Human Milk Oligosaccharides, Growth, and Body Composition in Very Preterm Infants
by
, and
Margaret L. Ong
1,*, 
Sara Cherkerzian
1,
Katherine A. Bell
1,
Paige K. Berger
1,
Annalee Furst
2,
Kristija Sejane
2,
Lars Bode
2 and
Mandy B. Belfort
1 1
Department of Pediatrics, Division of Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
2
Department of Pediatrics, Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence (MOMI CORE), Human Milk Institute (HMI), University of California San Diego, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
Nutrients 2024, 16(8), 1200; https://doi.org/10.3390/nu16081200
Submission received: 12 March 2024
/
Revised: 13 April 2024
/
Accepted: 14 April 2024
/
Published: 18 April 2024
(This article belongs to the Section Pediatric Nutrition)
Abstract
:Human milk oligosaccharides (HMOs) are bioactive factors that benefit neonatal health, but little is known about effects on growth in very preterm infants (<32 weeks’ gestation). We aimed to quantify HMO concentrations in human milk fed to very preterm infants during the neonatal hospitalization and investigate associations of HMOs with infant size and body composition at term-equivalent age. In 82 human-milk-fed very preterm infants, we measured HMO concentrations at two time points. We measured anthropometrics and body composition with air displacement plethysmography at term-equivalent age. We calculated means of individual and total HMOs, constructed tertiles of mean HMO concentrations, and assessed differences in outcomes comparing infants in the highest and intermediate tertiles with the lowest tertile using linear mixed effects models, adjusted for potential confounders. The mean (SD) infant gestational age was 28.2 (2.2) weeks, and birthweight was 1063 (386) grams. Exposure to the highest (vs. lowest) tertile of HMO concentrations was not associated with anthropometric or body composition z-scores at term-corrected age. Exposure to the intermediate (vs. lowest) tertile of 3FL was associated with a greater head circumference z-score (0.61, 95% CI 0.15, 1.07). Overall, the results do not support that higher HMO intakes influence growth outcomes in this very preterm cohort.
1. Introduction
Fortified human milk is recommended for very preterm infants (<32 weeks’ gestational age [GA]). Given their physiologic immaturity and vulnerability to injury across multiple organ systems, these infants are at heightened risk for impaired physical growth compared with infants born full-term, which has adverse consequences for their neurodevelopment [1,2]. Among very preterm infants, human milk protects against infection [3], modulates inflammation and immune function [4], contributes to microbiome development [5], and predicts improved brain development and neurodevelopmental outcomes [6,7,8,9,10]. In addition to its nutrient components, human milk contains many non-nutrient bioactive factors that support physiological processes related to nutrient digestion and absorption and confers unique health benefits in the very preterm infant, including decreasing the risk for necrotizing enterocolitis (NEC) [11,12,13,14,15,16]. Understanding how bioactive factors influence health outcomes in this vulnerable population is critical to developing new diet-based prevention and treatment strategies.
Human milk oligosaccharides (HMOs) are one class of bioactive factors of increasing interest. HMOs are the third most abundant solid component of human milk, with highest concentrations in colostrum and decreasing concentrations as the milk matures. Most HMOs are found exclusively in human milk. HMO composition is largely influenced by maternal genetics. In particular, a mother’s secretor and Lewis statuses are defined by the presence or near absence of specific fucosyltransferases, which dictate the HMOs that can be synthesized [17,18]. Other maternal factors, including body mass index and environmental variables like season, also influence HMO composition, although to a lesser extent than genetic determinants [19,20]. HMO exposure is modifiable through supplementation or fortification. For example, individual HMOs are added to some commercially available full-term infant formulas, but currently no strategies or products exist for preterm infants [21].
Emerging evidence from full-term infant cohorts suggests that HMOs may be associated with physical growth during infancy. In previous studies of breastfed full-term infants, among secretors, higher 2′FL (2′fucosyllactose) was associated with greater weight and length measures and 3′SL (3′sialyllactose) with higher weight, while higher 6′SL (6′sialyllactose), LNnT (lacto-N-neotetraose), and HMO diversity were associated with lower weight and length measures during the first year of life [22,23]. HMOs also appear to influence body composition. In those studies, higher 2′FL and DSLNT (disialyllacto-N-tetraose) were associated with increased fat mass, whereas higher LNnT and greater HMO diversity correlated with lower fat mass and body fat percentage [23,24]. However, the findings are variable, and the results are not consistent across all studies. Moreover, formula-randomized controlled trials and real-world studies have not shown added growth benefits among those receiving supplementation with select HMOs [25,26,27,28].
Among preterm infants, more rapid growth during NICU hospitalization predicts improved long-term neurodevelopmental outcomes [29]. Yet, the extent to which HMOs influence physical growth in hospitalized very preterm infants is uncertain. To our knowledge, only two prior studies have assessed associations of HMO exposures with growth outcomes in preterm infants. Although both identified several individual HMO exposures associated with improved anthropometric growth, results were inconsistent; in addition, the studies were limited by an incomplete assessment of body composition (only one measured body composition and focused exclusively on fat-free mass but did not consider fat mass), limited gestational age inclusion (<28 weeks or 27–34 weeks rather than all very preterm infants), and the timing of HMO measurements [30,31].
The goals of this study were to quantify HMO concentrations in milk fed to hospitalized very preterm infants and to investigate associations of HMOs with anthropometric and body composition outcomes close to discharge at term-equivalent age. Given the relevance to potential supplementation strategies, we were primarily interested in determining whether HMOs in highest vs. lowest concentrations predicted greater weight, length, head circumference, and fat-free mass, as these growth outcomes predict better neurodevelopment in children born very preterm [32,33,34]. Based on the available literature, 2′FL, 3-fucosyllactose (3FL), 3′SL, 6′SL, LNnT, DSLNT, and total HMOs were our primary exposures of interest. However, given the overall lack of data in very preterm infants, we also planned exploratory analyses on all quantified HMOs.
2. Materials and Methods
2.1. Study Design and Population
We conducted a longitudinal cohort study leveraging previously collected human milk samples and data from very preterm infants hospitalized at Brigham and Women’s Hospital in an academic Level III NICU from 2015 to 2018 [35]. Of 126 infants originally enrolled, the present study included 82 infants meeting the following criteria: (1) gestational age < 32 weeks; (2) two human milk samples available for HMO analysis; (3) ≥1 outcome measure collected; and (4) primarily maternal milk fed (defined as ≥75% of total enteral intake on day of life 28). Of these 82 participants, 65 had data for body composition. The most common reason for missing body composition data was a continued need for respiratory support, which cannot be accommodated during the assessment. The Partners Human Research Committee reviewed and approved this study. Parents provided written informed consent for their infant(s) to participate.
In our NICU, we use written clinical practice guidelines (available upon request) to standardize parenteral and enteral provision of nutrition. The enteral feeding goal for very preterm infants is 150–160 mL/kg/day. Human milk is routinely fortified to 24 kcal/oz with a multi-component bovine-based liquid human milk fortifier.
2.2. Milk Collection and HMO Analysis
Details of milk sample collection procedures have been published [35]. Briefly, sample collection began when mothers were producing sufficient milk to meet infant requirements, typically within 1–2 weeks after birth. On weekdays, bedside nurses collected 3–5 mL samples of unfortified, hand-warmed, and gently mixed milk just prior to feeding the infant. Samples may have comprised fresh milk, frozen milk, or a combination. Almost all samples were maternal milk only (3 comprised a combination of maternal and donor milk, 1 comprised donor milk only). Overall, we designed our approach to sample milk that best represented the infant’s actual diet. Milk samples were stored at −80 °C and subsequently thawed and aliquoted for HMO analysis. For the present study, we identified two milk samples for each participant, one early (Time 1, as close as possible to the establishment of full enteral nutrition) and one late (Time 2, as close as possible to NICU discharge). We calculated the average of the two measures to estimate cumulative exposure to HMOs over the entire NICU hospitalization.
