Association of vitamin D levels with anthropometric and adiposity indicators across all age groups: a systematic review of epidemiologic studies

Objectives It has not been established whether vitamin D deficiency is associated with anthropometric state; therefore, this systematic review examined the relationship between serum vitamin D levels with anthropometrics and adiposity across different ages. Methods Studies that examined vitamin D deficiency with adiposity measures in different age groups were searched in the PubMed, Scopus, Embase, and Google Scholar databases until November 2023. Two investigators independently reviewed titles and abstracts, examined full-text articles, extracted data, and rated the quality in accordance with the Newcastle–Ottawa criteria. Results Seventy-two studies, with a total of 59,430 subjects, were included. Of these studies, 27 cross-sectional studies and one longitudinal study (with 25,615 participants) evaluated the possible link between 25(OH)D serum concentrations and anthropometric/adiposity indices in the pediatric population. Forty-two cross-sectional studies and two cohort investigations (with 33,815 participants) investigated the relationship between serum 25(OH)D levels and adiposity measures in adults and/or the elderly population. There is evidence supporting links between vitamin D deficiency and obesity, and revealed an inverse association between vitamin D and adiposity indicators, specifically in female subjects. However, the effects of several confounding factors should also be considered. Conclusion Most published studies, most of which were cross-sectional, reported a negative association between vitamin D and female adiposity indicators. Therefore, serum vitamin D levels should be monitored in overweight/obese individuals.


Introduction
Obesity results from excess fat accumulation and a positive energy balance, contributing to various chronic diseases and reduced life expectancy (1).Approximately 650 million adults, roughly 13% of the global adult population, were overweight or obese, with 340 million children and adolescents aged 5-19 years classified as overweight or obese in 2016 (2).
Micronutrient deficiencies, notably hypovitaminosis D, are common in obese patients (3,4).Extensive observational studies like NHANES III and Framingham have linked obesity to an increased risk of hypovitaminosis D (5,6).Vitamin D serves various functions, including maintaining calcium homeostasis and bone health, while also influencing metabolic processes, immunity, cellular proliferation, and differentiation, among other effects such as antiinflammatory, antiatherogenic, cardioprotective, and neuroprotective impacts (7,8).A global prevalence of widespread vitamin D deficiency has been identified, with deficiency rates rising by 13%, insufficiency rates reaching 40%, and notably higher rates observed in Asian countries (9,10).
Obesity is commonly linked with reduced vitamin D levels regardless of various factors such as age, gender, season, study region, or smoking status (11).The coexistence of obesity and hypovitaminosis D represents a dual public health concern globally, prompting the need for investigating the underlying pathophysiology of this relationship.Mechanisms contributing to low vitamin D levels in obesity involve volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and reduced vitamin D synthesis in adipose tissue and the liver (11).Studies have suggested that low vitamin D levels may influence adipose tissue differentiation and growth, impacting obesity through gene expression regulation or by modulating parathyroid hormone (PTH), calcium, and leptin (11,12,13).While several observational studies have explored the link between vitamin D status and body weight, comprehensive evaluations of the relationship between serum vitamin D levels and anthropometric and adiposity indicators in both adults and children are lacking.
Hence, in this groundbreaking systematic review, we significantly contribute to the existing literature by taking a comprehensive and inclusive approach to evaluate the intricate relationship between serum 25(OH)D levels and adiposity.Unlike prior studies that primarily focused on specific age groups or relied on limited adiposity measures such as body mass index (BMI) and waist circumference (WC), our research spans diverse age groups and considers a broader set of indicators, including BMI, WC, HC (hip circumference), WHR (waist-to-hip ratio), and body fat mass percentage.Our findings reveal intriguing patterns across the life span, adding a valuable dimension to the understanding of vitamin D deficiency in the context of obesity.This holistic evaluation provides a nuanced perspective on the association between serum 25(OH)D levels and various aspects of adiposity, offering a more comprehensive overview compared to previous reviews.This research is important as it seeks to fill the existing gap in knowledge concerning the intricate association between vitamin D levels and obesity.By conducting a systematic review, the study intends to shed light on the underlying mechanisms and implications of this relationship, thereby contributing to the development of effective public health strategies.

