{"id":4543,"date":"2026-10-30T12:35:48","date_gmt":"2026-10-30T12:35:48","guid":{"rendered":"https:\/\/hjog.org\/?p=4543"},"modified":"2026-10-30T15:33:30","modified_gmt":"2026-10-30T15:33:30","slug":"_research-article-12-2-19-2-52-2","status":"publish","type":"post","link":"https:\/\/hjog.org\/?p=4543","title":{"rendered":"Vitamin D and Pregnancy Loss: Biological Plausibility, Clinical Evidence and Current Controversies"},"content":{"rendered":"

Review<\/span><\/p>\n

HJOG 2026, 25 (4), 335-345 | doi: 10.33574\/hjog.0640<\/p>\n

Dimitra Papakosta, Nikolaos Roussos, Tilemachos Karalis, Panagiotis Tsavalos, Grigorios F. Grimbizis, Angelos Daniilidis<\/p>\n

1st Department of Obstetrics & Gynecology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece<\/p>\n

Correspondence:\u00a0<\/em>Nikolaos Roussos, 1st Department of Obstetrics & Gynecology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, 56403 Thessaloniki, Greece. E-mail: nikosroussos1992@hotmail.com<\/a><\/p>\n

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Abstract<\/strong><\/h5>\n

Introduction:<\/strong> Vitamin D, beyond its classical role in calcium homeostasis and bone metabolism, exerts immunomodulatory and paracrine effects in reproductive tissues. Emerging evidence suggests a potential link between maternal vitamin D deficiency and miscarriage, particularly recurrent pregnancy loss (RPL). This review critically evaluates the biological plausibility and clinical evidence underlying this association.<\/p>\n

Material and Methods:<\/strong> A structured literature search was performed in PubMed\/MEDLINE, Embase, and Cochrane Library up to March 2026 using terms related to vitamin D and miscarriage. Eligible studies included human observational studies, interventional trials, and Mendelian randomization (MR) analyses assessing maternal 25-hydroxyvitamin D (25(OH)D) levels or supplementation in relation to miscarriage or RPL. Data extracted encompassed study design, population, vitamin D assessment, intervention, and pregnancy outcomes. Ten primary studies were included in the review, along with relevant meta-analyses and systematic reviews.<\/p>\n

Results:<\/strong> Observational studies consistently report that low maternal 25(OH)D levels are associated with an increased risk of first-trimester miscarriage and RPL. Meta-analyses and umbrella reviews confirm these associations but highlight significant heterogeneity. MR studies do not support a direct causal effect of low vitamin D on miscarriage risk, suggesting that deficiency may be a marker of other risk factors (38). Interventional trials in high-risk women demonstrate that vitamin D supplementation improves immunologic profiles (Treg\/Th17 balance, IL-23, IFN-\u03b3) and may reduce miscarriage rates. Mechanistic studies reveal that vitamin D influences trophoblast function, endometrial receptivity, and maternal immune tolerance via the VDR\/CYP27B1 pathway and HOXA10 expression.<\/p>\n

Conclusions:<\/strong> Vitamin D deficiency is prevalent among women experiencing miscarriage, particularly in early pregnancy and RPL. Evidence supports a biologically plausible immunomodulatory mechanism. While supplementation shows potential benefit in high-risk populations, routine vitamin D supplementation for miscarriage prevention cannot yet be universally recommended. Future large-scale, well-powered clinical trials are warranted to define optimal dosing, timing, and target populations.<\/p>\n

Keywords:<\/strong> Vitamin D, Pregnancy, Recurrent Pregnancy Loss, Miscarriage.<\/p>\n

Introduction<\/strong><\/h5>\n

Vitamin D is a fat-soluble secosteroid traditionally recognized for its role in calcium and phosphorus homeostasis, and bone metabolism (1,2). Endogenously, vitamin D is synthesized in the skin under ultraviolet B (UVB) radiation, while dietary intake and supplements provide an exogenous source. After hepatic conversion to 25-hydroxyvitamin D [25(OH)D], the main circulating form, it is hydroxylated in the kidneys to the biologically active 1,25-dihydroxyvitamin D [1,25(OH)\u2082D], which binds to vitamin D receptors (VDRs) expressed in multiple tissues, including ovarian and endometrial cells (1,3).<\/p>\n

Vitamin D influences female reproductive function by regulating ovarian steroidogenesis, endometrial receptivity, and local immune tolerance, processes critical for successful implantation and early pregnancy maintenance (3\u20135). Miscarriage, defined as spontaneous pregnancy loss before fetal viability, affects 10\u201315% of recognized pregnancies globally, with most losses occurring in the first trimester. Recurrent pregnancy loss (RPL), generally defined as two or more consecutive miscarriages, affects a subset of women and carries significant physical and psychological burdens (6-8).<\/p>\n

