Maternal vitamin D status and attention deficit hyperactivity disorder (ADHD),an under diagnosed risk factor;A review

Abstract

Vitamin D is important to mediate several brain processes such as proliferation, apoptosis, and neurotransmission in early stages of life. Vitamin D deficiency during critical periods of development can lead to persistent brain alterations. Vitamin D homeostasis during pregnancy is affected by two factors which includes an increase in mother’s calcitriol levels and an increase in mother’s Vitamin D Binding protein concentrations. Attention deficient hyperactivity disorder (ADHD) is an outcome of a complicated interaction between genetic, environmental, and developmental traits, and genetic factors cover about 80% of the cases. The efficiency of the immune system can be altered by a deficiency of Vitamin D in maternal body and maternal stress during gestation such as perinatal depression. Studies have proved that during gestation if there is a deficiency of vitamin D in maternal body, it can influence the brain development of the fetus and can also alter the synthesis of the brain-derived neurotropic factor. The current manuscript has been compiled to elaborate different factors which are associated with ADHD particularly focusing on the relationship of vitamin D deficiency in mothers. References material was selected from NCBI (PUBMED), Science direct, Google scholar, Publons etc. Using the terms ADHD, Vitamin D and Maternal nutritional status. Although, controversial relationship was found between the deficiency of Vitamin D level in pregnant women and development of ADHD in children but more controlled trials are required for future direction as well as to rule out other associated causes.

Keywords

nutritional supplements pregnancy fetal life Vitamin D brain development

Introduction

Attention deficit hyperactivity disorder (ADHD) is a neurons development disorder which effects growing children. ADHD has been become a serious developmental disorder specified by damaging symptoms of easy distraction, hyperactivity, and impulsive behavior that occur before 7 years of age. This disturbed behavior of children with attention deficit hyperactivity disorder remarkably effects their social, academic, or vocational capability.¹ Impulsive behavior, attention deficit, and hyperactivity are the main symptoms. Using data from 2016 to 2019, a national survey of parents in US estimates that 6 million (9.8%) children aged 3 to 17 have ADHD diagnosis. In this group, those aged 3-5 make up 265,000 (2%), those aged 6–11 2.4 million (10%), and those aged 13–17 3.3 million (13%). Compared to females (6%), boys (13%) are more likely to receive an ADHD diagnosis. Children who are Black and White, and who are non-Hispanic are more likely to have ADHD diagnoses (12% and 10%, respectively) than children who are Hispanic (8%) or Asian and non-Hispanic (3%).² ADHD is an outcome of a complicated interaction between genetic, environmental, and developmental factors, and genetic traits cover about 80% of the cases.³ ADHD has three sub-categories which involves the inattentive sub-category, the hyperactive/impulsive sub-category, and the combined sub-category.¹ It is very important to create an awareness in low socio-economic countries about the prevalence of ADHD and the time (age) of the occurrence of ADHD to address suitable treatment guidelines. According to Posner et al.³ stimulants (or psychostimulants) and non-stimulants are two categories of ADHD medications, and there are a variety of formulations, administration methods, and pharmacokinetic profiles available. Moreover, the availability of the therapeutic agents is the most important which widely varies from developed world to developing ones. Posner et al.³ also comprehensively described the medications used for the treatment of ADHD during different studies and these drug includes methylphenidate with immediate release including dexmethylphenidate, methylphenidate hydrochloride with sustained release; methylphenidate as long-acting including dexmethylphenidate with extended release; methylphenidate as osmotic release; methylphenidate hydrochloride with extended release; amphetamine as dextroamphetamine-amphetamine as extended release and sustained release; and Lisdexamfetamine were investigated in different research trials given in tablets, capsules or liquid preparations using oral and transdermal routes.³

In addition to stimulants Posner et al.³ also describes non-stimulant treatment strategies but it was found that these drugs are often used only in individuals who do not react well to stimulant formulations or who have unacceptable side effects because to their smaller effect sizes and lower response rates. The norepinephrine transporter inhibitor atomoxetine and the α-2 agonists’ guanfacine and clonidine are examples of non-stimulant drugs.³ Moreover, psychosocial interventions, behavioral interventions, school interventions, cognitive training therapies, learning training, biofeedback or neurofeedback, parent behavior training, dietary supplements, elimination diets, vision training, and chiropractic care are examples of nonpharmacological therapies.⁴

Many studies have proved that mental disorders are linked to the deficiencies of some major trace nutrients including Vitamin D and may have roots in fetal life. Vitamin D homeostasis during pregnancy is affected by two factors which includes an increase in mother’s calcitriol levels and an increase in mother’s Vitamin D Binding protein (VDBP) concentrations. Vitamin D is important to mediate several brain processes such as proliferation, apoptosis, and neurotransmission in early stages of life. The efficiency of the immune system can be altered by a deficiency of Vitamin D in maternal body and maternal stress during gestation such as perinatal depression. Studies have proved that during gestation if there is a deficiency of vitamin D in maternal body, it can influence the brain development of the fetus and can also alter the synthesis of the brain-derived neurotropic factor.⁵ This comprehensive review article have been compiled to discuss different factors which are associated with attention deficient hyperactivity disorder focusing on the relationship of vitamin D deficiency in mother’s with attention deficit hyperactivity disorder (ADHD). It has been investigated that vitamin D has a role in brain growth of fetus, differentiation of neurons and endocrine functions. Animal studies reported alterations in the brain of offspring may occur due to vitamin D deficiency.⁶

Literature search strategy and selection criteria

References material for the current review manuscript was searched using NCBI (PUBMED), Google scholar, Publons, Science Direct using the terms Vitamin D role in brain development, brain disorders and vitamin D, ADHD, Vitamin D and Maternal nutritional status. The latest reference material related to mentioned objectives was selected Articles resulting from these searches were reviewed and relevant references were cited in this review article.

