Human Milk Bioactive Components and Child Growth and Body Composition in the First 2 Years: A Systematic Review

Abstract

Human milk (HM) contains macronutrients, micronutrients, and a multitude of other bioactive factors, which can have a long-term impact on infant growth and development. We systematically searched MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. From 9992 abstracts screened, 141 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Bioactives including hormones, HM oligosaccharides (HMOs), and immunomodulatory components are reported here, based on 75 articles from 69 unique studies reporting observations from 9980 dyads. Research designs, milk collection strategies, sampling times, geographic and socioeconomic settings, reporting practices, and outcomes varied considerably. Meta-analyses were not possible because data collection times and reporting were inconsistent among the studies included. Few measured infant HM intake, adjusted for confounders, precisely captured breastfeeding exclusivity, or adequately described HM collection protocols. Only 5 studies (6%) had high overall quality scores. Hormones were the most extensively examined bioactive with 46 articles (n = 6773 dyads), compared with 13 (n = 2640 dyads) for HMOs and 12 (n = 1422 dyads) for immunomodulatory components. Two studies conducted untargeted metabolomics. Leptin and adiponectin demonstrated inverse associations with infant growth, although several studies found no associations. No consistent associations were found between individual HMOs and infant growth outcomes. Among immunomodulatory components in HM, IL-6 demonstrated inverse relationships with infant growth. Current research on HM bioactives is largely inconclusive and is insufficient to address the complex composition of HM. Future research should ideally capture HM intake, use biologically relevant anthropometrics, and integrate components across categories, embracing a systems biology approach to better understand how HM components work independently and synergistically to influence infant growth.

Keywords: anthropometry; bioactives; body composition; breastfeeding; breastmilk; growth; hormones; human milk; human milk oligosaccharides; immunomodulatory; infant; lactation; metabolomics.

FIGURE 1

Systematic review of associations between HM bioactives and infant growth in the first 2 y: PRISMA flow diagram. Reasons for study exclusion were recorded in the order listed in the figure. Though some studies had more than 1 reason for exclusion, each study was only counted once (for example, if a study reported no HM analytes of interest and was not in English, it was recorded as the former). Bioactive studies are reported in the current paper; Macronutrient and Micronutrient studies are reported separately. HM, human milk.

FIGURE 2

Summary of quality assessments of included articles. Quality scores are awarded based on the number of points assigned according to the criteria in Supplemental Table 1. Detailed numeric scores are presented in Supplemental Table 2. HM. HM, human milk. ∗Indicates the same study, but separate articles.

FIGURE 3

Mean directions of associations between HM hormones and infant growth in the first 2 y. Significant associations reflect results as reported by individual study authors (for example, using HM concentrations as the predictor variable, see Table 1). Value in cells indicates the number of studies examining each comparison. Red squares indicate mean positive associations, blue squares indicate mean inverse associations, white squares indicate a mean association of 0, and black squares indicate that association was not assessed. HCA, head circumference-for-age; HM, human milk; LFA, length-for-age; WFA, weight-for-age; WFL, weight-for-length; BFA, BMI-for-age; FFM, fat-free mass; FMI, fat mass index. ∗Indicates that equal numbers of positive and negative associations were observed, resulting in a gradient of zero (0).

FIGURE 4

Mean directions of associations between HMOs and infant growth in the first 2 y, regardless of secretor status (A), or separately for secretor (B) and non-secretor (C) milk. Significant associations between HMOs and infant anthropometrics reflect results as reported by individual study authors (for example, using HM concentrations as the predictor variable, see Table 1). Value in cells indicates the number of studies examining each comparison. Red squares indicate mean positive associations, blue squares indicate mean inverse associations, white squares indicate a mean association of 0, and black squares indicate that association was not assessed. Note that some studies did not stratify on secretor status while others only presented stratified data (i.e. the studies in A are not all represented in B&C, and vice-versa). Despite using the 'near absence' of 2'FL to define non-secretor status, some studies still reported on 2'FL in this group, though no associations with infant growth were observed. HCA, head circumference-for-age; HM, human milk; HMO, human milk oligosaccharide; LFA, length-for-age; WFA, weight-for-age; WFL, weight-for-length; BFA, BMI-for-age; FFM, fat-free mass; FMI, fat mass index. ∗Indicates that equal numbers of positive and negative associations were observed, resulting in a gradient of zero (0).

FIGURE 5

Mean directions of associations between HM immunomodulators and infant growth in the first 2 y. Significant associations between immunomodulators and infant anthropometrics reflect results as reported by individual study authors (for example, using HM concentrations as the predictor variable, see Table 1). Value in cells indicates the number of studies examining each comparison. Red squares indicate mean positive associations, blue squares indicate mean inverse associations, white squares indicate a mean association of 0, and black squares indicate that association was not assessed. HCA, Head circumference-for-age; HM, human milk; LFA, Length-for-age; WFA, weight-for-age; WFL, weight-for-length; BFA, BMI-for-age; FFM, fat-free mass; FMI, fat mass index. ∗Indicates that equal numbers of positive and negative associations were observed, resulting in a gradient of zero (0).