Vitamin D Deficiency in Pediatric Dentistry

*Elif Gül Aydin*

## **Abstract**

Vitamin D (vitD) deficiency has essential effects on general health. It is known that oral and dental health is an integral part of public health, and there is a close relationship between them. From the development and eruption stages of the teeth to the formation of caries, vitD deficiency has accepted significant effects on oral health. It is essential to understand the role of vitD deficiency in early childhood caries (ECC), which is considered one of the most critical problems, especially in pediatric patients. Low vitD levels during pregnancy have even been reported to increase ECC risk in infancy. For this reason, care should be taken to ensure that the mother's 25(OH)d level and later the child is in optimal conditions, starting from the pregnancy period, to improve the oral health status of children.

**Keywords:** pediatric dentistry, vitD deficiency, early childhood caries, primary teeth

## **1. Introduction**

Today, within the framework of increasing holistic health understanding, it is seen that the interest in the relationship between oral and systemic health has improved. The relationship between dental caries and nutrition is known from when caries are defined. 25-hydroxyvitamin D (25(OH)D) <30 nmol/L is accepted as a vitamin D deficiency, and it is stated that it may be associated with poor oral health. The incidence of periodontal disease, dental caries, and enamel hypoplasia is increased with vitamin D deficiency. In addition, 25-hydroxyvitamin D or its metabolites are involved in the immunological response together with the antimicrobial peptides cathelicidin and defensins that play an immunological role.

## **2. Vitamin D deficiency in pediatric dentistry**

Tooth caries seen in children remain its place as a significant disease that affects more than 600 million children worldwide. Early childhood caries (ECC) is defined as the presence of one or more decayed (non-cavitated or cavitated lesions), missing or filled (due to caries) surfaces in any primary tooth of a child under 6 years of age [1]. Permanent teeth under the primary teeth play a protective place to come to their appropriate places in the mouth. Due to caries in these teeth, chronic pain, infections, and nutritional problems occur in children. These problems have a negative impact on the quality of life of children and families and increase the burden of community health programs. For this reason, they should be considered an integral part of general health.

Early childhood caries, like other types of caries, is a dynamic disease that starts with biofilm, can persist in the presence of sugar, is considered multifactorial, and occurs with the deterioration of the balance between demineralization and remineralization of dental hard tissues. Tooth decay occurs due to the biological, behavioral, and psychosocial factors associated with the individual's environment. Common risk factors for ECC include improper infant feeding, exposure to sugar, poor oral hygiene, poverty, and late access to preventive dental care. ECC has common risk factors for other noncommunicable diseases associated with excessive sugar consumption, such as cardiovascular disease, diabetes, and obesity. Excessive sugar consumption causes prolonged acid production from the bacteria attached to the tooth and changes the composition of the oral microbiota and the pH of the biofilm. When this condition persists, the tooth structures demineralize [1]. Severe early childhood caries (S-ECC) is a more aggressive manifestation that frequently necessitates dental treatment under general anesthesia. Those with S-ECC often suffer from pain, sleep disturbance, behavior changes, and altered eating habits. In recent cross-sectional studies, children with S-ECC have been found to have lower vitamin D status, iron status, or anemia [2–6].

The relationship between nutrition, general health, and dental caries studies dates to the 1920s. The study by Mellanby and Pattison, published in 1928, provides the first evidence that vitamin D deficiency is associated with dental caries in children [7, 8]. A growing body of studies and evidence shows that low serum concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with increased caries experience [2, 8–11]. It has even been reported that low 25(OH)D levels in the mother during pregnancy increase the risk of ECC in children [9, 10, 12].

Minerals, such as magnesium, calcium, and phosphorus, the essential structural components of the tooth, should be taken at sufficient levels with the diet. These minerals play a role by interacting with vitamins in strengthening the tooth structure. A deficiency of magnesium, calcium, and phosphorus in diet and nutrition content usually results in loose teeth and premature tooth loss. If magnesium deficiency occurs during the formation stages of teeth, delay in eruption times, enamel or dentin hypoplasia appear. Also, the alveolar bone becomes brittle, and the gingiva becomes hypertrophic. It is stated that magnesium strengthens the antimicrobial environment, reduces oral inflammation, and increases the flexibility of tooth enamel by increasing calcium absorption in the teeth [13, 14], especially vitD is related to calcium, magnesium, and zinc. Without magnesium, the immune system cannot activate vitamin D, and sufficient calcium absorption does not occur in the teeth. vitD is a hormone essential for the intestinal absorption of Calcium, Magnesium and Phosphate. Vitamin D helps regulate calcium and phosphate balance to maintain healthy bone function. Magnesium helps activate vitamin D, which helps regulate calcium and phosphate homeostasis, influencing bone growth and maintenance. There is a synergistic relationship between vitD and magnesium [13].

Several different mechanisms have been proposed to express the role of vitD among the factors reducing caries.

One of these mechanisms is to play a role in the formation, calcification, mineralization, and protection of teeth by affecting serum calcium, phosphate levels, and parathyroid hormone. The balance between calcium and phosphate levels is

### *Vitamin D Deficiency in Pediatric Dentistry DOI: http://dx.doi.org/10.5772/intechopen.109278*

important for the formation, calcification, mineralization, and preservation of teeth, bone, hard tissue, maxilla, and mandible. Enamel and dentin defects-hypoplasia have been linked with hypocalcemia and hypophosphatemia [11, 15].

Dental caries and VDD (vitamin D deficiency) affect children worldwide. Changes in both enamel and dentin are observed in children with a VDD. Therefore, vitD has a significant role in forming oral hard tissue, comprising tooth enamel and dentin, and affects primary and permanent teeth development [8, 11, 16].

Vitamin D deficiency may cause defects in enamel and dentin and increase the risk of dental caries. In a systematic review of controlled clinical trials, 2827 children were included. As a result of this systematic review, the significant relationship found between vitamin D levels, and dental caries showed that vitamin D is a promising anticaries agent [4, 8, 17].

Vitamin D has a significant role in odontogenesis [11, 18]. The mechanism by which vitD excites the mineralization of tooth enamel involves binding to vitamin D receptors (VDR) expressed in both tooth and bone cells. VDR directs the transcription of several target genes, mostly defined by ameloblasts and odontoblasts [11, 15, 19]. It coordinates physiological functions by controlling calcium and phosphate metabolism, promotes growth, and induces necessary remodeling of the bones and teeth [4]. VDR stimulates the formation of structural gene products in dentin, together with calcium-binding proteins and diverse extracellular matrix proteins. The gene encoding VDR is positioned on chromosome 12q13.11 and comprises several polymorphisms [19]. The VDR gene adjusts the biological role of primary vitD metabolites; thus, having a vital role in the configuration of teeth, particularly in mineralizing dentin and enamel. Consequently, developmental deficiencies, for example, enamel hypoplasia, can result from VDD. Ultimately, vitD and VDR at the molecular level influence the tooth germ formation, supply the regulation of enamel and dentin structure and maturation, and organize the phases of dental crown growth [11, 15]. In addition to dental problems due to vitamin D deficiency, genetic polymorphism of VDR gene polymorphism has been associated with dental problems, such as external apical root resorption, periodontal diseases, dentinogenesis imperfecta, chronic periodontitis, and dental caries [20].

Tooth development and eruption are complex mechanisms involving the resorption of alveolar bone and the eruption pathway. A disorder in these processes causes persistent primary teeth and delays in permanent tooth eruption. It is stated that decreased vitamin D levels increase the rate of constant primary teeth and cause delays in eruption in permanent teeth. It was known that maternal vitamin D deficiency affects the formation and mineralization of primary teeth. It is considered among the dental effects of vitamin D deficiency, which cause tooth eruption delays in children [20].