Metabolism of vitamin D

general metabolism in our body

Vitamin D comes in two different forms, D2 and D3. Plants produce vitamin D2, also known as ergocalciferol, and mammals, including humans, produce vitamin D3, also known as cholecalciferol. Both types of the process require UV radiation, most specifically UVB in the 280–320 nm wavelength range. The transfer of epidermal 7-dehydrocholesterol to pre-vitamin D after exposure to UVB is the initial step in the production of vitamin D. Similar to other steroid hormones in the human body, which use 7-dehydrocholesterol as their primary substrate, vitamin D likewise needs sunlight with a particular wavelength and spectrum.⁷ This is important to note that without exposure to sunlight, our only supply of vitamin D is food. Pre-vitamin D is produced in human body and then undergoes a heat reaction to become vitamin D. 58 kD molecular weight a-globulin known as the VDBP and an ardent affinity for vitamin D moieties, is then primarily responsible for transporting it into the bloodstream. The 25-hydroxylase enzyme in the liver is responsible for most of the vitamin D’s conversion to 25(OH)D. This reaction can only happen in females who have healthy livers. 25(OH)D enters the circulation after being synthesized from vitamin D2 or vitamin D3 and is then strongly linked to VDBP; a minor portion also binds to albumin and other proteins. Only a minimal portion is free or unbound, but the unbound form is absorbed in the renal and other extra renal tissues for additional processing inside the cell.⁸

The traditional theory of vitamin D states that the kidneys absorb circulating 25(OH)D and then transform it into dihydroxy vitamin D (1,25 [OH]2 D or calcitriol), the active hormonal form of vitamin D, using the enzyme 1-a-hydroxylase, a cytochrome P450 enzyme. Some of the endocrine effects of 1,25(OH)2 D includes increased urine calcium reabsorption, increased intestinal absorption of calcium and phosphorus, and negative feedback loop regulation of parathyroid hormone. The body maintains calcium homeostasis by using 1,25(OH)2 D to increase intestinal absorption of calcium, reabsorb calcium from the urine, and mobilize calcium from bone. Since essential organs like the heart, muscles, and brain cannot perform without enough calcium, the human body will do this to scavenge calcium at the price of phosphorus to maintain calcium balance throughout the body. Only when vitamin D levels are high enough can calcium be preserved, as vitamin D needs enough substrate to make 25(OH)D, which is then transformed to 1,25(OH)2 D.^7–9

Metabolism in placenta during pregnancy

As a result of the physiological changes in vitamin D metabolism and maternal body composition brought on by maternal hemodilution during pregnancy, pregnant women and non-pregnant women respond to vitamin D supplementation differently. Although food may include trace quantity of vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol), manifestation to sunlight is by far the body’s main source of vitamin D, which is produced by the body from derivatives of cholesterol. Because to its raised concentration and longer short life than the active form, vitamin D is transported to the liver where it is hydroxylated to 25(OH)D, or calcidiol. However, this inactive form of vitamin D needs to be further hydroxylated in the kidneys to become 1,25-dihydroxyvitamin D (1,25 [(OH]2D), or calcitriol, which is the active form of vitamin D.^11,12

The placenta is a crucial organ that not only facilitates the transfer of nutrients but also plays a vital role in the pregnancy-related immunotolerance adaption. The fact that 1,25(OH)2D rationally cannot traverse placental tissue whereas its inactive precursor, 25(OH)D, can easily do so and enter the fetal compartment is significant. The placenta, in addition to the kidneys, has the ability to activate 25(OH)D because it contains the enzyme 1-hydroxilase, which produces 1,25(OH)2D. Additionally, the placenta controls vitamin D metabolism in a paracrine manner and has the ability to deactivate 25(OH)D through 24-hydroxylation to 24,25(OH)2D. Due to this, vitamin D levels can be locally regulated in the placental tissue, which may adjust its anti-inflammatory actions and influence pregnancy development and before pregnancy outcomes.^11,12 Through the inhibition of adaptative T-helper 1 responses and the stimulation of innate antimicrobial responses in human placental cells, calcitriol has strong immunomodulatory effects.¹² While other studies have not, some have reported a rise in 1,25(OH)2D maternal blood concentrations during the final trimester of pregnancy.^12,13 The levels of circulating vitamin D are significantly impacted by seasonal fluctuations.^12–14 Although the placenta is capable of producing 1,25(OH)2D, the maternal kidney is responsible for most of this metabolite’s production in the bloodstream of the mother. In fact, studies utilizing animals with autosomal recessive 1-hydroxilase deficiency show that the maternal kidneys are probably the main cause of the elevated maternal serum 1,25(OH)2D seen during pregnancy.¹⁵ The fetal kidneys can convert 25(OH)D into 1,25(OH)2D. In fact, 1,25(OH)2D levels in the umbilical artery are marginally greater than those in the venous cord, pointing to a potential function for the developing fetus’s kidneys in vitamin D activation. Additionally, in sheep and rat models, fetal nephrectomy decreases 1,25(OH)2D levels in the fetus, highlighting the significance of the fetal kidneys in preserving the amounts of active vitamin D in the blood.¹⁶

