Maternal factors influencing milk composition and offspring developmental trajectories

Maternal factors, including nutritional status, metabolic disorders, and/or psychosocial stress appear to play important roles in shaping non-nutritive milk composition (explored across 14 papers; Table 2), which in turn may influence the development and early life programming of offspring (explored across 13 papers; Table 2). Maternal nutritional status was the most investigated maternal factor reported to influence lactation biology and offspring outcomes. In particular, there is evidence that maternal obesity status (BMI > 30 kg/m²) alters miRNAs, ^{Reference Xi, Jiang, Li, Chen, Song and Li65} immune components, ^{Reference Fujimori, França, Morais, Fiorin, de Abreu and Honório-França66} pro-inflammatory fatty acid, ^{Reference Panagos, Vishwanathan and Penfield-Cyr50} and carotenoid levels ^{Reference Panagos, Vishwanathan and Penfield-Cyr50} in milk. These bioactive compounds are critical for offspring growth ^{Reference Ellsworth, Perng, Harman, Das, Pennathur and Gregg39} , visual and neural development, ^{Reference Panagos, Vishwanathan and Penfield-Cyr50} intestinal microbiota diversity and metabolic health. ^{Reference Lemas, Young and Baker42} Moreover, human and laboratory rodent studies have demonstrated that the initiation of lactation was delayed in mothers that were on a high fat diet, ^{Reference Hernandez, Grayson, Yadav, Seeley and Horseman67,Reference Liu, Smith, Dobre and Ferguson68} including disruption of mammary gland morphology and a notable decline of intact alveolar units that are essential for lactogenesis. ^{Reference Hernandez, Grayson, Yadav, Seeley and Horseman67} Several rodent studies also reported that mothers exposed to a high fat diet during pre-gestation, gestation, and lactation, exhibited increased nursing behaviors, where time spent in “arched-back” ^{Reference Purcell, Sun, Pass, Power, Moran and Tamashiro69} and “blanket” ^{Reference Abuaish, Spinieli and McGowan70} nursing increased during the dark phase of the circadian cycle. “Arched-back” nursing is a type of maternal care behavior, where the mother arches her back while nursing pups to allow more access to the teats, and “blanket” nursing is where the dam uses her body to lay over the pups while nursing. ^{Reference Champagne, Diorio, Sharma and Meaney71,Reference Myers, Brunelli, Squire, Shindeldecker and Hofer72} We previously postulated that the percent increase in time spent nursing may be a compensatory lactation-specific behavior to combat impaired milk production, prolactin insensitivity ^{Reference Buonfiglio, Ramos-Lobo and Freitas73} or delayed milk production due to increased mammary gland inflammation. ^{Reference Hernandez, Grayson, Yadav, Seeley and Horseman67,Reference Abuaish, Spinieli and McGowan70} Several human studies have shown that maternal obesity alters hormonal and immune components in milk, and that being obese and/or overweight during the pre-gestational period is associated with increased bodyweight and alterations in the metabolic profile of offspring during early childhood. ^{Reference Ellsworth, Perng, Harman, Das, Pennathur and Gregg39,Reference Larnkjær, Ong, Carlsen, Ejlerskov, Mølgaard and Michaelsen74,Reference Lagström, Rautava and Ollila75} For example, higher maternal post-pregnancy BMI was associated with increased levels of milk adiponectin, a hormone that affects development by regulating lipid metabolism, reducing pro-inflammatory cytokines and improving insulin sensitivity in offspring. ^{Reference Martin, Woo and Geraghty76–Reference Yu, Rong and Sun79} Other studies reported that adiponectin levels in maternal milk from healthy lactating women were found to be positively correlated with adiponectin in infant serum ^{Reference Savino, Lupica, Benetti, Petrucci, Liguori and Cordero Di Montezemolo80} and inversely associated with growth and weight gain during early infancy. ^{Reference Yu, Rong and Sun79,Reference van Rossem, Smit and Lentjes81} Another study reported that infants who were partially breastfed (defined as the combined use of maternal milk and formula) by mothers with obesity had elevated levels of insulin and adiponectin and lower levels of IGF-I (insulin growth factor 1) in the blood at 9 months of age compared to infants partially breastfed by normal weight mothers. ^{Reference Larnkjær, Ong, Carlsen, Ejlerskov, Mølgaard and Michaelsen74} Thus, the higher concentration of blood adiponectin reported in offspring who were born to as well as partially breastfed by mothers with obesity may indicate a positive, lactation-specific metabolic adaptation to prenatal maternal obesity exposure.