Moreover, vitD adjusts and adapts both the innate and adaptive immune systems. The immunological role of vitD is stimulating the arrangement of some antimicrobial peptides, for example, defensins and cathelicidin (LL-37), which defend against many pathogens, counting oral bacteria [4, 11, 12, 21]. Cathelicidin (LL-37 or hCAP-18) is controlled by vitD, which has antiendotoxin and antimicrobial properties [22]. Vitamin D induces cathelicidin (LL-37), which is found in the immune system. LL-37 exhibits both antimicrobial and antiendotoxin activity. It is stated that there is an inverse relationship between dental caries and LL-37, and the concentration of LL-37 is low in children with high caries activity. Epithelial antimicrobial peptides (LL-37 is one of them) are the protectors of the oral cavity. It is stated that these antimicrobial peptides have essential roles in reducing gingivitis in oral health. Therefore, vitamin

D may be helpful in the treatment of periodontitis due to its direct effects on bone metabolism and possible anti-inflammatory effects on periodontopathogens [13].

Early tooth loss, bone resorption, and bleeding tendency increase in mineral deficiencies due to absorption disorders [13]. The chewing efficiency of individuals provides the highest nutrient intake efficiency. Prematurely lost teeth have adverse effects on diet selection and nutritional efficiency. Deterioration of nutritional efficiency also causes deficiencies in vitamin intake. The resulting vitamin deficiency also negatively affects the formation of dental hard tissue. Vitamin deficiencies in the developmental stages of teeth cause disorders in the formation of hard tissue of the tooth. Therefore, it has been stated that there is a strong positive correlation between vitamin deficiencies. Malnutrition and dental hard tissue hypoplasia increase the risk of dental caries in children during the primary dentition period [2, 23]. In addition, mineral deficiencies cause bleeding in the gums, delayed tooth eruption, periodontal disease, and destruction patterns in the alveolar bone [13, 23].

It is stated that dental health in children has started to decrease in industrialized countries due to identifying risk factors and developing preventive strategies. However, it was determined that while the prevalence of caries decreased, enamel defects began to increase. It is considered a global burden, with the majority of enamel defects rising to 38% in Western European countries [24]. Developmental enamel defects are present when the affected tooth erupts. When the tooth newly erupts, it may appear hypo mineralized, porous, and more yellow-brown opaque in color. These impacted teeth are susceptible to fracture easily, and the permanent first molars are affected quite frequently. Although these defects predispose to atypical and extensive caries, they may result in the loss of the relevant permanent teeth in the early period of life [25]. Even if the developmental enamel defects are mild, they cause pain in children due to dentin sensitivity, poor esthetic color, and caries susceptibility. Considering the effects of enamel defects on quality of life and health care utilization, a significant public health problem arises [24–26]. Developmental enamel defects are associated with the calcification processes of the teeth. Since calcifications of primary and permanent teeth occur in the early postnatal period following the intrauterine period, it is necessary to examine these periods while investigating the etiological factors. Studies indicate maternal disease, drug use during pregnancy, premature birth, birth complications, and early childhood diseases as the etiological factors of enamel defects [27]. However, these pieces of evidence are unfortunately insufficient and therefore preventable. Vitamin D plays a crucial role in enamel formation, and vitamin D deficiency is now also considered a common health challenge in westernized societies [4].

A randomized controlled study conducted with high-dose vitamin D supplementary to mothers during pregnancy and early postpartum showed an inverse relationship between high-dose vitamin D intake and the formation of enamel defects. In other words, high-dose vitamin D supplementation taken during pregnancy and early postpartum showed a 50% reducing effect on enamel defects in 6-year-old children [26]. It is on the agenda to recommend vitamin D supplementation as a primary preventive measure for enamel defects, potentially impacting dental health. Considering the crucial role of vitamin D in enamel mineralization [19, 28], the biological relationship between vitamin D supplementation and these enamel defects is considered reasonable. Vitamin D has an effect on the function of ameloblasts and the mineralization of enamel in the early stages of tooth formation. It is stated that highdose vitamin D supplementation has a protective effect on the structural strength and development of enamel [26].

#### *Vitamin D Deficiency in Pediatric Dentistry DOI: http://dx.doi.org/10.5772/intechopen.109278*

Vitamin D is also very effective, along with minerals, in protecting oral health. Vitamin D helps maintain the calcium-phosphate balance and contributes to the shaping of the bone. The beneficial effects of vitamin D on oral health are not only limited to the direct impact on tooth mineralization. Still, they are also exerted through anti-inflammatory functions and the ability to stimulate the production of antimicrobial peptides. It also has essential functions by showing anti-inflammatory effects. It is reported that with sufficient Vit-D levels, the onset and progression of caries in the tooth structure can be stopped, caries can be formed, and enamel loss can be prevented [4, 11, 13].

Early childhood caries affects not only dental health but also has severe effects on general health. Malnutrition, iron deficiency anemia, and VDD are seen in children with ECC because their nutritional status is affected [11, 17]. When the relationship between vitamin D levels and caries was evaluated, it was determined that the incidence of dental caries was higher in the children of mothers with low serum vitamin D during pregnancy, and there was a strong correlation between vitamin D levels and DMFT scores in the early childhood period of children up to 6 years of age [3]. It is stated that the incidence of caries in the permanent first molar teeth is lower in children with serum vitamin D levels greater than 50 nmol in the 10–11 years of early adolescence period [3]. Similarly, in children aged 6–17 years, it was determined that every 10 mg/ml increase in serum vitamin D resulted in a 0.66 decrease in DMFT scores. It is also expected that malnutrition and related vitamin deficiencies increase the incidence of enamel hypoplasia [2, 5, 9, 11]. According to the results of an observational study, the rate of dental caries was found to be more than three times higher in 6-year-old children of mothers with 25 OHD deficiency in the third trimester of pregnancy compared to the children of mothers with adequate 25 OHD levels in the third trimester of pregnancy [3].

Vitamin D use may have a role in the protection of caries early in life. According to meta-analysis studies, it is thought to be a promising caries prevention agent, given that Vit-D supplementation relates to a 47% reduction in caries in children [3, 17]. Considering intrauterine life, an essential and critical stage for the development of teeth, and vitamin D deficiency during pregnancy plays a crucial role in the susceptibility to enamel hypoplasia and caries [2, 11, 23].

Improving vitD levels in children from an early stage appears to be an essential task. This requires awareness of pregnancy. Pregnant women should have their vitD levels tested routinely during the first trimester of pregnancy, and the risk of VDD, VDD, and vitD ingestion should be evaluated. Prenatal vitD levels appear to influence the development of primary dentition and ECC [3, 9, 11, 23]. In addition, a study found that pregnant women's poor oral hygiene and low vitamin D levels were positively correlated with preterm birth and low birth weight [29].

Vitamin D is an essential hormone for absorbing calcium, magnesium, and phosphorus from the intestine, which is necessary for properly mineralizing bones and teeth. Although there are no applications in children, it has been shown that coating the implant surfaces with vitD during dental implant application increases osteointegration. In addition, intraperitoneal application of vitD creates positive effects (such as facilitating acceleration) on tooth movements during orthodontic treatment [13].