Movement of Vitamin D across cell membrane

The presence of ligands in sufficient numbers at the location of action is necessary for a brain signaling system to work properly. The blood-brain barrier (BBB) and cell membranes are thought to be permeable to lipophilic substances like vitamin D and its metabolites through diffusion. The free hormone theory states that only a portion of the total vitamin D metabolites present in blood or extracellular fluid that are unbound (or free) may diffuse into the intracellular space, couple to receptors, and have an impact. However, 99% or more of all vitamin D metabolites bind to VDBP, resulting in Pico molar concentrations of the free fraction.¹⁷ VDBP can be detected in the interstitial space of many different organs in addition to being produced in the liver and circulating in high concentrations in the serum. VDBP, a low molecular weight protein that is smaller than albumin, is necessary to create a reservoir of circulating calcidiol and so delay the development of insufficiency. In addition, VDBP-bound vitamin D metabolites can be reabsorbed by the proximal tubule by endocytosis by the megalin/cubilin complex after being filtered in the renal glomerulus.¹⁸ Cubilin and Megalin are mostly expressed in the kidney, brain, and eyes. The complex undoubtedly contributes to healthy brain development because neurodegenerative conditions like Alzheimer’s disease are linked to a drop in the complex’s expression.¹⁹

Megalin can theoretically bind and internalize VDBP-bound calcidiol, making it easier for cells that express megalin to acquire calcidiol, however the presence of such a transport mechanism has not yet been shown.²⁰ As a result, it may be inferred that the free hormone model also applies to calcitriol. Finding explored the presence of vitamin D metabolites in rats and human brains was another significant indicator of vitamin D’s effects on the brain.^21,22 Although early autoradiographic investigations showed that calcitriol crosses the BBB and is distributed throughout the brain,²³ endogenous calcidiol or calcitriol has not before been quantified from brain tissue. Rats' serum and total calcidiol concentrations were shown to be correlated by Xue et al., but as residual blood from cerebral arteries was not corrected for, the data should be regarded with care.²¹ Notable is also the presence of VDBP in cerebral fluid (CSF), which suggests that vitamin D metabolites will probably bind to this. The free fractions of calcidiol and calcitriol, however, may vary and are extremely challenging to measure since the expression of VDBP in the CNS is altered by several clinical situations (for example, multiple sclerosis, meningitis).²⁴

Molecular evidence of the relationship between Vitamin D and neuropsychological function

Through a variety of mechanisms, including the induction of neuroprotection, oxidative stress modulation, calcium homeostasis regulation, and suppression of inflammatory processes, vitamin D can influence neuropsychological function.²⁵ The central nervous system contains a nuclear hormone receptor known as the vitamin D receptor (VDR), which is how vitamin D exerts its effects. Two zinc fingers make up the DNA-binding domain of the VDR protein; one of the zinc fingers binds DNA while the other is involved in the dimerization of the molecule. The specificity and selectivity of the response are guaranteed by the ligand-binding domain at the C-terminal end of the receptor. There is a lot of proof that vitamin D affects brain genomics. It has been demonstrated that the neuroepithelium and midbrain of a 12-day-old embryo contain VDR, a protein that is present in the developing and adult brains of rats (E12).²⁶ It is found in glia cells, neurons, and brain regions such the amygdala, nucleus accumbens, thalamus, and temporal, cingulate, and orbital cortex that are all necessary for the growth of cognitive abilities.²⁷ In both the rat and human brains, it is also expressed in the hippocampus pyramidal cells' CA1, CA2, CA3, and CA4 layers.²⁸ VDR is distributed in humans in a very similar manner to that seen in rats. VDR is localized in the olfactory, visual, and auditory systems, suggesting that it may also play a role in somatosensory functions, which could help individuals perform better on cognitive tasks. The presence of VDR in the hippocampus, cerebral cortex, and limbic system of humans and rodents supports the role of vitamin D in regulating learning and memory.^27,28

Additionally, it is possible that vitamin D has a role in neuronal proliferation and stem-cell differentiation given the variety of locations where VDR is found in the brain. The morphological abnormalities in the offspring of rats exposed to VDD provide indirect evidence for the significance of vitamin D in neurodevelopment. The first dietary developmental VDD model was developed by Eyles and co-workers and had increased brain cell proliferation.²⁹ However, it has also been shown that in rat embryos, developmental VDD has an impact on the expression of genes that control apoptosis and the cell cycle.^30,31 Cholecalciferol has recently been found to have neuroprotective properties in young rats. When examining the growth of the entire brain, they saw a decrease in hippocampus volume and an increase in the size of the lateral ventricles.³² However, it has recently been reported in individuals with moderate cognitive impairment.³³ This observation has not been validated in adult mice or rats.^34,35 Another study found that older adults with VDD had lateral ventricles that were 28% more numerous.³⁶

Developmental VDD has been shown to have long-term effects on the expression of genes and proteins in the brain. 74 genes whose expression was changed and believed to be involved in a variety of neural activities were discovered.³⁷ In proteomic research, the prefrontal cortex and hippocampus of adult rats showed deregulation of 36 proteins involved in calcium homeostasis, neurotransmission, synaptic plasticity, redox balance, oxidative phosphorylation, etc.³⁸ The imbalance of dopamine and serotonin neurotransmission has been associated with VDD. The VDR first arises in developing brains around E12, just when the dopaminergic system begins to mature.^39–41 According to some research, VDD impacts dopaminergic neuron-maturation factors, such as metabolizing enzymes, TGF-1, Nurr1, and neurotrophin brain-derived neurotrophic factor, which are all reduced (e.g. decrease in the expression of catechol-O-methyltransferase³³ and tyrosine hydroxylase.⁴² Additionally, Cui et al. showed that VDD decreased the expression of N-cadherin and tyrosine hydroxylase in embryonic mesencephalon whereas calcitriol elevated these markers in neuroblastomas that express VDR.^39,43 These results clearly imply that calcitriol causes dopaminergic neurons to differentiate.²⁶

