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The newborn metabolome: associations with gestational diabetes, sex, gestation, birth mode, and birth weight

Abstract

Background

Pathways towards many adult-onset conditions begin early in life, even in utero. Maternal health in pregnancy influences this process, but little is known how it affects neonatal metabolism. We investigated associations between pregnancy and birth factors and cord blood metabolomic profile in a large, population-derived cohort.

Methods

Metabolites were measured using nuclear magnetic resonance in maternal (28 weeks gestation) and cord serum from 912 mother–child pairs in the Barwon Infant Study pre-birth cohort. Associations between maternal (metabolites, age, BMI, smoking), pregnancy (pre-eclampsia, gestational diabetes (GDM)), and birth characteristics (delivery mode, gestational age, weight, infant sex) with 72 cord blood metabolites were examined by linear regression.

Results

Delivery mode, sex, gestational age, and birth weight were associated with specific metabolite levels in cord blood, including amino acids, fatty acids, and cholesterols. GDM was associated with higher cord blood levels of acetoacetate and 3-hydroxybutyrate.

Conclusions

Neonatal factors, particularly delivery mode, were associated with many cord blood metabolite differences, including those implicated in later risk of cardiometabolic disease. Associations between GDM and higher offspring ketone levels at birth are consistent with maternal ketosis in diabetic pregnancies. Further work is needed to determine whether these neonatal metabolome differences associate with later health outcomes.

Impact

  • Variations in blood metabolomic profile have been linked to health status in adults and children, but corresponding data in neonates are scarce.

  • We report evidence that pregnancy complications, mode of delivery, and offspring characteristics, including sex, are independently associated with a range of circulating metabolites at birth, including ketone bodies, amino acids, cholesterols, and inflammatory markers.

  • Independent of birth weight, exposure to gestational diabetes is associated with higher cord blood ketone bodies and citrate.

  • These findings suggest that pregnancy complications, mode of delivery, gestational age, and measures of growth influence metabolic pathways prior to birth, potentially impacting later health and development.

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Fig. 1: Sex and cord blood serum NMR metabolomic profiles.
Fig. 2: Birth weight z-score and cord blood serum NMR metabolomic profiles.
Fig. 3: Gestational age and cord blood serum NMR metabolomic profiles.
Fig. 4: Mode of delivery and cord blood serum NMR metabolomic profiles.
Fig. 5: Binary maternal measures and cord blood serum NMR metabolomic profiles.

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Acknowledgements

We thank the BIS participants for the generous contribution they have made to this project. We also thank current and past staff for their efforts in recruiting and maintaining the cohort and in obtaining and processing the data and biospecimens.

Funding

The establishment work and infrastructure for the BIS was provided by the Murdoch Children’s Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the National Health and Medical Research Council of Australia, The Jack Brockhoff Foundation, the Scobie Trust, the Shane O’Brien Memorial Asthma Foundation, the Our Women’s Our Children’s Fund Raising Committee Barwon Health, The Shepherd Foundation, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, GMHBA Limited, the Percy Baxter Charitable Trust, and Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. Research at Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships (1008396 to A.-L.P.; 1064629 to D.B.; 1045161 to R.S.) and NHMRC Investigator Grants to A.-L.P. (1110200) and D.B. (1175744). Funders did not participate in the work or writing of this manuscript.

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T.M., D.B., F.C., and R.S. conceptualised and developed this study. T.M. undertook all aspects of data analysis. F.C. managed collection of samples and coordinated sample shipping and measurement collation and quality control. T.M., D.B., and R.S. drafted the manuscript. All authors provided critical expert advice and critical review of the manuscript and approved the final version.

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Correspondence to Richard Saffery.

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Mansell, T., Vlahos, A., Collier, F. et al. The newborn metabolome: associations with gestational diabetes, sex, gestation, birth mode, and birth weight. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01672-7

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