Woo, Jessica G.*; Guerrero, M. Lourdes||; Guo, Fukun†; Martin, Lisa J.‡; Davidson, Barbara S.§; Ortega, Hilda||; Ruiz-Palacios, Guillermo M.||; Morrow, Ardythe L.§
Pediatric obesity is a critical public health problem, affecting an increasing number of children and adolescents worldwide (1,2). Breast-feeding has been identified as protective against later obesity compared with formula feeding, with the increased duration of breast-feeding often being associated with lower obesity in a dose-dependent manner (3–5); however, the mechanism of action by which breast-feeding confers a protective advantage is unclear. Although the macronutrient composition of human milk is stable, human milk is actually a complex mixture of bioactive factors associated with infant growth and metabolism, including insulin (6), leptin (7,8), adipocyte fatty acid–binding protein (9,10), several growth factors and their binding proteins (11,12), and ghrelin (13–15), the composition of which varies from mother to mother and during the course of lactation.
One intriguing component of human milk is adiponectin (APN) (9,10,16–18), which is secreted by breast adipose tissue (19). APN is an insulin-sensitizing and anti-inflammatory molecule, which is typically found in circulation at higher concentrations among individuals with lower adiposity and better metabolic health (20,21). Consistent with that concept, we have previously demonstrated that higher maternal milk APN is associated with lower infant weight-for-length (WFL) z scores in the first 6 months of life in 2 predominantly breast-fed cohorts (22). In contrast, however, another study reported that higher maternal milk APN concentrations were associated with an increased risk of overweight in breast-fed infants by age 2 years (23).
The present study examines the relation among maternal milk APN, maternal serum APN, infant serum APN, and infant growth using a well-characterized longitudinal cohort with frequent follow-up. In this same cohort, we previously reported that milk APN was associated with lower infant weight during the first 6 months of life (22), but longer-term relations with growth during the second year of life and with infant and maternal serum APN have not been examined. In particular, we tested the hypothesis that concentrations of human milk APN influence breast-fed infants’ growth trajectory during the second year of life, beyond the period of active breast-feeding. In addition, we examined the relations among maternal serum APN, maternal milk APN, and infant serum APN levels to clarify the maternal–infant links with respect to APN in breast-fed infants.
Methods for this study were described previously (22), and thus are described only briefly here. From March 1998 to April 2003, 306 infants in San Pedro Martir, Mexico City, were enrolled and monitored prospectively from birth to 2 years of age (24). All of the enrolled infants were healthy, full-term infants born with birth weights of at least 2.2 kg without congenital defects, whose mothers intended to breast-feed. The present study was approved by the institutional review boards of the National Institute of Medical Sciences and Nutrition (Mexico City) and Cincinnati Children's Hospital Medical Center, and all of the mothers provided written informed consent.
Demographic, maternal, household, and birth characteristics were ascertained by baseline questionnaire. Infant diet was ascertained by weekly 24-hour recall. Measurements of infant weight (±0.1 kg, Model MP25, CMS Weighing Equipment Ltd, London, UK) and length (±0.1 cm using recumbent length board) were collected monthly between 1 and 12 months and bimonthly between 12 and 24 months. Milk samples (n = 1074) collected at baseline (week 1) and months 1, 3, 5, and 6 were assayed after a single freeze-thaw cycle.
A maternal blood sample was collected at the baseline visit (2–20 days postpartum), and infant blood samples were collected at baseline, 3, 6, and 12 months of age. All of the blood samples were maintained on ice after collection, processed, aliquoted, and stored at −70°C until assaying. Serum samples from the mother at baseline (n = 274) and a subset of 92 infants at baseline (n = 87), 3 months (n = 84), 6 months (n = 66), and 12 months of age (n = 55) were included in the analysis.
Assay of Serum and Milk APN
Serum total APN was measured in duplicate using radioimmunoassay (Linco Research, St Charles, MO). Milk APN was measured in skimmed milk by radioimmunoassay (Linco Research) as described previously (17).