Serotonin has significant role in brain development due to its important modulatory function in regulating neuronal cell proliferation, migration, and brain wiring during foetal and early postnatal life,⁴⁴ the modulation of the tryptophan hydroxylase-2 and leptin genes may also have an impact on serotonin turnover.^45,46 TPH2 expression was discovered to rise in cultured serotonergic B14 cells taken from rat brain following brief exposure to calcitriol. The same study demonstrated that several human-derived cell lines reacted uniformly to calcitriol therapy.²⁰ Furthermore, Jiang et al. carried out an intricate investigation to offer concrete proof of the connections between calcitriol-dopamine and calcitriol-serotonin in the brain that were discussed before.⁴⁷ They discovered that prolonged calcitriol treatment elevated levels of glutamate and gamma-aminobutyric acid (GABA), but not dopamine or serotonin, in the prefrontal cortex and hippocampus. The elevated levels of 3,4-dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA), the metabolites of dopamine and serotonin, respectively, however, showed that dopamine- and serotonin-turnover were enhanced. However, they also demonstrated that the fast decomposition of the neurotransmitter may be caused by increased expression of the metabolizing enzymes, such as catechol-O-methyltransferase for dopamine and monoamine oxidase A for serotonin.⁴⁷ The binding of vitamin D to VDR is the common denominator in all of the actions listed above. Recently, however, it was also discovered that calcitriol-activated membrane receptors existed. A quick cellular reaction is produced by the activation of the 1,25D3 membrane-associated, rapid-response steroid-binding protein (1,25D3-MARRS), which also functions as protein disulfide isomerase A3 (PDIA3). PDIA3 can influence inflammatory response, apoptosis, and oxidative stress, among other crucial roles.⁴⁸ They hypothesized that Pdia3 is the primary vitamin D receptor in rat brain because neurons, astrocytes, and endothelial cells in comparison to the kidney and liver produce more Pdia3 mRNA.⁴⁹ PDIA3 may have neuroprotective effects against infections or harmful medications, according to early human investigations.^50,51 Exogenous PDIA3 also raised the expression of phosphorylated cAMP-response element-binding protein (pCREB) and brain derived neurotrophic factor (BDNF), boosting cell proliferation in the hippocampus under normal circumstances, but it was unable to lessen ischemic changes in gerbils.⁵² All of these findings agreed with the idea that calcitriol’s activities could entail activating 1,25D3-MARRS. Surprisingly, investigations using PDIA3 mutant mice revealed that the inflammatory response to traumatic brain damage was reduced.⁵³ As a result, the function of PDIA3 in neuropsychological processes is still unknown, and considering these new findings, additional study of PDIA3 may be appropriate. Additionally, PDIA3 expression has been suggested as a biomarker in several cancer types, and higher expression encourages the production of proinflammatory cytokines.⁵⁴

Possible mechanisms of Vitamin D′ responsible in brain development and function

The nuclear receptor for vitamin D has pluripotent effects. It is obvious that there may be a variety of molecular processes responsible for its varied activities in the growing and adult brain. Over the past 10 years, an astonishing variety of uses for this vitamin have been postulated in the brain.⁵⁵ The early occurrence and widespread distribution of the VDR in the developing brain suggest that there may possibly be direct vitamin D-mediated signaling in this tissue, even if there are also likely to be a variety of peripheral endocrine-like processes at work. Here, we tried to discuss the researches showing that vitamin D influences calcium signaling directly in the brain, regulates axonal development, modulates the synthesis of brain-derived reactive oxygen species, and stimulates the creation of neurotrophic factors (Figure 1). Many of these findings could be applicable to the various neuropsychiatric conditions including ADHD that are now being related to vitamin D deficiency. Following are the major mechanisms influenced by Vitamin D level and may leads to various neurological disorders in developing brain.

Figure 1.

Possible mechanisms of Vitamin D to regulate the normal development and function of growing brain.

Vitamin D is a potent differentiation agent for brain cells

Findings demonstrate that vitamin D is a critical differentiation factor for growing brain cells in embryonic Developmental Vitamin D (DVD) deficient brains.^29–31 The anatomical evidence for a larger brain at birth is likewise consistent with higher cell proliferation and lower cell elimination rates. In line with these results, adding 1,25(OH)2D3 to primary hippocampus explant cultures resulted in a reduction in the number of proliferating cells.⁵⁸ More recent in vitro research using a hippocampal cell line has not only confirmed that vitamin D inhibits cell division but also describes a limited time course for 1,25(OH)2D3 uptake within the nucleus that correlates with decreased expression of genes involved in cell division, neurite outgrowth, and the promotion of apoptosis.⁵⁹

Vitamin D and axonal growth

In an early experiment, the addition of 1,25(OH) 2D3 boosted neurite development in embryonic hippocampus explant cells.⁵⁸ The same dosage of 1, 25(OH) 2D3 was used to duplicate this discovery in individual hippocampus neurons more recently.⁵⁹ Both groups noted a modest but considerable increase in NGF and presumptively attributed causation to this effect. A different team decided to investigate ergocalciferol’s (Vitamin D2) potential to promote axon regeneration following peripheral denervation. These authors cite an earlier study as the basis for their decision, which stated that this form of vitamin D was more effective than vitamin D3 at raising 25OHD3 levels in rats.⁶⁰ These authors were able to show that ergocalciferol therapy started right away after lesioning enhanced axiogenesis, axon diameter, and greater functional recovery.⁶¹

Vitamin D down-regulates voltage sensitive L-type calcium channels

Normal neuronal function depends on calcium transients, yet unbuffered intracellular calcium is harmful to the brain. The intracellular calcium binding proteins, such as calbindin, function to safeguard the cell by chelating intracellular calcium, and vitamin D is known to boost their production. It was first suggested that vitamin D may regulate such proteins to provide some degree of neuroprotection against excessive calcium. Two crucial pieces of information, however, contradict this. First, even though 1,25(OH)2D3 can increase calbindin in the kidney, it seems to have little impact on the brain. Additionally, the baseline expression of these proteins is unaffected by genetic VDR ablation. This makes a system like that appear implausible. 1,25(OH)2D3 has long been recognized to alter calcium channel activity potently and quickly in osteoblasts and osteosarcoma cells at physiologically relevant doses.

