2023; 21(4): 617-633  https://doi.org/10.9758/cpn.22.1040
Correlation between Vitamin B12 and Mental Health in Children and Adolescents: A Systematic Review and Meta-analysis
Yongjun Tan1, Li Zhou1, Kaiqi Gu2, Caihong Xie2, Yuhan Wang2, Lijun Cha2, Youlin Wu1, Jiani Wang1, Xiaosong Song1, Xia Chen1, Hua Hu2, Qin Yang1
1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Correspondence to: Qin Yang
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, China
E-mail: xyqh200@126.com
ORCID: https://orcid.org/0000-0003-4040-1661

Hua Hu
Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, China
E-mail: huhuateam@126.com
ORCID: https://orcid.org/0000-0002-6816-2589
Received: November 17, 2022; Revised: December 29, 2022; Accepted: February 1, 2023; Published online: June 2, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
To conduct the association between vitamin B12 and mental health in children and adolescents. Five databases were searched for observational studies in any language reporting on mental health and vitamin B12 levels or intake in children and adolescents from inception to March 18, 2022. Two authors independently extracted data and assessed study quality. Qualitative and quantitative analysis of data were performed. The review was registered in the PROSPERO database (CRD42022345476). Fifty six studies containing 37,932 participants were identified in the review. Vitamin B12 levels were lower in participants with autism spectrum disorders (ASD) (standardized mean difference [SMD], −1.61; 95% confidence interval [95% CI], −2.44 to −0.79; p < 0.001), attention deficit hyperactivity disorders (SMD, −0.39; 95% CI, −0.78 to −0.00; p = 0.049) compared with control group. Vitamin B12 intake were lower in participants with ASDs (SMD, −0.86; 95% CI, −1.48 to −0.24; p = 0.006) compared with control group, but showed no difference between depression group (SMD, −0.06; 95% CI, −0.15 to 0.03; p = 0.17) and the control group. Higher vitamin B12 intake were associated with lower risk of depression (odds ratio [OR], 0.79; 95% CI, 0.63−0.98; p = 0.034) and behavioral problems (OR, 0.83; 95% CI, 0.69−0.99; p = 0.04). The vast majority of included studies supported potential positive influence of vitamin B12 on mental health, and vitamin B12 deficiency may be a reversible cause for some mental health disorders in children and adolescents.
Keywords: Vitamin B12; Child; Adolescents; Mental health; Meta-analysis
INTRODUCTION

Mental health disorders of childhood and adolescence are disorders of the psychological development, behavior and emotion that occur in childhood and adolescence [1]. In 2021, the World Health Organization (WHO) reported that 14.3% of adolescents (aged 10−19 years) suffered from mental health disorders worldwide, which accounted for 13% of the global burden of disease in this age group. If mental health disorders in childhood and adolescence are not fully controlled, they may extend into adulthood and severely affect the quality of life, work and school [2]. Therefore, it is particularly important to pay attention to mental health disorders in children and adolescents.

Mental health disorders are related to numerous factors. Dietary habits play an irreplaceable role in the occurrence and development of mental health disorders [3]. Studies showed that adherence to the Mediterranean diet was associated with better mental and physical health [4-6]. Vitamin B12, an essential nutrient for human, is mainly obtained from animal products, such as lean meat, fish, liver, and eggs [7]. The most two physiologically important derivatives of vitamin B12 are cobalamin (AdoCbl) and methylcobalamin (MeCbl) in mammals. AdoCbl is a co-enzyme of methylmalonyl-CoA mutase that converts meth-ylmalonyl-CoA to succinyl-CoA [8]. MeCbl is a cofactor of methionine-synthase which methylates homocysteine to methionine, thus providing methyl donors to regulate modification and processing of protein and nucleic acid, and methylation of lecithin and myelin [9]. Vitamin B12 deficiency may lead to the disturbance of the above biochemical processes, and the accumulated homocysteine is neurotoxic. These alterations of biochemistry and metabolism may lead to the occurrence of disease [10].

Vitamin B12 deficiency mainly causes a wide series of neurological and hematological symptoms. The classic manifestations of vitamin B12 deficiency were pernicious anaemia and subacute combined degeneration of spinal cord (sensory and motor disturbances, ataxia). Moreover, vitamin B12 levels or intake related to many mental health disorders or symptoms in adults and children. For example, in adults, an individually matched case-control study suggested that dietary patterns and depression were co-related via the intermediary role of vitamin B12 and folate [11]. In children, a case-control study showed that vitamin B12 levels were higher in depression group compared with control group and were positively correlated with depression severity [12]. Other mental health disorders, such as anxiety [13,14], schizophrenia [15,16], obsessive compulsive disorder [17,18] were also found to be related to vitamin B12 in adults and children.

There have been several systematic review or meta- analysis revealing their relationship in adults [19-21], while there are no systematic review or meta-analysis to demonstrate the correlation between vitamin B12 and mental health in children. Some mental health disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) commonly occurs in childhood. Anxiety and depression are most important and common emotional problems. Behavioral problems are diversified and may predict adult psychopathology. These mental disorders would be better to discuss among children and adolescents.

Therefore, we conducted a systematic review and meta- analysis via multiple databases for observational studies on the correlation between vitamin B12 (intake or levels) and mental health or mental health disorders in children and adolescents.

METHODS

The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22] and was registered in PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345476).

Definition

We used WHO definition of mental health, which explains mental health as ‘a state of well-being in which the individual realizes his or her own abilities, can cope with normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community’ and ‘mental health is more than just the absence of mental disorders or disabilities’ [23].

We adopted the definition of behavioral problems by Chinese scholars, which tends to have the following viewpoints: behavioral problems are all abnormal behaviors that hinder individual and social development, involving externalizing and internalizing behavioral problems. The core point is that difficult adaptation behaviors produced in the process of socialization for children and adolescents [24,25].