HMO analysis was performed by high-performance liquid chromatography at the University of California, San Diego as previously described [36]. In brief, maltose was added to each milk sample as an internal standard. HMO isolation was performed using solid-phase extraction, fluorescence labeling with 2-aminobenzamide, and subsequent high-performance liquid chromatography with fluorescence detection. Individual concentrations of 19 HMOs were quantified against standard response curves and the internal standard reference. Total HMO concentration was calculated as the sum of 19 measured HMOs. Simpson’s diversity index was calculated to represent diversity in HMO composition. Secretor status was determined by presence (versus near absence, <100 nmol/mL) of 2′FL.
Based on the available literature in preclinical models and full-term infant studies, we defined our primary HMO exposures of interest as concentrations (µg/mL) of six specific HMOs (2′FL, 3FL, 3′SL, 6′SL, LNnT, DSLNT) and total HMOs. We also assessed maternal secretor status as an HMO exposure and conducted exploratory analyses for the remaining quantified individual HMOs, HMO diversity index, HMO-bound sialic acid, HMO-bound fucose (nmol/mL), and total sialylated and fucosylated HMOs (µg/mL) to explore potential influences of fucose and sialic acid exposure from HMOs on outcomes.
2.3. Growth and Body Composition Outcomes
We assessed anthropometric body size at birth and term-equivalent age near NICU discharge. Bedside nurses weighed infants on calibrated digital scales to the nearest 1 g. Two NICU registered dietitians measured infant length with a recumbent length board to the nearest 0.1 cm and head circumference with a non-stretchable tape to the nearest 0.1 cm. We calculated z-scores of weight, length, and head circumference for sex and postmenstrual age (PMA) using references published by Fenton [37]. At term-equivalent age, for infants who were stable off respiratory support, we used air displacement plethysmography to assess body composition, including fat mass, fat-free mass, and body fat percentage (PEAPOD, COSMED, Concord, CA, USA). We calculated z-scores for body composition using published reference curves [38].
2.4. Statistical Analysis
We reported demographic and clinical characteristics as means and standard deviations (or medians and interquartile ranges (IQRs) for skewed distributions) for continuous variables and frequencies with percentages for categorical variables. We used repeated measures correlation [39] to assess the degree of correlation between measurements at Time 1 and Time 2 and tested for differences between median concentrations of each HMO at Time 1 and Time 2 using the Wilcoxon signed rank test given the non-normal distributions of most HMO variables. We calculated mean HMO concentrations of Time 1 and Time 2 measurements. Using these mean values, we divided the cohort into tertiles (high, intermediate, low) for analysis, with the low tertile used as the reference category. We estimated associations of HMO tertiles with anthropometric and body composition outcomes using linear mixed effects regression to account for intrafamilial correlation among multiple gestations. Adjusted models controlled for potential confounding determined a priori by GA at birth, birth size z-score (weight used for body composition analyses), PMA at outcome measurement, infant sex, and maternal age. Data were analyzed using the rmcorr (version 0.5.4) and nlme (version 3.1-160) packages for R statistical software (R Core Team, Vienna, Austria, 2022).
3. Results
Characteristics of mother–infant dyads (n = 82) are presented in Table 1. Mothers had a mean (SD) age of 32.0 (6.4) years at delivery, and 76% were classified as HMO secretors. Infants had a mean (SD) GA of 28.2 (2.2) weeks and birth weight of 1063 (386) g. HMO exposure at Time 1 was based on milk samples collected at mean (SD) 13.7 (7.1) days of life [30.2 (2.2) weeks’ PMA]. HMO exposure at Time 2 was based on milk samples collected at mean (SD) 62.8 (24.3) days of life [37.2 (2.8) weeks’ PMA].
When comparing the two time points, the concentration of almost all individual HMOs significantly decreased within individuals from Time 1 to Time 2 (Figure 1), except for 3FL, which increased [median (IQR) 352 (187, 783) vs. 638 (286, 1035) µg/mL, p < 0.01]. The repeated measures correlations between samples were mostly moderate to large, with r = 0.65 for 3FL and ranging from r = −0.37 to −0.75 for other HMO exposures (Supplemental Table S1). HMO exposures were categorized into tertiles based on the distribution of HMO concentrations in our cohort (Supplemental Table S2). We assessed term-equivalent outcomes at a mean (SD) of 39 (2) weeks’ PMA (Table 2).
For our primary HMOs of interest, exposure to mean HMO concentrations in the high (compared to low) tertiles was not associated with any of the anthropometric (Table 3) or body composition (Table 4) outcomes at term-equivalent age. We did observe an association of intermediate exposure compared to low exposure to 3FL with head circumference. Infants in the intermediate 3FL group had a 0.61 (95% CI: 0.15, 1.07) larger head circumference z-score at term-equivalent age than those in the low 3FL exposure group. Infants fed the highest concentration of 3FL also had a larger head circumference z-score (0.30, 95%CI: −0.15, 0.76) at term-equivalent age, but the confidence interval did not exclude the null.
Similarly, in exploratory analyses, being fed milk with the high tertile of mean HMO concentrations was not associated with higher anthropometric (Table 3) or body composition (Table 4) z-scores at term-equivalent age. Unexpectedly, we observed several significant associations of intermediate (vs. low) HMO exposures with length, head circumference, and body fat percentage. For example, infants exposed to the intermediate level of LS-tetrasaccharide c (LSTc) had a 0.48 (95% CI: −0.90, −0.05) lower length z-score compared to infants with low exposure, while infants with intermediate LS-tetrasaccharide b (LSTb) exposure had a 0.53 (95% CI: −0.99, −0.08) lower head circumference z-score than infants with low exposure. Additionally, intermediate lacto-N-tetraose (LNT) exposure was associated with a 0.73 (95% CI: −1.41, −0.06) lower body fat percentage z-score compared to low exposure. Maternal secretor status (comparing infants of secretor vs. non-secretor mothers) was not associated with anthropometric or body composition outcomes (Table 5).
4. Discussion
In this longitudinal cohort study of very preterm infants, we measured HMO concentrations at two time points spanning the NICU hospitalization. HMO concentrations varied substantially between participants and were moderately correlated within participants over repeated measurements. Most—but not all—HMO concentrations decreased modestly over time within individuals, consistent with prior studies [40,41]. Using the average value for each participant to reflect overall HMO exposures during the NICU hospitalization, we assessed the extent to which higher levels of specific HMOs were associated with a larger body size (weight, length, head circumference) and/or higher fat-free mass at term-equivalent age with the goal to identify future candidates for HMO supplementation or targeted pooling of donor human milk [42,43]. Overall, we did not observe significant associations of high (highest tertile) HMO exposures with a larger body size or composition at term-equivalent age compared with low HMO exposures, although the results suggest a possible association of higher 3FL with a larger head circumference.
There is a lack of data assessing the influence of HMO exposures on measures of physical growth among human-milk-fed preterm infants. While studies in full-term infants have identified certain associations with growth (positive associations of 2′FL and 3FL with weight, negative association of LNnT with weight and length), the results are inconsistent across studies [22,23,24,44]. Further, those findings may not generalize to the very preterm infant given the gastrointestinal immaturity, clinical illness, and overall vulnerability to growth impairment associated with prematurity. We identified only two prior studies of HMOs and physical growth among preterm infants. In one study of 106 extremely low-birth-weight (<1000 g) preterm infants, Wejryd et al. assessed anthropometric growth at 14 days, 28 days, and 36 weeks’ PMA in association with HMOs in maternal milk collected at day 14 [30]. Several individual HMOs were associated with higher anthropometric measurements in the first month of life, including LSTa with weight and head circumference and LNnT with head circumference; none of the associations persisted to 36 weeks’ PMA [30]. Another study by Roze et al. in 137 preterm infants found that 2′FL and total HMO were associated with greater linear growth and 6′SL with greater head circumference growth during NICU hospitalization; associations did not persist to the 2-year follow-up [31]. That study also assessed fat-free mass near discharge and found that 3′SL was associated with higher fat-free mass [31]. In contrast, we found that infants fed milk with intermediate levels of 3FL had higher head circumference z-scores at term-equivalent age compared to those with the lowest 3FL exposure; this finding is consistent with positive associations between 3FL and weight reported in studies of full-term infants [22,45,46] but was not identified in prior studies among preterm infants [30,31]. Notably, the other preterm studies and ours differed in GA; specifically, Wejyrd et al. included less mature infants (mean of 25 weeks at birth), whereas Roze et al. included more mature infants (31.3 ± 1.7 weeks at birth) [30,31]. It is possible that the effects of HMO exposure on growth may depend on GA at birth, which could explain differences in findings across studies. Moreover, the number of milk samples used to represent HMO exposure differed; Wejyrd et al. analyzed exposures at individual time points, while Roze et al. and our study utilized longitudinal HMO exposure averaged over repeated measures to capture exposure over time, which may be more robust to error. Modeling strategies also differed [30,31]. Notably, Wejyrd et al. reported unadjusted correlations without accounting for potential confounders [30], whereas Roze et al. adjusted for GA, birthweight z-score, infant sex, and days on antibiotics [31], and our study adjusted for GA, birth size z-score, infant sex, maternal age, and PMA at outcome. Taken together, findings are inconsistent across studies, which may be due in part to varying study design and analysis strategies. This also highlights the need for additional exploration with a longitudinal assessment of exposure and growth in larger preterm cohorts.