In cultured mesencephalic neurons, 1,25(OH)2D3 was able to prevent the harmful consequences of calcium influx, but the mechanisms underlying this activity were unknown.⁶⁴ Until Brewer and colleagues in a seminal work showed for the first time that 1,25(OH)2D3 down-regulated L-type voltage-sensitive calcium channels in hippocampus neurons.⁶⁵ Two recent investigations have strengthened this connection. In the first of these studies, it was demonstrated that L-type-A1C voltage-sensitive calcium channels but not A1D channels were increased at both the protein and mRNA levels when VDR expression was silenced utilizing RNA interference technology in primary cortical neurons. This is supported by the finding that 1,25(OH)2D3 reduced the expression of both calcium channels at the mRNA and protein levels in normal VDR tissue. The second investigation by the same team verified that 1,25(OH)2D3 decreased the activity of these same calcium channels in rat cortical neurons and protected them against calcium influx caused by amyloid b protein.⁶⁶ Vitamin D may thus, at least in part, provide some neuroprotection against excitotoxic chemicals through this route. These pathways may potentially be mediated by other ion channels. For instance, research on non-neuronal cell lines has revealed that 1,25(OH)2D3 modifies chloride channel function.^67,68 The potential anticonvulsant effects of vitamin D may be mediated through ion channel regulation.^69–71

Regulation of reactive oxygen species

Recently, it was demonstrated that administering 1,25(OH)2D3 might lessen the consequences of an acute oxidative injury to the dentate gyrus.⁷² Potent anti-oxidants in the brain, such glutathione, can rise in oxidative stress circumstances when 1,25(OH)2D3 is present in physiologically relevant amounts.^73,74 It would seem to accomplish this by inhibiting the synthetic glutathione-producing enzyme, gamma-glutamyl transpeptidase. 1,25(OH)2D3 also inhibits the absorption of reactive oxygen species, such as hydrogen peroxide, in mesencephalic tissue at these similar physiological levels. It appears that both transcriptional processes and de novo protein synthesis were necessary for these protective benefits, pointing to vitamin D-mediated genomic control as the likely cause, albeit the precise mechanism is still unclear.⁶⁴ There is some evidence to indicate a more direct and reversible interaction between such reactive oxygen species (ROSs) and 1,25(OH)2D3, even if ROSs themselves cause non-specific damage to lipid membranes. The complexation between the VDR and its co-receptor RXR is directly inhibited by nitric oxide, hydrogen peroxide, and peroxynitrite in a dose-dependent manner.⁷⁵ With the addition of 100 nM of 1,25(OH)2D3, this inhibition is mainly reversible. Thus, a crucial oxidant and signaling molecule called nitric oxide may be prevented from being produced as part of 1,25(OH)2D3’s function in the brain.⁷⁶

Regulation of neurotrophic factors

A variety of neurotrophic factors might be modulated by vitamin D, according to early research from the lab of Wion and colleagues. Nerve growth factor (NGF) is the most often mentioned of them.^77,78 NGF is necessary for the development and survival of many brain cells, but the cholinergic basal forebrain neurons that support hippocampal neurons tropically are of particular relevance.⁷⁹ In light of this, vitamin D could be crucial for the growth and maintenance of hippocampus neurons. There is some support for this approach, to be sure. Similar doses of 1,25(OH)2D3 stimulate NGF expression and neurite outgrowth in cultured hippocampus explants or individual neurons.^58,59 In cortical neurons more recently, this impact has been verified.⁸⁰ (Dursun et al., 2011). A recent study that temporarily suppressed VDR expression found that primary cortical neurons produced less NGF, which lends more credence to the findings.⁶⁶ NGF expression is also induced by administering 1,25(OH)2D3 directly to the hippocampus of adult rats.⁸¹ The usage of 1,25(OH)2D3 in non-neural cell lines suggests that 1,25(OH)2D3 may also control the synthesis of other elements crucial to the maintenance as well as growth of neuronal tissue.^77,82 nevertheless, neither in vivo nor in primary cultures has this been shown.⁸³

Maternal Vitamin D level and fetal health status

Fetal bone health and maternal Vitamin D level

The development and mineralization of the fetal skeleton is significantly influenced by vitamin D. Bone development starts during the embryonic stage, although the third trimester is the time when most of the skeletal mineralization occurs (80%).⁸⁴ Fetal plasma ionic calcium (Ca2+) concentration, which is reliant on placental Ca2⁺ transfer and fetal calciotropic hormones, is the primary determinant of skeletal mineralization in the uterus. Expression of the genes for plasma membrane calcium-dependent ATPases (PMCA 1–4) significantly influences the amount of Ca2 + transport throughout the placenta.⁸⁵ New born body’s bone mineral content (WB-BMC) at birth is predicted by PMCA3 mRNA expression,⁸⁶ and there is some experimental support for the hypothesis that 1,25(OH)2D may have an impact on PMCA gene expression.⁸⁷ The bioavailability of calcium to the fetus and placental calcium transport may both play a role in how Vitamin D affects skeletal development. The nutritional status of vitamin D during pregnancy or in cord blood has been linked to the parameters of bone mass, quality, and size in offspring as measured by various techniques, including DXA, ultrasound (US), and peripheral quantitative computed tomography (pQCT), in the last few decades.^88–91

