Table 4.

Studies Investigating Levels of Vitamin D in Autism Spectrum Disorder

Vitamin D in autism spectrum disorders
Authors	Sample	Study aims	Main findings
Azzam et al. [2015]	A prospective case–control 6‐month study was carried out including 21 children with ASD who were randomly assigned to one of two groups.	The patients in group I were administered a daily oral dose of vitamin D3 and the patients in group II were not administered any supplements. Symptoms of ASD were measured both presupplement and postsupplement using the Childhood Autism Rating Scale, social IQ, and Autism Treatment Evaluation Checklist.	Both groups exhibited improved ASD symptoms but the improvement found in the supplemented group did not differ significantly from that of the nonsupplemented group. Azzam et al. [2015] have administered 2,000 IU per day for 6 months (n = 21) and reported no changes on CARS scores. This treatment resulted only in a moderate improvement in children with ASD from their presupplementation average levels of 47 nmol/L to their post supplementation average levels of 70 nmol/L.
Bener, Khattab, and Al‐Dabbagh [2014]	254 children with ASD (mean age 5.51, SD = 1.58) and 254 healthy control children (mean age, 5.76 SD = 1.56)	To investigate the association between VitD and ASD, and the difference in level of VitD in children with ASD and children without ASD.	VitD deficiency was greater in children with ASD when compared to healthy children and providing infants with VD supplements may be a more effective intervention for lowering the risk of ASD. Compared to the control children, a lower level (mean value) of VitD in the children with ASD was found. Of total 254 children with ASD, 14.2% had severe VitD deficiency, 43.7% were moderately insufficient, 28.3% were mildly insufficient, and sufficient levels of VD was found in only 13.8% of the children with ASD. Of the 254 of control children 8.3% were found to have a severe VitD deficiency, 37% were moderately insufficient, 37.4% were mildly insufficient, and sufficient levels were found in only 17.3%. Serum level of VitD was also significantly different between the children with ASD and control children.
De Souza‐Tostes, Polonini, Gattaz, Raposo, and Baptista [2012]	24 children (18 male and 6 female, mean age = 7.4 ± 2.7 years) diagnosed with ASD.	To confirm previous evidence suggesting an association between autism and low VitD serum levels.	Findings showed that the serum levels of 25‐OHD were lower in children with autism compared to typically developing participants.
Fernell et al. [2015]	47 Gothenburg sibling pairs with mixed ethnicities and 11 Stockholm sibling pairs with Somali background.	The aim of the present study was to address the emerging hypothesis that low levels of VitD at birth increase the risk for ASD. First study whose findings excluded ASD‐related lifestyle mechanisms as a possible theory for deficient 25(OH)D levels given that samples were taken shortly after birth.	Collapsed group of children with ASD had significantly lower VitD levels compared with their siblings. VitD deficiency was found in both the children with ASD with African/Middle East background and their non‐ASD siblings. These findings are consistent with the hypothesis that during pregnancy, developmental VD deficiency may be one of the factors involved in increasing the risk of ASD in the child.
Gong et al. [2014]	48 confirmed ASD cases and 48 age‐matched and sex‐matched controls. Mean age (%) for ASD group = 40 (83.3) Mean age (%) for control group = 40 (83.3)	To investigate the serum 25(OH) D levels in Chinese children with ASD.	The mean serum 25(OH) D levels were significantly lower in children with ASD compared to the children without ASD. There was a significant negative relationship between circulating serum 25(OH) D levels and the severity of autism evaluated according to Childhood Autism Rating Scale scores, after adjustment for the possible covariates. Lower 25(OH) D levels may be independently associated with severity of ASD among Chinese patients, and lower serum 25(OH) D levels could be considered as an independent risk factor for ASD.
Humble et al. [2010]	Mean age 36.5 of group of individuals with ASD (n = 10). 40% were females.	To investigate 25(OH)VitD levels of individuals with ASD (including other psychiatric conditions).	Patients with ADHD had unexpectedly low intact parathyroid hormone (iPTH) levels. Middle East, South‐East Asian, or African ethnic origin, being a young male and having a diagnosis of ASD or schizophrenia predicted low 25‐OHD levels.
Jia et al. [2015]	Case study of a 32‐month‐old boy with ASD and vitamin D3 deficiency.	Investigating Vitamin D/D3 supplementation in a case of deficiency.	Following vitamin D3 supplementation, the boy's core ASD symptoms were significantly reduced indicating that vitamin D3 may be one of the factors contributing to the etiology of ASD.
Kočovská et al. [2014]	The case group consisting of a total population cohort of 40 individuals with ASD (aged 15–24 years) were compared to 62 typically‐developing siblings and their 77 parents and also 40 healthy age and gender matched comparisons.	To investigate, using a cross‐sectional population‐based study conducted in the Faroe Islands, levels of 25‐Hydroxyvitamin D3 (25(OH)D3) in a case group of a total population cohort of 40 individuals with ASD.	The ASD group were found to have a significantly lower 25(OH)D3 when compared to the 25(OH)D3 level in their 62 typically developing siblings and their 77 parents, as well as being significantly lower than 40 healthy age and gender matched comparison cases. A trend also revealed that males had lower 25(OH)D3 levels compared to females. Interestingly, there was no association between 25(OH)D3 and age, month/season of birth, IQ, various subcategories of ASD and, most interestingly, Autism Diagnostic Observation Schedule scores.