Although we did not observe any significant associations between high HMO exposure as compared with low HMO exposure and higher growth z-scores, in exploratory analyses, we unexpectedly found that, for certain HMOs, infants exposed to intermediate (vs. low) concentrations were smaller at term-equivalent age, suggesting slower growth. We observed that intermediate levels of LSTb and LSTc were associated with smaller head circumference and length z-scores, respectively. Associations of high levels compared with low levels of these HMOs were similarly in the negative direction, but their confidence intervals did not exclude the null. These results may be explained by chance, though are notably consistent with findings in the other preterm studies. Wejyrd et al. found that higher LSTb was associated with slower head growth and lower weight gain, and LSTc was associated with lower weight gain during NICU hospitalization [30]. While Roze et al. did not find associations with anthropometric growth, LSTc was associated with lower fat-free mass [31]. Although, we aimed to identify HMOs for which higher levels confer benefits to growth, our findings and other published findings identifying negative associations suggest potential benefits of exposure to lower (rather than higher) concentrations of specific HMOs for anthropometric outcomes.
In this study, HMO concentrations generally decreased over time during the NICU hospitalization, similar to other milk components such as protein [47], except for 3FL, which increased over time. The decrease in total and most individual HMOs and increase in 3FL are consistent with findings in most other preterm cohorts [30,48]. In contrast to our findings, Wejryd et al. observed a decrease in LNFPII and increase in LSTb and LNFPIII in extremely low-birth-weight infants [30]. Additionally, Roldan et al. found that 3FL and DFlac decreased, while several other fucosylated, sialylated, and neutral HMOs increased over time in very-low-birth-weight infants [49]. Overall, most HMO concentrations appear to decrease over time in preterm human milk. There is an overall similar pattern of decreasing concentrations in most HMOs over time among term infants [24,40]. Some differences have been observed between preterm and term milk for specific HMOs, including higher levels of specific sialylated HMOs (3′SL, DSLNT, LSTb, 6′SL, and LSTc) [48]. These predictable patterns of change over time may inform future supplementation or fortification strategies. Increasing concentrations of certain HMOs over time may hint at important biological functions at later stages of development but are not yet understood.
Although the mechanisms through which HMOs may influence growth remain largely unclear, the existing literature lends insight to potential hypotheses. Because HMOs are minimally digested and absorbed by the infant, effects may be linked to their primary prebiotic role within the gastrointestinal tract, shaping gut microbiota and subsequent nutrient accretion [40,46]. HMOs may also impact absorption by affecting intestinal barrier function [50,51]. Moreover, HMO activity may be indirect—through modulation of inflammation, which is detrimental to infant growth—or through other systemic effects mediated by the 1% of HMOs that are absorbed [4,20,52,53,54].
Our study has several strengths, including the repeated sampling of human milk and measurement of HMOs to represent cumulative exposure over time. We minimized measurement error in infant body length assessment by using a recumbent length board, and assessed the composition of body weight (fat mass, fat-free mass, body fat percentage) in addition to anthropometry. We measured and adjusted for several potential confounders, although residual confounding is a limitation of all observational studies. Our sample size limited our ability to detect small differences between groups and the ability to clearly elucidate non-linear relationships that may inform an optimal range for specific HMO concentrations. Chance associations are also possible given multiple comparisons. We assessed individual and total HMOs separately, but we acknowledge that interactions among HMOs as well as interactions of HMOs with other milk-borne bioactive factors as a biological system are possible [55,56].
5. Conclusions
In this cohort of very preterm infants, those exposed to the highest concentrations of individual and total HMOs did not differ in anthropometric or body composition outcomes at term-equivalent age compared to those with the lowest HMO exposures. Although specific HMOs may have other health benefits for very preterm infants, our results taken together with other studies do not support their individual current therapeutic potential to improve growth. Future work investigating the influence of HMOs on infant health should integrate the emerging concept of human milk as a biological system and consider HMOs’ interactions with each other and with other milk components.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu16081200/s1, Table S1: Repeated measures correlations between HMO concentrations at Time 1 and Time 2 in very preterm infants fed predominantly maternal milk during NICU hospitalization; Table S2: Medians and interquartile ranges by tertiles for HMO exposures among n = 82 very preterm infants fed predominantly maternal milk.
Author Contributions
Conceptualization: M.L.O., S.C., K.A.B., P.K.B., L.B. and M.B.B. Methodology/investigation: M.L.O., S.C., K.A.B., A.F., K.S. and M.B.B. Interpretation: M.L.O., S.C., K.A.B., P.K.B., L.B. and M.B.B. Writing—original draft preparation: M.L.O. and M.B.B. Writing—review and editing: M.L.O., S.C., K.A.B., P.K.B., A.F., K.S., L.B. and M.B.B. All authors have read and agreed to the published version of the manuscript.
Funding
This work is supported by the Allen Foundation, BWH Department of Pediatric Newborn Medicine and Stork Fund, Brigham Research Institute Fund to Sustain Research Excellence, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00 HD098288). MLO received support from NIH T32 HD 098061 (Boston Children’s Hospital Newborn Medicine), NIH/NIDDK T32DK007703 training grant (Harvard T.H. Chan School of Public Health, Department of Nutrition), and Harvard Catalyst|The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541), and financial contributions from Harvard University and its affiliated academic healthcare centers; the content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. L.B. is the UC San Diego Chair of Collaborative Human Milk Research endowed by the Family Larsson-Rosenquist Foundation (FLRF), Switzerland.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki. The Partners Human Research Committee reviewed and approved this study (Protocol #: 2014P001834, approval date 1 October 2014).
Informed Consent Statement
Parents provided written informed consent for their infant(s) to participate in this study.
Data Availability Statement
The data presented in this study are available from the corresponding author on reasonable request and with approval of the IRB. The data are not publicly available to maintain privacy of personally identifiable data for the participants.