At 34 weeks of pregnancy, a three-dimensional US of the femoral morphology revealed a favorable correlation between 25(OH)D levels and femoral volume.⁹⁰ In comparison to those with greater levels, lower WB-BMC, managed for weight by DXA, was seen in newborns with 25(OH)D 13.2 ng/mL and in 15-day-old infants born to mothers with 25OHD 15 ng/mL.^89,92 Studies using pQCT of the tibia indicated that newborns with 25(OH)D levels of 20.8 ng/mL had higher tibial bone mineral density (BMD), bone mineral content (BMC), and cross-sectional area than those with levels of 14.5 ng/mL.⁹¹ In 198 mother and child couples, Javaid et al. discovered substantially lower WB-BMC in the children (at age 9) of women with vitamin D deficiency (25(OH)D 11 ng/mL) than in those with 25(OH)D >20 ng/mL during late pregnancy. In 341 mother and children’s pairs, Zhu et al. showed reduced WB-BMC and WB-BMD in the offspring of women with Vitamin D deficiency (25(OH)D 20 ng/mL) during mid-pregnancy.⁹³ Studies with many participants, however, did not discover a connection between 25(OH)D levels during pregnancy and assessments of bone mass in children. There was no difference in WB and LS BMC, areal BMC, or BA between children whose mothers had Vitamin D deficiency (11 ng/mL) or insufficiency (11–20 ng/mL) during the first, second, or third trimester of pregnancy compared to those who had sufficiency (>20 ng/mL), according to a large cohort of 3960 mothers-children (average age 9.9 years) of the ALPSAC. Furthermore, the Generation R Study (n = 3034) found no association between 25(OH)D levels, which were assessed at week 20 of pregnancy, with offspring BMD.⁹⁴ These observational studies’ inconsistent results demonstrated the need for high-quality randomized controlled procedures to clarify the impact of vitamin D status and/or supplementation on bone metrics during infancy and youth.

Vitamin D and brain development during prenatal phase

Observational studies have recently shown evidence that vitamin D may have an impact on brain growth. The discovery of the vitamin D receptor (VDR) in several brain regions of the neonatal and adult central nervous systems of different species provided the first conclusive evidence that vitamin D signaling may have a role in brain development and function. Additionally, the discovery of 1-hydroxylase in the human brain raises the possibility that the brain’s central nervous system can synthesize 1,25(OH)2D from its inactive precursor, 25(OH)D, indicating that vitamin D may possibly have paracrine effects on the human brain.^27,95,96 Additional research has shown the significance of vitamin D in a number of brain development processes, such as neuronal differentiation, axonal connection, dopamine ontogeny, immunological modulation, and transcriptional control of numerous genes.^31,97 There has been a rapid increase in epidemiological research over the past 10 years on the potential effects of prenatal vitamin D status on the brain, cognition, and behavior of the offspring, but as of yet, no intervention studies have examined the impact of vitamin D supplementation on neurodevelopment.

Cognitive development or global intelligence quotient (IQ)

Nine research have looked at the relationship between prenatal vitamin D level and overall IQ or child cognitive development. Seven studies and found no correlation between prenatal vitamin D levels and global IQ or cognitive development at preschool. Although the impact estimates were extremely tiny, Keim et al. observed a positive correlation between maternal and cord blood 25(OH)D levels and IQ at age 7. Infants of mothers with 25(OH) D concentrations in the first trimester of pregnancy >30 ng/mL had higher cognitive scores at 14 months of age compared to those of mothers with 25(OH) D3 concentrations 20 ng/mL, according to Morales et al.⁶ In addition, a Chinese cohort study found a negative U-shaped relationship between toddlers' cognitive scores and their neonatal vitamin D level.^98–105

Development of psychomotor

Seven studies that evaluated the relationship between prenatal vitamin D level and psychomotor development produced mixed findings. Increased psychomotor scores at ages 14 months and 30 months were linked in two trials to greater maternal vitamin D concentrations during pregnancy. Some researchers did not discover any link, nevertheless. Additionally, Zhu et al. discovered an inverted-U relationship between toddlers' psychomotor scores and their neonatal vitamin D status. In conclusion, there is now conflicting data linking prenatal vitamin D status to global IQ, cognitive development, and psychomotor outcomes.^6,98–105

Autism spectrum disorders (ASD)

The term “autism spectrum disorders” (ASD) refers to a collection of conditions marked by a chronic impairment in social interaction, as well as limiting or monotonous behavioral patterns and verbal and nonverbal communication. There is no known pathophysiology. While the research suggests that genetic factors contribute to its occurrence, its pathophysiology is likely also influenced by non-genetic variables. It has been stated that the prevalence, which has been estimated at 1.5%, is rising, raising the question of whether this rise is genuine or the result of more diagnoses.¹⁰⁶ According to a 1995–1996 Swedish study, children from the Ugandan immigrant population had a substantially greater frequency of autism than Swedish kids,¹⁰⁷ and in 2008, it was reported that Swedish kids had a prevalence of 0.19% whereas it was 0.70% in the kids from the Somali community in the same country. It was believed that this disease would be at danger due to a decline in 25(OH)D levels.

It has been demonstrated that in northern Europe and the United States, more autistic children are born in the winter and spring, but not in places like California and Israel, where there is year-round good solar radiation. It has been established by numerous association studies that autistic people have a lower level of 25(OH) D than their siblings. A meta-analysis of 11 studies revealed that patients’ 25(OH) D was lower than that of controls. Additionally, this has already been found in samples collected at birth.¹⁰⁸ This association could be explained by a number of ways. First, vitamin D affects young children’s brain development. It affects synaptic functioning, neurotransmission (Figure 2), and neuronal differentiation. Second, a vitamin D shortage may change the pattern of T cell activation, disrupt adaptive immunity, and increase the risk of autism.¹¹⁰ Additionally, oxidative stress may make people more prone to autism through their deadly interactions with genes that are predisposed to the disorder. Controlling emotions requires the neurotransmitter serotonin. Vitamin D stimulates the enzyme tryptophan hydroxylase type 2, which enhances the synthesis of cerebral serotonin (but not peripheral).⁹⁷ Last but not least, a vitamin D shortage may make it more likely that genetic mutations will arise by preventing the repair of early mutations in DNA.¹⁰⁶

Figure 2.