Maternal psychosocial stress is another prominent factor that may influence cortisol levels in milk, ^{Reference Aparicio, Browne and Hechler82} which in turn has been associated with offspring development and behavioral trajectories. A study in rhesus macaques reported a positive correlation between increased maternal milk cortisol levels and changes in male offspring temperament, including increased activity, boldness, confidence and curiosity. ^{Reference Sullivan, Hinde, Mendoza and Capitanio83} Higher milk cortisol was also associated with increased social interactions in female macaques at 4–8 months of age. ^{Reference Dettmer, Murphy and Guitarra84} However, another study in rhesus macaques found that cortisol levels in milk were positively correlated with nervous temperament, and negatively correlated with confident temperament in offspring. ^{Reference Hinde, Skibiel, Foster, Del Rosso, Mendoza and Capitanio85} A study in humans reported a protective effect of increased milk cortisol exposure during early childhood, where increased milk cortisol levels were associated with decreased childhood obesity. ^{Reference Hahn-Holbrook, Le, Chung, Davis and Glynn86} However, there is other evidence that higher milk cortisol levels are associated with increased fear reactivity in female infants at 3 months ^{Reference Grey, Davis, Sandman and Glynn87} and 8 months of age. ^{Reference Nolvi, Uusitupa and Bridgett88} Despite mixed findings on the beneficial/deleterious effects of increased milk cortisol transfer across mother-offspring dyads, these studies illustrate the manner in which maternal psychosocial stress may alter milk composition and offspring behavior.

Additional studies in humans and other mammals reported that maternal immune status, group rank, and parity also influence not only cortisol, but adiponectin, growth factors and secretory immunoglobulin levels in milk. ^{Reference Sullivan, Hinde, Mendoza and Capitanio83,Reference Groer, Davis and Steele89,Reference Bunney, Zink, Holm, Billington and Kotz90} Gestational age and mode of delivery are two other maternal factors associated with altered milk composition. ^{Reference Carney, Tarasiuk and Diangelo91} Specifically, Carney et al. ^{Reference Carney, Tarasiuk and Diangelo91} reported that the expression profiles of milk miRNAs in lipid and skim fractions differed in preterm delivery compared to term birth. They found that two miRNAs showed increased transcript abundance, and six miRNAs showed decreased transcript abundance in both fractions of preterm milk, when compared to term milk. In addition, six miRNAs in maternal milk were correlated (three positively and three negatively) with mode of delivery. ^{Reference Carney, Tarasiuk and Diangelo91} None of the expression profiles of the milk miRNAs examined in the study were associated with maternal age, race, or ethnicity. ^{Reference Carney, Tarasiuk and Diangelo91}

Limitations in the current literature

We identified several common limitations in studies of human lactation to date. First, limited number of studies included large heterogeneous populations representing a wide range of ethnicities, socioeconomic status, and pre-gestational and gestational BMIs. Although it may be challenging to include multi-ethnic populations due to limitations in funding as well as difficulties in the recruitment of mothers belonging to underrepresented groups, the lack of diversity in these datasets limits the generalizability of the interpretations relating to lactation biology and offspring development. Interestingly, the few studies that included diverse populations reported differences in milk composition among ethnic groups as a function of regional maternal diets and breastfeeding practices. ^{Reference Gay, Koleva and Slupsky92,Reference Su, Thamarai Chelvi and Lim93} Second, a large proportion of studies lack detailed descriptions of the methods used for milk collection and analysis, including the time of milk collection, use of breast pumps, the interval from last feeding to the time of sample collection, storage and processing steps, and lactational age. Consideration of these factors is critically important for studies that use human milk, especially human mature milk since there are notable differences in bioactive composition as mature milk is produced over a longer period of time, ranging from 4 to 6 weeks post-partum until the end of the lactation period. ^{Reference Ballard and Morrow2} In addition, milk collected at the beginning of a feed (foremilk) contains lower fat and higher cellular content compared to the milk collected at the end of the feed (hindmilk). ^{Reference McGuire, Seppo and Goga19} Efforts to standardize the methods, protocols, techniques for milk sample collection and processing by following the technical guidelines set forth by the ISEV (referred to as the Minimal Information for Studies of Extracellular Vesicles, MISEV) could serve to limit these potential confounds. ^{Reference Théry, Witwer and Aikawa64}

Limitations of this scoping review

While we have attempted to provide a comprehensive analysis of the current literature on the biological associations between maternal factors, lactation biology and developmental outcomes in offspring, this scoping review is not without limitations. Despite compiling 40 papers from four different databases, we may have missed relevant studies in our search. Only peer-reviewed, primary literature published in English was included in our search criteria. A few published studies required specialty permission and journal subscriptions that limited our ability to access the full-print version to apply the exclusion and inclusion criteria. Moreover, the anthropometric controls, such as maternal obesity, used as fixed variables in epidemiological studies varied widely, and many studies investigated only one or two maternal factors at distinct timeframes. For instance, while some studies examined maternal pre-gestational obesity, ^{Reference Ellsworth, Perng, Harman, Das, Pennathur and Gregg39,Reference Lemas, Young and Baker42,Reference Panagos, Vishwanathan and Penfield-Cyr50} others investigated maternal gestational or post-gestational obesity. ^{Reference Zamanillo, Sánchez, Serra and Palou11,Reference Larnkjær, Ong, Carlsen, Ejlerskov, Mølgaard and Michaelsen74} This imposed limitations on our ability to draw clear conclusions from such findings concerning the roles of specific factors.