## **3. Conclusions**

When evaluated from a holistic perspective, it should be kept in mind that oral health is also a part of general health. When seeking solutions for dental problems in children, the vitamin values of individuals should be considered. Increasing social awareness in the fight against ECC and evaluating vitamin D deficiency is essential.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Elif Gül Aydin Faculty of Dentistry, Sakarya University, Sakarya, Turkiye

\*Address all correspondence to: eligul@sakarya.edu.tr

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 3**

## Vitamin D Deficiency and Critical Care in the Neonatal Period

*Pedram Ghahremani*

## **Abstract**

Neonates in critical care constitute a vulnerable group, and vitamin D status in this group is the subject of extensive research. Studies suggest that critically ill neonates and children have lower mean vitamin D levels than healthy ones, and there is evidence linking vitamin D deficiency to an increased risk of mortality, illness severity, and complications in these patients. Vitamin D deficiency in neonates and children with congenital heart disease (CHD) undergoing corrective surgical treatment has attracted particular attention. Overall, studies show high prevalence rates of vitamin D deficiency in this group. Moreover, several studies report significant associations between low vitamin D levels and unfavorable findings, such as increased requirements for vasoactive support and mechanical ventilation and prolonged ICU stays. Available data suggest vitamin D deficiency as a risk factor in neonatal and pediatric critical illness, specifically in CHD patients undergoing surgical treatment. Clinical trials have been proposed to examine the beneficial effect of preoperational vitamin D supplementation on the outcome in this group. However, for now, vitamin D supplementation should be considered in critically ill neonates, particularly those undergoing surgery for CHD, aiming to maintain vitamin D at safe levels over the threshold of vitamin D deficiency.

**Keywords:** vitamin D deficiency, neonatal period, critical care, congenital heart disease

## **1. Introduction**

The traditional roles of vitamin D in skeletal dynamics, renal calcium reabsorption, and intestinal calcium absorption have long been known, as are the effects of vitamin D deficiency on skeletal abnormalities such as rickets [1], but in recent years, our understanding of vitamin D functions has rapidly evolved, and the list of roles attributed to this compound in the body is greatly expanded. Basic science studies have demonstrated the presence of vitamin D receptors on a wide range of cell types in the body, from myocytes to white blood cells, implying a physiological role for vitamin D in these organs. Similarly, laboratory animal studies have shown that a large number of diseases can occur in genetically modified, vitamin D receptor knockout mice and also in normal animals with nutritionally-induced vitamin D deficiency. In humans, vitamin D deficiency is now linked to various disorders, from unfavorable pregnancy outcomes to an increase in all-cause mortality, cardiovascular and cerebrovascular events, infectious and autoimmune diseases, and numerous cancers [2]. As

a result, vitamin D is now studied as a crucial substance with potential effects on the initiation, progression, and outcome of a wide range of pathological conditions.

The possible links between vitamin D status and outcomes in critically sick patients are fascinating subjects of current research. It has been hypothesized that vitamin D deficiency may have a negative impact on the outcome in critically ill patients due to a variety of roles that this vitamin plays in vital organs and life processes [3]. Several studies have found a link between vitamin D deficiency and the risk of death in people receiving critical care, and clinical trials are conducted to look at the potential positive effect of supplemental vitamin D in this population of patients [4]. Neonates and infants in critical care constitute a particularly vulnerable group, and a considerable amount of research is focused on vitamin D status in this group. Studies suggest that neonates and children who are critically ill have lower mean vitamin D levels than healthy ones, and there is evidence linking vitamin D deficiency to an increased risk of mortality, illness severity, and complications in these patients [5, 6]. In this chapter, we look into the ongoing research on this exciting topic.

## **2. Defining vitamin D deficiency**

Experts generally agree that 25-hydroxyvitamin D [25(OH)D] concentration should be used to evaluate vitamin D status because it captures the contribution from both diet and dermal synthesis [7], but there has been much debate regarding the suggested thresholds (cut-offs) to define vitamin D deficiency. The Endocrine Society Task Force on Vitamin D in the US has recommended that people with serum 25(OH) D levels of less than 50 nmol/L be classified as vitamin D-deficient [8], while an international expert panel assembled by the European Society for Pediatric Endocrinology has suggested serum 25-hydroxyvitamin D levels of 30–50 nmol/L as vitamin D insufficiency and levels <30 nmol/L as deficiency [9].

In addition to clinical care guidelines, the question of vitamin D deficiency has been addressed from the population health perspective. Some expert bodies tasked with developing dietary recommendations for vitamin D propose 50 nmol/L as the concentration of serum 25(OH)D that would satisfy the physiological vitamin D requirement of nearly all "normal healthy persons" [7]. The Institute of Medicine (IOM) in the US chose calcium absorption, bone mineral density (BMD), and two well-studied clinical conditions- rickets in children and osteomalacia in adults- as indicators for developing their vitamin D recommendations, known as Dietary Reference Intakes (DRI) [7]. The DRI committee developed the Recommended Dietary Allowance (RDA) based on the estimate that serum 25(OH)D concentration of 50 nmol/L (15 μg/day for those aged 1 to 70 and 20 μg/day for those over 70) would satisfy the needs of nearly all (i.e., 97.5%) of "normal healthy persons" [7]. Likewise, the Scientific Advisory Committee on Nutrition (SACN) in the UK chose musculoskeletal status (rickets, osteomalacia, falls, muscle strength, and function) for developing their vitamin D recommendations, known as Dietary Reference Values (DRV). They believe that the evidence overall suggests the risk of poor musculoskeletal health increases at serum 25(OH)D concentrations below 20–30 nmol/L [10]. Based on this reasoning, SACN chose a serum 25(OH)D target of 25 nmol/L as the "population protective level" in order to safeguard the musculoskeletal health of people in the UK throughout the year. They suggest a Reference Nutrient Intake (RNI) of 10 μg/day for those aged 4 years and older [10].

Overall, according to guidelines, serum 25(OH)D concentrations above 50 nmol/L indicate vitamin D sufficiency for the majority of people, whereas concentrations between 50 and 30 nmol/L indicate a risk of vitamin D inadequacy or deficiency for some people [7]. Even though there is not yet universal agreement on what constitutes vitamin D deficiency, it is generally accepted that we do not want people in our populations to have 25(OH)D concentrations below 25/30 nmol/L. Preventing such vitamin D deficiency is a public health priority.

## **3. Vitamin D deficiency in neonates and infants**

Vitamin D deficiency is one of the most significant dietary deficits in children worldwide. The International Osteoporosis Foundation (IOF) estimates that vitamin D deficiency affected 84% of pregnant women and 96% of babies in 2009 [11]. A 2016 systematic review considered 25(OH)D concentrations in neonates and pregnant women worldwide from 1959 to 2014. Results showed that the mean maternal 25(OH)D concentrations ranged from 13 to 130 nmol /L, while the mean neonatal 25(OH)D concentrations ranged from 5 to 77 nmol/L. Around 54% of pregnant women and 75% of newborns had vitamin D deficiency, defined as a serum 25(OH)D concentration below 50 nmol /L, and 18% of pregnant women and 29% of newborns had severe vitamin D deficiency, defined as a serum 25(OH)D concentration below 25 nmol/L. There was a wide variation in vitamin D levels between WHO regions. In the Eastern Mediterranean region, the average maternal 25(OH)D concentration was <25 nmol /L, while it ranged from 75 to 100 nmol/L in the African region. In the Americas, the average newborn 25(OH)D concentration was >75 nmol/L, but it was <25 nmol/L in the Eastern Mediterranean. Similarly, 79% of pregnant women in the Eastern Mediterranean region had severe vitamin D deficiency. The prevalence of severe vitamin D insufficiency among pregnant women in the Americas, Western Pacific, and Europe were much lower (9%, 13%, and 23%, respectively). The prevalence of vitamin D deficiency in neonates from the South-East Asian region was very high (96%), while in the Americas, 30% of neonates were vitamin D deficient [12].

Leading causes of vitamin D deficiency in neonates include lower nutritional intake, exclusive breastfeeding when the mother has vitamin D deficiency, and decreased sun exposure due to seasonal changes. Maternal vitamin D deficiency is demonstrated to be a significant risk factor for newborns with vitamin D deficiency [11]. Neonatal 25(OH)D concentrations at delivery are generally lower than normal in babies born to mothers with deficient and insufficient vitamin D levels but not in babies of mothers with sufficient vitamin D status [13]. Infants in a disadvantaged socioeconomic position exhibit a higher rate of vitamin D deficiency. This could be explained by the likelihood of decreased calcium and vitamin D intake in these children. Likewise, preterm newborns are more susceptible to vitamin D deficiency due to diminished placental transfer, insufficient sun exposure, and lower vitamin D storage as a result of low-fat mass. Babies with nephrotic syndrome, cystic fibrosis, or malabsorption syndrome are also at higher risk of vitamin deficiency [14]. Drugs such as phenobarbital, carbamazepine, oxcarbazepine, and phenytoin can interfere with vitamin D metabolism [8]. The absorption, metabolism, or activation of vitamin D are also impacted by other medications, including corticosteroids and azole antifungals.