Methods
We conducted a systematic review of studies that assessed the relationship between serum vitamin D levels with anthropometric and adiposity indices in children, adolescents, adults, and the elderly.Serum 25(OH)D was used as a proxy measure for vitamin D levels.

Search strategy
The PubMed, Scopus, Embase, and Google Scholar databases were used to identify relevant publications.Two authors (BA and SA) independently searched papers published until November 2023 using ('25-hydroxy vitamin D' OR 'vitamin D' OR 'cholecalciferol' OR '25(OH)D') AND ('BMI' OR 'body mass index' OR 'weight' OR 'obese' OR 'obesity' OR 'waist' OR 'waist circumference' OR 'adiposity' OR 'adipose', OR 'fat') as keywords.No restrictions were imposed on publication time or language.The reference lists of relevant articles were also reviewed by the authors to determine whether any publications were missing.All of the studies included in this systematic review were published in English.Data extraction was done independently by two investigators (BA and MN).In the event of any disagreement, three authors (BA, MN, and FH) discussed it among them to resolve the disagreement.Owing to the differences in the comparisons of the included studies (differences in exposures, outcomes, participants, and settings), diversity of applied statistical tools in the comparisons of the included studies, and lack of data that could be pooled, we performed a qualitative systematic review.The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) Statement (14).
Table 1 shows the PICOS (population, intervention/ exposure, comparator, outcome, and setting) items used to conduct the systematic review.Owing to the methodological approach, no ethical approval was required.

Eligibility criteria
Publications with abstracts that suggested vitamin D levels were investigated in relation to anthropometric and adiposity variables were reviewed in full.Studies met the inclusion criteria if they: i) had observational design; (ii) were carried out in apparently healthy individuals (without chronic diseases, such as diabetes, liver diseases, cancer, or chronic kidney disease); and (iii) used serum 25(OH)D levels as a proxy for vitamin D state.However, clinical trials, reviews, editorials, and studies on nonhuman models, were excluded.Sex and age ranges were not strictly defined in this systematic review.

Study selection
Each title and abstract collected during the initial search was independently evaluated by two authors after removing duplicates.To ensure that eligibility and exclusion criteria were met, the two authors assessed full-text articles.The researchers consulted each other whenever they disagreed.

Data extraction and quality assessment
The following information was recorded in a data mining sheet: first author, publication year, country, ethnicity, design of the study, sample size, sex of participants, age, study population, method of 25(OH)D measurements, cut offs for vitamin D status, anthropometric indices investigated in the study and their cut off points, adjustments, and main findings.
We assessed the quality of observational studies using the Newcastle-Ottawa Scale (NOS) (15).

Characteristics of the studies conducted in children/adolescent population
The current systematic review identified 27 crosssectional studies (16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42) and one longitudinal study (43) that assessed the potential relationship between serum 25(OH)D levels and anthropometric/adiposity indices in children.The studies about the relation between 25(OH)D serum level and anthropometric indices in pediatric were carried out in the following countries: four studies from Turkey, three from Spain, two from Denmark, five from the USA, two from Brazil, four from Italy and eight others from Iran, Korea, China, Thailand, England, Saudi Arabia, Sri Lanka, and Germany.The included studies were conducted between 2008 and 2021.Tgncluded studies had samples ranging from 51 to 12292 in this age group.Participant ages ranged from 3 months to 21 years.
All included studies involved both sexes, except three investigations (26,39,40) that were conducted in females (39,40) and males (26) only.The included studies mostly considered the following potential confounders: sex, age, weight, BMI, cohort characteristics, Tanner stage, fat mass index, body fat mass percentage, BMI Z-score, parental education, pubertal breast stage, physical activity, dietary or supplemental vitamin D and calcium intake, race, ethnicity, season of blood collection, and height measures.

