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Pregnancy homocysteine and cobalamin status predict childhood metabolic health in the offspring

Pediatric Research (2022)Cite this article

Abstract

Background

Inadequate pregnancy cobalamin status has been associated with adverse offspring metabolic health in Indian and Nepalese studies. Studies of pregnancy cobalamin status and mid-childhood health outside of Asia are scarce.

Methods

Associations between pregnancy fasting plasma total homocysteine (tHcy), cobalamin status (plasma cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA)) and mid-childhood metabolic score (MetSco) ((including fat mass index (zFMI), homeostatic model assessment of insulin resistance (zHOMA-IR) and dyslipidemia (zTG − zHDLc)/2) z-scores)) were investigated in a prospective study of 293 mother–child dyads.

Results

Highest versus low–mid pregnancy tHcy tertile was associated with higher mid-childhood MetSco, specifically with higher child zFMI. Stratifying by sex, the maternal tHcy–child MetSco association was limited to boys and confirmed for zFMI and zHOMA-IR. The maternal tHcy-child zFMI association was not mediated by birth weight z-score. First trimester plasma cobalamin was not associated with child outcomes, but other indicators of cobalamin status were. Lowest versus mid–high plasma holoTC tertile was associated with MetSco (specifically zFMI and zHOMA-IR) and highest versus low–mid plasma MMA tertile with higher MetSco and dyslipidemia in boys.

Conclusions

Moderately elevated pregnancy tHcy and low cobalamin status were associated with mid-childhood metabolic score in boys. The pregnancy tHcy–child zFMI association was not mediated by birth weight.

Impact

  • Fasting plasma total homocysteine (tHcy) during pregnancy and low cobalamin status during early pregnancy are associated with mid-childhood metabolic score and its components in the offspring. These findings were only significant in male offspring.

  • The study provides new evidence that impaired one carbon metabolism during pregnancy is associated with negative health outcomes in the offspring, in a population with low prevalence of cobalamin deficiency.

  • The maternal–offspring associations were observed in the functional markers of cobalamin status (holotranscobalamin and methylmalonic acid) and tHcy, not with plasma cobalamin concentration.

  • Screening for low pregnancy cobalamin status should be considered.

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Fig. 1: Participant recruitment and follow-up.
Fig. 2: Mediation analysis34: association between first trimester tHcy–child z-fat mass index via birth weight z-score.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available because participant consent covers data exploration in response to hypothesis testing within a defined field and with the compromise that this will be vetted by the Principal Investigator (M.M.M.). The corresponding author (M.M.M.) is willing to provide the data to interested parties on reasonable request and agreement that it will be exploited under the terms of participant consent and following further approval by the Ethics Committees if required.

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Acknowledgements

We thank the families who participated in the study and the University, Clinical, Laboratory, and Biobank teams involved in the field work of the study.

Funding

This work was supported by grants from The Interministerial Science and Technology Committee (ALI 89-0388 and SAF2005-05096); The Carlos III Health Institute, National Scientific Research, Development and Technological Innovation Program Health Investigation Resources, cofinanced by The European Regional Development Fund (10/00335, 13/02500, 16/00506, 19/00844); The European Union Horizon 2020 Research and Innovation program (EPIBRAIN project, funded by the Joint Programming Initiative “A Healthy Diet for a Healthy Life” (ERA HDHL); JFA2 Nutrition and the Epigenome, Horizon2020 grant agreement number 696300, with funding provided by The Spanish State Agency for Investigation PCI2018-093098/AEI); Pere Virgili Health Research Institute (IISPV-2010/21); Biomedical Research Networking Center for the Pathophysiology of Obesity (CIBERobn); Agency for Management of University and Research grants, Generalitat de Catalunya (Support to Research Groups: 2009-1237, 2014-332); Italfarmaco S.A., Spain; predoctoral research fellowship from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie and from the Universitat Rovira i Virgili (URV) (713679 [to A.R.-G.]) and the URV Martí-Franques program [to P.S.-N., G.O.-M., C.R.-R.]. The funders played no role of any sort in the design and execution of the study or the reporting and interpretation of the results.

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Author notes

  1. Pol Solé-Navais

    Present address: Department of Obstetrics and Gynaecology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden

Authors and Affiliations

  1. Unit of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, IISPV, Universitat Rovira i Virgili, Reus, Spain

    Alejandra Rojas-Gómez, Pol Solé-Navais, Gemma Ornosa-Martin, Carla Ramos-Rodriguez, Joan Fernandez-Ballart & Michelle M. Murphy

  2. Area of Obstetrics and Gynecology, Hospital Universitari Sant Joan de Reus, IISPV, Reus, Spain

    Pere Cavallé-Busquets & Carme Grifoll

  3. CIBERObn (Instituto de Salud Carlos III), Madrid, Spain

    Pere Cavallé-Busquets, Joan Fernandez-Ballart & Michelle M. Murphy

  4. URL Unitat de Medicina Vascular i Metabolisme, Unitat de Recerca en Lipids i Arteriosclerosis, Hospital Universitari Sant Joan de Reus, IISPV, CIBERDEM, Universitat Rovira i Virgili, Reus, Spain

    Luis Masana

  5. Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain

    Mónica Ballesteros

  6. Bevital A/S, 5021, Bergen, Norway

    Per Magne Ueland

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Contributions

A.R.-G. and M.M.M. conceptualized and designed the study, the data collection instruments, collected data, analyzed data, drafted the initial manuscript, and reviewed and revised the manuscript. J.F.-B., P.C.-B., P.S.-N., G.O.-M., M.B., C.G., and C.R.-R. participated in the conceptualization and design of the study, designed the data collection instruments, collected data, and reviewed and revised the manuscript. P.M.U. and L.M. participated in the conceptualization and design of the study and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

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Correspondence to Michelle M. Murphy.

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Rojas-Gómez, A., Solé-Navais, P., Cavallé-Busquets, P. et al. Pregnancy homocysteine and cobalamin status predict childhood metabolic health in the offspring. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02117-5

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