Observational studies suggest that low maternal 25(OH)D levels are associated with increased miscarriage risk, particularly in early pregnancy and among women with RPL (9-11). However, evidence remains heterogeneous, with Mendelian randomization studies indicating that low vitamin D may be a marker rather than a causal factor, reflecting confounding variables such as maternal BMI, lifestyle, and supplement use (12). Mechanistic evidence supports a biologically plausible role of vitamin D in early pregnancy via modulation of trophoblast invasion, spiral artery remodeling, and local immunomodulation through T-regulatory cells and the VDR\/CYP27B1 pathway in the endometrium and placenta (13,14).<\/p>\n

This narrative review synthesizes current evidence on vitamin D and miscarriage, highlighting underlying biological mechanisms, observational and interventional study findings, and potential clinical implications for preconception and early pregnancy management.<\/p>\n

Methods<\/strong><\/h5>\n

A structured literature search was conducted to identify studies investigating maternal vitamin D status and pregnancy loss. Searches were performed in PubMed\/MEDLINE, Embase, and Cochrane Library, including publications up to March 2026. Search terms included “vitamin D” OR “25-hydroxyvitamin D” OR “cholecalciferol” AND “miscarriage” OR “spontaneous abortion” OR “early pregnancy loss” OR “recurrent pregnancy loss”.<\/p>\n

Eligible studies were human observational studies (cohort, case-control, cross-sectional) and interventional trials evaluating vitamin D levels, supplementation, or genetic predisposition (Mendelian randomization) in relation to miscarriage or RPL. Systematic reviews and meta-analyses were screened for additional relevant studies. Exclusion criteria included animal studies, case reports, and studies addressing infertility without pregnancy outcomes.<\/p>\n

The resulted studies of the aforementioned search strategy included 10 primary studies, along with several meta-analyses and systematic reviews addressing vitamin D deficiency and miscarriage risk (9,10,11,12,14,15,16,17,18,19).<\/p>\n

Two reviewers independently screened titles and abstracts, followed by full-text assessment. Extracted data included study design, sample size, population characteristics, vitamin D measurement method, thresholds for deficiency, interventions, outcomes, and effect estimates. Discrepancies were resolved by consensus. This approach allowed a comprehensive synthesis of mechanistic, observational, and interventional evidence linking vitamin D to miscarriage risk. A summary of the design, population characteristics, vitamin D assessment, interventions and main findings of the included studies is presented in Table 1<\/a>.<\/p>\n

Clinical Evidence: Vitamin D and Miscarriage<\/strong><\/h5>\n

Observational Evidence<\/strong><\/p>\n

Observational studies have consistently examined the association between maternal 25-hydroxyvitamin D (25(OH)D) levels and pregnancy outcomes, particularly miscarriage and recurrent pregnancy loss (RPL). Tamblyn et al. (2022) conducted a systematic review and meta-analysis of 10 studies including 7,663 women, finding that vitamin D deficiency (<50 nmol\/L) was associated with a significantly higher risk of miscarriage compared with adequate vitamin D levels (>75 nmol\/L), with a dose\u2013response relationship indicating greater risk at lower 25(OH)D concentrations (9). This meta-analysis highlighted substantial heterogeneity among studies in terms of measurement methods, population characteristics, and definitions of deficiency.<\/p>\n

A prospective cohort study in Denmark, the Odense Child Cohort, involving 1,683 women, reported that first-trimester 25(OH)D insufficiency (<50 nmol\/L) was associated with a two- to three-fold increased risk of early miscarriage. Interestingly, this association was limited to losses occurring in the first trimester, supporting the biological importance of vitamin D during early implantation and placentation (10).<\/p>\n

Ko et al. (2024) examined 371 women presenting with first-trimester threatened miscarriage and reported no overall difference in miscarriage rates between vitamin D deficient and sufficient women. However, in those presenting with bleeding before 6 weeks, miscarriage rates were paradoxically higher among women with sufficient vitamin D, suggesting that other factors such as inflammation or supplementation may modulate outcomes in this subgroup (15).<\/p>\n

Similarly, Subramanian et al. (2022) measured preconception 25(OH)D levels in 362 women attempting conception and found no statistically significant association with miscarriage, indicating that in low-risk populations, vitamin D deficiency may not be the primary driver of early pregnancy loss (16).<\/p>\n

An observational case-control study in Iraqi women by Kasim (2022) included 40 women with miscarriage and 40 controls, showing that 95% of women in the miscarriage group were vitamin D deficient compared to 17.5% of controls, reinforcing the high prevalence of deficiency in women experiencing pregnancy loss (11).<\/p>\n

Mendelian Randomization Studies<\/strong><\/p>\n

Mendelian randomization (MR) offers a method to infer causality while reducing confounding. Zhang et al. (2024) used UK Biobank data to examine genetic variants associated with lifelong differences in 25(OH)D levels and their relationship to miscarriage. The MR study found no evidence supporting a causal effect of genetically determined low vitamin D on miscarriage risk, suggesting that observational associations may be influenced by confounding variables such as maternal BMI, lifestyle factors, or supplement use (12).<\/p>\n