Secondary hyperparathyroidism, secondary hyperphosphatemia, and hypocalcemia are the main biochemical changes seen in babies with vitamin D deficiency [15]. Along with vitamin D deficiency, other factors that may contribute to hyperphosphatemia in this group include a decreased glomerular filtration rate, low intact parathyroid hormone (iPTH) levels, and renal tubular nonresponse to PTH, particularly in the first days after birth. It is possible that co-occurring metabolic bone disease especially in preterm, small-for-gestational-age (SGA) neonates—also contributes to these biochemical alterations.

Clinically, vitamin D deficiency in infants presents as rickets in extreme situations, which can cause bowing of the knees, wrist widening, frontal bossing, spontaneous fractures, and skeletal abnormalities. In older children, it can cause short stature, muscle weakness, and pain. In addition to skeletal signs, vitamin D insufficiency can cause developmental delay, growth failure, and recurrent respiratory infections [14]. Early vitamin D insufficiency can go undetected without clinical symptoms and later proceed to florid rickets in older children if undiagnosed. In fact, in the neonatal age group, the symptoms of hypocalcemia, there may the only clinical manifestations of vitamin D deficiency.

To avoid the risk of later skeletal abnormalities and reduce pulmonary morbidity, vitamin D insufficiency must be promptly identified and treated in neonates and infants. A dosage of 400–1000 international units (IU) of vitamin D per day for 8 to 12 weeks is the recommended course of treatment for newborns with vitamin D insufficiency, while infants after the newborn stage need 1000–5000 IU of vitamin D per day for 8–12 weeks [15]. To treat vitamin D deficiency and prevent the hungry bone syndrome, which develops as a result of underlying hypocalcemia, vitamin D therapy is combined with appropriate calcium administration. To attain ideal serum levels, children with malabsorption syndromes and those taking anticonvulsants, glucocorticoids, antifungals, or antiretroviral drugs require longer and higher oral doses of vitamin D [16].

Dietary consumption and cutaneous production both contribute to the maintenance of vitamin D levels. Neonates and children have a greater potential to generate vitamin D from sunshine because they have a higher body surface area to volume ratio than adults [17]. A 10- to 15-minute period of direct sunshine exposure can generate 10,000 to 20,000 IU of vitamin D. It has been demonstrated that completely dressed infants exposed to sunlight for 2 hours each week can avoid severe vitamin D insufficiency [18]. However, it should be noted that exposure to direct sunshine is not recommended in infants younger than 6 months. Geographical latitude, degree of skin pigmentation, and the amount of skin exposed to sunlight are among the most critical variables that affect vitamin D synthesis from sunlight. Therefore, children with more skin pigmentation are at a higher risk of vitamin D deficiency. Compared to children with less skin pigmentation, these children need five to ten times more time in the sun for the same amount of 25(OH) vitamin D to be produced. Asian children need three times more sun exposure than white American children to maintain adequate vitamin D levels due to their darker complexion.

## **4. Vitamin D deficiency and neonatal and pediatric health outcomes**

In addition to its well-defined classical functions related to calcium homeostasis and bone development, the relationship between vitamin D levels and health outcomes in infancy has also attracted exceptional attention in the scientific community. We begin our review of possible links between vitamin D status and health outcomes with pregnancy outcomes. Despite its critical importance, it is still unclear whether

### *Vitamin D Deficiency and Critical Care in the Neonatal Period DOI: http://dx.doi.org/10.5772/intechopen.107454*

maternal vitamin D status plays a role in proper fetal and placental development and consequently in pregnancy outcomes. One recent review found no clear evidence to suggest that low vitamin D levels in early pregnancy are associated with adverse pregnancy outcomes, mainly preeclampsia, fetal growth restriction, preterm birth, and stillbirths [19]. In contrast, another review concluded that pregnant women with low 25(OHD) levels had an increased risk of gestational diabetes, preeclampsia, small for gestational age infants, and lower birth weight infants but no association with delivery by cesarean section [20]. Aghajafari et al. reviewed five randomized controlled trials and suggested a protective effect of vitamin D supplement during pregnancy on low birth weight (LBW) but no effect on preterm delivery [21].

The relationship between maternal vitamin D levels and particular child health outcomes, such as infections, has been investigated. Evidence suggests a relationship between maternal vitamin D levels and infants' predisposition to infection. One study found a significantly higher risk of respiratory infections (colds, cough, whooping cough, chest infection, and ear infection) by 3 months of age among infants with cord blood levels of 25(OH)D less than 25 nmol/L [22]. In contrast, a cohort study followed-up children at the age of 9 months and found that mothers in the top quartile of 25 (OH) D statuses in late pregnancy were significantly more likely to report their children having been diagnosed with pneumonia or bronchiolitis compared with those in the bottom quartile [23]. One recent study showed an association between early-onset neonatal sepsis and low maternal vitamin D levels in term infants [24]. Studies have also suggested that vitamin D pathways may be involved in the susceptibility to and outcome of Hepatitis B Virus infection acquired early in life [25].

The epidemiological evidence of the link between maternal vitamin D levels and infection is inconclusive, but vitamin D has a direct role in the production of antimicrobial peptides such as cathelicidin, which may help prevent infection during pregnancy and early childhood. This mechanism suggests a plausible biological basis for the relationship between maternal vitamin D levels and infection in infancy. Preventive measures in pregnant women aim to ensure that they have enough vitamin D, either from sunlight exposure or the right vitamin D supplements, and protect the newborn against possible adverse effects of vitamin D deficiency.

## **5. Vitamin D deficiency in neonatal and pediatric critical care**

Accumulating evidence from various parts of the world points to a high prevalence of vitamin D deficiency among children admitted to neonatal and pediatric critical care units. Babies in the neonatal period are particularly vulnerable to a range of diseases requiring NICU hospitalization, and the study of vitamin D status in this group has attracted considerable interest in recent years. In a study by Bhimji et al. in Tanzania, about 80% of newborns admitted to the NICU of a tertiary care hospital showed vitamin D insufficiency [26]. A study from the U.S. discovered vitamin D inadequacy or insufficiency in 80% of preterm newborns with birth weights under 1500 g [27]. Another study from Australia found such conditions in 35.7% of preterm neonates admitted to NICU [28]. To determine the prevalence of vitamin D deficiency, Chacham et al. carried out an observational study on infants aged equal to or younger than 1 year at a tertiary care facility in Northern India. Neonates comprised 80% of the population under study and had a 79% prevalence of vitamin D insufficiency [29]. According to a recent study from Iran, 37% of neonates hospitalized in the NICU had vitamin D deficiency, while 58% had vitamin D insufficiency. Thus,

95% of neonates had abnormal vitamin D levels at admission [30]. Kim et al. studied vitamin D status in very-low-birth-weight neonates in Korea and reported a mean serum vitamin D level of 13.4 ± 9.3 ng/mL, with 79.8% of the subjects being vitamin D deficient. They found a higher prevalence of respiratory morbidities, such as bronchopulmonary dysplasia and respiratory distress syndrome in preterm neonates, that had severe vitamin D deficiency. Moreover, vitamin D deficiency was associated with a longer NICU stay [31].