Conflicts of Interest
M.L.O., S.C., K.A.B., P.K.B., A.F., K.S. and M.B.B. have no conflicts of interest to disclose. L.B. is a co-inventor on patent applications related to the use of HMOs in preventing NEC and other inflammatory diseases. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
References
- Cooke, R.; Foulder-Hughes, L. Growth impairment in the very preterm and cognitive and motor performance at 7 year. Arch. Dis. Child. 2003, 88, 482–487. [Google Scholar] [CrossRef] [PubMed]
- Serenius, F.; Kallen, K.; Blennow, M.; Ewald, U.; Fellman, V.; Holmstrom, G.; Lindberg, E.; Lundqvist, P.; Marsal, K.; Norman, M.; et al. Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden. JAMA 2013, 309, 1810–1820. [Google Scholar] [CrossRef] [PubMed]
- Miller, J.; Tonkin, E.; Damarell, R.A.; McPhee, A.J.; Suganuma, M.; Suganuma, H.; Middleton, P.F.; Makrides, M.; Collins, C.T. A Systematic Review and Meta-Analysis of Human Milk Feeding and Morbidity in Very Low Birth Weight Infants. Nutrients 2018, 10, 707. [Google Scholar] [CrossRef] [PubMed]
- Thai, J.D.; Gregory, K.E. Bioactive Factors in Human Breast Milk Attenuate Intestinal Inflammation during Early Life. Nutrients 2020, 12, 581. [Google Scholar] [CrossRef]
- Gregory, K.E.; Samuel, B.S.; Houghteling, P.; Shan, G.; Ausubel, F.M.; Sadreyev, R.I.; Walker, W.A. Influence of maternal breast milk ingestion on aquisition of the intestinal microbiome in preterm infants. Microbiome 2016, 4, 68. [Google Scholar] [CrossRef] [PubMed]
- Belfort, M.B.; Anderson, P.J.; Nowak, V.A.; Lee, K.J.; Molesworth, C.; Thompson, D.K.; Doyle, L.W.; Inder, T.E. Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks’ Gestation. J. Pediatr. 2016, 177, 133–139. [Google Scholar] [CrossRef] [PubMed]
- Ottolini, K.M.; Andescavage, N.; Kapse, K.; Jacobs, M.; Liperopoulos, C. Improved brain growth and microstructural development in breast milk–fed very low birth weight premature infants. Acta Paediatr. 2020, 109, 1580–1587. [Google Scholar] [CrossRef]
- Blesa, M.; Sullivan, G.; Anblagan, D.; Telford, E.J.; Quigley, A.J.; Sparrow, S.A.; Serag, A.; Semple, S.I.; Bastin, M.E.; Boardman, J.P. Early breast milk exposure modifies brain connectivity in preterm infants. NeuroImage 2019, 184, 431–439. [Google Scholar] [CrossRef]
- Belfort, M.B.; Knight, E.; Chandarana, S.; Ikem, E.; Gould, J.F.; Collins, C.T.; Makrides, M.; Gibson, R.A.; Anderson, P.J.; Simmer, K.; et al. Associations of Maternal Milk Feeding with Neurodevelopmental Outcomes at 7 Years of Age in Former Preterm Infants. JAMA Netw. Open 2022, 5, e2221608. [Google Scholar] [CrossRef]
- Belfort, M.B.; Inder, T.E. Human Milk and Preterm Infant Brain Development: A Narrative Review. Clin. Ther. 2022, 44, 612–621. [Google Scholar] [CrossRef]
- Autran, C.A.; Benjamin, K.P.; Kim, J.H.; Asztalos, E.; Blood, A.B.; Spence, E.C.H.; Patel, A.L.; Hou, J.; Lewis, N.E.; Bode, L. Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants. Gut 2018, 67, 1064–1070. [Google Scholar] [CrossRef] [PubMed]
- Van Niekerk, E.; Autran, C.A.; Nel, D.G.; Kirsten, G.F.; Blaauw, R.; Bode, L. Human Milk Oligosaccharides Differ between HIV-Infected and HIV-Uninfected Mothers and Are Related to Necrotizing Enterocolitis Incidence in Their Preterm Very-Low-Birth-Weight Infants. J. Nutr. 2014, 144, 1227–1233. [Google Scholar] [CrossRef] [PubMed]
- Jantscher-Krenn, E.; Zheretsov, M.; Nissan, C.; Goth, K.; Guner, Y.S.; Naidu, N.; Choudhury, B.; Grishin, A.V.; Ford, H.R.; Bode, L. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 2012, 61, 1417–1425. [Google Scholar] [CrossRef] [PubMed]
- Masi, A.C.; Embleton, N.D.; Lamb, C.A.; Young, G.; Granger, C.L.; Najera, J.; Smith, D.P.; Hoffman, K.L.; Petrosino, J.F.; Bode, L.; et al. Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis. Gut 2021, 70, 2273–2282. [Google Scholar] [CrossRef] [PubMed]
- Gila-Diaz, A.; Arribas, S.M.; Algara, A.; Martin-Cabrejas, M.A.; Lopez de Pablo, A.L.; Saenz de Pipaon, M.; Ramiro-Cortijo, D. A Review of Bioactive Factors in Human Breastmilk: A Focus on Prematurity. Nutrients 2019, 11, 1307. [Google Scholar] [CrossRef] [PubMed]
- Mank, E.; Naninck, E.F.G.; Limpens, J.; van Toledo, L.; van Goudoever, J.B.; van den Akker, C.H.P. Enteral Bioactive Factor Supplementation in Preterm Infants: A Systematic Review. Nutrients 2020, 12, 2916. [Google Scholar] [CrossRef] [PubMed]
- Cabrera-Rubio, R.; Kunz, C.; Rudloff, S.; Garcia-Mantrana, I.; Crehua-Gaudiza, E.; Martinez-Costa, C.; Collado, M.C. Association of Maternal Secretor Status and Human Milk Oligosaccharides with Milk Microbiota: An Observational Pilot Study. J. Pediatr. Gastroenterol. Nutr. 2019, 68, 256–263. [Google Scholar] [CrossRef]
- Kunz, C.; Meyer, C.; Collado, M.C.; Geiger, L.; Garcia-Mantrana, I.; Bertua-Rios, B.; Martinez-Costa, C.; Borsch, C.; Rudloff, S. Influence of Gestational Age, Secretor, and Lewis Blood Group Status on the Oligosaccharide Content of Human Milk. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 789–798. [Google Scholar] [CrossRef] [PubMed]
- Azad, M.B.; Robertson, B.; Atakora, F.; Becker, A.B.; Subbarao, P.; Moraes, T.J.; Mandhane, P.J.; Turvey, S.E.; Lefbvre, D.L.; Sears, M.R.; et al. Human Milk Oligosaccharide Concentrations Are Associated with Multiple Fixed and Modifiable Maternal Characteristics, Environmental Factors, and Feeding Practices. J. Nutr. 2018, 148, 1733–1742. [Google Scholar] [CrossRef]
- Bode, L. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 2012, 22, 1147–1162. [Google Scholar] [CrossRef]
- Reverri, E.J.; Devitt, A.A.; Kajzer, J.A.; Baggs, G.E.; Borschel, M.W. Review of the Clinical Experiences of Feeding Infants Formula Containing the Human Milk Oligosaccharide 2′-Fucosyllactose. Nutrients 2018, 10, 1346. [Google Scholar] [CrossRef] [PubMed]
- Lagstrom, H.; Rautava, S.; Ollila, H.; Kaljonen, A.; Turta, O.; Makela, J.; Yonemitsu, C.; Gupta, J.; Bode, L. Associations between human milk oligosaccharides and growth in infancy and early childhood. Am. J. Clin. Nutr. 2020, 111, 769–778. [Google Scholar] [CrossRef] [PubMed]
- Larsson, M.W.; Lind, M.V.; Laursen, R.P.; Yonemitsu, C.; Lamjaer, A.; Molgaard, C.; Michaelsen, K.F.; Bode, L. Human Milk Oligosaccharide Composition Is Associated with Excessive Weight Gain During Exclusive Breastfeeding—An Explorative Study. Front. Pediatr. 2019, 7, 279. [Google Scholar] [CrossRef]
- Alderete, T.L.; Autran, C.; Brekke, B.E.; Knight, R.; Bode, L.; Goran, M.I.; Fields, D.A. Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life. Am. J. Clin. Nutr. 2015, 102, 1381–1388. [Google Scholar] [CrossRef]
- Schönknecht, Y.B.; Tovar, M.V.M.; Jensen, S.R.; Parschat, K. Clinical Studies on the Supplementation of Manufactured Human Milk Oligosaccharides: A Systematic Review. Nutrients 2023, 15, 3622. [Google Scholar] [CrossRef]
- Jochum, F.; Meyer-Krott, M.; Hübler, T.; Lorenz, M.; Bedikian, R.; Zakarian, J.; Litzka, A.; Judex, G.; Hertzberg, H.; Klee, D.; et al. Real-world evidence study on tolerance and growth in infants fed an infant formula with two human milk oligosaccharides vs. mixed fed and exclusively breastfed infants. Mol. Cell Pediatr. 2023, 10, 7. [Google Scholar] [CrossRef]
- Puccio, G.; Alliet, P.; Cajozzo, C.; Janssens, E.; Corsello, G.; Sprenger, N.; Wernimont, S.; Egli, D.; Gosoniu, L.; Steenhout, P. Effects of Infant Formula with Human Milk Oligosaccharides on Growth and Morbidity: A Randomized Multicenter Trial. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 624–631. [Google Scholar] [CrossRef]
- Lasekan, J.; Choe, Y.; Dvoretskiy, S.; Devitt, A.; Zhang, S.; Mackey, A.; Wulf, K.; Buck, R.; Steele, C.; Johnson, M.; et al. Growth and Gastrointestinal Tolerance in Healthy Term Infants Fed Milk-Based Infant Formula Supplemented with Five Human Milk Oligosaccharides (HMOs): A Randomized Multicenter Trial. Nutrients 2022, 14, 2625. [Google Scholar] [CrossRef]