This finding contrasts with the positive associations observed in conventional cohort studies, emphasizing the need for careful interpretation and highlighting the complexity of vitamin D\u2019s role in reproductive outcomes.<\/p>\n

Systematic Reviews and Umbrella Analyses<\/strong><\/p>\n

Chien et al. (2024) performed an umbrella review of systematic reviews and meta-analyses including over 250,000 women, confirming that vitamin D deficiency is associated with increased risks of miscarriage, preeclampsia, preterm birth, and gestational diabetes. The strength of evidence for miscarriage was less robust due to methodological heterogeneity and variable thresholds for deficiency, but the review supports the concept that vitamin D contributes to early pregnancy success through immune, endocrine, and placental mechanisms (17).<\/p>\n

Tamblyn et al. (2022), in the previously mentioned meta-analysis, emphasized that women with severe deficiency (<30 nmol\/L) had the highest risk of miscarriage, suggesting a threshold effect. This aligns with recommendations that maintaining 25(OH)D levels above 50 nmol\/L is minimally required for optimal reproductive outcomes, with higher targets potentially beneficial in high-risk groups (9).<\/p>\n

Interventional Trials<\/strong><\/p>\n

Interventional data examining vitamin D supplementation for miscarriage prevention are limited but suggest potential benefits in high-risk populations.<\/p>\n

Samimi et al. (2017) conducted a double-blind randomized controlled trial (RCT) in women with unexplained recurrent spontaneous abortion. Participants received 400 IU vitamin D\u2083 daily versus placebo. The miscarriage rate was significantly lower in the intervention group (12.8%) compared to controls (34.2%), and IL-23 levels were reduced, indicating immunomodulatory effects of supplementation (19).<\/p>\n

Ibrahim et al. (2013) evaluated 0.25 \u03bcg vitamin D\u2083 twice daily in women with RPL and observed decreased IFN-\u03b3 levels, suggesting improved immune tolerance, although the reduction in miscarriage risk did not reach statistical significance (18). These findings point to potential mechanistic benefits even when clinical outcomes are not conclusive.<\/p>\n

Rafiee et al. (2015) administered high-dose vitamin D\u2083 (300,000 IU) to women with RPL and reported decreased Th17 cell numbers and a lower Th17\/Treg ratio, further demonstrating the immunoregulatory role of vitamin D in early pregnancy (20).<\/p>\n

These trials, while promising, are limited by small sample sizes, heterogeneity in dosing, and differences in baseline deficiency levels. Nevertheless, they provide mechanistic and preliminary clinical evidence supporting vitamin D supplementation in selected high-risk women.<\/p>\n

Integration of Evidence<\/strong><\/p>\n

Overall, the evidence from observational studies, systematic reviews, and interventional trials suggests a consistent pattern: vitamin D deficiency is common among women with early miscarriage or RPL, and low 25(OH)D levels correlate with increased risk, particularly in early gestation. Mechanistic studies provide a plausible biological basis through immune modulation, endometrial receptivity, and trophoblast function. However, MR studies indicate that deficiency may act as a marker rather than a causal factor, underscoring the complexity of the vitamin D\u2013miscarriage relationship (12).<\/p>\n

The strongest clinical signal is observed in high-risk populations, including women with prior RPL, limited sun exposure, high BMI, or chronic inflammatory conditions. These findings suggest a targeted approach for screening and supplementation may be beneficial, pending confirmation in larger, well-powered RCTs (9,10,14,18,19,21).<\/p>\n

Biological Plausibility and Mechanisms of <\/strong>Vitamin D in Miscarriage<\/strong><\/h5>\n

Vitamin D is increasingly recognized as a multifunctional hormone that extends beyond calcium and bone metabolism, influencing immune, endocrine, and reproductive systems. Mechanistic studies provide a biologically plausible explanation for the observed associations between low maternal 25-hydroxyvitamin D (25(OH)D) levels and miscarriage risk, particularly in early pregnancy and recurrent pregnancy loss (RPL). These mechanisms involve local intracrine activation, modulation of the maternal-fetal immune interface, regulation of trophoblast function, and control of endometrial receptivity (1,13,14,22).<\/p>\n

Local Activation of Vitamin D in Reproductive <\/strong>Tissues<\/strong><\/p>\n

Maternal decidua and placental trophoblasts express both the vitamin D receptor (VDR) and the enzyme CYP27B1, which converts circulating 25(OH)D into its biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)\u2082D) (13). This intracrine pathway allows localized regulation of gene expression, independent of circulating calcitriol levels. Active vitamin D in the endometrium and placenta modulates genes involved in immune tolerance, angiogenesis, and cellular differentiation, directly influencing implantation success and early placental development (13,14).<\/p>\n

Immunomodulatory Effects<\/strong><\/p>\n

A central component of early pregnancy maintenance is immune tolerance, allowing maternal acceptance of the semi-allogenic fetus. Vitamin D contributes to this process through several mechanisms:<\/p>\n