Included
Reports sought for retrieval Reports not retrieved (n = 5) Figure 1 PRISMA flow diagram for the selection process of the studies.Age, physical activity, smoking In women, 25(OH)D levels did not differ among the BMI groups.In men, 25(OH)D was lower in obese men than in normal-weight.Altogether, obese subjects had lower 25(OH)D than normal-weight.In women, PTH was significantly higher in obese compared to normal weight Altogether, the difference was significant.Age, lifestyle, iPTH 25(OH)D3 was inversely associated with BMI, HC, and BF in women.Total BF was a negative predictor of 25(OH)D3 in women even after controlling for confounders, whereas the associations between BMI, HC, and 25(OH)D3 lost statistical significance after adjusting for iPTH.Age, sex and seasons PTH was directly correlated with total, truncal and extremity FM, while 25(OH)D was related inversely to truncal FM.Age, sex, BMI, %FM, season Insufficient 25(OH)D was associated with higher BMI.
Elevated PTH levels were linked to higher BMI and higher FM percentage.The cross-sectional study by Alemzadeh et al. (42) among 127 subjects aged 13.0 ± 3.0 years, found that hypovitaminosis D and vitamin D-deficient subjects had higher BMI, fat mass, and iPTH compared to vitamin D-sufficient subjects (P < 0.01).Also, fat mass was negatively correlated with 25(OH)D (r = −0.40,P < 0.0001) regardless of seasonal and racial/ethnic factors.In other works, by the same research group (24,35) between obese adolescents, a negative correlation was found between fat mass and 25(OH)D (P < 0.001).
As reported by Chung et al. (31), the level of 25(OH)D in overweight children was significantly lower than that of normal weight children (17.1 ± 5.1 ng/mL vs 19.1 ± 6.1 ng/mL, P < 0.001).There was an independent association between overweight and vitamin D deficiency (OR 2.21; 95% CI 1.62-3.01).
According to Buyukinan et al.'s study (36), children and adolescents with a BMI ≥95th percentile did not show any significant differences in terms of weight, height,

NM
Low levels of 25(OH)D are linked to higher BMI.
There was also a cross-sectional study, by Durá-Travé et al. (20), showing that adolescents with severe obesity who had vitamin D deficiency had significantly (P < 0. In the study by Foo et al. (39), in adolescent girls, lean body mass and plasma 25(OH)D levels were significantly correlated (r = 0.446; P = 0.001).However, the correlation between body fat percentage and vitamin D status was not significant (r = 0.104; P > 0.05).
According to Giudici et al. (23), compared to normalweight participants, those with overweight had a lower 25(OH)D.All measures of BMI, weight, and WC were negatively associated with 25(OH)D (P < 0.05).Other researchers (16) found that serum vitamin D levels were negatively correlated with BMI in overweight/ obese subjects with vitamin D levels <20 ng/mL (r = −0.186,P < 0.01).
Bioavailable and free vitamin D were lower in the obese group.However, the total vitamin D level between the two groups did not differ, according to Küçükali et al. (19).In another study by Turer et al., vitamin D deficiency is highly prevalent in overweight and obese children.(37).In a study by Oliveira et al. (33) serum 25(OH)D levels were statistically lower in adolescents with excess weight, abdominal obesity, and a high level of PTH (P < 0.05).
Another cross-sectional study by Petersen et al. (27) showed a negative relationship between serum 25(OH)D and BMI Z-scores and fat mass index (P = 0.001).However, the association with BMI Z-scores became nonsignificant when the model was adjusted for parental education (−0.03, 95% CI −0.07, −0.001, P = 0.14).
Plesner et al. (22) found that 16.5% of obese children and adolescents showed vitamin D deficiency, with an OR 3.41 (CI 2.27-5.71;P < 0.0001) in comparison with peers with normal weight.An increase in risk of hypovitaminosis D was observed in overweight (OR 5.02) and obese (OR 5.36) subjects compared to normal weight subjects (32).
There was a difference in BMI percentile between children with hypovitaminosis D and children who have sufficient vitamin D (56.7 ± 33.9 vs 42.6 ± 36.0;P = 0.04) according to a cross-sectional study (28).
According to a multivariate analysis, high BMI percentile and high PTH levels were the parameters related to 25(OH)D concentration <75 nmol/L.
Another evaluation (21) among children with obesity could not observe any significant associations between vitamin D deficiency and the anthropometric or metabolic derangements.
In the study by Rusconi et al. (29), 59 had 25(OH)D <20 ng/mL (group Ι) and 61 had 25(OH)D > 20 ng/mL (group ΙΙ) were recruited.The two groups were similar for BMI SDS and fat mass SDS.
Razzaghy-azar et al. (38) reported that 25(OH)D level had a negative correlation with BMI-SDS and height-SDS in girls (P = 0.01 and 0.039, respectively), but these correlations were not significant in boys.Healthier WC was also associated with better 25(OH)D concentrations among adults (63).Other studies found no significant correlation between 25(OH)D with WC (45,51) and BMI (51).According to Macdonald et al. (82), women in the top quintile of BMI had lower 25(OH)D (P < 0.01).There was a significant correlation between 25(OH)D and BMI (r = 0.58; P = 0.01).In addition, BMI was highly predictive of 25(OH)D level (r = −0.52;P < 0.01).