Vitamin D status has also been studied beyond the neonatal period and in the pediatric critical care setting. Rey et al. studied vitamin D levels of critically ill children in PICU and healthy kids in Spain. They found a nearly twofold higher rate of vitamin D deficiency in PICU patients compared to healthy controls [32]. In a multicenter study of critically ill children across Canada by McNally et al., the mean 25(OH)D levels (43 nmol/L) were much lower than the 67–75 nmol/L mean levels observed among healthy Canadian and US children. In patients who needed catecholamine infusions, required mechanical breathing, and received more than 40 ml/kg of fluid resuscitation, 25(OH)D levels were lower. Vitamin D deficiency was also independently associated with a 2-day increase in PICU stays [33]. The authors hypothesized that, during critical illness, sudden reductions in vitamin D levels might be more physiologically relevant than chronic deficiency because compensatory mechanisms are affected by inflammation and multiorgan failure in this setting. Similarly, in their study of a tertiary care PICU in India, Sankar et al. found a vitamin D deficiency prevalence of 74%. Furthermore, vitamin D deficiency was associated with a longer duration of PICU stay in this study [34].

A prospective study by Madden et al. at Boston Children's Hospital's pediatric intensive care unit (PICU) examined vitamin D levels at the time of admission. The study did not include patients undergoing heart surgery. The 25(OH)D deficiency was significantly associated with poorer clinical outcomes. In patients with vitamin D deficiency, the scores of illness severity were higher, and they were more likely to need vasopressor treatment. However, no association was discovered between 25(OH)D levels and the time spent on mechanical ventilation, and ionized serum calcium levels were normal in almost all cases [35]. The authors suggested that these findings were secondary to vitamin D's function in immunological regulation, inflammation, and calcium homeostasis and not due to fluid shifts and hemodilution.

## **6. Vitamin D deficiency and critical care in congenital heart disease**

Congenital heart disease (CHD) and its surgical treatment is one the conditions that necessitate ICU admission and critical care in neonates and pediatric patients. In recent years, a considerable amount of research has been dedicated to vitamin D status in children with cardiac disease and the relationship between vitamin D levels and treatment outcomes in this group. In the study by Rippel et al. on critically ill children, two-thirds of the patients were postoperative cardiac patients. The researchers found no association between 25(OH)D deficit and the requirement for mechanical ventilation, the need for vasoactive support, the length of hospital or ICU stays, the severity of disease scores, or mortality. However, the likelihood of being vitamin D deficient in patients with cardiac diseases was almost twice that of non-cardiac patients in this study (40% vs. 22%) [36].

In 2013, McNally et al. reported the findings of a prospective cohort study on the vitamin D status of 54 children with CHD who underwent open heart surgery at a

## *Vitamin D Deficiency and Critical Care in the Neonatal Period DOI: http://dx.doi.org/10.5772/intechopen.107454*

mean age of 8.4 months and 4 children who had coarctation of the aorta and underwent closed heart surgery. Forty-two percent of patients had a preoperative 25OHD deficiency (<50 nM), with the mean value being 58.0 nM (SD, 22.4). Following surgery, there was a 40% reduction in mean 25OHD to 34.2 nM (SD, 14.5), with 86% of subjects having vitamin D deficiency. The open-heart surgery group's decline in vitamin D levels was more remarkable. Intraoperative measurements showed a sudden drop in vitamin D with the start of cardiopulmonary bypass. Additionally, the authors investigated the need for catecholamines and discovered an association between lower postoperative- but not preoperative- vitamin D levels and the need for catecholamines [37]. A study of the vitamin D levels in 20 children with CHD having open heart surgery was published in 2017 by Abou Zahr et al. Prior to surgery, 40% of the patients had 25OHD deficiency, with values <20 ng/mL. After cardiac bypass surgery, the investigators found that the mean vitamin D level had significantly decreased [38]. Dohain et al. examined the vitamin D status of 69 CHD children following open heart surgery in 2020. Of the patients, 34 (49.5%) had vitamin D deficiency before surgery, and 63 (91.3%) after surgery. They found a 42.03% reduction in 25(OH)D after surgery and noted an association between decreased postoperative vitamin D levels and a rise in inotropic support requirement. These findings suggest a link between unfavorable circumstances and the postoperative decline in vitamin D levels [39]. In 2021, Ye et al. evaluated the relationship between preoperative vitamin D deficiency and the maximum vasoactive-inotropic score 24 hours after surgery in 900 children with CHD. The median total serum 25(OH)D level before surgery was 24.0 ng/mL, and 32.6% of the patients had vitamin D deficiency (25(OH)D < 20 ng/mL). They discovered an association between low vitamin D levels and the need for more postoperative inotropic support 24 hours after cardiac surgery [40].

A number of studies have focused on vitamin D status in neonates with CHD in critical care settings. In 2013, Graham et al. studied the vitamin D status of 70 neonates with CHD having open heart surgery. Before the procedure, 84% (59/70) of the subjects had vitamin D insufficiency. There was no significant decline in vitamin D levels after the operation. However, higher inotropic support was required when postoperative 25(OH)D levels were lower [41]. In 2022, Mosayebi et al. studied changes in vitamin D status in neonates with CHD having heart surgery. The study included 33 open-heart surgery patients and 13 patients with closed-heart surgery. This wide coverage allowed researchers to compare vitamin D status in the open- and closedheart surgeries. Before the procedure, 66.7% of the patients were vitamin D deficient. This number rose to 84.4% after surgery. After surgery, vitamin D levels declined significantly in patients who had open heart surgery but not those who had closed heart surgery. A significant association was found between the rate of postoperative decrease in vitamin D levels and an unfavorable outcome while preoperative vitamin D levels did not demonstrate a link with the outcome and did not predict the rate of postoperative vitamin D decline. The authors suggested a sharp decrease in vitamin D levels after surgery as an indicator of an unfavorable outcome [6].

Citing the evidence that links vitamin D deficiency to poor outcomes in neonate and infant CHD surgery, in 2020, McNally et al. conducted a dose evaluation feasibility study in preparation for a clinical trial of vitamin D supplementation in children with CHD undergoing corrective surgery. They reported that supplementation with a daily high dose of vitamin D before surgery improved vitamin D status at the time of pediatric ICU admission. The authors recommended modifying the trial protocol and giving vitamin D supplements to patients for at least 1 month before surgery or considering a loading dose [42].

## **7. Conclusion**

With the gradual recognition of the crucial role of Vitamin D status in many physiological and pathological processes, vitamin D deficiency has been proposed as a possible modifiable risk factor for ICU outcomes. The discovery of the role of vitamin D in stress response in the immune, cardiovascular, and respiratory systems has lent support to this possibility. Moreover, numerous clinical studies have identified a high prevalence of vitamin D deficiency among ICU patients.

Neonates and pediatric patients constitute a particularly vulnerable group, and the vitamin D status in this group in critical illness has come under increasing scrutiny in recent years. The studies have predominantly shown a high prevalence of vitamin D deficiency in critically ill neonates and pediatric patients, pointing to a potential role for vitamin D status in critical illness in these patients. Vitamin D deficiency in CHD patients undergoing corrective surgical treatment has attracted particular attention, and a number of studies have focused on this topic. Overall, these studies report high prevalence rates of vitamin D deficiency in this group of neonates and pediatric patients. Moreover, several studies report significant associations between low vitamin D levels and unfavorable findings, such as increased requirements for vasoactive support and mechanical ventilation and prolonged ICU stays, in these patients.

An evaluation of available data suggests vitamin D deficiency as a modifiable risk factor in neonatal and pediatric critical illness, specifically in CHD patients undergoing surgical treatment. Clinical trials have been proposed to examine the potential beneficial effect of preoperational vitamin D supplementation on the outcome of heart surgery in this group. Studies on this topic are still in progress. However, for now, vitamin D supplementation should be considered in critically ill neonates in general and in those undergoing surgery for CHD in particular. Such supplementation aims to maintain serum/plasma 25(OH)D concentrations at safe levels over the threshold of vitamin D deficiency.