Search Strategy

The literature searching covered observational studies included in databases of PubMed, Web of Science, Embase, Ovid MEDLINE(R), Cochrane Library in any language from inception to March 18, 2022. The search terms used Medical Subject Heading (MeSH) terms and text words for “Vitamin B12”, “Methylmalonic Acid”, “Mental Health”, and “Mental Disorders”. Additionally, truncated wildcard terms such as “Depress*”, “Anxi*”, “Schizophren*”, “Behaviour Disorder*”, “Personality Dis-order*”, and “Mood Disorder*” were also included. Sup-plementary Tables 1−5 (available online) demonstrates the detailed search strategy. Reference lists of the screened full-texts were hand searched for any relevant studies.

Selection of Studies

We focused on studies reporting the correlation between the mental health or mental health disorders and vitamin B12 levels or intake in children and adolescents.

The inclusion criteria were as follows: (1) observational (cohort or cross-sectional or case-control) studies; (2) participants were children or adolescents. It was acceptable for the age of all participants younger than 25 years old; (3) exposure was vitamin B12 intake or the levels of markers indicating vitamin B12 status (serum/plasma vitamin B12, methylmalonic acid or holotranscobalamin). If one study reported maternal or paternal B12 levels or intake, it can be accepted when it also reported results for children; (4) outcome measures were containing any mental health aspect assessed based on any method (e.g., medical diagnosis, questionnaire).

The exclusion criteria were as follows: (1) studies presented physical diseases or primarily cognitive impairment as the main diagnosis or recruitment criteria and mental health disorders as comorbidities; (2) mental health disorders associated with dietary restraint or restriction closely (e.g., eating disorder); (3) no association was presented between vitamin B12 status or intake and mental health disorders; (4) no control group; (5) reviews, comments, case reports, study protocol, letters; (6) pregnant adolescents; (7) no full paper.

To ensure the most rigorous research methodology, unpublished studies and conference proceedings were not included. Two independent reviewers (Yongjun Tan and Kaiqi Gu) screened titles and abstracts for suitable articles and solved disagreements by consensus and discussion. Then we read the full text in the same way and screened out suitable articles according to the inclusion and exclusion criteria. All exclusion reasons were recorded during the selection process as shown in Figure 1.

Data Extraction and Quality Assessment

Data were extracted by two reviewers (Yongjun Tan and Kaiqi Gu) and organized into tables systematically. The extracted information included: first author, study type, location, sample size, participants’ age and gender, follow-up time (if applicable), vitamin B12 levels or intake of the patients and controls, mental health disorders, psychological measure, applied intervention (if applicable), details on data analysis and results (p, multivariable- adjusted odds ratio [OR], hazard ratio [HR], or relative risk [RR] and 95% confidence intervals [95% CI]).

Two independent reviewers (Caihong Xie and Li Zhou) assessed the risk of bias and methodological quality of the inclusion studies. In the event of a dispute, a third person (Professor Yang) would conduct an evaluation. The qualities of the observational studies were assessed by the Newcastle-Ottawa Scale (NOS) [26]. The follow-up rate > 80% was defined as follow-up within the acceptable range. According to the total score, the qualities were divided into: low (0−3 points), moderate (4−6 points), and high (7−9 points).

Data Synthesis and Statistical Analysis

The meta-analysis was performed using Stata statistical software 14.0 (Stata Co.). A random effects model was used because of heterogeneity in clinical (demographic characteristics) and methodological (measurement method) aspects of included studies. If there were three or more comparable studies, we conduct a meta-analysis, otherwise we conduct a descriptive analysis. There were sufficient data to conduct 2 meta-analyses. The first compared the mean levels or intake of vitamin B12 between each mental health disorder and its control group. DerSimonian and Laird random-effects method was used to calculate the standardized mean difference (SMD, Hedge’s g) and 95% CI. For studies not reporting mean or standard deviation (SD) values, we calculated from median, low and high end of the range [27]. The second pooled multivariable- adjusted OR or RR for each mental disorder by levels or intake of vitamin B12 using DerSimonian and Laird random-effects method.

Heterogeneity was assessed using chi-squared test and the I2 statistic. I2 < 25%, 50%, and 75% was considered as low, moderate and high heterogeneity, respectively [28]. Subgroup analysis was performed to explain the source of heterogeneity. A meta-regression was performed with effect size as the dependent variable if the number of included studies was greater than 10. This enabled us to examine the moderator variables which examined in the subgroup analyses as predictors of outcome.

Sensitivity analysis was performed to identify the source of heterogeneity and to check the robustness of the results by omitting studies 1 by 1. A funnel plot and Egger’s test were conducted to detect the publication bias [29]. If there was publication bias, the Duval and Tweedie [30] nonparametric trim-and-fill methods were conducted to estimate the unbiased effect size. Statistical significance was p < 0.05.

RESULTS

Literature Search

Figure 1 illustrated the study flow-chart. Fifty six studies involving 37,932 participants were included in the review. Thirty five studies presented the relationship between vitamin B12 levels and mental health disorders and 21 studies addressed the relationship between vitamin B12 intake and mental health disorders. Forty two studies involving 22,584 participants were eligible for meta-analysis.

Study Characteristics

Details of study characteristics were showed in Tables 1−3. The following categories of mental health disorders were discussed: ASDs (n = 26) [31-51], attention deficit hyperactivity disorder (n = 9) [32,34,36,52-57], behavior problems (n = 9) [58-62], emotional problems (n = 9) [12,14,59,61,63-65], socio-emotional development (n = 1) [66], fatigue (n = 1) [14], obsessive compulsive disorder (n = 1) [18].