The relationship between vitamin D with anthropometric and adiposity indicators in adult/elderly population
According to another study (69) An analysis by George et al. (57) showed 25(OH)D was not correlated with BMI (P = 0.38) and WC (P = 0.99).
In the Sharma et al. study (74), women with a higher visceral adipose tissue quartile had significantly lower 25(OH)D levels (P = 0.05).
Analysis of the subjects aged ≥65 years, in the Longitudinal Aging Study Amsterdam (67), revealed that after adjusting for potential confounders, higher BMI, WC, and sum of skin folds were statistically significantly related to lower 25(OH)D (standardized β values were −0.136, −0.137, and −0.140, respectively; all P < 0.05) and with higher PTH (0.166, 0.113, and 0.114, respectively; all P < 0.05).In comparison to anthropometric measurements, total body fat percentage had a stronger relationship with 25(OH)D (−0.261).
Bell et al. (46), in their study among 12 obese and 14 nonobese White subjects, demonstrated that mean serum 25(OH)D (8 ± 1 vs 20 ± 2 ng/mL, P < 0.001) was significantly lower in the obese than in the nonobese subjects.
There was a significant inverse association between abdominal obesity and the quintiles of 25(OH)D levels in another cross-sectional study (44) involving both sexes.
Serum 25(OH)D was found to be inversely related to visceral abdominal fat and percentage fat in a crosssectional study of overweight and obesity (77).
After adjusting for the confounders, Shan et al. (13) found that low 25(OH)D levels were significantly related to elevated WC among women (OR = A study by Gariballa et al. (48) found that, although BMI did not differ statistically significantly between groups, it was higher among vitamin D deficient older subjects and women <50 years, respectively, compared to individuals with adequate vitamin D or optimal concentrations (P = 0.05).
Another cross-sectional investigation (84) among community-dwelling men and women reported that compared with normal weight, obese individuals had lower 25(OH)D levels (P < 0.05).
In 2023, Avila Castillo et al. (85), in their study on the 1032 adult population of the LIFE-Adult-Study, concluded that low levels of 25(OH)D were linked to higher BMI, while fat mass areas showed a negative correlation with 25(OH)D concentrations only in women.