Breast-feeding durations were calculated using weekly 24-hour recalls, excluding data from the first 7 days of life. Duration of exclusive breast-feeding (EBF) was calculated based on the World Health Organization (WHO) definition as the last age in days at which the infant was reported to receive 100% of all feeds as breast milk. A second breast-feeding variable (BF85%) denoted the last age at which breast-feeding was reported to account for at least 85% of all feeds, regardless of the composition of the rest of the diet; this definition corresponds to “full or nearly full breast-feeding” (25). Age of introduction of solid food was determined as the first age (in days) at which the infant was reported to have consumed any solid or semisolid foods (eg, cereals, soups, yogurt, fruits, vegetables).
Infant anthropometrics were standardized to the WHO Child Growth Standards (26), and the resulting z scores for weight-for-age (WEI), length-for-age (LEN), and WFL were analyzed.
Longitudinal assessment of the relation between milk APN (measured only during the first 6 months) and 2-year growth required 2 special data manipulations. First, to avoid the use of a single proxy milk APN value to represent longitudinal characterization of milk, individual-level milk APN values were summarized as the median of each mother's milk APN values across her available samples. In this phase, 1 outlier sample was excluded from 4 individuals.
Second, to avoid confounding introduced by the decline in milk APN through lactation, which was reported for this cohort previously (22) (eg, with more or later samples resulting in lower median values), the individual's median was determined to be either above or below the median of the group of mothers with the same number of milk measurements. Group sizes were as follows: 3 (1%) mothers had a single milk measurement, 29 (10%) women had 2 measurements, 38 (14%) had 3 measurements, 140 (51%) had 4 measurements, and 67 (24%) had all 5 measurements of milk APN. Figure 1 shows the median and interquartile range (IQR) of the milk APN values for the above-median and below-median groups of women within each measurement stratum. This manipulation resulted in a designation of above-median or below-median milk APN across the cohort that is not confounded by the duration of breast-feeding or number of samples available. Infant serum APN measurements from months 0, 3, 6, and 12 were treated in the same manner because 21 infants (23%) had 2 serum APN measurements, 33 (36%) had 3 measurements, and 38 (41%) had all of the 4 measurements.
All of the analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC). Descriptive statistics were calculated for the entire cohort (n = 277) and were also compared between participants with <12 months’ follow-up (n = 85) or ≥12 months’ follow-up (n = 192) because the latter group was the subset used for the longitudinal anthropometric models. Differences between these follow-up groupings were determined using the Student t or χ2 tests, as appropriate.
Infant serum APN values were normally distributed at each time point, so they were analyzed in original units (micrograms per milliliter). Analysis of longitudinal patterns of infant serum APN and comparisons between time points were conducted using repeated measures modeling (PROC MIXED; SAS Institute). This allows for missing data and accounts for both the intra- and interindividual variability present in this data, resulting in larger and more valid estimates of standard error (SE) (27). Differences between infant and maternal serum APN concentrations were evaluated using the Student t test. For visual presentation only, serum APN values were plotted using medians and IQR because the SEs on the estimates were not distinguishable from the plotted symbol. Cross-sectional Spearman correlations among infant serum, maternal serum, maternal milk, and infant anthropometry z scores during the first year of life were calculated in the entire cohort.
Longitudinal analysis of WFL, WEI, and LEN z scores were conducted using data from months 12 through 24 to examine growth trajectories during the second year of life. The analysis set for this model therefore included only those with at least 12 months of follow-up (n = 192). Modeling used repeated measures models, as above, with the intercept and infant's growth trajectory across time (slopes) allowed to vary by individual. Other covariates considered for model inclusion were infant sex, birth weight, duration of EBF, age at introduction of solid food, change in WFL z score or WEI z score between birth and 6 months, maternal age at delivery, parity, type of delivery, maternal education, and maternal marital status. Changes in WFL and WEI z scores during the first 6 months were specifically included to account for the previous finding in this cohort that milk APN was negatively associated with these parameters during this time period (22) and could confound the relations between 1 and 2 years of age. Covariates were tested in multivariate models if bivariate P ≤ 0.10, and retained if P ≤ 0.05. Interaction terms between month and indicators for above-median or below-median APN were specifically tested to determine whether high or low milk or serum APN groups demonstrated different weight trajectories in year 2.
