Vitamin D deficiency and restless legs syndrome during pregnancy: walking in sunshine?Kathryn A. Lee Journal of Clinical Sleep MedicineVolume 19, Issue 1 2023
INTRODUCTION
We thank Miyazaki and colleagues1 for shining a light on
women with restless legs syndrome (RLS) in their research on optimal cutoff values for 25-hydroxyvitamin D [25(OH)D] during pregnancy. Most prior research on this “sunshine vitamin” has been focused on its role in calcium absorption and bone health. Miyazaki and colleagues rightly point out that vitamin D’s hypothesized involvement in RLS involves different body tissues and possibly a different, disease-specific definition of deficiency.2–4
Before considering the primary outcome in their research, a review of the participants’ pregnancy characteristics, self-reported sleep, and birth outcomes provides valuable knowledge. Only singletons were included because research indicates that RLS risk increases with twins.5,6 Participants were all in third trimester, when RLS is most prevalent.6 Half (54%) were expecting their first child, and
risk of RLS increases with each subsequent pregnancy.5,6
Significantly more women in the RLS group (77%) had poor sleep quality (Pittsburgh Sleep Quality Index score > 5) compared to 52% in the non-RLS group, and difficulty initiating sleep (Insomnia Severity Index) was present in 54% of the RLS group compared to only 28% of the non-RLS group. Supplemental tables indicated no difference in sleep quality between vitamin D-deficient and nondeficient groups but there was a longer sleep onset latency in the folate-deficient group compared to the nondeficient group.1
It is reassuring that the newborns’ birth outcomes did not significantly differ for women with RLS compared to women without RLS or differ with vitamin D or folate deficiency. For the mothers in this study, the overall cesarean birth rate may have been low (14.5%) relative to the United States (30%); however, women in the RLS group had a higher cesarean rate (23%) than the non-RLS group (13%), which was not significant, although this was a small sample size and larger samples from other racial/ethnic groups are needed to inform these findings. Because of the association between cesarean birth and short sleep duration,7–9 clinicians should be concerned about both the 43% in the RLS group and 30% in the non-RLS group who self-reported sleep duration < 6 hours in the third trimester.
Miyazaki and colleagues1 argue that a lower cutoff for serum 25(OH)D is warranted because of the serodilution seen in pregnancy and conclude that the Liquid chromatography-tandem mass spectrometry (LC-MC/MS) method may be superior to chemiluminescent enzyme immunoassay (CLEIA). Before accepting a universal cutoff value, more studies are needed with well-characterized time of diagnosis, symptom burden throughout gestation, and geographic variation, with particular attention to sunlight exposure and dietary influences on micronutrients. The authors report significant seasonal variations in their serum levels of 25(OH)D, with lowest levels January to March, a finding that replicates other studies on season and geographic location.10 Their serum samples were obtained at various times of day during a scheduled clinic visit. Given the circadian fluctuation in serum 25(OH)D values, with lowest values during the evening and throughout the night, time of day may be important in evaluating a cutoff value for vitamin D deficiency.11
Only 36% of the entire sample was taking iron supplements and, as expected with iron storage depletion in late pregnancy, the ferritin levels were very low for both groups. Results stratified by iron status, a micronutrient with more evidence for causal involvement in RLS, would be of interest in future studies. Finally, the regression tree analysis comparing 25(OH)D values using the LC-MS/MS method showed only 15 women (7%) with values < 8.1 ng/mL (20 nmol/L) and half (n =
were in the RLS group. In the group with vitamin D levels ≥ 8.1 ng/ml (n = 188), folate deficiency was found in 74% of the RLS group vs. 40% of the non-RLS group, a notable interaction that should also be assessed and replicated in future studies.
Before clinicians rush to prescribe vitamin D supplements based on these findings, it is important to consider five key points:
(1) vitamin D is included in most perinatal multivitamin products;
(2) a small randomized placebo-controlled trial of vitamin D over 12 weeks showed no benefit for men or women with RLS12;
(3) high doses of vitamin D can be toxic with notable symptoms of nausea and vomiting or depression13 or adverse infant outcomes14;
(4) there is great variability in geographic exposure to sunlight as a source of vitamin D and variability in consumption of foods high in vitamin D like oily fish; and
(5)
perinatal vitamin supplementation will increase serum levels, but as with folate, levels may never reach the desired level while the fetus has increasingly high nutritional demands.15,16 Ideally more effort should be made to assess nutritional deficiencies when planning the pregnancy.
In summary Miyazaki and colleagues add to knowledge about gestational RLS, vitamin D deficiency, folate deficiency, and sleep in third trimester. Their findings support the need for more research to address seasonality and geographic location. Most women of childbearing age are motivated to have a healthy infant and unwilling to risk adverse effects from supplements or pharmacological agents (note that no participant reported use of hypnotics). Causal inferences cannot be made based on the descriptive findings from Miyazaki and colleagues1 but, based on associations between RLS and biomarkers such as vitamin D and folate, perhaps the best prescription for effective relief from gestational RLS is to
encourage walking in sunlight to get adequate vitamin D and promote physical activity beginning early in first trimester.