Discussion
The present systematic review investigated the correlation between serum 25(OH)D levels and anthropometric and adiposity measurements in healthy individuals of various ages.Some previous metaanalyses included studies that reported BMI (86) and WC (87)  According to the results of the studies included in the systematic review, overweight and obese individuals of different ages have similar chances of becoming vitamin D-deficient.Hence, age does not appear to have a significant impact on this association.
As a result of the heterogeneity in study characteristics, findings on vitamin D status and adiposity were inconsistent, with the inverse association being more prominent in females.It has been speculated that ethnicity, sex, and age may have a mediating effect on the relationship between 25(OH)D levels and anthropometric measures.It is likely that the differences in associations between females and males stem from the fact that women have a higher percentage of body fat and a different body composition than men.With the same BMI, men have less body fat than women.Thus, men store less vitamin D in adipose tissue and more remains in the blood.Furthermore, serum 25(OH)D levels are not stable throughout the year due to inadequate levels of 25(OH)D in the adipose tissue.In addition, vitamin D-binding protein could also contribute to sex differences in vitamin D status (94).It has been demonstrated that vitamin D-binding protein and adiposity are negatively correlated in men and positively correlated in women (94).
In reviewing the studies included in the systematic review, critical issues were raised, which could contribute to bias and confounding.There are several limitations, including heterogeneity in participant characteristics, the diversity of methods used to determine vitamin D levels and the analytical challenges involved, the use of variable definitions of hypovitaminosis D, the absence of adjustment for various confounding factors that influence vitamin D levels, and the reliability of various adiposity measures for describing obesity.The results of these studies may also be affected by a number of other factors related to the population studied, such as cultural and religious factors, dressing codes that mandate covering the majority of the body surface, and behavioral and lifestyle differences (95).It is also possible that variations in socioeconomic and developmental status could cause heterogeneity among studies that influence nutrition and lifestyle.Various socioeconomic and developmental factors influence the prevalence of obesity and vitamin D level (96,97).Moreover, the amount of air pollution may affect vitamin D status, especially in urban areas where UVB wavelengths of sunlight are mostly blocked by pollutants (98).As a result of differences in health policies regarding the fortification of food with vitamin D in Europe and the USA and in national recommendations regarding vitamin D supplement use, vitamin D intake may differ significantly between countries (99).Vitamin D levels are also affected by genetic factors; however, without population-based genetic analyses, it is difficult to quantify their impact (100).(101).Additionally, vitamin D may regulate uncoupling proteins, which may play a role in energy metabolism (102).Despite this, Walsh et al. (53) found that PTH was not affected by BMI or sex and was not correlated with BMI.In obese individuals, there may be alterations in the relationship between 25(OH)D and PTH levels (53).To optimally determine the vitamin D status, the 25(OH)D threshold for maximum suppression of PTH has been suggested (103).A previous study showed that patients with a BMI ≥30 kg/m 2 had a lower threshold for suppressing PTH levels (5 ng/mL) than patients with a BMI <30 kg/m 2 (10 ng/mL) (104).This suggests that a very low 25(OH)D level is required to activate the PTH axis, leading to secondary hyperparathyroidism and bone loss (104).
The BMI has been used as an indicator of obesity in the majority of studies included in this systematic review.
However, although BMI is the most widely accepted method for defining obesity, it is not an accurate measure of fat mass and distribution of body fat.Compared with subcutaneous fat, excess visceral fat confers a greater risk of metabolic and cardiovascular diseases for the same BMI value (105,106).Several more meaningful measures of adiposity have been developed to resolve this methodological issue, including fat mass, WC, and WHR.
The present systematic review investigated the correlation between serum 25(OH)D and anthropometric and adiposity measurements in healthy individuals of various ages.However, some limitations must be considered.As not all included studies separately reported the relationship between serum vitamin D and adiposity measures in men and women, accurate estimates for men and women could not be provided.Different cutoff points were used for defining obesity and vitamin D deficiency in the included studies.This systematic review also examined the relationship between obesity and vitamin D deficiency using crosssectional studies, which made the causality findings more difficult.Finally, we did not have access to the complete data of all related papers.

Conclusion
Our systematic review highlights the prevalence of vitamin D deficiency among overweight/obese individuals and its inverse correlation with adiposity measures.Despite this association, it is essential to acknowledge the influence of various confounding factors, including dietary intake, physical activity, educational level, and seasonal variations, which could impact the serum 25 Not observational (n = 170) Not useful outcomes (n = 57) Studies conducted in the group of unhealthy participants (n = 298) Records identified from: Citation searching (n = 28) Reports assessed for eligibility (n = 14) Reports excluded: Not useful outcomes (n = 3) Studies conducted in the group of patients only (n = 9) Studies included in systematic review (n = 72)

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(OH)D <20 ng/mL; and ≥20 ng/mL as sufficiency Weight, height, BMI, WC, HC, body composition.Overweight and obese groups had higher PTH and lower 25(OH)D levels than normal weight group.The overweight group had higher 25(OH)D and lower PTH than obese group.group Liquid chromatography-tandem mass spectrometry/ chemiluminescence Sufficient vitamin D >50 nmol/L, insufficient: 25-50 nmol/L and deficient: <25 nmol/L Weight, height, BMI.Sex, age, education, residence type, BMI and smoking 25(OH)D levels were significantly lower in obese females than in the normal weight females.In the males, the 25(OH)D levels did not differ among the BMI groups.The increase in BMI by 1 kg/m2 was associated with an increase in the prevalence of vitamin D deficiency in the young females by 1%.Higher serum levels of PTH and lower 25(OH)D in the obese subjects compared to leaner subjects were observed.Weight, height, BMI, WC, HC.Age, sex, season, iPTH, and presence of diabetes Neither obesity at baseline nor the development of obesity were significantly associated with vitamin D status.In nonobese subjects 25(OH)D ≤17 ng/mL was associated with an increased risk of developing obesity in the next of the longitudinal study on nutrition and health status.Direct electrochemiluminescence immunoassay 25(OH)D <25.0 nmol/L as deficient, 25.0-49.9nmol/L as insufficient and ≥50.0 nmol/L as adequate Weight, height, BMI, WC, HC, body composition.

