Comparison study of the correlation between free and total 25(OH)D in maternal and umbilical blood and early-life physical development parameters
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Zhihong Tian
,
Xiaoyan Xu
und
Jian Li
Abstract
Objectives
To investigate the association between free and total 25(OH)D levels and fetal growth during pregnancy, and to evaluate whether free 25(OH)D is a better indicator of vitamin D status compared to total 25(OH)D.
Methods
A total of 160 pregnant women and their newborns were consecutively recruited from a Jiangsu hospital (March–May 2019). Maternal blood was collected before delivery, and cord blood was collected after umbilical cord disconnection. Serum free and total 25(OH)D were measured by ELISA. Clinical data, including pregnancy records, neonatal assessments, and 6-month follow-ups, were extracted from electronic medical records. Associations between vitamin D levels and developmental outcomes were analyzed using univariate correlation analysis and multivariable linear regression in SPSS 20.0 (p<0.05).
Results
Maternal-umbilical free 25(OH)D correlation was stronger than total (rho=0.699 vs. 0.475; both p<0.001). Maternal free 25(OH)D showed stronger associations with early pregnancy femur length (11.37 ± 3.39 mm; β=2.053), late pregnancy biparietal diameter (82.65 ± 4.60 mm; β=−0.273), and femur length growth efficiency (0.89 ± 0.15 mm/week; β=−0.289) than total 25(OH)D (all p<0.05). Umbilical free 25(OH)D correlated with mid-pregnancy transverse cerebellar diameter (22.0[21.0–23.0] mm; β=−0.231) and femur length growth efficiency (0.92[0.78–1.05] mm/week; β=−0.224) (p<0.05 and p<0.01). Maternal free 25(OH)D negatively associated with late pregnancy head circumference (330.11 ± 7.89 mm; β=−9.050, p<0.01).
Conclusions
Compared to total 25(OH)D, free 25(OH)D in maternal and umbilical blood may be more strongly associated with early-life physical growth parameters.
Funding source: Natural Science Foundation of Hunan Province
Award Identifier / Grant number: 2024JJ5286
Funding source: Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province
Award Identifier / Grant number: 202312652001
Funding source: Huxiang Youth Talent Support Program
Award Identifier / Grant number: 2021RC3094
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Research ethics: The Ethics Committee of Dafeng People’s Hospital in Yancheng, Jiangsu, China, approved this study (approval No: 2019-02).
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Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: This study was partially supported by research grants from Huxiang Young Talents project (NO. 2021RC3094), the Natural Science Foundation of Hunan Province (NO. 2024JJ5286), and Key Support Area Project of the National College Student Innovation and Entrepreneurship Training Program (NO. 202312652001).
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Data availability: The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.
References
1. Kulda, V. [Vitamin D metabolism]. Vnitrni Lek 2012;58:400–4.Suche in Google Scholar
2. Urena-Torres, P, Souberbielle, JC. Pharmacologic role of vitamin D natural products. Curr Vasc Pharmacol 2014;12:278–85. https://doi.org/10.2174/15701611113119990020.Suche in Google Scholar PubMed
3. DeLuca, HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 2004;80:1689s–96s. https://doi.org/10.1093/ajcn/80.6.1689s.Suche in Google Scholar