Quality Assessment

For the quality of studies accessed by NOS, 19 studies (33.9%) were considered as high quality. Thirty studies (53.6%) were considered as of moderate quality and 7 studies (12.5%) were rated as low quality. The most common unmet items were representativeness of cases and selection of controls. Eleven studies did not present an appropriate definition of controls. Ten studies had no adjustment for age and gender as confounders. Detailed of quality assessment are summarized in Supplementary Table 6 (available online).

Meta-analysis

Correlation between vitamin B12 levels or intake and ASD

Fifteen studies [31-44], involving 1,042 (521 vs. 521) children and adolescents, were analyzed to compare mean vitamin B12 levels between patients with ASD and the controls. Vitamin B12 levels were lower in the ASD group as compared to the control group (SMD, −1.61; 95% CI, −2.44 to −0.79; I2 = 97%; p < 0.001) (Fig. 2). Despite this heterogeneity, no study suggested higher vitamin B12 levels in patients with ASD compared with controls. A subgroup analysis was conducted to investigate the source of heterogeneity (Supplementary Table 7; available online). Several subgroups showed effect sizes which were different from the overall effect size, including subgroup of sample size < 40, testing vitamin B12 by ELISA, testing vitamin B12 by ECLIA. The heterogeneity substantially decreased (I2 < 50%) were in subgroups of sample size < 40 (I2 = 0). There was no collinearity between all the variables. The meta-regression analysis showed that whether vitamin B12 was below normal value in controls (p < 0.04) and whether patients presented the typical triad of autistic traits (p < 0.01) contributed considerably to the heterogeneity (Supplementary Table 8; available online). The sensitivity analysis demonstrated the stable results (Supplementary Fig. 1; available online). The funnel plot showed asymmetry (Supplementary Fig. 2; available online). The Egger’s test (p = 0.003) suggested significant publication bias. To adjust for this publication bias, we recomputed the effect sizes using trim and fill method and then found four missing studies would be needed to make funnel plot symmetry. The adjusted effect size (SMD, −2.60; 95% CI, −3.67 to −1.53; p < 0.001) was not significantly different as compared to original effect size.

Nine studies [33,39,40,45-48,50,51], involving 911 (469 vs. 442) children and adolescents, were analyzed to compare mean vitamin B12 intake between patients with ASD and controls. Vitamin B12 intake were lower in the ASD group as compared to the controls (SMD, −0.86; 95% CI, −1.48 to −0.24; I2 = 94%; p = 0.006) (Fig. 2). No study suggested that vitamin B12 intake was higher in the ASD group compared with the controls. Subgroups of studies conducted in middle-income economies, sample size > 80, study quality of low and moderate showed effect sizes significantly different from the overall effect size (Supplementary Table 9; available online). The heterogeneity substantially decreased (I2 < 50%) were in subgroups of studies conducted in high-income economies (I2 = 39%), sample size ≤ 80 (I2 = 0), studies of high quality (I2 = 0). The sensitivity analysis suggested the stable results (Supplementary Fig. 3; available online), while the I2 value changed from 94% to 61% when the study by Meguid et al. [46] was removed. The funnel plot was symmetry (Supplementary Fig. 4; available online). The Egger’s test (p = 0.39) suggested no publication bias.

Correlation between vitamin B12 levels and ADHD

Seven studies [32,34,36,52-55], involving 1,030 (516 vs. 514) children and adolescents, were analyzed to compare mean vitamin B12 levels between patients with ADHD and the controls. Vitamin B12 levels were lower in the ADHD group compared with the control group (SMD, −0.39; 95% CI, −0.78 to −0.00; I2 = 88%; p = 0.049) (Fig. 3). Only one study demonstrated higher vitamin B12 levels in patients with ADHD compared with controls [34]. Subgroups of sample size ≤ 80, testing vitamin B12 with CLIA, study quality of moderate and high showed effect sizes consistent with the overall effect size (Supplementary Table 10; available online). The heterogeneity substantially decreased (I2 < 50%) were in subgroups of testing vitamin B12 with CLIA (I2 = 0). Sensitivity analysis suggested that there was no significant difference in vitamin B12 levels between ADHD and controls if any studies other than the study by Topal et al. [34] were excluded (Supplementary Fig. 5; available online). The funnel plot was symmetry (Supplementary Fig. 6; available online). The Egger’s test (p = 0.31) suggested no publication bias.

Correlation between vitamin B12 intake and depression

Considering anxiety and depression were most important and common emotional problems, we mainly focused on discussion of them. While studies presented the relationship between anxiety and vitamin B12 were less than 3, a descriptive analysis was conducted in the next part. In this part, we pooled the results on depression.

Three studies [63,64], involving 7,227 (1,913 vs. 5,314) participants, showed that there was no significant difference (SMD, −0.06; 95% CI, −0.15 to 0.03; I2 = 55%; p = 0.17) in the vitamin B12 intake between depression and the control group (Fig. 4). Sensitivity analysis showed stable results (Supplementary Fig. 7; available online), while I2 value changed from 55% to 0 after excluding study by Rubio-López et al. [63].

Three studies [64,65] (7,366 children and adolescents) reported OR for association of depression with vitamin B12 intake. The results showed that a higher vitamin B12 intake was associated with a lower risk of depression (OR, 0.79; 95% CI, 0.63−0.98; p = 0.034), with low heterogeneity (I2 = 6%) (Fig. 4). Sensitivity analysis showed unrobust results (Supplementary Fig. 8; available online). When study conducted in boys by Murakami et al. [64] or study by Kim et al. [65] was removed, the effect size changed. Due to the small number of studies included, subgroup analysis and publication bias tests were not performed in above 2 analyses.

