Poor Stroke Prognosis And Inadequate Vitamin D Levels: A Systematic Review And Meta-Analysis
Overview
The study aimed to explore the relationship between serum vitamin D levels and the risk of stroke.
Researchers conducted a comprehensive search across three electronic databases—Cochrane Library, EMBASE, and PubMed—from their inception until July 29, 2022. The studies were screened based on specific inclusion and exclusion criteria. Quality assessment and data extraction were performed by two independent investigators. A meta-analysis was subsequently conducted using Stata 16.0 software.
The meta-analysis included 27 studies with a combined total of 45,302 participants. Among these, 20 studies focused on the risk of stroke, and 7 examined stroke prognosis. The results indicated that lower serum vitamin D levels were associated with a higher risk of stroke, with a combined relative risk (RR) of 1.28 (95% CI: 1.15–1.42). Moreover, lower vitamin D levels correlated with a poorer prognosis following a stroke (RR = 2.95, 95% CI: 1.90–4.60). Specifically, a significant link was found between decreased serum vitamin D levels and an increased risk of ischemic stroke (RR = 1.72, 95% CI: 1.78–2.03). However, there was no significant association between reduced vitamin D levels and the risk of hemorrhagic stroke (RR = 1.93, 95% CI: 0.95–3.95).
The study concluded that lower serum vitamin D levels are associated with an increased risk of stroke, particularly ischemic stroke, and are also related to a poorer prognosis after a stroke.
Introduction
Stroke is a leading cause of death and a major contributor to disability globally, impacting approximately 13.7 million people and causing around 5.5 million deaths annually (Campbell et al., 2019). Ischemic cerebral infarctions account for about 87% of strokes, with a higher prevalence in developing countries, while hemorrhagic strokes, which make up 10-15% of all strokes, are associated with high mortality rates. Between 1990 and 2016, stroke incidence rose in low- and middle-income countries, but decreased by 42% in high-income countries (Roger et al., 2011). Despite a reduction in stroke prevalence, its socioeconomic burden persists due to factors like age, gender, and geographic location (GBD 2016 Stroke Collaborators, 2019). In China, stroke remains a significant public health challenge, as indicated by a 2019 national survey (Tu & Wang, 2023; Tu et al., 2023; Wang et al., 2022).
Vitamin D, specifically 1,25-dihydroxyvitamin D (25-OHD), exists in two forms: D2 and D3. Vitamin D2, or ergosterol, is synthesized by plants, fungi, and yeast under UVB exposure, while vitamin D3, or cholecalciferol, is produced in human skin through sunlight exposure, converting 7-dehydrocholesterol to vitamin D3 (Aspell et al., 2018; Tripkovic et al., 2012). The synthesis of vitamin D3 is influenced by factors such as time of day, season, sunscreen use, and age (Kennel et al., 2010). Studies show that plasma 25-OHD levels decrease with higher latitudes, although factors like skin pigmentation, temperature, and clothing also impact UVB exposure (Andersen et al., 2020). Vitamin D, a crucial fat-soluble vitamin, plays a vital role in the skeletal system and other bodily tissues (DeLuca, 2004). Deficiency in vitamin D has been linked to various conditions including rickets, osteomalacia, osteoporosis, dermatological disorders, and cardiovascular diseases (CVDs) (Holick, 2007; Norman & Powell, 2014; Wadhwa et al., 2015).
Research suggests that insufficient vitamin D levels may increase stroke risk (Judd et al., 2016; Talebi et al., 2020; Wang et al., 2021; Zhou et al., 2018), and stroke prognosis tend to be worse in individuals with low serum vitamin D levels (Hu et al., 2019; Kim et al., 2020; Wang et al., 2021). However, some studies argue that vitamin D deficiency does not elevate stroke risk (Skaaby, 2015). Additionally, a lack of vitamin D is associated with higher risks of stroke-related adverse events in China (Wei & Kuang, 2018). Stroke occurrence involves a complex interplay of multiple factors, necessitating the identification of more predictable risk factors or biomarkers for prevention. The primary objective of the study was to investigate the impact of low vitamin D levels on stroke risk and stroke prognosis.