Infant Feeding and Anthropometric Characteristics
The patterns of breast-feeding in the present cohort were indicative of a highly breast-fed cohort (Fig. 2A). The median duration of EBF was 68 days (IQR 19–130 days) and the duration of breast-feeding comprising at least 85% of feeds (BF85%) was 151 days (IQR 49–182 days). Solid food was also introduced at a median of 150 days (IQR 118–177 days). Other previously reported characteristics of the infants in the present study (22) are included in Table 1.
Compared with the WHO growth standard, WFL z scores peaked between 1 and 2 months of age and WEI and LEN z scores peaked between 3 and 6 months of age (Fig. 2B). During the second year of life, both WEI and WFL z scores demonstrate an upward trend relative to WHO growth curves, whereas LEN z scores declined steadily between 5 and 16 months of age.
Associations Among Infant Serum, Maternal Serum, and Maternal Milk APN During the First Year of Life
Serum APN concentrations were 22.5 ± 0.6 μg/mL higher in infants than their mothers at baseline (P < 0.0001; Fig. 3). Infants’ serum APN concentrations significantly increased between baseline (mean ± SE 31.1 ± 0.6 μg/mL) and 3 months (33.2 ± 0.5 μg/mL, P = 0.002 vs baseline), then significantly declined by 6 months (28.6 ± 0.6 μg/mL, P < 0.0001 vs 3 months) and continued to decline to 12 months of age (23.5 ± 0.8 μg/mL, P < 0.0001 vs 6 months; Fig. 3 presents medians and IQR of data for clarity). Infant serum APN was not associated with median milk APN concentrations at baseline (Table 2), but by 3, 6, and 12 months of age, higher infant serum APN was associated with higher exposure to milk APN. Infant serum APN at 12 months but not at earlier ages was also associated with lower concurrent WEI and LEN z scores (both P < 0.01).
Despite differences in mean levels, maternal and infant serum APN concentrations were directly correlated with each other at baseline (Table 2, r = 0.29, P = 0.007) and 6 months of age (r = 0.32, P < 0.01). Maternal serum APN was also significantly correlated with her own median milk APN concentration (r = 0.37, P < 0.0001). Both maternal baseline serum APN and median milk APN were associated with lower infant WEI z scores at 0, 3, and 6 months, as previously reported.
Second-Year Weight Trajectories Differ by Milk APN Concentration, but Not Infant or Maternal Serum APN
Final longitudinal models for year 2 WFL and WEI z scores were adjusted for infant sex, birth weight, change in WFL or WEI between birth and 6 months (as appropriate), and marital status (married vs not); WFL z score models were further adjusted for delivery type (vaginal vs C section). Other covariates were not significantly associated with infant anthropometry in the second year of life.
Infants exposed to high milk APN experienced increasing WEI z score during the second year of life, whereas those exposed to lower milk APN experienced little change in WEI z scores between 12 and 24 months of age (Fig. 4A). These differences in trajectory over time are significant, even after adjusting for covariates (P for interaction of group by time = 0.02). By 24 months of age, WEI z scores in infants exposed to high milk APN were 0.21 ± 0.10 U higher than those in the lower milk APN group, after adjusting for covariates (P = 0.04). Similar patterns are evident for WFL z score trajectories (P for interaction = 0.054, Fig. 4B); however, milk APN concentrations did not affect LEN z score trajectories (data not shown).