Correlation between vitamin B12 intake and behavioral problems

Five studies [58,61] with 5,008 participants suggested that high vitamin B12 intake was associated with a decreased risk of behavioral problems (OR, 0.83; 95% CI, 0.69−0.99; p = 0.04), with no heterogeneity (I2 = 0) (Fig. 5). Sensitivity analysis showed unrobust results (Supplementary Fig. 9; available online). Only after omitting study by Mohseni et al. [58] or study about peer problems by Miyake et al. [61], the combined OR consistent with original OR. Because four of the five studies included were from the same article, no subgroup analysis was performed. Due to the small number of studies included, publication bias tests were not performed, either.

Descriptive Analysis

Vitamin B12 and ASD

Emond et al. [49] reported that lower vitamin B12 intake of children was not associated with ASD (OR, 0.90; 95% CI, 0.65−1.25; p = 0.54). Raghavan et al. [67] indicated that very high maternal vitamin B12 level (≥ 536.8 pmol/L) at birth increased risk of ASD in children (OR, 2.5; 95% CI, 1.4−4.5; p < 0.05), compared with middle 80th percentile (≥ 247.0 to < 536.8 pmol/L) levels.

Vitamin B12 and ADHD

Sourander et al. [57] suggested that lower maternal vitamin B12 levels was not associated with offspring ADHD (OR, 0.97; 95% CI, 0.79−1.18; p = 0.75). Jamshidnia et al. [56] reported that vitamin B12 intake in the ADHD group was lower than that in control group (p = 0.02). OR (95% CI) of ADHD was 0.76 (0.52−1.13) for the highest tertile of vitamin B12 intake compared to lowest [56].

Vitamin B12 and emotional or behavior problems

Esnafoglu and Ozturan [12] showed that vitamin B12 levels in children with depression were lower than those in control group (p < 0.001). Kazanci et al. [14] showed that low vitamin B12 (< 300 pg/ml) was associated with increased risk of depression (RR, 1.5; 95% CI, 1.13−2.00; p < 0.05), anxiety (RR, 1.41; 95% CI, 1.12−1.79; p < 0.05), and fatigue (RR, 2.3; 95% CI, 1.78−2.99; p < 0.05) of children.

Miyake et al. [61] showed that maternal vitamin B12 intake were not associated with emotional problems (OR, 0.68; 95% CI, 0.41−1.10; p > 0.05). Ars et al. [59] showed that prenatal vitamin B12 levels were not associated with risk of emotional problems (OR, 0.81; 95% CI, 0.41−1.63; p > 0.05) and behavioral problems (OR, 0.56; 95% CI, 0.27−1.67; p > 0.05). Duong et al. [60] reported that vitamin B12 deficiency (< 148 pmol/L) increased risk of grade repetition (OR, 2.34; 95% CI, 1.03−5.41; p = 0.04) in children. Robinson et al. [62] showed that mean externalizing problem scores of the Youth Self-Report questionnaire among adolescent boys were increased 2.7 (95% CI, 0.4−4.9; p < 0.05) units in vitamin B12 ≤ 204 pmol/L group compared with vitamin B12 levels > 204 pmol/L group.

Vitamin B12 and other mental health disorders

Metwally et al. [66] suggested that vitamin B12 levels were lower in infants with socio-emotional composite score below average than those of above average, but subnormal serum vitamin B12 (< 203 pg/ml) did not convey a risk for socio-emotional development (OR, 3.35; 95% CI, 0.74−15.61; p > 0.05). Esnafoğlu and Yaman [18] illustrated that vitamin B12 levels were lower in children and adolescents with obsessive compulsive disorder compared with the control group (p < 0.001).

DISCUSSION

The present meta-analysis summarized the existing evidences and synthesized the results of studies between vitamin B12 levels or intake and mental health or mental health disorders in children and adolescents. The result showed vitamin B12 levels and intake were lower in ASD group compared with the control group. In ADHD, vitamin B12 levels also were lower compared with the control group. No significant difference was observed in the vitamin B12 intake between the patients with depression and the control group, while a higher vitamin B12 intake was associated with a lower risk of depression and behavioral problems. Moreover, vitamin B12 were also found to be associated with fatigue, obsessive compulsive disorder, and socio-emotional development. These results suggest that potential positive influence of vitamin B12 on mental health, and vitamin B12 deficiency may be a reversible cause for some mental health disorders in children and adolescents.

Prades et al. [68] reported vitamin B12 levels in children and adolescents were lower in the ASD group (MD, −100.38 pg/ml; 95% CI, −158.52 to −42.24; p < 0.05) and ADHD group (MD, −199.14 pg/ml; 95% CI, −212.00 to −186.28; p < 0.05) compared with the control group, respectively. Similar results were reported by Chen et al. [69] (SMD, −0.47; 95% CI, −0.85 to −0.09; p < 0.05) for ASD. Esteban-Figuerola et al. [70] revealed that vitamin B12 intake was significantly lower in ASD group than that in the control group (SMD, −0.52; 95% CI, −0.95 to −0.09; p < 0.05). The above conclusions were similar to our analysis about ASD and ADHD, but these researches only presented the relationship between a mental condition with vitamin B12 intake or vitamin B12 levels. Our research included as many as mental health disorders, and both intake and levels of vitamin B12 were taken into consideration, which made our analysis more comprehensive and systematic. These results can be the basis for etiological study and formation of the therapeutic strategy for ASD and ADHD in the future.