Method
The study was in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Page et al., 2021). Comprehensive searches of PubMed, Cochrane Library, and Embase databases were conducted up to July 29, 2022, utilizing both medical subject terms and free text terms, with the retrieval strategy detailed in the study. Two independent readers assessed each study for bias risk, resolving discrepancies with a third reviewer. Case-control and cohort studies were evaluated using the Newcastle–Ottawa Scale (NOS), with details and scoring criteria provided in Supplementary Document 1. Scores between 4 and 6 indicated significant bias risk, while scores between 7 and 9 indicated minimal bias risk (Lo et al., 2014; Stang, 2014). The Cochrane risk-of-bias tool was used for assessing RCTs (Higgins & Green, 2011).
Two readers independently selected articles and extracted relevant data, resolving any discrepancies through discussion or with input from a third reviewer. The selection process adhered strictly to predefined inclusion and exclusion criteria. Extracted data included the primary author’s name, study title, country of research, study type, sample size, calculated odds ratio (OR) or relative risk (RR) with 95% confidence interval (CI), adjustment variables considered and stroke subtypes and corresponding vitamin D statuses.
Inclusion Criteria
The inclusion criteria for the studies includes:
- Publications in English.
- Research on human subjects.
- Studies utilizing case-control design, randomized controlled trials (RCTs), or cohort design.
- Clear inclusion criteria for acute ischemic or hemorrhagic stroke.
- Stroke diagnosis confirmed by CT or MRI prior to treatment.
- Articles containing keywords related to stroke, vitamin D, and stroke prognosis.
- Availability of complete data.
Exclusion Criteria
Studies with incomplete data or duplicates were excluded after a review of supplementary materials.
Statistical Analysis
In the prospective cohort study, the relative risk (RR) was employed, while the retrospective study utilized the odds ratio (OR), with 95% confidence intervals calculated based on the Mantel-Haenszel random-effects model. Heterogeneity was assessed using the I² statistic and the Q test. A random-effects model was applied to all analyses within this study. Data analysis was conducted using Stata version 16.0 (Stata Corp, College Station, TX, USA).
Result
This study incorporated 27 research articles, including works by Alfieri et al. (2017), Anderson et al. (2010), Bolland et al. (2009), Drechsler et al. (2010), Ford et al. (2014), Hu et al. (2019), Huang et al. (2019), Ji et al. (2017), Judd et al. (2016), Kim et al. (2020), Kojima et al. (2012), Kühn et al. (2013), Larsson et al. (2018), Leung et al. (2017), Marniemi et al. (2005), Michos et al. (2012), Perna et al. (2013), Schierbeck et al. (2012), Schneider et al. (2015), Skaaby et al. (2013), Sun et al. (2012), Szejko et al. (2022), Tan et al. (2017), Wei & Kuang (2018), Xu et al. (2017), Xu et al. (2016), and Zittermann et al. (2016). The selection process is detailed in Figure 1, with the search strategies for various databases outlined in Table 1. Tables 2 and 3 respectively provide the attributes of the included trials and demographic details of the patients, and the quality assessment results.
Of the studies included, 20 articles explored the relationship between vitamin D levels and stroke risk. The pooled relative risk (RR) for stroke was 1.45 (95% CI: 1.20–1.74), with significant heterogeneity (I² = 92.32%).
Seven articles suggested a link between low vitamin D levels and poor stroke prognosis in ischemic stroke patients, with a pooled RR of 2.95 (95% CI: 1.90–4.60).