In the subset of infants with serum APN and at least 12 months’ follow-up (n = 71), above-median infant serum APN during the first 12 months was modestly associated with lower mean WFL z score (adjusted β ± SE −0.28 ± 0.14 Z-units, P = 0.05; Fig. 4C) but not significantly lower mean WEI z scores (adjusted β ± SE −0.22 ± 0.13 Z-units, P = 0.10; Fig. 4D) during the second year of life; however, infant serum APN did not alter the infant's growth trajectory between 12 and 24 months (both P for interaction of group by time >0.4). Maternal serum APN at baseline was not significantly associated with mean WFL z score, WEI z score, or growth trajectories during the second year of life (Fig. 4E and 4F).
The present study provides evidence that high exposure to milk APN is part of a complex series of factors associated with increasing weight gain in the second year of life. Using a cohort of breast-fed infants and their mothers, we explored the complex relations among milk APN, maternal serum APN, infant serum APN, and changes in infant weight in the second year of life. We found that breast-fed infants’ weight trajectories during the second year of life are associated with their exposure to human milk APN during breast-feeding, independent of birth weight or growth during the first 6 months of life.
Previous studies of human milk APN and infant growth have been conflicting. Our previous work in this and a second birth cohort demonstrated that high milk APN concentrations were associated with lower infant weight and WFL z scores during the first 6 months of life (22); however, the present analysis demonstrated that even adjusting for this early growth pattern, by 24 months of age these same infants exposed to high levels of human milk APN were significantly heavier and had higher WEI z scores than those exposed to low levels, indicating a reversal of effect. A recent study also found that higher human milk APN at 6 weeks postpartum was associated with greater odds of overweight at age 2 (23). By confirming the previous counterintuitive finding, the present study suggests that human milk APN may have different effects during versus after the period of active breast-feeding. This relation does not appear to be associated with the duration of breast-feeding or the timing of introduction of solid foods, and appears to be independent of several other covariates in our study.
Potential reasons for why higher milk APN is paradoxically associated with greater second-year weight gain suggest avenues for future analysis. Milk APN has been reported to be positively associated with maternal prepregnancy (9) or postpregnancy body mass index (BMI) (17), although this association is not consistent (23,28). It is possible that higher milk APN exposure is a proxy for higher maternal BMI, which may indirectly affect infant weight gain during the first 2 years of life (29). Alternately or additionally, milk APN may be physiologically active in infants during the time of active breast-feeding, limiting early weight gain in children who would otherwise be at risk for obesity. A limitation of the present study is that maternal anthropometry was not collected, so it was not possible to test these hypotheses.
Milk APN may also act as a proxy measurement for any one of a number of potentially biologically relevant components of human milk that may be contributing to increased second-year growth. For example, human milk leptin has been associated with infant weight gain and BMI (23,30,31), is postulated to affect food intake and food preferences (32), and has been positively correlated with milk APN (17,18). Leptin and other components of human milk were not assessed in the present study, but research is clearly needed to elucidate the relative roles of the several components of human milk.
Recent studies have pointed to low birth weight and increased growth rates during infancy as important determinants of obesity during childhood, adolescence, and even adulthood (33). Although the birth weights of this cohort are not low by design, the WEI and LEN z scores are consistently below the median, and overweight by age 2 is rare. Thus, it is possible that the weight gain observed in this cohort during the second year of life represents not pathology (early obesity) but rather positive adaptation (catch-up growth). In this light, higher exposure to milk APN may be delaying catch-up growth that may otherwise occur in the first 6 months. Previous studies have noted that weight gain in the first 6 months is preferentially fat mass, whereas weight gain thereafter is associated with gain in lean mass (34–36). Following this reasoning, a delay in catch-up growth in infants exposed to high milk APN may also be associated with less accrual of fat mass during the first 6 months and greater accrual of lean mass later in infancy. Although this is speculative and extends far beyond the scope of the present study, our hypothesis may provide a structure for future investigations on this question.
