Effects of maternal vitamin D supplementation during pregnancy and lactation on immune development in offspring: A systematic review

Kurnia  Maidarmi Handayani; Ghaniyyatul  Khudri; Laura  Zeffira; Widia  Sari

Authors

Kurnia Maidarmi Handayani Faculty of Medicine, Universitas Baiturrahmah, Padang, Indonesia
Ghaniyyatul Khudri Faculty of Medicine, Universitas Baiturrahmah, Padang, Indonesia
Laura Zeffira Faculty of Medicine, Universitas Baiturrahmah, Padang, Indonesia
Widia Sari Faculty of Medicine, Universitas Baiturrahmah, Padang, Indonesia

Keywords:

Immune system, lactation, pregnancy, rodents, vitamin D

Abstract

Background: Vitamin D, a fat-soluble prohormone, is essential for skeletal health and plays a key role in immune regulation. Deficiency is common among pregnant and lactating women, raising concerns that fetal and neonatal vitamin D status depends largely on maternal stores. Insufficiency during these periods has been associated with adverse birth outcomes and immune-mediated disorders.

Objective: To examine the effects of maternal vitamin D supplementation during pregnancy and/or lactation on offspring immune development.

Methods: This study followed PRISMA guidelines and was registered with PROSPERO (No. CRD420251117397). Experimental studies published in English between August 2015 and 2025 were eligible. Reviews, in vitro examinations, without full text or prenatal vitamin D exposure, and did not assess immunerelated offspring outcomes, or included offspring, were excluded. PubMed, ScienceDirect, and EBSCOhost were searched, most recently on August 10, 2025. Risk of bias was assessed with the SYRCLE tool, and findings were synthesized narratively. This study was funded by the KNB Scholarship, Ministry of Higher Education, Science, and Technology, the Republic of Indonesia (https://knb.kemdiktisaintek.go.id/).

Results: Finally, four studies were included, and evidence was limited to a small number of heterogeneous rodent studies. Maternal vitamin D supplementation enhanced T helper (Th) 1 responses and regulatory T-cell function; suppressed Th2 and Th17 subsets; reduced interleukin (IL)-6, IL-17, and IL-23; and elevated IL-10 and transforming growth factor-beta expression. It also elevated vitamin D receptor and forkhead box P3 levels and interferon-gamma promoter methylation, suggesting epigenetic reprogramming.

Conclusion: Maternal vitamin D may influence early-life immune programming and improve offspring immune resilience. Human studies with standardized protocols and long-term follow-up are needed.

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References

Chien MC, Huang CY, Wang JH, Shih CL, Wu P. Effects of vitamin D in pregnancy on maternal and offspring health-related outcomes: An umbrella review of systematic review and meta-analyses. Nutr Diabetes 2024;14:35.

https://doi.org/10.1038/s41387-024-00296-0

Ueda K, Chin SS, Sato N, Nishikawa M, Yasuda K, Miyasaka N, et al. Prenatal vitamin D deficiency exposure leads to long-term changes in immune cell proportions. Sci Rep 2024;14:19899.

https://doi.org/10.1038/s41598-024-70911-8

Cyprian F, Lefkou E, Varoudi K, Girardi G. Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond. Front Immunol 2019;10:2739.

https://doi.org/10.3389/fimmu.2019.02739

Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O'Connor GT, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years. JAMA 2016;315:362-70.

https://doi.org/10.1001/jama.2015.18589

Wolsk HM, Chawes BL, Litonjua AA, Hollis BW, Waage J, Stokholm J, et al. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. PLoS One 2017;12:e0186657.

https://doi.org/10.1371/journal.pone.0186657

Durá-Travé T, Gallinas-Victoriano F. Pregnancy, breastfeeding, and vitamin D. Int J Mol Sci 2023;24:11881.

https://doi.org/10.3390/ijms241511881

Zhu B, Yang J, Fan R, Song H, Zhong L, Zeng T, et al. Maternal vitamin D regulates the metabolic rearrangement of offspring CD4+ T cells in response to intestinal inflammation. Cell Rep 2025;44:115857.

https://doi.org/10.1016/j.celrep.2025.115857

Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res 2014;14:579.

https://doi.org/10.1186/s12913-014-0579-0

Jiao X, Wang L, Wei Z, Liu B, Liu X, Yu X. Vitamin D deficiency during pregnancy affects the function of Th1/Th2 cells and methylation of IFN-γ gene in offspring rats. Immunol Lett 2019;212:98-105.

https://doi.org/10.1016/j.imlet.2019.06.012

Wang G, Li Y, Li Y, Zhang J, Zhou C, Wu C, et al. Maternal vitamin D supplementation inhibits bisphenol A-induced proliferation of Th17 cells in adult offspring. Food Chem Toxicol 2020;144:111604.

https://doi.org/10.1016/j.fct.2020.111604

Zhang L, Ni H, Zhou Z, Yuan X, Xia J, Jiang B, et al. 1α,25-dihydroxyvitamin D3 supplementation during pregnancy Is associated with allergic rhinitis in the offspring by modulating immunity. J Immunol Res 2021;2021:6638119.

https://doi.org/10.1155/2021/6638119

Zhang Q, Zhao J, Ni M, Shen Q, Zhou W, Liu Z. Vitamin D3 reverses the transcriptional profile of offspring CD4+ T lymphocytes exposed to intrauterine inflammation. J Steroid Biochem Mol Biol 2022;221:106120.