- Ehrenkranz, R.A.; Dusick, A.M.; Vohr, B.R.; Wright, L.L.; Wrage, L.A.; Poole, K. Network ftNIoCHaHDNR: Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants. Pediatrics 2006, 117, 1253–1261. [Google Scholar] [CrossRef] [PubMed]
- Wejryd, E.; Marti, M.; Marchini, G.; Werme, A.; Jonsson, B.; Landberg, E.; Abrahamsson, T.R. Low Diversity of Human Milk Oligosaccharides is Associated with Necrotising Enterocolitis in Extremely Low Birth Weight Infants. Nutrients 2018, 10, 1556. [Google Scholar] [CrossRef]
- Roze, J.-C.; Hartweg, M.; Simon, L.; Billard, H.; Chen, Y.; Austin, S.; Boscher, C.; Moyon, T.; Darmaun, D.; Garcia Rodenas, C.I.; et al. Human milk oligosaccharides in breast milk and 2-year outcome in preterm infants: An exploratory analysis. Clin. Nutr. 2022, 41, 1896–1905. [Google Scholar] [CrossRef] [PubMed]
- Cordova, E.G.; Cherkerzian, S.; Bell, K.; Joung, K.E.; Collins, C.T.; Makrides, M.; Gould, J.; Anderson, P.J.; Belfort, M.B. Association of Poor Postnatal Growth with Neurodevelopmental Impairment in Infancy and Childhood: Comparing the Fetus and the Healthy Preterm Infant References. J. Pediatr. 2020, 225, 37–43.e5. [Google Scholar] [CrossRef] [PubMed]
- Pfister, K.M.; Zhang, L.; Miller, N.C.; Ingolfsland, E.C.; Demerath, E.W.; Ramel, S.E. Early body composition changes are associated with neurodevelopmental and metabolic outcomes at 4 years of age in very preterm infants. Pediatr. Res. 2018, 84, 713–718. [Google Scholar] [CrossRef] [PubMed]
- Ramel, S.E.; Gray, H.L.; Christiansen, E.; Boys, C.; Georgieff, M.K.; Demerath, E.W. Greater Early Gains in Fat-Free Mass, but Not Fat Mass, Are Associated with Improved Neurodevelopment at 1 Year Corrected Age for Prematurity in Very Low Birth Weight Preterm Infants. J. Pediatr. 2016, 173, 108–115. [Google Scholar] [CrossRef] [PubMed]
- Belfort, M.; Cherkerzian, S.; Bell, K.; Soldateli, B.; Ramos, E.C.; Palmer, C.; Steele, T.; Pepin, H.; Ellard, D.; Drouin, K.; et al. Macronutrient Intake from Human Milk, Infant Growth, and Body Composition at Term Equivalent Age: A Longitudinal Study of Hospitalized Very Preterm Infants. Nutrients 2020, 12, 2249. [Google Scholar] [CrossRef] [PubMed]
- Berger, P.K.; Hampson, H.E.; Schmidt, K.A.; Alderete, T.L.; Furst, A.; Yonemitsu, C.; Demerath, E.; Goran, M.I.; Fields, D.A.; Bode, L. Stability of Human-Milk Oligosaccharide Concentrations Over 1 Week of Lactation and Over 6 Hours Following a Standard Meal. J. Nutr. 2023, 152, 2727–2733. [Google Scholar] [CrossRef] [PubMed]
- Fenton, T.R.; Kim, J.H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 2013, 13, 59. [Google Scholar] [CrossRef] [PubMed]
- Norris, T.; Ramel, S.E.; Catalano, P.; Caoimh, C.N.; Roggero, P.; Murray, D.; Fields, D.A.; Demerath, E.W.; Johnson, W. New charts for the assessment of body composition, according to air-displacement plethysmography, at birth and across the first 6 mo of life. Am. J. Clin. Nutr. 2019, 109, 1353–1360. [Google Scholar] [CrossRef] [PubMed]
- Bakdash, J.Z.; Marusich, L.R. Corrigendum: Repeated Measures Correlation. Front. Psychol. 2019, 10, 1201. [Google Scholar] [CrossRef]
- Cheema, A.S.; Trevenen, M.L.; Turlack, B.A.; Furst, A.J.; Roman, A.S.; Bode, L.; Grideneva, Z.; Lai, C.T.; Stinson, L.F.; Payne, M.S.; et al. Exclusively Breastfed Infant Microbiota Develops over Time and Is Associated with Human Milk Oligosaccharide Intakes. Int. J. Mol. Sci. 2022, 23, 2804. [Google Scholar] [CrossRef]
- Plows, J.F.; Berger, P.K.; Jones, R.B.; Alderete, T.L.; Yonemitsu, C.; Najera, J.A.; Khwajazada, S.; Bode, L.; Goran, M.I. Longitudinal Changes in Human Milk Oligosaccharides (HMOs) Over the Course of 24 Months of Lactation. J. Nutr. 2021, 151, 876–882. [Google Scholar] [CrossRef] [PubMed]
- Friend, L.L.; Perrin, M.T. Fat and Protein Variability in Donor Human Milk and Associations with Milk Banking Processes. Breastfeed. Med. 2020, 15, 370–376. [Google Scholar] [CrossRef]
- Fu, T.T.; Schroder, P.E.; Poindexter, B.B. Macronutrient Analysis of Target-Pooled Donor Breast Milk and Corresponding Growth in Very Low Birth Weight Infants. Nutrients 2019, 11, 1884. [Google Scholar] [CrossRef] [PubMed]
- Brockway, M.; Daniel, A.I.; Reyes, S.M.; Gauglitz, J.M.; Granger, M.; McDermid, J.M.; Chan, D.; Refvik, R.; Sidhu, K.; Musse, S.; et al. Human Milk Bioactive Components and Child Growth and Body Composition in the First 2 Years: A Systematic Review. Adv. Nutr. 2024, 15, 100127. [Google Scholar] [CrossRef]
- Saben, J.L.; Sims, C.R.; Abraham, A.; Bode, L.; Andres, A. Human Milk Oligosaccharide Concentrations and Infant Intakes Are Associated with Maternal Overweight and Obesity and Predict Infant Growth. Nutrients 2021, 13, 446. [Google Scholar] [CrossRef] [PubMed]
- Cheema, A.S.; Gridneva, Z.; Furst, A.J.; Roman, A.S.; Trevenen, M.L.; Turlack, B.A.; Lai, C.T.; Stinson, L.F.; Bode, L.; Payne, M.S.; et al. Human Milk Oligosaccharides and Bacterial Profile Modulate Infant Body Composition during Exclusive Breastfeeding. Int. J. Mol. Sci. 2022, 23, 2865. [Google Scholar] [CrossRef] [PubMed]
- Gildrewicz, D.A.; Fenton, T.R. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr. 2014, 14, 216. [Google Scholar]
- Austin, S.; De Castro, C.A.; Sprenger, N.; Binia, A.; Affolter, M.; Garcia-Rodenas, C.L.; Beauport, L.; Tolsa, J.-F.; Fumeaux, C.J.F. Human Milk Oligosaccharides in the Milk of Mothers Delivering Term versus Preterm Infants. Nutrients 2019, 11, 1282. [Google Scholar] [CrossRef] [PubMed]
- Roldan, V.D.T.; Uretecho, M.S.; Gupta, J.; Yonemitsu, C.; Carcamo, C.P.; Bode, L.; Ochoa, T.J. Human milk oligosaccharides and their association with late-onset neonatal sepsis in Peruvian very-low-birth-weight infants. Am. J. Clin. Nutr. 2020, 112, 106–112. [Google Scholar] [CrossRef]
- Chleilat, F.; Klancic, T.; Ma, K.; Schick, A.; Nettleton, J.E.; Reimer, R.A. Human Milk Oligosaccharide Supplementation Affects Intestinal Barrier Function and Microbial Composition in the Gastrointestinal Tract of Young Sprague Dawley Rats. Nutrients 2020, 12, 1532. [Google Scholar] [CrossRef]
- Lee, S.; Goodson, M.L.; Vang, W.; Rutkowsky, J.; Kalanetra, K.; Bhattacharya, M.; Barile, D.; Raybould, H.E. Human milk oligosaccharide 2′-fucosyllactose supplementation improves gut barrier function and signaling in the vagal afferent pathway in mice. Food Funct. 2021, 12, 8507–8521. [Google Scholar] [CrossRef] [PubMed]
- Rasmussen, S.O.; Martin, L.; Ostergaard, M.V.; Rudloff, S.; Roggenbuck, M.; Nguyen, D.N.; Sangild, P.T.; Bering, S.B. Human milk oligosaccharide effects on intestinal function and inflammation after preterm birth in pigs. J. Nutr. Biochem. 2017, 40, 141–154. [Google Scholar] [CrossRef] [PubMed]
- Kong, C.; Beukema, M.; Wang, M.; de Haan, B.J.; de Vos, P. Human milk oligosaccharides and non-digestible carbohydrates prevent adhesion of specific pathogens via modulating glycosylation or inflammatory genes in intestinal epithelial cells. Food Funct. 2021, 12, 8100–8119. [Google Scholar] [CrossRef] [PubMed]
- Belfort, M.B.; Ramel, S.E.; Martin, C.R.; Fichorova, R.; Kuban, K.C.K.; Heeren, T.; Fry, R.C.; O’Shea, T.M. Systemic Inflammation in the First 2 Weeks after Birth as a Determinant of Physical Growth Outcomes in Hospitalized Infants with Extremely Low Gestational Age. J. Pediatr. 2022, 240, 37–43. [Google Scholar] [CrossRef]
- Christian, P.; Smith, E.R.; Lee, S.E.; Vargas, A.J.; Bremer, A.A.; Raiten, D.J. The need to study human milk as a biological system. Am. J. Clin. Nutr. 2021, 113, 1063–1072. [Google Scholar] [CrossRef]
- Mainardi, F.; Binia, A.; Rajhans, P.; Austin, S.; Deoni, S.; Schneider, N. Human milk oligosaccharide composition and associations with growth: Results from an observational study in the US. Front. Nutr. 2023, 10. [Google Scholar] [CrossRef]
Figure 1.