4. Khazai, N, Judd, SE, Tangpricha, V. Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep 2008;10:110–7. https://doi.org/10.1007/s11926-008-0020-y.Suche in Google Scholar PubMed PubMed Central
5. Yousefzadeh, P, Shapses, SA, Wang, X. Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions. Int J Endocrinol 2014;2014:981581. https://doi.org/10.1155/2014/981581.Suche in Google Scholar PubMed PubMed Central
6. Tsuprykov, O, Chen, X, Hocher, CF, Skoblo, R, Lianghong, Y, Hocher, B. Why should we measure free 25(OH) vitamin D? J Steroid Biochem Mol Biol 2018;180:87–104. https://doi.org/10.1016/j.jsbmb.2017.11.014.Suche in Google Scholar PubMed
7. Ryan, BA, Kovacs, CS. Maternal and fetal vitamin D and their roles in mineral homeostasis and fetal bone development. J Endocrinol Investig 2021;44:643–59. https://doi.org/10.1007/s40618-020-01387-2.Suche in Google Scholar PubMed
8. Fu, L, Chen, YH, Xu, S, Ji, YL, Zhang, C, Wang, H, et al.. Vitamin D deficiency impairs testicular development and spermatogenesis in mice. Reprod Toxicol 2017;73:241–9. https://doi.org/10.1016/j.reprotox.2017.06.047.Suche in Google Scholar PubMed
9. Bennour, I, Haroun, N, Sicard, F, Mounien, L, Landrier, JF. Recent insights into vitamin D, adipocyte, and adipose tissue biology. Obes Rev Off J Int Assoc Study Obes 2022;23:e13453. https://doi.org/10.1111/obr.13453.Suche in Google Scholar PubMed
10. Pérez-López, FR, Pasupuleti, V, Mezones-Holguin, E, Benites-Zapata, VA, Thota, P, Deshpande, A, et al.. Effect of vitamin D supplementation during pregnancy on maternal and neonatal outcomes: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2015;103:1278–88.e4. https://doi.org/10.1016/j.fertnstert.2015.02.019.Suche in Google Scholar PubMed
11. Gallo, S, McDermid, JM, Al-Nimr, RI, Hakeem, R, Moreschi, JM, Pari-Keener, M, et al.. Vitamin D supplementation during pregnancy: an evidence analysis center systematic review and meta-analysis. J Acad Nutr Diet 2020;120:898–924.e4. https://doi.org/10.1016/j.jand.2019.07.002.Suche in Google Scholar PubMed
12. Gray, TK, Lowe, W, Lester, GE. Vitamin D and pregnancy: the maternal-fetal metabolism of vitamin D. Endocr Rev 1981;2:264–74. https://doi.org/10.1210/edrv-2-3-264.Suche in Google Scholar PubMed
13. Lewis, S, Lucas, RM, Halliday, J, Ponsonby, AL. Vitamin D deficiency and pregnancy: from preconception to birth. Mol Nutr Food Res 2010;54:1092–102. https://doi.org/10.1002/mnfr.201000044.Suche in Google Scholar PubMed
14. Saraf, R, Morton, SM, Camargo, CAJr., Grant, CC. Global summary of maternal and newborn vitamin D status - a systematic review. Matern Child Nutr 2016;12:647–68. https://doi.org/10.1111/mcn.12210.Suche in Google Scholar PubMed PubMed Central
15. Tsuprykov, O, Buse, C, Skoblo, R, Hocher, B. Comparison of free and total 25-hydroxyvitamin D in normal human pregnancy. J Steroid Biochem Mol Biol 2019;190:29–36. https://doi.org/10.1016/j.jsbmb.2019.03.008.Suche in Google Scholar PubMed
16. Mendel, CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 1989;10:232–74. https://doi.org/10.1210/edrv-10-3-232.Suche in Google Scholar PubMed
17. Chun, RF, Peercy, BE, Orwoll, ES, Nielson, CM, Adams, JS, Hewison, M. Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol 2014;144 Pt A:132–7. https://doi.org/10.1016/j.jsbmb.2013.09.012.Suche in Google Scholar PubMed PubMed Central
18. Liu, M, Wang, J, He, Y. Serum 25-Hydroxyvitamin D were associated with higher risk of both albuminuria and impaired GFR incidence: a cohort study based on CLHLS study. BMC Nephrol 2019;20:20. https://doi.org/10.1186/s12882-019-1202-8.Suche in Google Scholar PubMed PubMed Central
