BackgroundVitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality.MethodsIn a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488.FindingsWe analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L.InterpretationIn the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

The objective of this study was to investigate the effects of vitamin D supplementation versus placebo on muscle health. For this systematic review and trial-level meta-analysis of placebo-controlled trials, a systematic search of randomized controlled trials published until October 2020 was performed in Medline, Embase, and Google Scholar. We included studies in humans (except athletes) on supplementation with vitamin D2 or D3 versus placebo, regardless of administration form (daily, bolus, and duration) with or without calcium co-supplementation. The predefined endpoints were physical performance reported as timed up and go test (TUG; seconds), chair rising test (seconds), 6-minute walking distance (m), and Short Physical Performance Battery (SPPB; points). Furthermore, endpoints were maximum muscle strength (Newton) measured at handgrip, elbow flexion, elbow extension, knee flexion, and knee extension, as well as muscle (lean tissue) mass (kg). Falls were not included in the analysis. Cochrane Review Manager (version 5.4.1.) calculating mean difference (MD) using a random effect model was used. In total, 54 randomized controlled trials involving 8747 individuals were included. Vitamin D versus placebo was associated with a significantly longer time spent performing the TUG (MD 0.15 [95% confidence interval (CI) 0.03 to 0.26] seconds, N = 19 studies, I 2 = 0%, n = 5223 participants) and a significant lower maximum knee flexion strength (MD -3.3 [À6.63 to À0.03] Newton, N = 12 studies, I 2 = 0%, n = 765 participants). Total score in the SPPB showed a tendency toward worsening in response to vitamin D compared with placebo (MD À0.18 [À0.37 to 0.01] points, N = 8 studies, I 2 = 0%, n = 856 participants). Other measures of muscle health did not show between-group differences. In subgroup analyses, including studies with low vitamin D levels, effects of vitamin D supplementation did not differ from placebo. Available evidence does not support a beneficial effect of vitamin D supplementation on muscle health. Vitamin D may have adverse effects on muscle health, which needs to be considered when recommending vitamin D supplementation.

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

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Background: Reduced muscle strength is an acknowledged symptom of Graves' disease, but the knowledge on severity is sparse. This study aimed to investigate muscle strength, balance, and muscle function in patients with Graves' disease compared to age-and sex-matched healthy controls. Methods: Using a cross-sectional design, 55 patients newly diagnosed with Graves' disease were compared to 55 euthyroid controls, matched on sex, age, and menopausal status. Isometric muscle strength (N) and maximum force production (N/s) were measured across different muscles groups using a dynamometer chair and postural stability (balance) in different positions using a stadiometer. Muscle function was assessed using the Timed-Up-and-Go test and the Repeated Chair Stand test. Results: Patients and controls were well matched. Handgrip maximum muscle strength as well as strength at elbow and knee flexion and extension were significantly impaired in patients compared to controls. Maximum force production was only significantly reduced at elbow flexion. Patients performed the Timed-Up-and-Go and the Repeated Chair Stand test significantly slower than controls, and postural stability was significantly reduced in patients compared to controls in all positions. Free triiodothyronine correlated with reduced muscle strength and postural stability. Conclusions: At the time of diagnosis, Graves' disease is associated with impaired maximum muscle strength, performance, and balance, whereas maximum force production is overall comparable to euthyroid controls.

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| INTRODUC TI ONThyroid disorders are among the most common diseases in women of reproductive age with a reported prevalence ranging between 5% and 20% depending on the underlying population and reference range applied. 1 Thyroid disorders such as hypothyroidism and presence of anti-thyroid peroxidase autoantibodies (TPOab) have been associated with lower pregnancy rates, pregnancy loss, and preterm birth in spontaneous conception. 2,3 Pregnancy imposes a considerable strain on the hypothalamicpituitary-thyroid axis, 4 as the demand for thyroid hormones may increase by 50% during gestation. Subclinical hypothyroidism (SCH) is defined as a condition with elevated thyrotropin (TSH) and normal levels of thyroid hormones. It is proposed that in conditions with SCH or the presence of TPOab, the maternal thyroid gland fails to meet this increased demand, so causing a potential risk for the fetus and the pregnancy. 5,6 This has directed specific Abstract Introduction: Thyroid disorders have been associated with adverse reproductive outcome. Whether the preconceptional level of thyrotropin (TSH) in euthyroid women impacts on in vitro fertilization (IVF) outcome has been debated. This study reports the outcome of first IVF cycle in euthyroid women in relation to TSH level. Material and methods:A retrospective study was conducted in women referred for fertility treatment in the period 1 January 2012 until 31 March 2014. Among the exclusion criteria were thyroid medication at referral and comorbidities. TSH was measured as part of the fertility workup, and women were followed until pregnancy loss or live birth. Outcome as well as patient characteristics were prospectively collected from a treatment database. Results:A total of 623 euthyroid women underwent their first IVF cycle. The live birth rate was 27.0% (n = 168). Comparing women with a preconceptional TSH level above vs below 2.5 mIU/L, we found lower odds for clinical pregnancy (adjusted odds ratio [aOR] 0.52; 95% CI 0.29-0.95), and lower odds for live birth (aOR 0.53; 95% CI 0.29-0.99). Conclusions:A preconceptional TSH level >2.5 mIU/L was associated with lower odds for clinical pregnancy and live birth in euthyroid healthy women undergoing first IVF cycle. K E Y W O R D S anti-thyroid peroxidase autoantibodies, euthyroid pregnancy loss, in vitro fertilization, live birth rate, thyrotropin S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Grove-Laugesen D, Aaskov C, Ebbehøj E, Knudsen UB. Preconceptional thyrotropin level in euthyroid women is inversely associated with the live birth rate in first in vitro fertilization cycle. Acta Obstet Gynecol Scand. 2019;98:929-936. https://doi.

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