HMO exposures at two time points during NICU hospitalization among n = 82 very preterm infants fed predominantly maternal milk. Boxplots represent medians, interquartile ranges, and ranges with outliers (≥1.5 × IQR) notated as dots. Time 1 samples were taken as close as possible to the establishment of full enteral nutrition (13.7 (7.1) days of life [30.2 (2.2) weeks’ PMA]). Time 2 samples were collected as close as possible to NICU discharge (62.8 (24.3) days of life [37.2 (2.8) weeks’ PMA]).
Figure 1.
HMO exposures at two time points during NICU hospitalization among n = 82 very preterm infants fed predominantly maternal milk. Boxplots represent medians, interquartile ranges, and ranges with outliers (≥1.5 × IQR) notated as dots. Time 1 samples were taken as close as possible to the establishment of full enteral nutrition (13.7 (7.1) days of life [30.2 (2.2) weeks’ PMA]). Time 2 samples were collected as close as possible to NICU discharge (62.8 (24.3) days of life [37.2 (2.8) weeks’ PMA]).
Table 1.
Participant characteristics.
| Maternal Characteristics (n = 76) | |
| Maternal age, years | 32.0 (6.4) |
| Race | |
| Asian | 5 (7%) |
| Black | 23 (33%) |
| Multiple | 3 (4%) |
| Other | 3 (4%) |
| White | 35 (51%) |
| Ethnicity—Hispanic | 12 (16%) |
| Parity | 1.6 (0.9) |
| Mode of delivery—Cesarean | 50 (67%) |
| Infant Characteristics (n = 82) | |
| Gestational age, weeks | 28.2 (2.2) |
| Male | 46 (56%) |
| Multiple gestation | 16 (20%) |
| Maternal milk at DOL 28—% | 99 (4) |
| Postnatal steroid treatment | 13 (16%) |
| NEC | 2 (2%) |
| Late-onset sepsis | 6 (8%) |
| IVH grade 3 or 4 | 3 (4%) |
| Infant Birth Measurements | |
| Weight (g) | 1063 (386) |
| Weight z-score | −0.21 (1.05) |
| Length (cm) | 36.2 (4.0) |
| Length z-score | −0.14 (1.22) |
| Head circumference (cm) | 25.1 (2.7) |
| Head circumference z-score | −0.40 (1.10) |
Data are represented as mean (SD) or n (%). Maternal milk at DOL 28 is represented as percentage of total enteral intake. NEC: necrotizing enterocolitis. IVH: intraventricular hemorrhage. Z-scores for anthropometric measurements were calculated based on reference curves published by Fenton [37].
Table 2.
Anthropometric and body composition outcomes at term-equivalent age (39 ± 2 weeks postmenstrual age) for very preterm infants fed predominantly maternal milk.
Table 2.
Anthropometric and body composition outcomes at term-equivalent age (39 ± 2 weeks postmenstrual age) for very preterm infants fed predominantly maternal milk.
| Outcome | n | Raw | Z-Score |
|---|---|---|---|
| Weight (g) | 82 | 2792 ± 610 | −1.07 ± 1.30 |
| Length (cm) | 79 | 46.8 ± 2.9 | −1.20 ± 1.36 |
| Head circumference (cm) | 78 | 33.4 ± 1.5 | −0.47 ± 1.15 |
| Fat mass (kg) | 65 | 0.55 ± 0.21 | 1.79 ± 1.12 |
| Fat-free mass (kg) | 65 | 2.28 ± 0.46 | −1.30 ± 1.56 |
| Body fat percentage (%) | 65 | 18.5 ± 4.7 | 2.23 ± 1.11 |
Table 3.
Adjusted associations of mean HMO concentrations in human milk (tertiles indicating high, intermediate, or low exposure) with anthropometric z-scores at term-equivalent age among primarily maternal-milk-fed very preterm infants.
Table 3.
Adjusted associations of mean HMO concentrations in human milk (tertiles indicating high, intermediate, or low exposure) with anthropometric z-scores at term-equivalent age among primarily maternal-milk-fed very preterm infants.
