due to the observational
nature of the research. Two papers in this issue demonstrated an absence of relationship
between diet and macronutrients [7,8]. Similarly, no relationships were observed between
maternal dietary intakes of the micronutrients choline and zinc and their respective
HM concentrations [9]. For breastfeeding women in a population with a high prevalence
of zinc deficiency, zinc supplementation during pregnancy did not impact postnatal
maternal serum zinc levels, which likely reflect HM concentrations [10]. Relationships
were noted between diet and HM fatty acid profiles, as previously documented [8].
Interestingly, Bzikowska-Jura et al made the observation that maternal adiposity was
related to HM protein and energy content at 3 months lactation, irrespective of diet
[11]. Appropriate HM sampling methods are imperative when examining variability of
milk components. In this context, Bzikowska-Jura et al found a weak relationship between
HM fat content and maternal BMI using an intense sampling regime to account for changes
in fat over the course of 24 h. Kent et al trialed hourly expression of breast milk
over 3 h (4 expressions) in an effort to estimate rates of milk fat synthesis. Unfortunately,
this was not a reliable measure when compared to 24 h milk sampling [12]. George et
al has highlighted sampling as one of the major challenges when examining milk lipids
[13].
The idea of maternal-infant signaling via milk is attractive to explain both milk
composition and infant outcome variability. Maternal adiposity is related to lower
lean infant mass across 12 months of lactation [14], and while a review in the issue
suggests that milk is tailored according to sex of the infant, there is yet to be
strong evidence of this in humans [15].
3. Relationships of Milk Composition with Infant Protection, Growth and Development
Historically very few milk components have been associated with infant outcomes. Two
papers in this issue highlight that the dose, rather than concentrations, of milk
components are associated with infant body composition development over the first
12 months of life. Specifically, Gridneva and colleagues showed that the 24 h dose
of appetite hormones adiponectin and whole milk leptin [16], along with casein [17],
are differentially related to the development of infant body composition. The mechanisms
by which the components exert their effects are still not clear.
Interestingly, endogenous satiety factors produced in the small intestine have been
detected in HM and have been related to infant weight gain and weight for age z scores
[18]. Whilst more work has to be done to verify the results, it is becoming increasingly
clear that both the composition and volume of milk consumed by the infant modulates
growth and development.
Growth of the preterm infant is critical, as these vulnerable infants are at high
risk for morbidities both early and later in life. Whilst HM is recommended as the
optimal nutrition for preterm infants, fortification is almost universal to ensure
adequate growth of those born < 33 weeks gestation. The delivery of human milk during
continuous enteral feeding therefore is an area where enhancement may be needed to
avoid the potential loss of nutrients to the infant. Zozaya et al. [19] found a reduction
in the total fat delivered to the preterm infant via continuous enteral feeding, with
long chain fatty acids more likely to be adsorbed to the feeding tube. These losses,
while statistically significant, were considered clinically small. Once preterm infants
are able to feed orally a dilemma exists about how to feed the infant in the absence
of the breastfeeding mother. Geddes et al compared breastfeeding with use of a novel
teat that required the infant to apply a vacuum and use a tongue movement mimicking
that of breastfeeding to remove milk. They observed that although the infants’ intra-oral
vacuums were lower with the teat than at the breast, more milk was transferred [20].
This finding is indicative of the immaturity of the preterm infant’s oral motor systems
and should be taken into account when transitioning to full breastfeeding.
Many of the preterm infant’s systems are immature, in particular the gastrointestinal
system. This increases the preterm infant’s susceptibility to infection and may impact
the digestion of milk and subsequent absorption of nutrients and immune components.
Indeed, Demers-Mathiew et al. [21] have described differences in the digestion of
HM immunoglobulins between the preterm and term infant. The impacts of these findings
are yet to be determined.
One of the major reasons HM feeding is recommended for preterm infants is that it
markedly decreases the risk for necrotizing enterocolitis. However, controversy exists
over whether raw or pasteurized HM should be fed to infants less than 32 weeks corrected
age or less than 1500g in weight due to the high prevalence of cytomegalovirus in
the milk. Lopes et al. [22] describe the heterogeneity in feeding practices between
French neonatal units highlighting lack of consensus within the medical field. Pasteurization
of HM is of concern because it reduces the impact of several immune factors in milk,
including lactoferrin, which plays a significant role in antimicrobial and immunomodulatory
functions. Telang provided a comprehensive review of the structure and functions of
lactoferrin, and discussed the importance of continued clinical trials in determining
the role of lactoferrin in prevention of neonatal sepsis [23].
An in-depth understanding of both the complex processes that impact HM and the impact
of HM on the infant is critical to understanding lactation dysfunction, and may inform
the identification of windows of potential intervention. An understanding of physiological
and clinical dilemmas in lactation is also important.
In this context, insufficient milk supply is the most common reason for early weaning.
Currently evidence-based treatments are limited for women with low milk supply. While
galactogogues are often prescribed, the effect is modest for pharmacologic galactogogues
as reviewed by Asztalos [24]. In light of this review, much more research is required
to understand the causes of low milk supply along with more controlled studies of
the efficacy of galactogogues.
Low milk supply may follow delayed secretory activation, or may be associated with
breast inflammation. While both conditions are characterised by an elevated HM sodium
concentration and sodium:potassium ratio, to date there are no clinical tools available
to track these complications of lactation. Lai et al validation of handheld devices
for determining sodium and potassium levels in HM indicates these may offer a promising
point of care tool for monitoring secretory activation, the onset of mastitis and
evaluation of treatment [25].
Mothers face many other barriers to successful breastfeeding, including their perceptions
and own wellbeing [26,27]. Early hospital practices can also impact lactation, including
early introduction of formula in the hospital, which was estimated at 28% in the UK
[28]. The authors found many of the factors implicated in early supplementation to
be modifiable. Further early recognition of infant feeding cues and responsive feeding
is facilitated by increased mother-infant contact [29].
Finally, one must not discount the health benefits reaped by the lactating mother.
The incidence of gestational diabetes mellitus is increasing and is associated with
greater maternal risk for type 2 diabetes. However, breastfeeding is associated with
lower risk of maternal type 2 diabetes, and in a new analysis maternal thyroid function
also appears to be positively affected out to 6–16 years post-partum [30].
4. Conclusions
While HM is traditionally thought of primarily as a source of infant nutrition, evidence
from lactation research shows a diverse range of functions, including protection from
infection and disease, and programming of future health and development of both mother
and infant through microbial and hormonal signaling. Interactions between maternal
endocrine and mammary function, as well as diet, also impact milk composition and
production. New evidence presented in this special edition of Nutrients contributes
to the growing body of lactation and breastfeeding research, and informs our understanding
of the complex composition of HM and its impact on infant health.