19. Lopez-Molina, M, Santillan, C, Murillo, M, Valls, A, Bosch, L, Bel, J, et al.. Measured free 25-hydroxyvitamin D in healthy children and relationship to total 25-hydroxyvitamin D, calculated free 25-hydroxyvitamin D and vitamin D binding protein. Clin Biochem 2018;61:23–7. https://doi.org/10.1016/j.clinbiochem.2018.08.007.Suche in Google Scholar PubMed
20. Bikle, DD, Malmstroem, S, Schwartz, J. Current controversies: are free vitamin metabolite levels a more accurate assessment of vitamin D status than total levels? Endocrinol Metab Clin N Am 2017;46:901–18. https://doi.org/10.1016/j.ecl.2017.07.013.Suche in Google Scholar PubMed PubMed Central
21. Gopal-Kothandapani, JS, Evans, LF, Walsh, JS, Gossiel, F, Rigby, AS, Eastell, R, et al.. Effect of vitamin D supplementation on free and total vitamin D: a comparison of Asians and Caucasians. Clin Endocrinol 2019;90:222–31. https://doi.org/10.1111/cen.13825.Suche in Google Scholar PubMed
22. Holick, MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 2017;18:153–65. https://doi.org/10.1007/s11154-017-9424-1.Suche in Google Scholar PubMed
23. Holick, MF. Vitamin D deficiency. N. Engl J Med 2007;357:266–81. https://doi.org/10.1056/nejmra070553.Suche in Google Scholar
24. Yu, X, Wang, W, Wei, Z, Ouyang, F, Huang, L, Wang, X, et al.. Vitamin D status and related factors in newborns in Shanghai, China. Nutrients 2014;6:5600–10. https://doi.org/10.3390/nu6125600.Suche in Google Scholar PubMed PubMed Central
25. Courbebaisse, M, Souberbielle, JC, Baptiste, A, Taieb, J, Tsatsaris, V, Guibourdenche, J, et al.. Vitamin D status during pregnancy and in cord blood in a large prospective French cohort. Clin Nutr (Edinburgh, Scotland) 2019;38:2136–44. https://doi.org/10.1016/j.clnu.2018.08.035.Suche in Google Scholar PubMed
26. Zhao, W, Li, C, Shen, WZ, Li, KY, Cai, YX, Li, F, et al.. Cord blood vitamin A and vitamin D levels in relation to physical growth in exclusively breastfed infants aged 0–6 months. Front Endocrinol 2024;15:1394408. https://doi.org/10.3389/fendo.2024.1394408.Suche in Google Scholar PubMed PubMed Central
27. Treiber, M, Mujezinović, F, Pečovnik Balon, B, Gorenjak, M, Maver, U, Dovnik, A. Association between umbilical cord vitamin D levels and adverse neonatal outcomes. J Int Med Res 2020;48:300060520955001. https://doi.org/10.1177/0300060520955001.Suche in Google Scholar PubMed PubMed Central
28. Zhang, H, Wang, S, Tuo, L, Zhai, Q, Cui, J, Chen, D, et al.. Relationship between maternal vitamin D levels and adverse outcomes. Nutrients 2022;14. https://doi.org/10.3390/nu14204230.Suche in Google Scholar PubMed PubMed Central
29. Mansur, JL, Oliveri, B, Giacoia, E, Fusaro, D, Costanzo, PR. Vitamin D: before, during and after pregnancy: effect on neonates and children. Nutrients 2022;14. https://doi.org/10.3390/nu14091900.Suche in Google Scholar PubMed PubMed Central
30. Agarwal, S, Kovilam, O, Agrawal, DK. Vitamin D and its impact on maternal-fetal outcomes in pregnancy: a critical review. Crit Rev Food Sci Nutr 2018;58:755–69. https://doi.org/10.1080/10408398.2016.1220915.Suche in Google Scholar PubMed PubMed Central
31. Zheng, J, Liu, X, Zheng, B, Zheng, Z, Zhang, H, Zheng, J, et al.. Maternal 25-hydroxyvitamin D deficiency promoted metabolic syndrome and downregulated Nrf2/CBR1 pathway in offspring. Front Pharmacol 2020;11:97. https://doi.org/10.3389/fphar.2020.00097.Suche in Google Scholar PubMed PubMed Central