| HMO | Weight (n = 82) | Length (n = 73) | Head Circumference (n = 74) | |||
|---|---|---|---|---|---|---|
| High vs. Low | Intermediate vs. Low | High vs. Low | Intermediate vs. Low | High vs. Low | Intermediate vs. Low | |
| Primary Analyses | ||||||
| 2′FL | −0.02 (−0.55, 0.51) | 0.22 (−0.28, 0.73) | −0.11 (−0.54, 0.32) | 0.10 (−0.32, 0.51) | −0.13 (−0.59, 0.33) | 0.29 (−0.16, 0.73) |
| 3FL | −0.04 (−0.57, 0.49) | 0.05 (−0.48, 0.58) | 0.12 (−0.32, 0.56) | 0.25 (−0.20, 0.70) | 0.30 (−0.15, 0.76) | 0.61 (0.15, 1.07) * |
| 3′SL | 0.04 (−0.47, 0.55) | −0.15 (−0.67, 0.38) | −0.25 (−0.67, 0.18) | −0.16 (−0.59, 0.26) | −0.03 (−0.48, 0.43) | 0.10 (−0.37, 0.57) |
| 6′SL | 0.23 (−0.27, 0.73) | −0.29 (−0.77, 0.20) | −0.11 (−0.52, 0.31) | 0.03 (−0.39, 0.45) | 0.01 (−0.46, 0.47) | 0.10 (−0.36, 0.55) |
| LNnT | −0.40 (−0.90, 0.10) | −0.45 (−0.94, 0.05) | −0.23 (−0.65, 0.19) | −0.19 (−0.60, 0.23) | −0.39 (−0.83, 0.05) | −0.01 (−0.46, 0.45) |
| DSLNT | −0.06 (−0.59, 0.46) | −0.32 (−0.84, 0.20) | −0.25 (−0.70, 0.20) | −0.18 (−0.61, 0.25) | −0.05 (−0.55, 0.44) | 0.11 (−0.37, 0.60) |
| Total HMO | −0.04 (−0.56, 0.48) | −0.06 (−0.58, 0.47) | −0.14 (−0.56, 0.29) | −0.21 (−0.64, 0.22) | −0.13 (−0.60, 0.34) | 0.01 (−0.47, 0.50) |
| Exploratory Analyses | ||||||
| DFlac | −0.27 (−0.79, 0.26) | −0.09 (−0.61, 0.43) | −0.01 (−0.43, 0.41) | −0.07 (−0.50, 0.36) | 0.20 (−0.27, 0.67) | 0.27 (−0.21, 0.75) |
| LNT | 0.08 (−0.44, 0.60) | 0.002 (−0.51, 0.51) | 0.12 (−0.30, 0.54) | 0.21 (−0.22, 0.65) | 0.05 (−0.42, 0.53) | 0.15 (−0.31, 0.61) |
| LNFPI | −0.01 (−0.55, 0.54) | −0.01 (−0.53, 0.50) | −0.14 (−0.60, 0.32) | 0.14 (−0.26, 0.54) | −0.23 (−0.72, 0.26) | 0.07 (−0.38, 0.51) |
| LNFPII | 0.20 (−0.32, 0.71) | 0.11 (−0.41, 0.63) | 0.07 (−0.35, 0.49) | −0.14 (−0.57, 0.29) | −0.004 (−0.44, 0.44) | 0.38 (−0.09, 0.85) |
| LNFPIII | −0.01 (−0.56, 0.53) | −0.21 (−0.74, 0.31) | 0.13 (−0.30, 0.56) | 0.43 (−0.003, 0.86) | −0.02 (−0.52, 0.48) | 0.07 (−0.40, 0.54) |
| LSTb | 0.08 (−0.42, 0.59) | −0.42 (−0.93, 0.09) | −0.35 (−0.78, 0.08) | −0.17 (−0.59, 0.26) | −0.33 (−0.80, 0.14) | −0.53 (−0.99, −0.08) * |
| LSTc | −0.03 (-0.55, 0.48) | −0.03 (−0.56, 0.50) | −0.15 (−0.56, 0.25) | −0.48 (−0.90, −0.05) * | −0.33 (−0.78, 0.13) | −0.16 (−0.65, 0.33) |
| DFLNT | −0.19 (−0.71, 0.33) | −0.11 (−0.65, 0.43) | −0.09 (−0.54, 0.36) | −0.13 (−0.57, 0.30) | 0.26 (−0.22, 0.74) | 0.25 (−0.23, 0.72) |
| LNH | −0.21 (−0.72, 0.30) | −0.30 (−0.81, 0.21) | 0.21 (−0.22, 0.64) | −0.04 (−0.49, 0.42) | −0.11 (−0.58, 0.37) | −0.01 (−0.48, 0.45) |
| FLNH | −0.03 (−0.57, 0.51) | −0.14 (−0.66, 0.38) | 0.05 (−0.38, 0.48) | −0.21 (−0.64, 0.21) | −0.04 (−0.51, 0.43) | 0.21 (−0.27, 0.69) |
| DFLNH | −0.09 (−0.61, 0.42) | −0.46 (−0.96, 0.03) | 0.28 (−0.13, 0.70) | −0.13 (−0.53, 0.27) | 0.06 (−0.41, 0.53) | 0.20 (−0.27, 0.66) |
| FDSLNH | 0.27 (−0.24, 0.77) | 0.20 (−0.31, 0.71) | 0.01 (−0.41, 0.43) | −0.26 (−0.69, 0.17) | 0.19 (−0.26, 0.65) | −0.12 (−0.58, 0.35) |
| DSLNH | 0.13 (−0.39, 0.65) | −0.31 (−0.81, 0.18) | 0.01 (−0.42, 0.44) | 0.01 (−0.42, 0.44) | 0.11 (−0.34, 0.57) | −0.08 (−0.54, 0.39) |
| Diversity | 0.23 (−0.28, 0.74) | 0.16 (−0.35, 0.66) | 0.07 −0.34, 0.49) | 0.02 (−0.39, 0.43) | 0.28 (−0.17, 0.73) | 0.08 (−0.37, 0.54) |
| HMO-bound sialic acid | 0.35 (−0.16, 0.87) | −0.25 (−0.75, 0.24) | −0.15 (−0.56, 0.27) | 0.03 (−0.38, 0.44) | 0.05 (−0.43, 0.53) | −0.15 (−0.61, 0.31) |
| HMO-bound fucose | −0.02 (−0.56, 0.52) | 0.09 (−0.44, 0.62) | −0.07 (−0.50, 0.35) | −0.08 (−0.52, 0.36) | −0.20 (−0.66, 0.26) | −0.10 (−0.58, 0.38) |
| Total sialylated | 0.36 (−0.17, 0.88) | −0.15 (−0.64, 0.35) | −0.10 (−0.51, 0.32) | 0.02 (−0.39, 0.44) | 0.09 (−0.39, 0.57) | −0.12 (−0.58, 0.34) |
| Total fucosylated | 0.21 (−0.33, 0.75) | 0.18 (−0.35, 0.71) | 0.13 (−0.31, 0.58) | 0.06 (−0.38, 0.51) | −0.11 (−0.58, 0.36) | 0.02 (−0.44, 0.49) |
Linear mixed effects models were adjusted for intrafamilial correlation among multiple gestations and controlled for potential confounding by gestational age at birth, birth size z-score, post-menstrual age at outcome measurement, infant sex, and maternal age. Beta estimates (95% confidence interval) indicate the z-score mean difference in outcome between the two indicated tertiles of HMO exposure. Individual, total sialylated, total fucosylated, and overall total HMOs were measured in µg/mL; HMO-bound sialic acid and fucose were measured in nmol/mL. Medians and interquartile ranges of HMO concentrations by tertiles are detailed in Supplemental Table S2. Bolded starred results represent findings for which the 95% confidence interval does not include the null (p < 0.05).
Table 4.
Adjusted associations of mean HMO concentrations in human milk (tertiles indicating high, intermediate, or low exposure) with body composition z-scores at term-equivalent age among primarily maternal-milk-fed very preterm infants (n = 65).
Table 4.
Adjusted associations of mean HMO concentrations in human milk (tertiles indicating high, intermediate, or low exposure) with body composition z-scores at term-equivalent age among primarily maternal-milk-fed very preterm infants (n = 65).