Role of Vitamin D in the regulation of normal serotonin neurotransmission and executive function, sensory gating, and prosocial behavior under the influence of Vitamin D level adopted and modified from Hemamy et al.,¹⁰⁹ where EPA = Eicosapentaenoic acid; DHA = Docosahexaenoic acid; 5HT = Serotonin, also known as 5-hydroxytryptamine; 5HTR = 5-hydroxytryptamine Receptor; TPH2 = Tryptophan hydroxylase.

Attention deficit hyperactivity disorder

In a population-based registered study involving 850 women and their offspring born in 1988–1989, Strom et al. found no evidence that maternal 25(OH)D concentrations between 50 and 75 nmol/L (20–30 ng/mL or higher) at pregnancy week 30 were linked to a higher chances of attention deficit hyperactivity disorder (ADHD), in the child till 22 years during follow-up study.¹⁰⁷ On the other hand, Morales et al. reported that the prevalence of ADHD and similar symptoms in preschool children age 4-5 minimized by 11% on 10 ng/mL increasing of maternal 25(OH)D3 at 13 weeks of gestation found by analyzing data from 1650 mother and children pairings included in the INMA birth cohort in Spain.¹⁰⁸ Both the hyperactivity-impulsivity subscale and the inattention subscale showed the inverse correlation. Results from the Greek Rhea birth cohort have consistently demonstrated an association between lower risk of hyperactivity-impulsivity symptoms and ADHD-like symptoms in children at age 4 with higher maternal vitamin D levels (>50.7 nmol/L) in the early stages of pregnancy (at 13 weeks).¹¹⁰

Vitamin D deficiency during critical periods of development can lead to permanent brain damage. A study conducted in Australia observed that vitamin D (25-OH-D) deficiency during pregnancy is strongly associated with increase in attention switching subscale score of autism spectrum quotient. Dutch studies reported autism characteristics at 6 years of age as a result of 25OH vitamin D level below 7.9 ng/mL and decreased 25(OH) D level is strongly associated with ASD diagnosis at age of 9 years.¹¹⁰

Risk factors associated with ADHD

Key risk factors of attention deficit hyperactivity disorder (ADHD) include pregnancy, smoking in pregnancy and nasty family environment. Its etiology is not recognized clearly. However, a few studies reported the involvement of genetic and neurological abnormality. Disruption in the fronto-subcortical pathways, dopaminergic and noradrenergic systems increased the risk of ADHD.⁹⁷ Globally, 50% people are affected by inadequate level of vitamin D. About 1 billion people are vitamin D deficient worldwide. COVID-19 pandemic increased the risk of hypovitaminosis D due to decreased sun exposure and outdoor activities. Vitamin D deficiency is a public health problem as hypovitaminosis D increases risk of mortality. To protect both mother and baby, adequate vitamin D level should be fulfilled during gestational period. Appropriate vitamin D during pregnancy ensures good fetus health in the long run. On reviewing data available at different search engines following major risk factors have been reported to be associated with ADHD.

Pre-pregnancy body mass index and ADHD

The pre-pregnancy body mass index and the amount of the fat-soluble vitamin 25(OH)D are negatively correlated. Given the probable link between inadequate vitamin D intake and poor outcomes for both pregnant women and their newborns. BMI (body mass index) before the pregnancy is closely associated with ADHD. The relationship between maternal obesity and mental illnesses in kids has been investigated. Chen et al. examined the relationship between high mother pre-pregnancy BMI and higher risk of child Attention-deficit/hyperactivity disorder using sibling comparisons.¹¹¹ A population-based cohort study analyzed 174 (mean age = 7.3 ± 0.9 years), 55% girls’ children to find out any linkage between pre-pregnancy body mass index and ADHD. The start of this study was taken from gestation period to birth, infancy and childhood along with measurement of maternal, child prenatal and postnatal factors. BMI of mother before the pregnancy was an indicator of ADHD in the child. These results also indicate that the initiation of pathophysiology of neurological disorders like ADHD took place very early in the life.⁵⁴

Maternal age and risk of ADHD

Early pregnancy is a crucial time for the growth and development of the children and the neurons development. Vitamin D is considered as a hormone which is important for skeletal growth and calcium metabolism, but it also performs various extra-skeletal functions. As the amount of vitamin D required for the growing fetus is dependent on mother’s body stores, maternal vitamin D deficiency is of great importance for its outcomes in the children.¹⁰ Recent studies have revealed that even the countries which have plenty of sunshine have a high number of pregnant women who are Vitamin D deficient mostly due to high rate of alcohol consumption, frequently using sunscreen lotions, due to chain smoking, and stayed in shadows or not have habit to take sun bath at holidays or weekend. The number of maternal vitamin D deficiency cases during pregnancy is equal to or even higher in southern European countries as compared to central or northern countries.⁵⁴

Treatment

Studies reported that mothers who gave childbirth in the earlier stage of their reproductive duration, those child are more prone to ADHD and the involvement of genetic factors is the main etiology behind it. A study conducted among 14, 95,543 Swedish children (30,674 children with ADHD) born during 1988–2003 to evaluate the association between maternal age and ADHD in the children. Mothers having age <20 years were associated with increased risk (78%) of ADHD in children. This study clearly depicting the association between ADHD and mother who are younger in age.⁵⁴