## **Conflict of interest**

The author declares no conflict of interest.

## **Author details**

Pedram Ghahremani Medical School, Zanjan University of Medical Sciences, Zanjan, Iran

\*Address all correspondence to: gharamanip@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 4**

## Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism?

*Teodoro Durá-Travé and Fidel Gallinas-Victoriano*

## **Abstract**

Obesity childhood is related to vitamin D deficiency, but the mechanisms for this association still remain questionable. We hypothesized that behavioral factors would be decisive in reducing the body content of vitamin D in patients with obesity. A cross-sectional clinical and analytical study (calcium, phosphorus, calcidiol, and parathyroid hormone) was carried out in a group of 377 patients with obesity (BMI-DS >2.0), 348 patients with severe obesity (BMI-DS >3.0), and 411 healthy children. The place of residence was categorized as urban or rural. Vitamin D status was defined according to the US Endocrine Society criteria. The prevalence of vitamin D deficiency was significantly higher (p < 0.001) in severe obesity (48.6%) and obesity groups (36.1%) than in the control group (12.5%). Vitamin D deficiency was more frequent in severe obesity and obesity groups living in urban areas than in those living in rural areas (not in the control group). The patients with obesity living in urban residence did not present significant seasonal variations in vitamin D deficiency throughout the year in contrast to those patients with obesity living in rural residence. These findings suggest that the most probable mechanism for vitamin D deficiency in children and adolescents with obesity, rather than altered metabolic, is the behavioral factors (sedentary lifestyle and lack of adequate sunlight exposure).

**Keywords:** adolescents, children, calcidiol, obesity, parathyroid hormone, rural areas, urban areas, vitamin D

## **1. Introduction**

Vitamin D is currently assigned a pleiotropic profile [1–3]. In point of fact, basically every human tissue and cell contains vitamin D receptors, and its biological effects are categorized as skeletal (bone metabolism and calcium homeostasis) and extraskeletal (hypovitaminosis D appears to be involved in autoimmune diseases, infections, neuropsychiatric disorders, cardiovascular risk, prostate and breast cancer, etc.), a circumstance that justifies the interest in monitoring its body content.

Furthermore, the prevalence of childhood obesity has gradually increased in the course of the last decades, establishing as the most relevant nutritional disorder in our environment [4–6]. Even though obesity is considered as a multifactorial disorder, the celerity of its increase in prevalence is related essentially to behavioral factors: scarce

healthy nutrition habits as well as a sedentary lifestyle conditioned, in large part, by new technologies (screen time, including television viewing, use of computers and video games) [7, 8].

Several studies have demonstrated that obesity childhood is related to vitamin D deficiency [9–12]. The main source of vitamin D is the exposure to natural sunlight (cutaneous synthesis through ultraviolet B radiation) and, therefore, the higher prevalence of vitamin D deficiency in children and adolescents with obesity could be secondary to a more sedentary lifestyle (less mobility and participation in outdoor activities) and, consequently, a lack of adequate sun exposure. However, many explanations have been proposed for this association, but, interestingly, they hardly introduce theoretical mechanisms that imply limited sun exposure: storage or sequestration in adipose tissue, volumetric dilution, impaired hepatic 25-hydroxylation, etc. [3, 13–16].

The main causes of vitamin D deficiency are generally ascribed either to some physical agent that obstructs solar radiation (clothing, sunscreen, etc.) or to geographical characteristics, such as latitude and season of the year, cloudy weather, altitude, etc. [2, 17]. In fact, recent studies using an objective and accurate method for ultraviolet radiation monitoring in children and adolescents have revealed that rural residents receive higher levels of ultraviolet radiation exposure than urban residents do [18, 19].

This study aims to compare vitamin D status between children and adolescents with obesity living in an urban area and in a rural area in Navarra, Spain (latitude between 43°16″42 and 41°55″22 North). We hypothesized that behavioral factors (outdoor activities and sun exposure) would be decisive in reducing the body content of vitamin D in patients with obesity.

## **2. Methods**

### **2.1 Participants**

We conducted a cross-sectional study in a group of 377 patients, aged 6.50–15.7 years, previously diagnosed with obesity (obesity group, BMI-DS >2.0, 97th percentile) and 348 patients, aged 7.4–15.3 years, diagnosed with severe obesity (severe obesity group, BMI-DS >3.0, 99th percentile). The participants were assessed in a clinical evaluation in the Pediatric Endocrinology Unit in this hospital in January 2014–December 2021. Clinical features (sex, age, season of study visit, place of residence, and BMI) and blood testing data (calcium, phosphorus, calcidiol, and PTH) were collected. Tanner's classification was used for the assessment of pubertal staging, and the individuals were subsequently classified in school subgroup (Tanner stage I) and adolescent subgroup (Tanner stages II–V). Additional classification based on the place of residence (population or the city, higher or less than 10,000 inhabitants, respectively) was made, establishing urban or rural subgroups.

These features and measurements (clinical examination and blood testing) were estimated in a control group made up of 411 healthy children, aged 7.1–14.9 years, with BMI-DS in a range of −1.0 (15th percentile) to +1.0 (85th percentile).

Every participant in the study was Caucasian and lived in Navarra, Spain. Clinical records were surveyed in order to exclude any condition that could affect bone health, or any chronic pathology that could affect growth, body composition, food ingestion, or physical activity, or the previous intake of any medication (antiepileptic drugs or glucocorticoids), vitamin D, or calcium supplements.

*Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism? DOI: http://dx.doi.org/10.5772/intechopen.105819*

#### **2.2 Clinical examination**

A previously published standardized protocol was applied for the anthropometric measurements [20]: participants were placed in underwear and barefoot, and we used an Año-Sayol scale (reading interval 0–120 kg and a precision of 100 g) for weight measures, and a Holtain wall stadiometer (reading interval 60–210 cm, precision 0.1 cm) for height measures.

The program Aplicación Nutricional, from the Spanish Society of pediatric gastroenterology, hepatology, and nutrition (Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica, available at http://www.gastroinf.es/nutritional/) was used to calculate the standard deviation (DS) values for the BMI. The graphic charts from the study of Ferrández et al. (Centro Andrea Prader, Zaragoza 2002) were used as the reference pattern [21].

## **2.3 Blood testing**

The blood sample for biochemical determinations (calcium, phosphorus, 25(0H) D, and PTH) was obtained in basal fasting conditions (between 8:00 h and 9:00 h after an overnight fast).

The medical device used for the determination of calcium and phosphorous plasma levels was a COBAS 8000 analyzer (Roche Diagnostic, Mannheim, Germany). The determination of calcidiol levels was made with a high-specific chemiluminiscence-immunassay (LIAISON Assay, Diasorin, Dietzenbach, Germany), and the determination of PTH levels using a highly specific solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay in an Immulite analyzer (DPC Biermann, Bad Nauheim, Germany).

The criteria of the United States Endocrine Society [22, 23] were applied to distribute individuals according to vitamin D plasma levels. In this way, a determination of calcidiol plasma level below 20 ng/ml (<50 nmol/L) was considered vitamin D deficiency, calcidiol plasma levels between 20 and 29 ng/ml (50–75 nmol/L), vitamin D insufficiency, and concentrations equal to or higher than 30 ng/ml (> 75 nmol/L) vitamin D sufficiency.

### **2.4 Statistical analysis**

Tables show the results as percentages (%) and means (M) with corresponding standard deviations (SD). The program Statistical Packages for the Social Sciences version 20.0 (Chicago, IL, USA) was used to perform the statistical analysis (descriptive statistics, Student's t-test, analysis of variance, χ2 test, and Pearson's correlation). Statistical significance was assumed when P value was <0.05.

Parents and/or legal guardians were informed and provided consent for the participation in this study in all cases. This study was approved by the Ethics Committee for Human Investigation at our institution (in accordance with the ethical standards laid down in the 1964 Declaration of Hensinki and later amendments).

