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Maternal vitamin D levels and male reproductive health: a population-based follow-up study

  • REPRODUCTIVE EPIDEMIOLOGY
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Abstract

Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI − 19 to − 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI − 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.

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Data availability

The dataset analysed in the study is not publicly available due to national data security legislation on sensitive personal data. Researchers may apply for access to data from the DNBC. Please see https://www.dnbc.dk/data-available or write to dnbc-research@ssi.dk for additional information.

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Acknowledgements

This publication is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V ÖKS (20200407). The FEPOS project was also funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Region Skåne, and the Medical Faculty at Lund University, Sweden, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt’s Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation and Dagmar Marshall’s Fond. In addition, this study was supported by Aarhus University and Independent Research Fund Denmark (9039-00128B). We are grateful to all participants and to biomedical laboratory technicians Marianne Lipka Flensborg and Joan Dideriksen for running the clinics and collecting data. We also thank Josefine Rahbæk Larsen for assisting with recruitment and data entry, Lone Fredslund and Inge Eisensee for data management, Cecilia Tingsmark for conducting the morphology analysis, and Anna Rönnholm, Marie Bengtsson, and Åsa Amilon at the Division of Occupational and Environmental Medicine at Lund University, Sweden, for performing the analyses of 25(OH)D3. The Danish National Birth Cohort (DNBC) was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B), the Lundbeck Foundation (195/04, R100-A9193), The Innovation Fund Denmark 0603-00294B (09-067124), the Nordea Foundation (02-2013-2014), Aarhus Ideas (AU R9-A959-13-S804), University of Copenhagen Strategic Grant (IFSV 2012), and the Danish Council for Independent Research (DFF – 4183-00594 and DFF—4183-00152).

Funding

This publication is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V ÖKS (20200407). The FEPOS project was further funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Region Skåne, and the Medical Faculty at Lund University, Sweden, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis’s Grant, Axel Muusfeldt’s Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation and Dagmar Marshall’s Fond. In addition, this study was supported by Aarhus University and Independent Research Fund Denmark (9039-00128B).

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Authors and Affiliations

  1. Department of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, 8000, Aarhus C, Denmark

    Anne Gaml-Sørensen, Nis Brix, Birgit Bjerre Høyer, Andreas Ernst, Linn Håkonsen Arendt, Pernille Jul Clemmensen, Onyebuchi A. Arah & Cecilia Høst Ramlau-Hansen

  2. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Anne Gaml-Sørensen, Onyebuchi A. Arah & Cecilia Høst Ramlau-Hansen

  3. Department of Clinical Genetics, Aarhus University Hospital, 8200, Aarhus N, Denmark

    Nis Brix

  4. Department of Occupational and Environmental Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, 2400, Copenhagen NV, Denmark

    Katia Keglberg Hærvig, Sandra Søgaard Tøttenborg & Jens Peter Ellekilde Bonde

  5. Division of Occupational and Environmental Medicine, Lund University, 22363, Lund, Sweden

    Christian Lindh

  6. Department of Public Health, University of Copenhagen, 1014, Copenhagen K, Denmark

    Sandra Søgaard Tøttenborg, Karin Sørig Hougaard & Jens Peter Ellekilde Bonde

  7. National Research Centre for the Working Environment, 2100, Copenhagen Ø, Denmark

    Karin Sørig Hougaard

  8. Department of Regional Development, Region of Southern Denmark, 7100, Vejle, Denmark

    Birgit Bjerre Høyer

  9. Department of Urology, Aarhus University Hospital, 8200, Aarhus N, Denmark

    Andreas Ernst

  10. Department of Obstetrics and Gynaecology, Aarhus University Hospital, 8200, Aarhus N, Denmark

    Linn Håkonsen Arendt

  11. Perinatal Epidemiology Research Unit, Aarhus University, Aarhus C, Denmark

    Tine Brink Henriksen

  12. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark

    Tine Brink Henriksen

  13. Steno Diabetes Center Aarhus, Aarhus University Hospital, 8200, Aarhus N, Denmark

    Gunnar Toft

  14. Department of Statistics, Division of Physical Sciences, UCLA College, Los Angeles, CA, 90024, USA

    Onyebuchi A. Arah

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  1. Anne Gaml-Sørensen
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  2. Nis Brix
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Contributions

BBH and CHR-H planned and acquired the funding for this specific study, and CL acquired the data on vitamin D levels. AG-S performed data management in close collaboration with KKH. The analysis strategy was designed by AG-S, who also performed the statistical analyses, and wrote the first draft in close collaboration with NB, GT, TBH, and CHR-H. The instrumental variable analysis was supervised by OAA. The funding for FEPOS was acquired by SST and JPEB. Data collection in FEPOS was planned and headed by GT, BBH, SST, KKH, KSH, JPEB and CHR-H. All authors interpreted the data, revised the manuscript critically, approved and accepted responsibility of the final manuscript.

Corresponding author

Correspondence to Anne Gaml-Sørensen.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The Committee for Biomedical Research Ethics in Denmark approved data collection in the DNBC ((KF) 01-471/94). The establishment of the FEPOS cohort was approved by the Scientific Research Ethics Committee for Copenhagen and Frederiksberg (No. H-16015857) and the Knowledge Centre on Data Protection Compliance under the records of processing regarding health science research projects within the Capitol Region of Denmark (P-2019-503). This specific study was approved by the Danish Data Protection Agency (2015-57-0002, rec no 231) and the Steering Committee of the DNBC (Ref. No. 2020-27). Written informed consent was provided by all participants at enrolment. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

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Gaml-Sørensen, A., Brix, N., Hærvig, K.K. et al. Maternal vitamin D levels and male reproductive health: a population-based follow-up study. Eur J Epidemiol 38, 469–484 (2023). https://doi.org/10.1007/s10654-023-00987-5

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