Maternal Vitamin D and risk of ADHD

ADHD risk may increase due to vitamin D deficiency during brain development period in gestation. Adequate level of vitamin D3 during pregnancy decrease the risk of ADHD in children. A study conducted on 1650 mothers showed that increased level of vitamin D reduces the risk for ADHD and ICD-10 hyperkinetic disorder.¹⁰⁸ Vitamin D and ADHD association was observed among 50 ADHD children admitted in hospital and 50 healthy children during 2014–2015 in Iran. Level of active form of vitamin D was low and parathyroid hormone level was higher in ADHD children than healthy ones. Vitamin D level was severely deficient in the children with ADHD.^112,116 During pregnancy, if vitamin D level is higher in mother, behavioral issues during preschool age will be lower. A study was conducted in Greece in which 487 mother–child pairs from the prospective pregnancy cohort were included. Children of women with the high 25(OH) D level (>50.7 nmol/l) had 37% decreased number of hyperactivity–impulsivity symptoms (IRR 0.63, 95% CI 0.39, 0.99, p-trend = 0.05) and 40% decreased number of total ADHD-like symptoms (IRR 0.60, 95% CI 0.37, 0.95, p-trend = 0.03) at 4 years of age, compared to children of women in the low 25(OH) D level which showed important role of Vitamin D for the brain health of children.¹⁹ Vitamin D supplementation during pregnancy may affectively lower the ADHD risk in children. Research conducted in China included 1125 mother-infant pairs to check the linkage between maternal vitamin D status and ADHD. According to this research, vitamin D level was lower in ADHD children (16.6 ± 7.8) than healthy children (23.5 ± 9.9).¹¹³ The relationship between calcium metabolism and the symptoms of ADHD was also the subject of another study by Varmiş and his Colleagues.¹¹⁴ Total 106 participants between the ages of 7 and 13 were included in this study. Vitamin D, PTH, calcium, magnesium, phosphorus, and alkaline phosphatase (ALP) levels were assessed using blood samples. According to the findings, PTH levels were lower in ADHD patients, and there was a significant inverse relationship between PTH and symptom severity. Vitamin D, calcium, and magnesium readings were considerably higher while PTH, P, and ALP values were significantly (p < 0.05) reduced in the ADHD group. PTH and CTRS hyperactivity, CGI-RI and CGI-EL sub-scores, CGI-Total, DSM-IV-Inattention, DSM-IV Hyperactivity/Impulsivity, and DSM-IV-Total scores all showed a negative connection.¹¹⁴ Furthermore, various findings revealed an association between the maternal Vitamin D level and ADHD in children (Table 1).

Table 1.

Different investigations revealing the association of Vitamin D level and ADHD.

Research design	ADHD measure	Sample size	Cognitive domain affected	Serum concentration	Significance of association between vit D and ADHD	Ref
Cohort study	Strengths and difficulties questionnaire and attention deficit hyperactivity disorder test	487 mother–child pairs	Neuro-developmental outcomes	25(OH) D	Yes	⁵⁵
Case control	Conners parent rating scale (CPRS) test	50 ADHD cases and 50 healthy controls	ADHD severity	25(OH)D	Yes	⁵⁶
Prospective cohort study	Diagnostic and statistical manual of mental disorders	1650 mother–child pairs	ADHD-like symptoms	25(OH)D3	Yes	¹¹¹
RCT	Strength and difficulties questionnaire	66 ADHD children (n = 33 in treatment and placebo group each)	emotional Problems, conduct problems, peer problems, prosocial score	25(OH)D	Yes	⁵⁷
RCT	Conners parent rating scale (CPRS) test	96 ADHD children (51 in treatment, 45 in placebo group)	ADHD symptoms	25(OH)D3	Yes	⁹⁸

Limitations and future recommendations

As ADHD investigation involved the direct contribution of pregnant females and growing foetus, therefore it is the major limitation to take consent from such subject to investigate the clear linkage between vitamin D deficiency and ADHD. Moreover, vitamin D dose during pregnancy in not clear yet and follow-up investigations required a comparatively long time upto 10–15 years. It is recommended for researchers to get involve the Health Governments at National level to explore the relationship between Vitamin D and ADHD to resolve the controversial findings.

Conclusion

Different agencies including Institute of Medicine (IOM) at USA/Canada, Nordic Council of Ministers (NORDEN) at Nordic, Scientific Advisory Committee on Nutrition (SACN) at United Kingdom and European Food Safety Authority (EFSA) at European Union recommended adequate intake of Vitamin D for the healthy lives of both women and their infants. It is recommended to maintain the vitamin D level a minimum of 600 IU (15 μg) per day by a combination of supplements and dietary sources. For females aged 19 to 50, including those who are pregnant or nursing, the recommended daily intake is 600 IU (15 g) while tolerable upper intake level is 4000 IU (100 g) per day. Though, there is controversy in the recommended intake of vitamin D during pregnancy. The mechanisms about how early-life Vitamin D deficiency can mediate the effect of prenatal stress on the fetal brain are unknown. Indeed, vitamin D is a powerful immune modulator as well as act as strong antioxidant agent might be responsible for normal brain development in fetal life and during childhood. Therefore, the deficiency of Vitamin D during gestational phase have negative impact on neuropsychological functions of the fetus. Still more studies are required to set the recommended doses to prevent the possibility of the onset of ADHD due to vitamin D deficiency due to controversial findings.

Footnotes

Acknowledgements

We really appreciate the guidance of Doctors of “Eman Diagnostic Laboratories, Lahore‐Pakistan (PHC Regd # R‐14074)” in compiling the data in presentable form for this drastic condition in children.

Author contributions

HT, NM and SSI are the authors who compiled and design the manuscript. UB, SA and HU constructed the figures and tables. MR, IMT, SMAS, AS, and MA critically reviewed the manuscript to finalize the structure as well as contents of the manuscript. Finally all the authors have carefully read and approved the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Naveed Munir

Muhammad Riaz

Imtiaz Mahmood Tahir

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