Depression or anxiety, the most common and important emotional problems in children and adolescents, were not analyzed in relation to vitamin B12 in any systematic review or meta-analysis among children and adolescents previously. To our knowledge, only several studies showed their relationship in adults. A meta-analysis showed that the pooled RR (95% CI) of depression for the highest vs. the lowest category of vitamin B12 intake was 0.86 (0.75−0.99) in participants of all ages [71]. Notably, the upper limit of the 95% CI, 0.99 was close to 1. In the included studies of our systematic review, no significant difference was observed in the vitamin B12 intake between depression and control group. Higher vitamin B12 were associated with lower risk of depression with unrobust results. This may suggest that vitamin B12 intake were not related to depression or had weak connection with depression. Noteworthily, most of included studies in these systematic review or meta-analysis were cross- sectional or case-control studies, so current vitamin B12 intake cannot reflect previous vitamin B12 intake. What’s more, the intake of vitamin B12 were mostly assessed by self-report 24-hour food recalls or food dairy, so the recalling bias and incorrect estimate of food take may affect the results. The results on the relationship may be in-accurate. This reminded us more prospective longitudinal studies were needed. Vitamin B12 levels, measured by laboratory instrument, were objective indicator for vitamin B12 status. All included studies on relationship between vitamin B12 levels and anxiety/depression, presented a negative correlation between them [12,14].

Vitamin B12 were also correlated to multiple behavioral problems, fatigue, socio-emotional development and obsessive compulsive disorder. Considering most of included studies were not prospective longitudinal studies, causal inference cannot be made between vitamin B12 and mental health disorders. Moreover, confounding factors, such as participants’ characteristics (age, gender, race, genotype, body mass index, diary, personality, socioeco-nomic status), the method of diagnosis, assessment tools, study design, statistics should be taken into consideration for the analysis.

When we combined the results of the studies, a large degree of heterogeneity was observed, especially in meta- analysis of vitamin B12 levels and ASD (I2 = 97%), vitamin B12 intake and ASD (I2 = 94%), vitamin B12 levels and ADHD (I2 = 88%). Subgroup analysis, meta-regression and sensitivity analysis were conducted to explore the source of heterogeneity. In the meta-analysis of vitamin B12 levels and ASD, the subgroup analysis showed that the I2 value in subgroup of sample size < 40 was 0, which may attribute to the small individual heterogeneity in small sample size. Although meta-regression suggested whether vitamin B12 was below normal value in controls (p < 0.04) and whether patients presented the typical triad of autistic traits (p < 0.01) contributed considerably to the heterogeneity, the heterogeneity in their respective subgroups was large. Some children may show only one or two core symptoms (the concomitant occurrence of impaired social interaction; restricted, perseverative, and stereotypical behavior; and abnormal communication skills) at an early stage of ASD, and whether they were included in the study may become a source of hetero-geneity. Theoretically, the vitamin B12 levels of the healthy controls recruited in a study should be consistent with that of healthy people (≥ 300 pg/ml). However, the mean levels of vitamin B12 in controls of the studies by Ali et al. [37], Topal et al. [34], and Tu et al. [44] were lower than normal levels, which suggested that the controls may have a concomitant disease related to vitamin B12 insufficiency and then may interfere with the results. In the meta-analysis of vitamin B12 intake and ASD, subgroups analysis can explain partial heterogeneity greatly. More-over, after excluding the study by Meguid et al. [46], the I2 value changed from 94% to 61%. This may be because this was the only study conducted in Africa. In the meta- analysis of vitamin B12 levels and ADHD, after excluding the study by Altun et al. [52], the I2 value changed from 88% to 63%. It may be because the sample size (60) of this study was the smallest in studies included.

This study has several advantages. Firstly, the pooled OR/HR extracted from original studies were all adjusted values which made the results more credible. Secondly, the meta-analysis included studies of various types (case- control, cross-sectional, cohort) and various mental health conditions, which made the analysis complete and com-prehensive. Thirdly, the review included an enlarged sample size, which reduced the sampling error and was more likely to draw the reasonable conclusions.

This study also has several limitations. Firstly, although we excluded studies which discussed mental health disorders associated with dietary restraint or restriction closely, we have to admit that the vast majority of mental illnesses are related to changes in appetite and food intake, such as food selectivity in ASD, reduced appetite and food intake in depression. On the one hand, causal inference cannot be made between the vitamin B12 intake and mental disorders. On the other hand, other components related to vitamin B12 in food may contribute to the incidence of mental disease. Secondly, too few prospec-tive cohort studies included affected causal inference. Thirdly, we didn’t perform a dose–response analysis of the correlation between vitamin B12 and mental health dis-orders. Lastly, slight publication bias was observed in the meta-analyses of the pooled affect size of vitamin B12 levels in ASD, which might due to the limited numbers and the small sample sizes of studies included. In addition, grey literature was not searched.

These results suggested that parents should take their children to assess vitamin B12 levels regularly and remind children to take food rich in vitamin B12 to ensure adequate B12 intake. In addition, pregnant women should also assess vitamin B12 levels regularly and take moderate vitamin B12 to prevent offspring from mental health problems. Moreover, clinicians must keep in mind that vitamin B12 deficiency may be a reversible cause of some mental disorders in children and adolescents.

CONCLUSION

This systematic review and meta-analysis revealed that vitamin B12 were associated with some mental health disorders in children and adolescents. However, it needs further high-quality cohort studies to better understand the correlation between vitamin B12 and mental health disorders in children and adolescents.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant no. 82171456 and 81971229) and the Natural Science Foundation of Chongqing Science and Technology Commission (Grant no.cstc2021jcyj-msxmX0263).

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Qin Yang, Yongjun Tan. Data acquisition: Yongjun Tan, Kaiqi Gu, Caihong Xie, Li Zhou, Lijun Cha, Yuhan Wang. Formal analysis: Yongjun Tan, Hua Hu, Qin Yang. Funding: Qin Yang. Supervision: Qin Yang, Hua Hu. Writing—original draft: Yongjun Tan, Youlin Wu, Xia Chen, Jiani Wang, Xiaosong Song, Hua Hu, Qin Yang. Writing—review & editing: Qin Yang, Yongjun Tan.