Meguid et al. [2010]	The mean age ± standard deviation (SD) of the children with ASD was 5.3 ± 2.8 years. Controls included 42 age‐matched randomly selected healthy children of the same socioeconomic status (mean age ± SD, 6.1 ± 1.8 years).	To measure the potential role of VitD in ASD through serum level assessment.	Findings showed that the children with ASD exhibited a significantly lower 25(OH)D and 1,25(OH)2D compared to controls. The children with ASD also exhibited significantly lower calcium serum values compared to the controls. A significant positive correlation was found between 25(OH)D and calcium within the children with ASD.
Molloy, Kalkwarf, Manning‐Courtney, Mills, and Hediger [2010]	Three groups of Caucasian males age 4–8 years old: (1) ASD and an unrestricted diet (n = 40), (2) ASD and a casein‐free diet (n = 9), and (3) unaffected controls (n = 40).	To examine the plasma 25(OH)D concentration levels across three groups (1) ASD and an unrestricted diet, (2) ASD and a casein‐free diet, and (3) unaffected controls.	A total of 54 (61%) of the children in the entire cohort had a plasma 25(OH)D concentration of less than 20 ng/mL Children with and without ASD have low plasma concentrations of 25(OH)D. There were no significant group differences. 25(OH)D concentrations do not differ between children with ASD and typically developing controls.
Mostafa and Al‐Ayadhi [2008]	50 children with ASD, aged between 5 and 12 years, and 30 healthy‐matched children.	This is the first study to investigate the relationship between serum levels of 25‐hydroxy VitD and anti‐myelin‐associated glycoprotein (anti‐MAG) auto‐antibodies in children with ASD.	Children with ASD had significantly lower serum levels of 25‐hydroxy VitD than healthy children with 40 and 48% being VitD deficient and insufficient, respectively. Serum 25‐hydroxy VitD had significant negative correlations with Childhood Autism Rating Scale. Increased levels of serum anti‐MAG auto‐antibodies were found in 70% of children with ASD.
Saad et al. [2015]	122 children with ASD (3–9 years of age, mean age = 5.09). 100 control cases (3–9 years of ages, mean age = 4.88).	To investigate individuals with ASD VitD status compared to controls and the relationship between VitD deficiency and the severity of ASD. Also, to conduct an open trial of VitD supplementation in children with ASD.	57% of the patients had VitD deficiency, and 30% had VitD insufficiency. Mean 25‐OHD levels in patients with severe ASD were significantly lower compared to those with mild/moderate ASD. Serum 25‐OHD levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores. Of the ASD group, 106 patients with low‐serum 25‐OHD levels (<30 ng/mL) participated in the open label trial. They received VitD3 (300 IU/kg/day not to exceed 5,000 IU/day) for 3 months. 83 participants completed 3 months of daily VitD treatment. Collectively, 80.72% (67/83) of participants who received VitD3 treatment had significantly improved outcome, mainly in the sections of the CARS and aberrant behavior checklist subscales that measure behavior, stereotypy, eye contact, and attention span.
Schmidt et al. [2015]	ASD (n = 474) and typical development (TD, n = 281). Age range for both groups = 24–60 months.	To investigate the associations (if any) between ASD and common, functional polymorphisms in VitD pathways.	Preliminary evidence that paternal and child VitD metabolism may contribute to some degree in the etiology of ASD. Paternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case–control analysis and there was a trend toward increased risk associated with VDR BsmI. Further analyses identified parental imprinting, with greater effects of paternally derived VDR alleles.
Ucuz et al. [2014]	64 toddlers with developmental delay.	In the initial assessment, a psychiatric examination and developmental tests were carried out and VitD was measured.	Individuals found to have low VitD levels in the initial assessment received supplementary treatment. Six months later, the same measures were repeated which revealed a significant improvement in ASD symptoms and development scores for the group who received VitD supplementation. Study found evidence which supports the importance of measuring VitD levels and supplementing them if they are low in individuals with ASD.
Utur and Gurkan [2014]	54 young children, aged 3–8 years, with ASD and 54 age and gender matched normal controls.	First preliminary evidence that paternal and child vitamin D metabolism could play a role in the etiology of ASD. To investigate the serum levels of VitD, calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and folate in children with ASD compared to children without ASD.	Paternal homozygous variant genotypes for the TaqI and BsmI polymorphisms on the VDR gene, and CYP27B1 rs4646536 were associated with increased risk for ASD. The CYP2R1 enzyme catalyses the transformation of vitamin D3 to 25(OH)D3, the main circulating VitD metabolite. The CYP2R1 GG genotype associated with higher risk for ASD in this study was also associated with lower circulating 25(OH)D3 concentrations and with type 1 diabetes in Caucasians. Interestingly, their results suggested that the risk associated with the child's CYP2R1 GG genotype could be counteracted by increasing maternal VitD intake. An inherited gene from a father combined with male sex seems to play an important role and mother's VitD deficiency during pregnancy is an additional risk factor.

SD, standard deviation; M, mean; ASD, autism spectrum disorders; VitD, vitamin D; nmol/L, nanomoles (nmol) per litre (L); 25‐OHD, a particular form of vitamin D; 25(OH) D, a particular form of Vitamin D; CARS, the childhood autism rating scale; Ca, calcium; P, phosphorus; ALP, alkaline phosphatase.