Among the 20 studies on vitamin D and stroke risk, 7 focused on ischemic stroke, 6 on hemorrhagic stroke, and 11 did not specify the stroke type. The combined RR for hemorrhagic stroke was 1.93 (95% CI: 0.95–3.95), with high heterogeneity (I² = 94.57%). For ischemic stroke, the combined RR was 1.72 (95% CI: 1.08–2.73), with very high heterogeneity (I² = 98.21%). The studies not specifying stroke type had a combined RR of 1.29 (95% CI: 1.12–1.48) and lower heterogeneity (I² = 28.50%).
Due to high heterogeneity, case-control studies and RCTs were excluded, and a separate analysis of cohort studies was conducted. This analysis revealed that excluding certain studies reduced heterogeneity significantly. For example, excluding studies by Ford et al. (2014), Sun et al. (2012), Tan et al. (2017), Xu et al. (2017), and Xu et al. (2016) resulted in a combined RR of 1.32 (95% CI: 1.16–1.49) with an I² of 55.96%. Similarly, excluding studies by Larsson et al. (2018), Sun et al. (2012), and Tan et al. (2017) gave a combined RR of 1.38 (95% CI: 1.03–1.84) and an I² of 78.13%.
The quality assessment of all studies is presented in Table 3. Sensitivity analysis showed that excluding RCTs and case-control studies, as well as studies with small sample sizes, significantly changed the results, reducing publication bias. For instance, after excluding studies with a high proportion of female participants, the RR for stroke risk associated with low vitamin D was 1.34 (95% CI: 1.18–1.51), with an I² of 21.69%. Excluding certain studies on major illnesses and vitamin D intake showed an increased RR of 1.86 for ischemic stroke risk and an I² of 99.41%.
This meta-analysis highlights a significant relationship between low vitamin D levels and increased stroke risk, particularly ischemic stroke, as well as poorer prognosis in ischemic stroke patients. The high heterogeneity observed suggests variability among studies, which was partly addressed by excluding specific studies and focusing on cohort studies. The findings underscore the need for further research to clarify these associations and address potential biases.
Conclusion
Stroke is a widespread acute cerebrovascular disease and the leading cause of adult disability in China. Current stroke prevention strategies emphasize the importance of identifying both controllable and uncontrollable risk factors. This study examines the link between vitamin D levels and stroke incidence, analyzing 27 studies. Of these, 20 studies explored whether low vitamin D levels increase stroke risk, revealing a potential association. Additionally, seven studies focused on the relationship between serum vitamin D levels and stroke prognosis, finding that low vitamin D levels correlate with poorer outcomes.
The analysis of the 20 studies indicated a significant connection between vitamin D levels and the risk of various stroke types, particularly ischemic and unspecified strokes, but not hemorrhagic strokes. However, considerable heterogeneity among the included studies prompted an exploration of its sources. Excluding case-control studies and RCTs reduced heterogeneity significantly, highlighting that sample size, gender, dietary habits, and age differences contribute to variability.
Vitamin D, synthesized through ultraviolet exposure of 7-dehydrocholesterol and ergosterol, impacts multiple systems, including endocrine, skeletal, and cardiovascular. It also benefits the nervous system by enhancing synaptic plasticity, reducing oxidative stress, and protecting the blood-brain barrier (BBB). Research shows vitamin D’s role in mitigating BBB injury during ischemic stroke, potentially through pathways involving PPAR-γ and brain-derived neurotrophic factor (BDNF).
Despite these findings, clinical trials have shown inconsistent results regarding vitamin D supplementation’s impact on stroke outcomes. Factors such as gender, underlying conditions, and sunlight exposure may influence these outcomes. This meta-analysis uniquely addresses the relationship between vitamin D, stroke risk, and prognosis, suggesting that low vitamin D levels may increase ischemic stroke risk and worsen stroke prognosis. However, further research is necessary to confirm these findings and explore the potential benefits of vitamin D supplementation.
In conclusion, low vitamin D levels are linked to an increased risk of ischemic stroke and poorer stroke prognosis, but not hemorrhagic stroke. Further investigation is required to understand if vitamin D supplementation can reduce stroke risk and improve outcomes. Future studies should also consider the impact of dietary habits on vitamin D intake.
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