Figures
Fig. 1. The inclusion procedure in a systematic review and meta-analysis of the literature.
VB12, vitamin B12; SD, standard deviation; OR, odds ratio; RR, relative risk; HR, hazard ratio.
Fig. 2. Meta-analysis of vitamin B12 levels (A) and intake (B) between ASD and control group. Weights are from random effects analysis.
ASD, autism spectrum disorders; SMD, standardized mean difference; CI, confidence interval; AD, autistic disorder; PDD-NOS, Pervasive Developmental Disorders Not Otherwise Specified; AS, Asperger syndrome; MMA, methylmalonic acid.
Fig. 3. Meta-analysis of vitamin B12 levels between ADHD and control group. Weights are from random effects analysis.
ADHD, attention-deficit/hyperactivity disorder; SMD, standardized mean difference; CI, confidence interval.
Fig. 4. Meta-analysis of vitamin B12 intake (A: SMD, B: OR) between de-pression and control group. Weights are from random effects analysis.
SMD, standardized mean difference; OR, odds ratio; CI, confidence interval.
Fig. 5. Meta-analysis of vitamin B12 intake between behavioral problems and control group. Weights are from random effects analysis.
OR, odds ratio; CI, confidence interval.
Tables

Correlation between vitamin B12 levels and mental health disorders in children and adolescents: cross-sectional and case-control studies

First author Type Location Participants (girls) Age Vitamin B12 level (pg/ml) Mental disorders; psychological measure pvalue/OR/RR/HR (95% CI) Quality
Case Control
Ali [37] CCS Oman 80 (-) 3−5 yr 191.1 ± 0.9 288.9 ± 1.3 ASD; DSM-IV-TR, the typical triad of autistic traits, CARS < 0.05 Moderate
Al-Farsi [39] CCS Oman 80 (40) 3−5 yr 183.6 ± 12.3 341.2 ± 27.4 ASD; DSM-IV-TR, the typical triad of autistic traits, CARS 0.02 High
Altun [38] CCS Turkey 105 (17) 3−12 yr 181.5 ± 41.61 382.06 ± 71.34 ASD; DSM-IV-TR, CARS < 0.001 High
Bala [36] CCS Turkey 43 (20) 2−18 yr 235.13 ± 68.68 424.04 ± 167.94 ASD; DSM-IV, DSM-V, CARS < 0.05 Moderate
61 (25) 2−18 yr 371.72 ± 160.63 424.04 ± 167.94 ADHD; DSM-V, DSM-IV, DBDRS < 0.05 Moderate
Bala [42] CCS Turkey 42 (19) 2−18 yr 233.62 ± 60.73 428.50 ± 173.86 ASD; DSM-V, DSM-IV-TR, CARS < 0.001 Moderate
Garipardic [32] CCS Turkey 43 (20) 2−18 yr 232.06 ± 65.17 428.50 ± 173.86 ASD;DSM-V, DSM-IV-TR, CARS < 0.05 Moderate
61 (25) 2−18 yr 371.03 ± 155.74 428.50 ± 173.86 ADHD; DSM-V, DSM-IV-TR, SSEDBD < 0.05 Moderate
Erden [43] CCS Turkey 69 (12) 30−80 mo 632.25 ± 106.65 707.96 ± 160.97 ASD; DSM-V, K-SADS-PL, CARS 0.026 High
Paşca [41] CCS Romania 28 (7) 5.10 ± 0.45 yr vs. 5.89 ± 0.61 yr 747.09 ± 94.26 724.50 ± 140.51 ASD (AD); DSM-IVR NS Moderate
41 (15) 8.83 ± 0.84 yr vs. 9.05 ± 0.91 yr 608.50 ± 67.82 833.02 ± 127.34 ASD (PDD-NOS); DSM-IVR NS Moderate
13 (0) 9.23 ± 1.82 yr vs. 10.22 ± 1.05 yr 536.04 ± 87.63 542.47 ± 175.57 ASD (AS); DSM-IVR NS Moderate
Topal [34] CCS Turkey 142 (38) 2−17 yr 233.01 ± 89.84 210.20 ± 81.17 ASD; DSM-V criteria with a non-structured interview, GARS-2, K-SADS-PL, NS Low
131 (36) 2−17 yr 239.79 ± 86.43 210.20 ± 81.17 ADHD; K-SADS-PL, DSM-V criteria with a non-structured interview, TDCABDSRS NS Mow
Tu [44] CCS China 60 (10) 2−6 yr 279.1 ± 6.61 283.1 ± 7.36 ASD; DSM-IV, the typical triad of autistic traits NS Moderate
Zou [35] CCS China 178 (22) 3−12 yr 500.11 ± 178.70 657.40 ± 271.45 ASD; DSM-V, ADOS, ADI-R < 0.001 Moderate
Hollowood- Jones [31] CCS USA 59 (59) 2−5 yr Maternal 355 ± 196 Maternal 473 ± 173 ASD; ADI-R 2.40E-03 High
0.15 ± 0.06a 0.15 ± 0.08a ASD; ADI-R NS
Altun [38] CCS Turkey 60 (16) 6−15 yr 259.75 ± 44.40 388.64 ± 73.11 ADHD; DSM-V, KSADS-PL, CPRS-R:L, CTRS, TDCABDSRS, WISC-R < 0.001 Moderate
Wang [53] CCS China 432 (60) 9.2 ± 1.7 yr vs. 9.2 ± 1.8 yr 573.8 ± 203 626.8 ± 205 ADHD; DSM-IV, CTRS, WWPAS 0.007 High
Üskül [54] CCS Turkey 207 (60) 5−15 yr 434.57 ± 219.98 435.03 ± 205.59 ADHD; DSM-IV, CPRS, CTRS, Turgay ADHD Scale (Turgay DEHB Ölçeği) NS Low
Saha [55] CCS India 78 (-) 6−12 yr 232.61 ± 306.43 371.08 ± 245.43 ADHD; DSM-IV-TR, CPRS-R, WIS, DST 0.01 Moderate
Sourander [57] CCS Finland 2,052 (-) 0−7 day Maternal holotransco-balamin levels Maternal holotransco-balamin levels ADHD; ICD-8, ICD-9, ICD-10, DSM-IV 0.97 (0.79−1.18) for a 1-SD increase; 0.96 (0.73−1.27) by the lowest (< 1.2 pmol/L) vs. highest quintile (≥ 7.1 pmol/L) High
Metwally [66] CCS Egypt 655 (-) 6−24 mo 981.6 ± 422.0 1,109.4 ± 433.3 Socio-emotional development; Bayley-III, WPPSI-III, PLS-4, PDMS-2, BSID-III 3.35 (0.74−15.61) for low (< 203 pg/ml) vs. normal Moderate
Esnafoglu [12] CCS Turkey 132 (100) 15.08 ± 1.46 yr vs. 14.41 ± 2.32 yr 246 ± 92.17b 379 ± 138.93b Depression; DSM-V, CDI, STAI-1, STAI-2 < 0.001 Moderate
Kazanci [14] CSS Turkey 524 (272) 8.3 ± 4.2 yr Vitamin B12 levels Vitamin B12 levels Depression 1.5 (1.13−2.00) for low (< 300 pg/ml) vs. normal Low
Anxiety 1.41 (1.12−1.79): low (< 300 pg/ml) vs. normal Low
Fatigue 2.3 (1.78−2.99): low (< 300 pg/ml) vs. normal Low
Esnafoğlu [18] CCS Turkey 82 (42) 14.7 ± 2.3 yr vs. 14.2 ± 2.6 yr 243.6 ± 105.3 355.6 ± 115.6 OCD; DSM-V, Y-BOCS, CDI, STAI-1, STAI-2 < 0.001 Moderate