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Competitive protein binding assay/ radioimmunoassay NM Weight, height, BMI.NM PTH was higher and 25(OH)D was lower in the obese than in the nonobese individuals.Obese patients before intestinal bypass r gastric partitioning versus healthy normal controls Competitive protein-binding assay NM Weight, height, BMI.NM The mean plasma 25(OH)D level was significantly lower in the obese group than in age-matched controls.Adult population of LIFE-Adult-Study Chemiluminescent enzyme immunometric assay Deficiency: 25(OH)D <20 ng/mL BMI, WC, HC, WHR, %BF.
05) elevated BMI Z-scores, waist Z-scores, body fat percentages, fat mass indexes, and PTH values than those with normal vitamin D state.The serum 25(OH)D levels were negatively correlated (P < 0.05) with body fat percentage, fat mass index, and PTH.Lean and overweight boys (based on CDC-BMI percentiles) had similar mean 25(OH)D levels (P = 0.160) and were below sufficiency thresholds according to an analysis by Di Nisio et al. (2015) (26).However, there was a large proportion of subjects with insufficient or deficient 25(OH)D in both groups (normal weight: 45/59, 76 %; overweight/obese: 45/49, 92%, P = 0.03).
On the other hand, it has been suggested that low serum 25(OH)D concentrations reduce calcium absorption.PTH is secreted in response to low serum calcium concentrations, which stimulates the production of 1,25(OH) 2 D. The (nearly) normal serum levels of 1,25(OH) 2 D are maintained at the expense of high serum PTH concentrations, known as 'secondary hyperparathyroidism'. Considering that serum 25(OH)D is the substrate for serum 1,25(OH) 2 D, serum 25(OH)D levels tend to decrease when serum 1,25(OH) 2 D increases.PTH may contribute to fat accumulation by increasing insulin resistance and inhibiting lipolysis

Table 1 PICOS
(population, intervention/exposure, comparator, outcome, and setting) criteria used to perform the systematic review.

Table 2
Characteristics of the studies investigating the association between vitamin D and/or PTH with anthropometric indices in children/adolescents.

Study population Method of 25(OH)D measurement Cutoffs for vitamin D status Anthropometric indices investigated in the study and their cutoff points Adjustments Main findings
4BMI, body mass index; F/M, female/male; FMI, fat mass index; iPTH, intact parathyroid hormone; NOS, Newcastle-Ottawa Scale; PA, physical activity; PTH, parathyroid hormone; SDS, standard deviation score; WC, waist circumference; WHO, World Health Organization.

Table 3
Characteristics of the studies investigating the association between vitamin D and/or PTH with anthropometric indices in adult and/or elderly population.

Table 3 Continued.
Anthropometric status was assessed based on weight, BMI, WC, WHR, and body composition.

Table 3 Continued.
(OH)D levels.Further prospective investigations are warranted to establish a causal relationship between vitamin D levels and obesity, shedding light on the underlying mechanisms.Additionally, the findings underscore the importance of monitoring serum vitamin D levels in individuals with excess weight.Considering the variability in climate and dietary patterns across different regions, standardizing the 25(OH)D cut-off points would benefit from additional research.Increased awareness of the interplay between obesity and vitamin D levels can prompt adjustments in clinical approaches among nutritionists and health-care professionals.Because the field of vitamin D research is dynamic and continues to evolve, and new studies may indeed provide further insights into the relationship between serum 25(OH)D levels and adiposity.In addition, the scarcity of cohort studies underscores the need for further longitudinal investigations to elucidate the causative mechanisms linking vitamin D with adiposity.So, we recommend that future researchers consider conducting updated systematic reviews to integrate the latest evidence on this important topic.