| HMO | Fat Mass | Fat-Free Mass | Body Fat Percentage | |||
|---|---|---|---|---|---|---|
| High vs. Low | Intermediate vs. Low | High vs. Low | Intermediate vs. Low | High vs. Low | Intermediate vs. Low | |
| Primary Analyses | ||||||
| 2′FL | 0.005 (−0.73, 0.74) | 0.16 (−0.52, 0.83) | 0.08 (−0.49, 0.64) | −0.01 (−0.54, 0.51) | 0.14 (−0.62, 0.89) | 0.11 (−0.59, 0.81) |
| 3FL | 0.18 (−0.59, 0.95) | 0.45 (−0.25, 1.15) | 0.10 (−0.50, 0.69) | 0.30 (−0.24, 0.85) | 0.09 (−0.72, 0.89) | 0.29 (−0.44, 1.02) |
| 3′SL | −0.07 (−0.75, 0.60) | −0.39 (−1.08, 0.31) | 0.23 (−0.30, 0.75) | −0.12 (−0.66, 0.42) | −0.15 (−0.83, 0.54) | −0.53 (−1.25, 0.19) |
| 6′SL | 0.06 (−0.65, 0.78) | −0.26 (−0.93, 0.40) | 0.03 (−0.53, 0.59) | 0.01 (−0.51, 0.53) | −0.13 (−0.87, 0.61) | −0.37 (−1.06, 0.32) |
| LNnT | −0.64 (−1.31, 0.03) | −0.59 (−1.25, 0.06) | −0.03 (−0.58, 0.51) | −0.09 (−0.62, 0.44) | −0.66 (−1.36, 0.03) | −0.59 (−1.26, 0.07) |
| DSLNT | −0.53 (−1.24, 0.19) | −0.12 (−0.79, 0.56) | −0.27 (−0.83, 0.29) | −0.24 (−0.77, 0.29) | −0.55 (−1.27, 0.18) | −0.23 (−0.92, 0.46) |
| Total HMO | −0.21 (−0.92, 0.51) | 0.10 (−0.58, 0.77) | −0.06 (−0.61, 0.49) | −0.13 (−0.66, 0.39) | −0.26 (−1.00, 0.47) | 0.02 (−0.67, 0.72) |
| Exploratory Analyses | ||||||
| DFlac | −0.21 (−0.90, 0.47) | −0.51 (−1.19, 0.18) | 0.09 (−0.43, 0.60) | −0.44 (−0.96, 0.08) | −0.28 (−0.99, 0.42) | −0.51 (−1.22, 0.21) |
| LNT | −0.42 (−1.13, 0.29) | −0.41 (−1.09, 0.27) | −0.0001 (−0.56, 0.56) | −0.11 (−0.64, 0.43) | −0.63 (−1.34, 0.08) | −0.73 (−1.41, −0.06) * |
| LNFPI | −0.32 (−1.07, 0.44) | 0.20 (−0.46, 0.85) | −0.10 (−0.69, 0.50) | 0.18 (−0.33, 0.69) | −0.25 (−1.04, 0.53) | 0.16 (−0.53, 0.84) |
| LNFPII | −0.12 (−0.82, 0.58) | −0.15 (−0.86, 0.56) | 0.10 (−0.44, 0.64) | 0.25 (−0.30, 0.79) | −0.32 (−1.04, 0.40) | −0.47 (−1.18, 0.25) |
| LNFPIII | −0.06 (−0.80, 0.68) | −0.10 (−0.85, 0.64) | −0.17 (−0.74, 0.40) | −0.02 (−0.60, 0.55) | 0.03 (−0.74, 0.79) | −0.07 (−0.84, 0.70) |
| LSTb | −0.29 (−0.98, 0.40) | −0.54 (−1.21, 0.13) | −0.44 (−0.97, 0.08) | −0.47 (−0.98, 0.04) | −0.18 (−0.90, 0.53) | −0.57 (−1.26, 0.12) |
| LSTc | −0.41 (−1.07, 0.24) | −0.43 (−1.12, 0.26) | −0.15 (−0.66, 0.36) | 0.13 (−0.40, 0.67) | −0.45 (−1.13, 0.23) | −0.34 (−1.05, 0.36) |
| DFLNT | −0.33 (−1.03, 0.37) | 0.19 (−0.56, 0.95) | −0.11 (−0.64, 0.43) | −0.50 (−1.08, 0.08) | −0.40 (−1.10, 0.31) | 0.28 (−0.48, 1.05) |
| LNH | −0.27 (−0.98, 0.43) | −0.10 (−0.80, 0.59) | −0.06 (−0.61, 0.49) | 0.02 (−0.52, 0.56) | −0.44 (−1.16, 0.29) | −0.37 (−1.07, 0.34) |
| FLNH | −0.01 (−0.76, 0.74) | −0.28 (−0.95, 0.39) | 0.09 (−0.49, 0.67) | −0.23 (−0.74, 0.29) | −0.20 (−0.97, 0.57) | −0.39 (−1.06, 0.29) |
| DFLNH | 0.37 (−0.36, 1.11) | 0.12 (−0.52, 0.76) | 0.07 (−0.51, 0.64) | −0.03 (−0.53, 0.47) | 0.25 (−0.51, 1.02) | 0.02 (−0.64, 0.69) |
| FDSLNH | 0.04 (−0.64, 0.72) | 0.03 (−0.66, 0.71) | 0.28 (−0.24, 0.81) | 0.03 (−0.50, 0.56) | −0.25 (−0.96, 0.45) | −0.13 (−0.84, 0.58) |
| DSLNH | 0.11 (−0.62, 0.85) | −0.09 (−0.74, 0.56) | −0.31 (−0.88, 0.26) | −0.14 (−0.64, 0.35) | 0.07 (−0.69, 0.83) | −0.23 (−0.90, 0.43) |
| Diversity | −0.38 (−1.07, 0.31) | −0.20 (−0.87, 0.47) | −0.16 (−0.68, 0.36) | 0.27 (−0.23, 0.78) | −0.59 (−1.28, 0.11) | −0.50 (−1.18, 0.17) |
| HMO-bound sialic acid | −0.10 (−0.80, 0.60) | −0.29 (−0.93, 0.35) | 0.01 (−0.53, 0.55) | −0.27 (−0.76, 0.22) | −0.27 (−0.98, 0.45) | −0.47 (−1.11, 0.17) |
| HMO-bound fucose | −0.01 (−0.71, 0.69) | 0.13 (−0.57, 0.84) | 0.11 (−0.43, 0.65) | 0.04 (−0.51, 0.59) | 0.001 (−0.72, 0.72) | 0.11 (−0.62, 0.85) |
| Total sialylated | −0.08 (−0.77, 0.62) | −0.18 (−0.83, 0.48) | 0.02 (−0.52, 0.55) | −0.20 (−0.70, 0.30) | −0.27 (−0.98, 0.44) | −0.38 (−1.04, 0.27) |
| Total fucosylated | −0.03 (−0.73, 0.67) | 0.11 (−0.60, 0.81) | 0.12 (−0.42, 0.65) | 0.32 (−0.22, 0.86) | −0.12 (−0.84, 0.60) | −0.12 (−0.85, 0.60) |
Linear mixed effects models were adjusted for intrafamilial correlation among multiple gestations and controlled for potential confounding by gestational age at birth, birth weight z-score, post-menstrual age at outcome measurement, infant sex, and maternal age. Beta estimates (95% confidence interval) indicate the z-score mean difference in outcome between the two indicated tertiles of HMO exposure. Individual, total sialylated, total fucosylated, and overall total HMOs were measured in µg/mL; HMO-bound sialic acid and fucose were measured in nmol/mL. Medians and interquartile ranges of HMO concentrations by tertiles are detailed in Supplemental Table S2. The bolded starred result represents a finding for which the 95% confidence interval does not include the null (p < 0.05).
Table 5.
Adjusted associations of maternal secretor status with infant body size and composition z-scores at term-equivalent age for primarily maternal-milk-fed very preterm infants.
Table 5.
Adjusted associations of maternal secretor status with infant body size and composition z-scores at term-equivalent age for primarily maternal-milk-fed very preterm infants.
| Outcome Z-Score | n | Beta Estimate (95% CI) |
|---|---|---|
| Weight | 82 | −0.14 (−0.64, 0.36) |
| Length | 73 | −0.06 (−0.46, 0.34) |
| Head Circumference | 74 | 0.13 (−0.31, 0.58) |
| Fat Mass | 65 | −0.14 (−0.81, 0.53) |
| Fat-Free Mass | 65 | −0.04 (−0.56, 0.48) |
| Body Fat Percentage | 65 | −0.11 (−0.81, 0.59) |
Beta estimates (95% confidence interval) indicate the z-score mean difference in outcome between infants born to secretor mothers compared to infants born to non-secretor mothers (reference). Linear mixed effects models were adjusted for intrafamilial correlation among multiple gestations and controlled for potential confounding by gestational age at birth, birth size z-score, post-menstrual age at outcome measurement, infant sex, and maternal age. Secretor status was determined during HMO analysis based on the presence of 2′FL.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Ong, M.L.; Cherkerzian, S.; Bell, K.A.; Berger, P.K.; Furst, A.; Sejane, K.; Bode, L.; Belfort, M.B. Human Milk Oligosaccharides, Growth, and Body Composition in Very Preterm Infants. Nutrients 2024, 16, 1200. https://doi.org/10.3390/nu16081200
AMA Style
Ong ML, Cherkerzian S, Bell KA, Berger PK, Furst A, Sejane K, Bode L, Belfort MB. Human Milk Oligosaccharides, Growth, and Body Composition in Very Preterm Infants. Nutrients. 2024; 16(8):1200. https://doi.org/10.3390/nu16081200
Chicago/Turabian StyleOng, Margaret L., Sara Cherkerzian, Katherine A. Bell, Paige K. Berger, Annalee Furst, Kristija Sejane, Lars Bode, and Mandy B. Belfort. 2024. "Human Milk Oligosaccharides, Growth, and Body Composition in Very Preterm Infants" Nutrients 16, no. 8: 1200. https://doi.org/10.3390/nu16081200
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