Interestingly, the present study also demonstrates that human milk APN is associated with both the mother's and infant's circulating APN within the first year of life. Weyermann et al (37) also found positive correlations between maternal milk and maternal serum APN, and additional studies note that APN is secreted from human breast adipose tissue (19). Furthermore, ingested APN appears in the serum of neonatal mice shortly after administration (38), indicating that milk APN survives digestion in infants. Taken together, these findings suggest that human milk may provide a link between mothers and their infants with regard to this important adipokine.
The present study also extends knowledge about the patterns of infant serum APN during the first year of life in relation to maternal APN and infant growth. Similar to previous studies of cord blood APN (39–42), we report that infants’ circulating APN levels during the first month of life are much higher than their mothers’. In addition, we report that maternal and infant serum APN levels are significantly correlated with each other not only at birth but also at 6 months of age. Previous studies have not typically reported significant correlations between cord blood and maternal APN (39,41,43), but this may be because of differences in the timing of measurements, cohort composition, or breast-feeding exposures. The present study suggests that despite differences in mean levels, infant serum APN levels are associated with their mothers’ levels, whether the reasons for this are genetic, environmental, or in utero or breast-feeding exposures.
Serum APN levels are also dynamic during infancy and early life. We report that total circulating APN significantly increases from birth to 3 months of age, then declines for the remainder of the first year of life. This is consistent with data from other studies showing that total APN increases significantly during late gestation (42,44–46), increases through the first month after birth (47), then declines during the first year (47) and between the first and second years of life (48). Circulating high molecular weight (HMW) APN also appears to follow the same pattern (47,49), which is not surprising given that most cord blood and infant APN occurs in the HMW form (47,50), and milk APN is also predominantly HMW (38). The reasons for these fluctuations in infant serum APN are not clear, and future work would be required to determine whether infant serum APN is associated with body composition, as it is in older children.
Infant serum APN does not appear to be related to longitudinal growth patterns in the present study. We found no association of infant serum APN with WFL z score during the first year, and during the second year of life, higher serum APN was associated with lower mean WFL z score but no difference in growth trajectory. Other studies have also found no association between APN at birth or 1 month of age with concurrent anthropometric parameters (46,51), suggesting that the negative association of circulating APN and obesity seen in older children and adults develops after infancy. The decline in serum APN between 1 and 2 years of age has been correlated to greater increases in body fatness, particularly in girls (48). One study noted that high cord blood APN was associated with greater birth weight and, consistent with our findings, lower weight gain in the first 6 months of life, yet higher central adiposity by age 3 (52), suggesting a complex relation between APN and adiposity in early life that is not reported at older ages.
The longitudinal nature of the present study, concurrent serum and milk samples, and detailed infant feeding and anthropometric data provided a unique opportunity to study growth trajectories in breast-fed infants in relation to milk composition. Despite these strengths, some limitations of the present study should be noted. Only APN was measured in the human milk samples, so the potential influence of other human milk bioactive components cannot be quantified here. Also, because the original study was designed to focus on infant infectious disease outcomes, maternal BMI was not ascertained, and only a single maternal blood sample was collected. Infant blood samples were limited to a subset of participants. These factors limited inferences about the effect of maternal adiposity, but the strength of the findings suggests that the sample size did not impede our ability to detect significant associations.
The present study highlights the potential role of high human milk APN exposure in the accelerated weight trajectory of infants during the second year of life, despite being associated with lower weight gain during the first 6 months in the same cohort. Infant serum APN is also independently associated with lower WEI and WFL z scores between 12 and 24 months, and may be influenced by maternal serum and milk APN. These complex relations in infant growth and feeding in the first 2 years require additional study because they may have long-lasting effects on childhood obesity risk and metabolic adaptation in later life.
The authors thank Ms Luz del Carmen Mendez, Ms Rosa Maria Garcia-Loperena, and the participants in the study.
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