Values are presented as number only, range, or mean ± SD.

Vitamin B12, 1 pg/ml = 0.738 pmol/L. Turgay DEHB Ölçeği means ADHD scale in Turkish.

AD, autistic disorder; ADHD, attention-deficit/hyperactivity disorder; ADI-R, Autism Diagnostic Interview-Revise; AS, Asperger syndrome; ASD, autism spectrum disorders; Bayley-III, Bayley Scales of Infant and Toddler Development-Third Edition; BSID-III, Bayley Scales of Infant and Toddler Development-Third Edition; CARS, Childhood Autism Rating Scale; CCS, case-control study; CDI, Children’s Depression Inventory; CI, confidence interval; CPRS-R:L, Conners’ Parent Rating Scale-Revised:Long Form; CSS, cross-sectional study; CTRS, Conners’ Teacher Rating Scale; DBDRS, Disruptive Behavior Disorder Rating Scale; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised, Text Revision; DST, Developmental Screening Test; GARS-2, Gilliam Autism Rating Scale-Second Edition; HR, hazard ratio; ICD-8, International Classification of Disease version 8; K-SADS-PL, Kiddie-Schedule for Affective Disorders & Schizophrenia, Present & Lifetime Version; MMA, methylmalonic acid; NS, not significant; OCD, Obsessive Compulsive Disorder; OR, odds ratio; PDD-NOS, Pervasive Developmental Disorders Not Otherwise Specified; PDMS-2, Peabody Developmental Motor Scales 2nd Edition; PLS-4, Preschool Language Scale-Fourth Edition; RR, relative risk; SD, standard deviation; SSEDBD, Scale for Screening/Evaluation for Disruptive Behavior Disorders; STAI-1/2, State-Trait Anxiety Inventory 1/2; TDCABDSRS, the Turgay DSM-IV-based Child and Adolescent Behavior Disorders Screening and Rating Scale; WIS, Wechsler Intelligence Scale; WISC-R, Wechsler Intelligence Scale for Children-Revised; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence; WWPAS, Werry-Weiss-Peters Activity Scale; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; -, none.

aMaternal MMA levels; bcalculated by means of Hozo et al. [27].

Correlation between vitamin B12 intake and mental health disorders in children and adolescents: cross-sectional and case-control studies