32. Moon, RJ, Cooke, LDF, D’Angelo, S, Curtis, EM, Titcombe, P, Davies, JH, et al.. Maternal and fetal genetic variation in vitamin D metabolism and umbilical cord blood 25-hydroxyvitamin D. J Clin Endocrinol Metab 2022;107:e3403–10. https://doi.org/10.1210/clinem/dgac263.Suche in Google Scholar PubMed PubMed Central
33. Tian, Y, Holzman, C, Siega-Riz, AM, Williams, MA, Dole, N, Enquobahrie, DA, et al.. Maternal serum 25-hydroxyvitamin D concentrations during pregnancy and infant birthweight for gestational age: a three-cohort study. Paediatr Perinat Epidemiol 2016;30:124–33. https://doi.org/10.1111/ppe.12262.Suche in Google Scholar PubMed PubMed Central
34. Fernando, M, Coster, TG, Ellery, SJ, Guingand, D, Lim, S, Harrison, CL, et al.. Relationships between total, free and bioavailable vitamin D and vitamin D binding protein in early pregnancy with neonatal outcomes: a retrospective cohort study. Nutrients 2020;12. https://doi.org/10.3390/nu12092495.Suche in Google Scholar PubMed PubMed Central
35. Knabl, J, Vattai, A, Ye, Y, Jueckstock, J, Hutter, S, Kainer, F, et al.. Role of placental VDR expression and function in common late pregnancy disorders. Int J Mol Sci 2017;18. https://doi.org/10.3390/ijms18112340.Suche in Google Scholar PubMed PubMed Central
36. Francis, EC, Hinkle, SN, Song, Y, Rawal, S, Donnelly, SR, Zhu, Y, et al.. Longitudinal maternal vitamin D status during pregnancy is associated with neonatal anthropometric measures. Nutrients 2018;10. https://doi.org/10.3390/nu10111631.Suche in Google Scholar PubMed PubMed Central
37. Clark, SA, Stumpf, WE, Sar, M. Effect of 1,25 dihydroxyvitamin D3 on insulin secretion. Diabetes 1981;30:382–6. https://doi.org/10.2337/diabetes.30.5.382.Suche in Google Scholar
38. Fowden, AL. The insulin-like growth factors and feto-placental growth. Placenta (Eastbourne) 2003;24:803–12. https://doi.org/10.1016/s0143-4004(03)00080-8.Suche in Google Scholar PubMed
39. Schwartz, JB, Lai, J, Lizaola, B, Kane, L, Weyland, P, Terrault, NA, et al.. Variability in free 25(OH) vitamin D levels in clinical populations. J Steroid Biochem Mol Biol 2014;144 Pt A:156–8. https://doi.org/10.1016/j.jsbmb.2013.11.006.Suche in Google Scholar PubMed PubMed Central
40. Bahrami, A, Sadeghnia, HR, Tabatabaeizadeh, SA, Bahrami-Taghanaki, H, Behboodi, N, Esmaeili, H, et al.. Genetic and epigenetic factors influencing vitamin D status. J Cell Physiol 2018;233:4033–43. https://doi.org/10.1002/jcp.26216.Suche in Google Scholar PubMed
41. Mithal, A, Wahl, DA, Bonjour, JP, Burckhardt, P, Dawson-Hughes, B, Eisman, JA, et al.. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2009;20:1807–20. https://doi.org/10.1007/s00198-009-1030-y.Suche in Google Scholar
42. Park, CY, Han, SN. Vitamin D and obesity. Adv Food Nutr Res 2024;109:221–47. https://doi.org/10.1016/bs.afnr.2023.12.006.Suche in Google Scholar PubMed
43. Cashman, KD, Dowling, KG, Škrabáková, Z, Gonzalez-Gross, M, Valtueña, J, De Henauw, S, et al.. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr 2016;103:1033–44. https://doi.org/10.3945/ajcn.115.120873.Suche in Google Scholar PubMed PubMed Central
44. Marwaha, RK, Tandon, N, Chopra, S, Agarwal, N, Garg, MK, Sharma, B, et al.. Vitamin D status in pregnant Indian women across trimesters and different seasons and its correlation with neonatal serum 25-hydroxyvitamin D levels. Br J Nutr 2011;106:1383–9. https://doi.org/10.1017/s000711451100170x.Suche in Google Scholar
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