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Incidence Autism and ADHD reduced 18 percent per 10 ng of Vitamin D during pregnancy – meta-analysis Jan 2022

Maternal serum 25-hydroxy vitamin D levels and risk of autism spectrum and attention-deficit hyperactivity disorders in offspring: A systematic review and dose-response meta-analysis

Psychiatry Research Volume 319, January 2023, 114977 https://doi.org/10.1016/j.psychres.2022.114977


Vitamin D deficiency during pregnancy is a public health problem worldwide. The global prevalence of vitamin D deficiency during pregnancy (defined as serum 25-hydroxy vitamin D or 25(OH)D less than 50 nmol/L or 25 ng/mL) has been reported to be 54%. In addition, serum 25(OH)D levels less than 25 nmol/L or 10 ng/mL, which is known as severe vitamin D deficiency, have been observed in 18% of pregnant women (Saraf et al., 2016). Several factors such as maternal age, social class, physical activity, smoking, and vitamin D supplementation contribute to vitamin D deficiency or insufficiency in pregnant women (Krieger et al., 2018; Rodriguez et al., 2016; Salamon et al., 2015). Over the recent decades, there has been an increasing interest in exploring the relationship between maternal vitamin D levels with offspring development and health. A growing body of evidence has suggested that vitamin D deficiency during pregnancy may be linked to adverse offspring outcomes such as preterm birth, short term gestational age, and deleterious anthropometric and neurodevelopmental outcomes (Aghajafari et al., 2013; Tous et al., 2020; Wei et al., 2013).

The association between low maternal vitamin D levels during pregnancy and brain development has been highlighted in some experimental and epidemiological studies. Several rodent studies have demonstrated that maternal vitamin D deficiency is associated with impaired fetal brain morphology, cellular differentiation, and expression of genes involved in neuronal survival, dopamine synthesis, and language development (Eyles et al., 2003; Hawes et al., 2015; Ko et al., 2004). Some cohort studies have also pointed out that vitamin D deficiency in pregnant women is associated with neurodevelopmental impairments (Darling et al., 2017; Whitehouse et al., 2012). The Western Australian Pregnancy cohort revealed a higher risk of language impairment in children of mothers with vitamin D insufficiency (≤46 nmol/L) in the second trimester of pregnancy (Whitehouse et al., 2012). Another cohort study on 7065 mother-child pairs in the United Kingdom also found that vitamin D deficiency during pregnancy (<50 nmol/L) adversely affects some aspects of motor and social development in children under the age of four (Darling et al., 2017).

Neurodevelopmental disorders are known as significant causes of childhood morbidity that impose a great health burden on children, their families, and society (Jeste, 2015). Autism spectrum disorder (ASD) and attention-deficient hyperactivity disorder (ADHD) are among the most common and debilitating neurodevelopmental disorders of early life. Global prevalence estimates of ADHD and ASD are 5% and 1%, respectively (Sayal et al., 2018; Zeidan et al., 2022). Additionally, ASD and ADHD are usually comorbid with shared pathophysiological and clinical features (Antshel and Russo, 2019; Kern et al., 2015). Recently, several studies have investigated the relation of maternal vitamin D status during pregnancy with the risk of ASD/ADHD; however, the results of these studies have been inconsistent. For instance, a nested case-control study based on a Finnish cohort study showed that deficient and insufficient gestational 25(OH)D levels were linked to a higher risk of ASD (Sourander et al., 2021). Moreover, studies from Sweden, Netherlands, and China have reported similar results (Chen et al., 2016; Lee et al., 2021; Vinkhuyzen et al., 2017). However, a large case-control study of Southern Californian births found no association between mid-gestation vitamin D deficiency and risk of ASD in offspring (Windham et al., 2020). In addition, an inverse significant association was reported between maternal serum 25 (OH)D levels during pregnancy and offspring ADHD risk in epidemiological studies of the USA, Finland, and Greece (Chu et al., 2022; Daraki et al., 2018; Sucksdorff et al., 2021). Whereas, a cohort study of 4–5 years old children in Spain indicated no significant association between gestational circulating level of 25(OH)D and risk of ADHD (Morales et al., 2015). The Danish birth cohort has also revealed no significant relation between maternal vitamin D status during pregnancy and the risk of ADHD in offspring (Strøm et al., 2014). Thus, the current systematic review and dose-response meta-analysis were done to explore if there are any association between serum vitamin D levels during pregnancy and the risk of ASD and ADHD in offspring.

Section snippets

Search strategy
A systematic search was conducted in the MEDLINE (PubMed), ISI (Web of Science), and Embase databases and Google Scholar, up to May 2022, without any time or language restrictions, Details of search strategy are provided in Supplementary Table 1 and 2. The reference list of eligible studies and relevant review articles were also searched manually for additional publications. The combinations of MeSH and non-MeSH keywords used in the search strategy were outlined as follow: (“Vitamin D” OR . . . . .

Study characteristics
The characteristics of the included investigations in the systematic review of the association between maternal serum vitamin D levels and the risk of offspring ASD are presented in Table 1. These 5 included studies have been published between the year of 2016 and 2021. The sample size of these studies ranged between 136 and 3895. These studies encompassed a total of 2671 ASD cases (ranged from 62 to 1558) and were performed in United States of America (USA) (Windham et al., 2020), Finland (. . . . .

Discussion" Reduce 19% Autism, 18% ADHD

The present meta-analysis revealed significant inverse associations between maternal serum vitamin D levels with both offspring ASD and ADHD when the highest versus the lowest level of maternal serum vitamin D was compared.
Dose-response analyses documented that each
25 nmol/L (or 10 ng/mL) increment in maternal serum vitamin D was associated with

  • 19% and
  • 18% reduced risk of offspring ASD and ADHD, respectively.

Furthermore, a non-linear association was found between maternal serum vitamin D

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