Is Preoperative Vitamin D Supplementation Beneficial in Preventing Post‐Thyroidectomy Hypocalcemia?

Hypocalcemia is the most common complication after thyroidectomy, with the reported rate of transient postoperative hypocalcemia being approximately 30% and permanent hypocalcemia in approximately 4% 1. A variety of clinical and surgical factors increase the risk of postoperative hypocalcemia after total or completion thyroidectomy, including age, female sex, preoperative vitamin D deficiency, Graves' disease, thyroid cancer, central compartment dissection, and parathyroid excision or autotransplantation 1. Of these, preoperative vitamin D deficiency is one of the only modifiable clinical risk factors, which makes this an attractive potential target for intervention. Several randomized controlled trials have examined the effect of preoperative vitamin D supplementation either with or without calcium supplementation on postoperative hypocalcemia after thyroidectomy. However, the results of individual studies have been mixed, prompting several recent systematic reviews and meta-analyses. This Best Practice review evaluates the recent literature on the role of preoperative vitamin D supplementation in preventing post-thyroidectomy hypocalcemia. Several recent large-scale meta-analyses of published randomized controlled trials have been conducted and are summarized in Table 1 below. Due to a small number of trials on preoperative vitamin D supplementation alone, all the meta-analyses included trials with preoperative calcium supplementation in addition to vitamin D. However, each conducted sub-analyses to examine the effect of preoperative vitamin D supplementation alone. Alhakami et al. 2 identified nine trials including 1079 patients. Five trials supplemented vitamin D only and four with both vitamin D and calcium. Their pooled analysis revealed lower rates of postoperative laboratory hypocalcemia (risk ratio(RR) = 0.77 0.60–1.00, p = 0.05), symptomatic hypocalcemia (RR = 0.54 0.38–0.76, p = 0.0005), as well as higher mean postoperative calcium levels (mean difference = 0.10 0.07–0.12, p < 0.00001) in the supplemented groups. There were no differences in length of stay (p = 0.98) or permanent hypoparathyroidism (RR = 0.20 0.03–1.11, p = 0.07). They conducted one sub-analysis examining the five studies that used preoperative vitamin D supplementation only. This sub-analysis demonstrated no significant difference between vitamin D alone and vitamin D with calcium supplementation on decreasing rates of laboratory hypocalcemia (p = 0.66), however the actual decrease in laboratory hypocalcemia did not reach statistical significance when looking only at the vitamin D supplemented group (RR = 0.79 0.62–1.01, p = 0.06). Jullamusi et al. 3 included 13 studies with 1504 patients. They included several trials in which the intervention group received combined pre and postoperative supplementation with vitamin D and calcium. The results from this meta-analysis were similar, with higher postoperative calcium levels (mean difference = 0.30 0.15–0.44, p = 0.0002), lower rates of postoperative laboratory hypocalcemia (odds ratio (OR) = 0.41 0.27–0.62, p < 0.0001), lower rates of symptomatic hypocalcemia (OR = 0.38 0.24–0.62, p < 0.0001), and also decreased need for intravenous calcium supplementation (OR = 0.32 0.18–0.58, p = 0.0002) and shorter hospital length of stay (mean difference = −0.29 −0.51 to −0.07, p = 0.009) in the intervention group. Sub-analyses on vitamin D supplementation only showed that vitamin D supplementation alone was also associated with higher mean postoperative calcium levels (four studies, mean difference = 0.33 0.09–0.58, p = 0.008), lower rates of laboratory hypocalcemia (six studies, OR = 0.44 0.22–0.90, p = 0.02), and lower rates of symptomatic hypocalcemia (five studies, OR = 0.35 0.14–0.84, p = 0.02). They found no significant differences between preoperative vitamin D supplementation alone and vitamin D with calcium supplementation. Notably, one study utilizing preoperative calcium supplementation alone showed no benefits. Canali et al. 1 included eight trials with 902 patients. Four supplemented vitamin D only, three supplemented both calcium and vitamin D, and one supplemented vitamin D pre-operatively and calcium both pre- and post-operatively. Again, results were consistent with decreased laboratory (RR = 0.77 0.62–0.96, p = 0.02) and symptomatic hypocalcemia (RR = 0.56 0.34–0.93, p = 0.023) in the intervention group. Sub-analysis of vitamin D only supplementation demonstrated reduced risk of laboratory hypocalcemia (RR = 0.74 0.57–0.96, p = 0.03) as well. One patient in a study supplementing high dosages of calcitriol developed severe hypercalcemia following the preoperative supplementation; this was the only complication associated with vitamin D supplementation identified in any of the three meta-analyses. Overall, these pooled results provide evidence for the benefit of preoperative vitamin D supplementation in reducing rates of hypocalcemia after thyroidectomy, and that vitamin D supplementation alone is likely sufficient to provide this benefit. Questions still remain on the optimal supplementation regimen. Studies differed on the dosage, timing of supplementation, and use of cholecalciferol or calcitriol, with regimens ranging from a single large supplemental dose 1 day before surgery to 4–6 weeks of lower dose supplementation. Canali et al. 1 performed a sub-analysis examining the type of vitamin D supplementation used and found no statistically significant impact of cholecalciferol versus calcitriol on effect sizes (p = 0.50). Further investigation is warranted into the optimal vitamin D supplementation regimen. Additionally, there is debate about whether the benefit of vitamin D supplementation is limited to patients with vitamin D deficiency. One study which was included in all three recent meta-analyses specifically recruited patients with preoperative vitamin D deficiency and had positive results. This study found significant improvements in rates of symptomatic hypocalcemia (8% vs. 2%, p = 0.04) and decreased need for intravenous calcium supplementation (6% vs. 1%, p = 0.03) in the supplemented group. Low prevalence of vitamin D deficiency in particular populations may explain negative results in individual studies. Jullamusi et al. 3 conducted a sub-analysis comparing the effect of preoperative supplementation in countries near and far from the equator, presumably as a proxy for vitamin D deficiency prevalence, and found no significant difference in mean postoperative calcium levels, though proximity to the equator may not be a sufficient proxy for vitamin D deficiency status. Sanabria wrote a Letter to the Editor in response to the Canali et al. meta-analysis and re-analyzed the included studies based on prevalence of vitamin D deficiency in each respective country. Vitamin D supplementation had a statistically significant effect when the study was conducted in countries with high vitamin D deficiency prevalence, but this effect disappeared when pooling studies conducted in countries with low or intermediate rates of vitamin D deficiency 4. Based on these data, it may be reasonable to pre-operatively screen patients for vitamin D deficiency and supplement only those patients who are deficient. This updated evidence is in accordance with the American Thyroid Association's published guidelines on postoperative hypoparathyroidism in which they state, “Given the present evidence, it would appear preferable to diagnose vitamin D deficiency and initiate appropriate corrective supplementation prior to surgery” 5. Preoperative vitamin D supplementation is a low cost and low risk intervention which improves rates of postoperative hypocalcemia after thyroidectomy. Further investigation is warranted into optimal supplementation regimens and the role of preoperative testing for vitamin D deficiency. These recommendations are based on multiple systematic reviews and meta-analyses (level I). The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.