https://doi.org/10.1016/j.jsbmb.2022.106120

Chen WJ, Hou XJ, Yang SF, Yin XH, Ren L. Effect of vitamin D supplementation during pregnancy on the Th1/Th2 cell balance of rat offspring. Pharmazie 2014;69:385-90.

https://doi.org/10.31083/ph.2014.3619

Maidarmi Handayani K, Sari W, Khudri G, Dhuha A, Malik R, Susanti M, et al. Dose-dependent effects of maternal vitamin D₃ on offspring IL-6 and IL-1β in a rat model. Turk J Immunol 2025;13:158-68.

https://doi.org/10.36519/TJI.2025.761

Shimizu M, Kato T, Adachi Y, Wada T, Murakami S, Ito Y, et al. Maternal dietary vitamin D intake during pregnancy is associated with allergic disease symptoms in children at 3 years old: the Japan environment and children's study. Int Arch Allergy Immunol 2023;184:1106-15.

https://doi.org/10.1159/000531970

Briceno Noriega D, Savelkoul HFJ. Vitamin D and allergy susceptibility during gestation and early life. Nutrients 2021;13:1015.

https://doi.org/10.3390/nu13031015

Daryabor G, Gholijani N, Kahmini FR. A review of the critical role of vitamin D axis on the immune system. Exp Mol Pathol 2023;132-3:104866.

https://doi.org/10.1016/j.yexmp.2023.104866

Bivona G, Agnello L, Ciaccio M. The immunological implication of the new vitamin D metabolism. Cent Eur J Immunol 2018;43:331-4.

https://doi.org/10.5114/ceji.2018.80053

Moore JR, Hubler SL, Nelson CD, Nashold FE, Spanier JA, Hayes CE. 1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease. J Neuroimmunol 2018;324:100-14.

https://doi.org/10.1016/j.jneuroim.2018.09.008

Palmer MT, Lee YK, Maynard CL, Oliver JR, Bikle DD, Jetten AM, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D3 on the development of effector CD4 T cells. J Biol Chem 2011;286:997-1004.

https://doi.org/10.1074/jbc.M110.163790

Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem 2010;285:38751-5.

https://doi.org/10.1074/jbc.C110.185777

Tamblyn JA, Hewison M, Wagner CL, Bulmer JN, Kilby MD. Immunological role of vitamin D at the maternal-fetal interface. J Endocrinol 2015;224:R107-21.

https://doi.org/10.1530/JOE-14-0642

Shahbazi M, Jeddi-Tehrani M, Zareie M, Salek-Moghaddam A, Akhondi MM, Bahmanpoor M, et al. Expression profiling of vitamin D receptor in placenta, decidua and ovary of pregnant mice. Placenta 2011;32:657-64.

https://doi.org/10.1016/j.placenta.2011.06.013

Ma R, Gu Y, Zhao S, Sun J, Groome LJ, Wang Y. Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies. Am J Physiol Endocrinol Metab 2012;303:E928-35.

https://doi.org/10.1152/ajpendo.00279.2012

Li Q, Xu X, Liu Y, Yin S, Hu Q, Ji Q, et al. The effects of prenatal vitamin D supplementation on respiratory and allergy-related outcomes in children: A systematic review and meta-analysis of randomized controlled trials. World Allergy Organ J 2025;18:101075.

https://doi.org/10.1016/j.waojou.2025.101075

Huang F, Ju Y, Wang H, Li Y. Maternal vitamin D deficiency impairs Treg and Breg responses in offspring mice and deteriorates allergic airway inflammation. Allergy Asthma Clin Immunol 2020;16:89.

https://doi.org/10.1186/s13223-020-00487-1

Mailhot G, White JH. Vitamin D and immunity in infants and children. Nutrients 2020;12:1233.

https://doi.org/10.3390/nu12051233

Woon F, Chin Y, Ismail I, Abdul Latiff A, Batterham M, Chan Y. Maternal vitamin D levels during late pregnancy and risk of allergic diseases and sensitization during the first year of life-a birth cohort study. Nutrients 2020;12:2418.

https://doi.org/10.3390/nu12082418

Wei Z, Zhang J, Yu X. Maternal vitamin D status and childhood asthma, wheeze, and eczema: A systematic review and meta‐analysis. Pediatr Allergy Immunol 2016;27:612-9.

https://doi.org/10.1111/pai.12593

El-Heis S, D'Angelo S, Curtis EM, Healy E, Moon RJ, Crozier SR, et al. Maternal antenatal vitamin D supplementation and offspring risk of atopic eczema in the first 4 years of life: evidence from a randomized controlled trial. Br J Dermatol 2022;187:659-6.

https://doi.org/10.1111/bjd.21721

Zhang Q, Yang D, Shen Q, Li W, Li R, Tang Y, et al. Correlation of maternal vitamin D status in early pregnancy and vitamin D supplementation during pregnancy with atopic dermatitis in infants: a prospective birth cohort study. Nutrients 2024;16:2168.

https://doi.org/10.3390/nu16132168

Wierzejska RE, Szymusik I, Bomba-Opoń D, Rzucidło-Szymańska I, Wojda B, Biskupski-Brawura-Samaha R. Vitamin D concentration in the blood of women with twin pregnancies and in the umbilical cord blood of newborns in relation to environmental factors. Front Nutr 2024;11:1433203.

https://doi.org/10.3389/fnut.2024.1433203