## **3. Results**

**Table 1** shows and compares the distribution of demographic features in the severe obesity, obesity, and control groups. No significant differences were found in the


## **Table 1.**

*Distribution of geographic/demographic features in severe obesity, obesity, and control groups.*

distribution in relation to sex, age group, season of blood sample collection, and place of residence.

The mean values for age in the severe obesity, obesity, and control groups were 11.4 ± 2.9, 11.3 ± 2.7, and 11.1 ± 2.5 years, respectively, and there were no significant differences (p = 0.650) in age between the different groups. Obviously, the mean values for BMI-SD were significantly higher (p < 0.001) in the severe obesity (4.27 ± 1.28) and obesity groups (2.48 ± 0.28) with respect to control group (0.24 ± 0.23).

**Figure 1** depicts and compares the prevalence of vitamin D status in the control, obesity, and severe obesity groups. The prevalence of vitamin D deficiency was significantly higher (Chi2: 159.8, p < 0.001) in severe obesity (48.6%) and obesity groups (36.1%%) than in the control group (12.5%). That is, only 12.2% and 16.2% of

**Figure 1.**

*Prevalence of vitamin D status in control, obesity, and severe obesity groups.*

*Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism? DOI: http://dx.doi.org/10.5772/intechopen.105819*


*\*\*ANOVA between groups (p < 0.001).*

#### **Table 2.**

*Biochemical determinations according to vitamin D status in severe obesity, obesity, and control groups (M ± SD).*

patients of the severe obesity and obesity groups showed levels of 25 (OH)D higher than 30 ng/mL, respectively, in contrast to 42.6% of the participants in the control group (p < 0.01).

**Table 2** shows and compares the mean values for biochemical determinations in both groups in accordance to vitamin D status. There were not any significant differences in calcium and phosphorus levels between the different groups of vitamin D status, and obviously 25(OH)D levels were significantly lower (p < 0.001) in vitamin D insufficiency and deficiency individuals than in vitamin D sufficiency individuals in each group. PTH levels were significantly higher (p < 0.001) in the group with vitamin D insufficiency and deficiency than in vitamin D sufficiency within each group. In addition, there were not any significant differences in calcium, phosphorus, and 25(OH)D levels in each vitamin D status group between the different groups. However, PTH levels were significantly higher (p < 0.001) for each vitamin D status in the severe obesity and obesity groups with respect to the control group.

**Figure 2** presents and compares the prevalence of vitamin D deficiency according to the seasons of the year between control, obesity, and severe obesity groups. In each group, the highest prevalence of vitamin D deficiency (Chi2: 65.01, p < 0.001) corresponded to winter (severe obesity group: 65.1%, obesity group: 40.4%, and control group: 19.5%), and they reached a minimum in the summer (severe obesity group: 26.7%, obesity group: 26.1%, and control group: 3.8%). The prevalence of vitamin D deficiency in the different seasons of the year was significantly higher (p < 0.001) in the severe obesity and obesity groups with respect to the control group.

**Figure 3** exposes and compares the prevalence of vitamin D deficiency in relation to the place of residence between control, obesity, and severe obesity groups. In the

#### **Figure 2.**

*Prevalence of vitamin D deficiency according to the seasons of the year in control, obesity, and severe obesity groups.*

#### **Figure 3.**

*Prevalence of vitamin D deficiency in relation to the place of residence in control, obesity, and severe obesity groups.*

control group, there were no significant differences (p = 0.466) in vitamin D deficiency between urban (14.7%) and rural (10.5%) subgroups. As for the obesity group, vitamin D deficiency was significantly more frequent (p < 0.01) in the urban (48.6%) than in the rural subgroup (24.1%); additionally, in the severe obesity group, also vitamin D deficiency was significantly more frequent (p < 0.01) in the urban (61.3%) than in the rural subgroup (36.9%).

**Figure 4** displays and compares the prevalence of vitamin D deficiency according to the seasons of the year between the individuals in the control, obesity, and severe obesity groups that lived in urban residence. In the control group, there were significant seasonal variations (Chi2: 38.1, p < 0.01) in vitamin D deficiency, which showed the lowest prevalence of vitamin D deficiency during the summer (7.1%) and the highest during the winter (25%). In contrast, there were no significant seasonal variations in the prevalence of vitamin D deficiency throughout the year in both the severe obesity and obesity groups. In fact, in severe obesity group, the prevalence of vitamin D deficiency during the summer was 51.6% and during the winter 67.6% (Chi2: 9.1, p = 0.170), and within the obesity group, vitamin D deficiency was 47% in the summer and 49.6% in the winter (Chi2: 9.2, p = 0.161).

**Figure 5** shows and compares the prevalence of vitamin D deficiency according to the seasons of the year between the participants in the control, obesity, and severe obesity groups that lived in rural residence. All groups presented significant seasonal variations in vitamin D deficiency throughout the year. In each group, the lowest

*Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism? DOI: http://dx.doi.org/10.5772/intechopen.105819*

#### **Figure 4.**

*Prevalence of vitamin D deficiency according to the seasons of the year in individuals in the control, obesity, and severe obesity groups that lived in urban residence.*

#### **Figure 5.**

*Prevalence of vitamin D deficiency according to the seasons of the year in participants in control, obesity, and severe obesity groups that lived in rural residence.*

prevalence of vitamin D deficiency corresponded to summer, and they reached a maximum in the winter. In severe obesity group, the prevalence of vitamin D deficiency during the summer was 9.1% and during the winter 57.1% (Chi2: 50,1, p < 0.01). In obesity group, vitamin D deficiency was 7.7% in the summer and 33.3% in the winter (Chi2: 21,9, p < 0.01). And, finally, in the control group, vitamin D deficiency was 0.0% during the summer and 10.4% during the winter (Chi2: 27,9, p < 0.01).

A negative correlation (p < 0.01) between calcidiol and PTH levels (r = −0.375) was detected. In addition, a positive correlation (p < 0.01) between PTH and BMI-SD (r = 0.345) and a negative correlation (p < 0.01) between calcidiol and BMI-SD (r = −0.363) were observed.

## **4. Discussion**

This study verifies that vitamin D deficiency is a common condition in children and adolescents with obesity. Furthermore, our data suggest that this higher prevalence of vitamin D deficiency in these patients could be ascribed to inadequate sunlight exposure, since there was a weaker trend to vitamin D deficiency in those patients living in rural areas than in those living in urban areas.

Different geographic/demographic specificities, such as gender, age, season, or place of residence, have been described as factors associated with vitamin D

deficiency [9–12, 24]; however, in this case, no significant differences were detected in the distribution of these characteristics among the participants included in this study (severe obesity, obesity, and control groups). This eventuality allows the comparison of the results obtained, avoiding confounding factors. The age range selected in the different groups of participants was due to the fact that they usually have enough autonomy to carry out their extracurricular and/or leisure activities at these ages.

The higher prevalence of vitamin D deficiency in obesity has been sustained by several studies [9–12], even though the potential mechanisms for this association still remain questionable. Nevertheless, at present, the most qualified hypotheses about the inverse relationship between vitamin D deficiency and obesity refer either to storage or sequestration of vitamin D in adipose tissue or volumetric dilution of vitamin D. Clinical studies have shown that obesity does not affect the cutaneous synthesis of vitamin D, but as it is a fat-soluble vitamin, it is accumulated and retained in the adipose tissue (storage site or sequestration hypothesis). Therefore, the greater the storage capacity of this vitamin in adipose tissue (severe obesity and obesity groups), the lower the serum levels of calcidiol [25, 26]. In fact, we found that calcidiol levels in the participants included in this study (severe obesity, obesity, and control groups) were inversely correlated with body mass index; this is an anthropometric measurement that has been frequently used in the diagnosis and follow-up of children and adolescents with obesity since it shows a good correlation with body fat content [27, 28]. A second probable mechanism of the inverse relationship between vitamin D deficiency and obesity could be a volumetric dilution; that is, vitamin D would be distributed in body compartments that increase with obesity (serum, fatty tissue, liver, etc.), thereby making serum levels lower [13, 15]. It has also been suggested that lower levels of calcidiol in obese patients could be due to impaired hepatic 25-hydroxylation related to nonalcoholic fatty liver disease, a condition that is common in obese adults but less frequent in childhood obesity [29]. However, none of the previously mentioned hypotheses would explain by itself, for example, the stronger trend to vitamin D deficiency in patients with obesity (severe obesity and obesity groups) living in urban areas than in those living in rural areas, as we identified in this study.