First author Type Location Participants (girls) Age Vitamin B12 intake (mcg/day) Mental disorders; psychological measure pvalue/OR/RR/HR (95% CI) Quality
Case Control
Al-Farsi [39] CCS Oman 80 (40) 3−5 yr 1.30 ± 0.90 2.20 ± 0.80 ASD; DSM-IV-TR, the typical triad of autistic traits, CARS 0.02 High
Barnhill [33] CCS USA 143 (17) 2−8 yr 2.43 ± 1.83 3.80 ± 2.76 ASD; DSM-IV, DSM-V, SCQ, ADI-R, ADOS, ABAS-II < 0.001 High
Meguid [46] CCS Egypt 160 (35) 4−6 yr 390 ± 120 850 ± 150 ASD; DSM-IV-TR, CARS, ADI-R 0.001 Moderate
Shmaya [51] CCS Israel 79 (16) 3−6 yr 2.4 ± 0.9 3.3 ± 1.4 ASD; DSM-IV, CARS, ADOS, ASQ NS High
Zimmer [50] CCS USA 44 (14) 8.2 ± 3.2 yr vs. 8.1 ± 3.3 yr 4.69 ± 3.03 6.66 ± 2.04 ASD; ADOS, ADI-R < 0.05 Moderate
Malhi [48] CCS India 113 (34) 4−10 yr 510 ± 240 510 ± 300 ASD; DSM-IV NS Moderate
Marí-Bauset [40] CCS Spain 153 (55) 6−10 yr 4.81 ± 3.74 5.43 ± 3.26 ASD; ADOS-G, ADI-R NS Moderate
Graf-Myles [45] CCS USA 106 (22) 1−6 yr 2.51 ± 0.30a 2.67 ± 0.17a ASD; DSM-IV, ADI-R, ADOS < 0.002 High
Johnson [47] CCS USA 34 (-) 2−4 yr 5.28 ± 2.62 6.32 ± 2.35 ASD; DSM-IV, ADOS, MSEL, CBCL NS Moderate
Emond [49] CCS UK 9,860 (-) 38 mo Vitamin B12 intake Vitamin B12 intake ASD; clinical records, the national educational database 0.90 (0.65−1.25) for a 1-SD increase Moderate
Jamshidnia [56] CCS Iran 345 (83) 7−13 yr 4.51 ± 5.27 6.47 ± 8.75 ADHD; DSM-V 0.76 (0.52−1.13) by tertile of intake (T3/T1) High
Rubio-López [63] CSS Spain 710 (372) 6−9 yr 5.21 ± 1.38 5.89 ± 3.36 Depressive symptoms; CES-DC 0.016 Low
Murakami [64] CSS Japan 3,067 (0) 12−15 yr 6.40 ± 2.99b 6.52 ± 2.63b Depressive symptoms; CES-D 0.76 (0.53−1.10) by quintile of intake (Q5/Q1) Moderate
3,450 (3,450) 12−15 yr 5.53 ± 2.55b 5.56 ± 2.23b Depressive symptoms; CES-D 0.88 (0.66−1.18) by quintile of intake (Q5/Q1) Moderate
Kim [65] CCS Korea 849 (849) 12−18 yr Vitamin B12 intake Vitamin B12 intake Depression; K-BDI 0.53 (0.28−0.98) by tertile of intake (T3/T1) Moderate
Mohseni [58] CCS Iran 212 (212) 9−13 yr 3.84 ± 1.50 4.35 ± 1.23 Aggressive behavior; BPAQ 0.974 (0.943−1.780) per unit increase of intake Moderate

Values are presented as number only, range, or mean ± SD.

ABAS-II, Adaptive Behavior Assessment System Second Edition; ADI-R, Autism Diagnostic Interview-Revise; ADOS-G, Autism Diagnostic Observation Schedule-Generic; ASD, autism spectrum disorders; ASQ, Ages and Stages Questionnaires; BPAQ, Buss-Perry Aggression Questionnaire; CARS, Childhood Autism Rating Scale; CBCL, Child Behavior Checklist; CES-D, Center for Epidemiologic Studies Depression; CCS, case-control study; CES-DC, Center for Epidemiologic Studies Depression Scale for Children; CI, confidence interval; CSS, cross-sectional study; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised, Text Revision; HR, hazard ratio; K-BDI, Korean version of the Beck Depression Inventory; MSEL, Mullen Scales of Early Learning; OR, odds ratio; RR, relative risk; SCQ, Social Communication Questionnaire; SD, standard deviation; -, none.

aLog10 of vitamin B12 intake; bcalculate based on the mean energy intake (kcal/day) and vitamin B12 intake (mcg/1,000 kcal).

Correlation between vitamin B12 levels or intake and mental disorders in children and adolescents: longitudinal studies

First author Type Location Participants (girls) Age Follow-up baseline vitamin B 12 levels (pg/ml) Outcome Psychological measure/ No. of cases Association/effect measures Result (95% CI) Quality
Raghavan [67] Cohort USA 1,257 (/) 0 yr 12 yr Maternal 486.9 ± 155.87 Incidence of ASD 86 HR (95% CI) for low (≤ 247.0 pmol/L) vs. middle 80th percentile (≥ 247.0 to < 536.8 pmol/L) status 0.7 (0.3, 1.7) High
HR (95% CI) for high (≥ 536.8 pmol/L) vs. middle 80th percentile (≥ 247.0 to < 536.8 pmol/L) status 2.5 (1.4, 4.5)
Ars [59] Cohort Netherlands 256 (122) 0 yr 6.2 yr (median) Prenatal 296.59 ± 148.31 Emotional problems CBCL (emotional scale) OR (95% CI) for low (< 150 pmol/L) vs. normal status 0.81 (0.41, 1.63) High
Behavioural problems CBCL (behavioural scale) OR (95% CI) for low (< 150 pmol/L) vs. normal status 0.56 (0.27, 1.67) High
Duong [60] Cohort Colombia 3,156 (1,613) 5−12 yr 1 school year Vitamin B12 levels Incidence of grade repetition 155 RR (95% CI) for low (< 148 pmol/L) vs. normal status 2.36 (1.03, 5.41) Moderate
Robinson [62] Cohort Bogotá 1,042 (584) 5−12 yr 6.2 yr (median) 437 ± 141 (boy); 459 ± 142 (girl) Behavior problems YSR (total externalizing problems scores) Mean differences (95% CI) for low (204 pmol/L) vs. higher status Boy, 2.7 (0.4, 4.9) Moderate
Mean differences (95% CI) for low (218 pmol/L) vs. higher status Girl, 1.0 (−0.8, 2.9) Moderate
Miyake [61]

Values are presented as number only or mean ± standard deviation.

ASD, autism spectrum disorders; CBCL, Child Behavior Checklist; CI, confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk; YSR, Youth Self Report; SDQ, Strengths and Difficulties Questionnaire.

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Funding Information
  • National Natural Science Foundation of China
      10.13039/501100001809
      82171456, 81971229
  • Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission
      10.13039/501100012669
      cstc2021jcyj-msxmX0263

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