Vitamin D Status a Relevant Prognostic Factor in FET Cycles: Recent Cureus Systematic Review Finds

The systemic review and meta-analysis was published in the journal Cureus in January 2026.

The Link Between Vitamin D and Endometrial Receptivity for Implantation

As clinicians increasingly transition to FET to avoid the supraphysiological hormonal states of fresh cycles, identifying modifiable prognostic factors like vitamin D has become a clinical priority. Vitamin D is biologically active within the reproductive system with the help of vitamin D receptors (VDRs) that regulate homeobox A10 (HOXA10) expression and modulate immune response critical for implantation. However, most prior studies pooled fresh and frozen cycles together, potentially masking vitamin D's impact since supraphysiologic estradiol in fresh cycles may override its immunomodulatory effects. Consequently, this systematic review and meta-analysis specifically evaluated how maternal vitamin D status influences clinical pregnancy and live birth rates in the controlled physiological context of FET.

Study Overview

The systematic review and meta-analysis, registered with the international prospective register of systematic reviews (PROSPERO) and adhering to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, synthesized data from four cohort studies involving 2,061 autologous FET cycles from women of reproductive age (≥18 years) undergoing programmed or natural endometrial preparation protocols. The investigation was conducted across Egypt, Hong Kong, and Belgium, utilizing a random-effects model to compare reproductive outcomes between women with sufficient vitamin D and those with deficient or insufficient levels (<20–30 ng/mL), with maternal serum 25(OH)D measured before the FET cycle. The analysis specifically excluded fresh transfers and supplementation trials to focus on baseline prognostic significance. Methodological quality was rigorously appraised using the Newcastle-Ottawa Scale, with clinical pregnancy and live birth rates serving as the primary endpoints.

Key Findings from the Study include:

• Impact on Clinical Pregnancy: In a high-quality sensitivity analysis involving 1,769 cycles, women with vitamin D deficiency faced a statistically significant 20% reduction in the likelihood of clinical pregnancy (OR: 0.80; 95% CI: 0.65-0.99), p=0.03), whereas the overall pooled analysis of all 2,061 cycles showed non-significant results (OR: 0.37, 95% CI: 0.12-1.08) due to substantial heterogeneity.
• Live Birth Trends: The pooled data from three studies comprising 1855 cycles showed a decline in live birth rates for women with low vitamin D by 19% (OR: 0.79; p=0.08).
• Study Heterogeneity: Initial analysis of all four studies showed high heterogeneity for pregnancy rates (I²=92.7%), which was completely resolved (I²=0%) when the analysis was limited to the most rigorous, high-quality studies that utilized precise assay methods [liquid chromatography-mass spectrometry (LC-MS) or automated immunoassays] and adjusted for confounders including age, BMI, and season.

The analysis also highlights that two studies (Ko et al. and van de Vijver et al.) achieved maximum Newcastle-Ottawa Scale scores (9/9), a validated tool assessing study quality across selection, comparability, and outcome domains, demonstrating robust design with multivariable adjustments, whereas moderate-quality studies lacked comprehensive confounder control.

By exclusively analyzing frozen embryo transfers and excluding fresh cycles, this review isolated vitamin D's impact on endometrial receptivity independent of the supraphysiological estradiol levels (often >2000-3000 pg/mL) that characterize controlled ovarian stimulation. This methodological focus makes the findings particularly relevant for contemporary assisted reproductive technologies (ART) practice, where freeze-all strategies are increasingly adopted to optimize endometrial-embryo synchrony and minimize ovarian hyperstimulation syndrome (OHSS) risk.

Clinical Implications for Clinicians

Maternal vitamin D deficiency should be recognized as a prognostic marker associated with reduced FET success. While optimization is a low-cost, biologically plausible intervention, universal screening cannot be recommended until randomized controlled trials (RCTs) confirm causality. Clinicians may consider targeted assessment in patients with recurrent implantation failure or repeated FET failures, aiming for serum 25(OH)D ≥30 ng/mL before cycle initiation.

Reference

Abdelgader, M. A. A., Abdallah, A. A. A., Alkahtani, K., et al. (2026). The Association Between Pre-cycle Maternal Vitamin D Status and Reproductive Outcomes in Frozen-Thawed Embryo Transfer: A Systematic Review and Meta-Analysis. Cureus, 18(1), e100977. DOI: 10.7759/cureus.100977.