Vitamin D receptors are present in a large variety of tissues and cells in the body (muscle, heart, blood vessels, neurons, immune cells, breast, colon, prostate, etc.), and additionally, they have the capacity to produce calcitriol from circulating calcidiol. This fact supports the biological importance of sufficient calcidiol serum levels [1, 22]. Moreover, adipose tissue also expresses vitamin D receptors, and 1α-hydroxylase enzyme locally converts calcidiol to calcitriol (biological active form of vitamin D), and that process is not regulated by parathyroid hormone, in contrast with renal 1α-hydroxylase [30]. Additionally, some experimental data support that vitamin D could have an antiobesity effect by inhibiting adipogenesis during early adipocyte differentiation and independently of PTH. That is, vitamin D might be implicated in the pathogenesis of obesity, rather than being a consequence [3, 16]. These findings suggest, on one side, that adipose tissue could play a role in vitamin D metabolism rather than being a passive store of fat-soluble nutrients and, on the other side, that a bidirectional causal relationship between vitamin D deficiency and obesity cannot be excluded. However, several studies have shown no effect of vitamin D treatment on reducing body weight and/or body composition, suggesting that although vitamin D deficiency is associated with obesity, it is not bidirectional [31, 32].

In accordance with most authors [9, 10, 12, 24], we found a negative correlation between PTH and calcidiol levels, and this would be consistent with the physiological

### *Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism? DOI: http://dx.doi.org/10.5772/intechopen.105819*

feedback mechanism of vitamin D on PTH secretion. But, interestingly, it is worth noting our finding that PTH levels were also significantly higher—independent of vitamin D status—in the patients with obesity (severe obesity and obesity groups) with respect to the control group. Many researchers have postulated that this elevation of PTH might increase calcium influx into adipocytes, which then leads to increased lipogenesis and potentially reduces catecholamine-induced lipolysis and, consequently, fosters fat storage [33, 34]. Additionally, several observational studies have shown that PTH levels in obesity are independent of vitamin D status, and it does not represent, as is commonly assumed, secondary hyperparathyroidism from hypovitaminosis D [35]. However, despite the above biological assumptions that obesity is related with vitamin D deficiency and elevated parathyroid hormone levels, the reason given for this association remains unexplained. In fact, some authors are currently questioning whether vitamin D deficiency is a consequence or cause of obesity [16], or whether the association between obesity and vitamin D deficiency is causality or casualty [3].

Obviously, unhealthy eating habits are related to childhood obesity, and this entails a lower intake of vitamin D. However, the main source of vitamin D is exposure to natural sunlight, while approximately 10% comes from natural dietary sources [1, 2]. Few foods naturally contain vitamin D (oily fish such as salmon, sardines, mackerel, and tuna, as well as shiitake mushrooms and eggs yolk) and, depending on the country, additional sources include fortified foods such as dairy products, orange juice, breakfast cereals, cookies, and butter or margarine [2, 36]. Therefore, even though diet seems to be probably an irrelevant factor in the acquisition of optimal levels of vitamin D, it could not be completely excluded.

Because geographical conditions affect body vitamin D levels, we cannot refer to a vitamin D status in a determined population without mentioning them. In our case, it should be noted that Navarre is a Spanish region located in the north of the Iberian peninsula with a population of 661,537 inhabitants (2021 census, National Institute of Statistics), 58.1% of whom live in urban areas and 41.9% in rural areas. Besides, it is characterized by a high frequency of precipitations and/or cloudiness and, especially, a high latitude (between 41°55″22 and 43°16″42 North). When the zenith angle of the sun is oblique, as occurs in the winter months in both hemispheres, type B ultraviolet radiation barely reaches the earth's surface above and below 40°N and 40°S latitude, causing a very low or absence cutaneous synthesis of vitamin D, even with prolonged sun exposure [17, 22, 23]. In compliance with several studies [9, 24, 37, 38], this is a potential explanation for the seasonal variations in the prevalence of vitamin D deficiency (maximum prevalence in the winter months and minimum in the summer months) that we found in the control group.

Recent studies using personal electronic ultraviolet radiation dosimeters have displayed higher ultraviolet radiation exposure in children and adolescents living in rural areas compared with those living in urban areas due to differences in types of activity. Children and adolescents living in rural areas spend more time after school and during weekdays practicing outdoors chores during peak ultraviolet radiation hours (10 am–4 pm), compared with those living in urban areas who spend more time participating in indoor sports and/or leisure activities and, therefore, reducing exposure to sunlight [18, 19]. These data allowed us to hypothesize a much simpler explanation for the relationship between obesity and vitamin D deficiency: behavioral factors (outdoor activities and sun exposure) would be determined in reduced body content of vitamin D in patients with obesity.

Indeed, we also found seasonal variations in the prevalence of vitamin D deficiency (maximum prevalence in the winter months and minimum in the summer months)

in patients with obesity (obesity and severe obesity groups), although showing significantly lower values with respect to control group. That is, on the one hand, this would confirm that sunlight exposure has a large impact on vitamin D status also in patients with obesity and, on the other hand, we found a stronger trend to vitamin D deficiency in patients with obesity (obesity and severe obesity groups) living in urban areas than in those living in rural areas. No significant differences were observed in the prevalence of vitamin D deficiency in the control group in relation to place of residence (urban or rural). Nevertheless, the most remarkable finding of this study was that patients with obesity (obesity and severe obesity groups) living in urban residence did not present significant seasonal variations in vitamin D deficiency throughout the year in contrast to those patients with obesity (obesity and severe obesity) living in rural residence, who presented a maximum prevalence of vitamin D deficiency in the winter months and a minimum in the summer months. Therefore, these findings would support the hypothesis that the greater tendency to present vitamin D deficiency in obese children and adolescents would be related to a sedentary lifestyle and, consequently, to the lack of adequate sun exposure. Otherwise, the participants of the control group, who presumably did not have a sedentary lifestyle, showed no differences in vitamin D status in relation to the place of residence (rural or urban).

## **5. Conclusion**

At present, and despite the hypotheses recounted above, vitamin D photobiology suggests that the most probable mechanism for vitamin D deficiency in children and adolescents with obesity, rather than altered metabolic (sequestration in adipose tissue, volumetric dilution, impaired hepatic 25-hydroylation, etc.), is the behavioral factors (reduced sunlight exposure), such as our findings outline. However, other mechanisms cannot be completely excluded, as they may contribute concurrently.

## **Funding**

The authors received no financial support for the research, authorship, and/or publication of this article (none declared).

## **Conflict of interest**

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this study (none declared).

*Vitamin D Deficiency in Childhood Obesity: Behavioral Factors or Altered Metabolism? DOI: http://dx.doi.org/10.5772/intechopen.105819*

## **Author details**

Teodoro Durá-Travé1,2,3\* and Fidel Gallinas-Victoriano2,3

1 Department of Pediatrics, School of Medicine, University of Navarra, Pamplona, Spain

2 Department of Pediatrics, Navarra University Hospital, Pamplona, Spain

3 Navarrabiomed (Biomedical Research Center), Pamplona, Spain

\*Address all correspondence to: tdura@unav.es

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Section 3
