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. 2024 Dec 2;7(12):e2450467.
doi: 10.1001/jamanetworkopen.2024.50467.

Gestational Diabetes, the Human Milk Metabolome, and Infant Growth and Adiposity

Emily M Nagel  1   2 , Armando Peña  3 , Jonathan M Dreyfuss  4 , Eric F Lock  5 , Kelsey E Johnson  6 , Chang Lu  4   7 , David A Fields  8 , Ellen W Demerath  1 , Elvira Isganaitis  4
Affiliations

Gestational Diabetes, the Human Milk Metabolome, and Infant Growth and Adiposity

Emily M Nagel et al. JAMA Netw Open. .

Erratum in

  • Error in Funding.
    [No authors listed] [No authors listed] JAMA Netw Open. 2025 Jan 2;8(1):e2459711. doi: 10.1001/jamanetworkopen.2024.59711. JAMA Netw Open. 2025. PMID: 39792392 Free PMC article. No abstract available.

Abstract

Importance: Gestational diabetes (GD) is linked to health risks for the birthing parent and infant. The outcomes of GD on human milk composition are mostly unknown.

Objective: To determine associations between GD, the human milk metabolome, and infant growth and body composition.

Design, setting, and participants: Cohort study using data from the Mothers and Infants Linked for Healthy Growth and the Maternal Milk, Metabolism, and the Microbiome studies at the University of Oklahoma and University of Minnesota, large prospective US cohorts with a high proportion of exclusive breastfeeding. Participants were mother-infant dyads recruited between October 2014 and August 2019 who planned to exclusively breastfeed for 3 or more months. Data were analyzed from July 2022 to August 2024.

Exposure: GD diagnosed via oral glucose tolerance test.

Main outcomes and measures: The milk metabolome was assessed by untargeted liquid chromatography-gas chromatography-mass spectrometry at 1 month post partum. Infant growth (weight for length z score, length for age z score, and rapid weight gain) and body composition (percentage body fat and fat-free mass index) from 0 to 6 months were assessed. Linear regression analyses tested associations between GD and milk metabolites, with adjustment for covariates and potential confounders.

Results: Among 348 dyads (53 with GD), 27 (51%) of the GD-exposed infants were female and 157 (53%) of nonexposed infants were male; 10 (19%) were Asian, 2 (4%) were Black or African American, and 37 (70%) were White. The mean (SD) age was higher in the GD group (with GD, 34.0 [4.3] years; without GD, 30.7 [4.1] years). In adjusted models, GD was associated with differential levels of 9 metabolites of 458 tested (FDR<0.05); 3 were higher (2-hydroxybutyric acid, 3-methylphenylacetic acid, and pregnanolone sulfate) and 6 were lower in women with GD (4-cresyl sulfate, cresol, glycine, P-cresol sulfate, phenylacetic acid, and stearoylcarnitine). Phenylacetic acid was associated with length for age z score (β = 0.27; SE, 0.13; 95% CI, 0.02 to 0.16), 2-hydroxybutryic acid with percentage body fat (β = -1.50; SE, 0.66; 95% CI, -2.79 to -4.82), and stearoylcarnitine with greater odds of rapid weight gain (odds ratio, 1.66; 95% CI, 1.23 to 2.25). GD was associated with greater length for age z scores (β = 0.48; SE, 0.22; 95% CI, 0.04 to 0.91).

Conclusions and relevance: In this observational cohort study, GD was associated with altered concentrations of several human milk metabolites. The associations between these metabolites and infant growth suggest that milk compositional differences in mothers with GD may beneficially moderate the growth and body composition of their infants.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fields reported receiving grants from the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr Demerath reported receiving grants from University of Minnesota during the conduct of the study. Dr Isganaitis reported receiving grants from National Institute of Diabetes and Digestive and Kidney Diseases and grants from NICHD during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Metabolomic Analysis of Human Milk According to Gestational Diabetes Status
Metabolomics data summary of A, the principal component (PC) analysis plot of milk metabolites by nongestational diabetes (GD) (0) and GD (1) status; B, partial least-squares discriminant analysis (PLS-DA) plot of milk metabolites by non-GD (0) and GD (1) status; and C, volcano plot of metabolites significantly associated with GD vs non-GD status with the horizontal line across the plot indicating the FDR-corrected P < 0.05 cutoff for statistical significance and the top 3 metabolites labeled. Orange circles represent GD group and blue circles represent non-GD. All figures created in MetaboAnalyst. FC indicates fold change.
Figure 2.
Figure 2.. Association of Gestational Diabetes (GD)–Related Metabolites With Infant Growth and Body Composition
Nine milk metabolites were significantly associated with maternal GD in covariate-adjusted models (FDR-corrected P < 0.05). The color of each cell represents the β coefficients in linear regression models. The first column is the association of each milk metabolite with maternal GD. Subsequent columns are β coefficients of association of each milk metabolite with infant body composition measures in unadjusted and adjusted models. Only significant associations (P < .05) are shown. Figure created in Morpheus (Broad Institute). %BF indicates percentage body fat; FFMI, fat-free mass index; LAZ, length for age z score; WLZ, weight for length z score.
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