Adjunctive vitamin D therapy in various diseases in children: a scenario according to standard guideline

The body fulfills vitamin D requirements from a variety of dietary sources and the penetration of UV light in the dermis. Vitamin D deficiency is prevalent in 1 billion people around the globe [1]. Several studies suggested that vitamin D deficiency exacerbate various disease conditions including; osteoporosis, autoimmune diseases, certain cancer, cardiovascular diseases, rickets in pediatrics, osteomalacia, bacterial infections such as tuberculosis, influenza, chronic kidney diseases, and many more [2‐5]. Pregnant and nursing women, infants, pediatrics, elder and housebound people are at special risk for developing vitamin D deficiency. A Study conducted in Turkey reported mother vitamin D deficiency associated with infant’s vitamin D level [6]. Social and religious customs, socioeconomic status, illiteracy and skin pigmentation are crucial factors of vitamin D deficiency in the Asian region including Pakistan [7, 8].

Vitamin D deficiency is more prevalent in children, pregnant and nursing women in Pakistan [9], India [10], and Germany [11]. A study reported from Karachi, vitamin D deficiency in 75% of children associated with low socioeconomic communities [12]. Another study conducted in Multan showed severe vitamin D deficiency in 94% nursing mothers [13]. Vitamin D supplementation and vitamin D food fortification products are useful to combat vitamin D deficiency at any age [14]. The UK started the “Healthy Start” program in 2006 to provide free vitamin D supplementation vouchers to low-income pregnant women and children to combat vitamin D deficiency [15]. In Turkey, the “vitamin D prophylaxis augmentation program” started in 2005 to combat vitamin D deficiency in infants. In Pakistan, no such interventional program is available to the population [16]. Different guidelines on vitamin D supplementation are available e.g. Institute of Medicine (IOM) by the USA and Canada [17]; Endocrinology society by USA [18]; Scientific advisory committee on nutrition (SACN) by the UK [19]; European food safety authority (EFSA) [20]; nutritional society of Germany [21]; Polish society of pediatric endocrinology and diabetes [22] clinical practice guidelines by the United Arab Emirates [23]. All these guidelines unanimously recommend vitamin D prescribing according to the patient’s needs and condition of the disease, also emphasize vitamin D consumption during pregnancy and breastfeeding [18, 19, 21‐23].

Despite availability of several standard guidelines low adherence to vitamin D prescribing has been seen worldwide even in developed countries. A study conducted in the USA showed poor adherence to vitamin D supplementation in 60% of infants after revised vitamin D guidelines by the American Academy of Pediatrics in 2008 [24]. Another study conducted in Serbia showed poor vitamin D supplementation adherence in osteoporosis in 82% patients [25]. In the UK vitamin testing and prescribing cost is increased 17 folds due to non-adherence to standard guidelines in primary care settings [26]. A study conducted in Turkey reported good adherence to national vitamin D supplementation program to combat vitamin D deficiency in different age groups [27]. Adherence to vitamin D standard guidelines improves the prescribing practices, health outcomes of patients, and disease burden associated with vitamin D deficiency [28]. The unavailability of standard local guidelines in hospital settings is one of the crucial factors for non-evidence-based prescribing [29]. Adherence to standard guidelines is mandatory for adjunctive vitamin D therapy in various disease management in terms of vitamin D testing and prescribed dose. Unfortunately, in Pakistan no such data is available. Most studies have focused on vitamin D deficiency in a particular single disease but to our knowledge, there is a lack of evidence in documenting the adherence to standard guidelines of vitamin D in clinical settings in various diseases along with different co-morbidities especially in Pakistan. To close this gap, this study aimed to evaluate the adjunctive vitamin D therapy in various diseases in children along with different co-morbidities, its adherence to standard guideline and the effect of socioeconomic status on the consumption of vitamin D in children.

The present study demonstrated the adherence of adjunctive vitamin D therapy in various diseases in children which is the first of its kind in Pakistan. It encompasses all important aspects regarding adjunctive vitamin D therapy in various diseases along with different co-morbidities and socioeconomic effects on vitamin D consumption in children. It will help to understand that proper evidence-based prescribing will help to develop good clinical practices in the future. Also, the study will be helpful to indicate current prescribing practices of adjunctive vitamin D therapy in various disease management along with different co-morbidities in children. Total 9 diseases and 21 comorbid conditions (Tables 2 and 3) were found in which adjunctive vitamin D therapy was prescribed and adherence to the guideline was assessed. Results of this study indicated poor adherence to guideline for adjunctive vitamin D therapy in term of vitamin D testing and prescribed dose in high-risk diseases seizures (5%), steroid-resistant nephrotic syndrome (0.0%), meningitis (14.3%), cerebral palsy (5.9%) and bone deformities (13.3%). The level of 25-hydroxyvitamin D must be tested in high-risk vitamin D deficiency diseases according to recommended guidelines [18, 23]. Only 4% of patients were tested for their 25-(OH) D level in all diseases indicating poor adherence to the guideline. Results of this are in line with a study conducted in Sweden indicating poor guideline adherence with Vitamin D level testing in high-risk diseases [30]. A study conducted by Uday S et al., across 29 countries, infant vitamin D supplements policies adherence rank was better in Austria and Hungary (98%), Netherland, France and Estonia (90%), Russia (80%), Germany (90–70%), Norway (70%) while Denmark (60–70%), Ireland (59%), Greece (30%), and UK (20%) has low rank to vitamin D supplementation policies adherence at national level [31].

Empirically vitamin D was added to therapy in low-risk vitamin D deficiency diseases e.g. RTIs (70.6%), general weakness (85.7%), urinary tract infections (80%), diarrhea (64.3%) without testing 25-hydroxyvitamin D levels because it is an expensive test. A Survey conducted in India reported vitamin D was prophylactically prescribed in infants according to the Indian academy of pediatrics (25.6%) and the American academy of pediatrics (19.2%). These results are contradicting with the present study in which slightly better adherence was seen in low risk diseases [32].

Twenty-one (21) comorbidities (Table 3) were identified as low-risk and high-risk comorbidities in which vitamin D was adjunctively prescribed. In comorbid conditions, chances of vitamin D deficiency are higher due to the cumulative effect of individual disease. According to recommendations in comorbid conditions confirmed vitamin D testing is necessary for definitive diagnosis [18]. Since vitamin D deficiency cannot be compensated with an empirical maintenance dose of 400–1000 IU. Overall poor compliance to guidelines was seen in this study. A population-based cohort study conducted in the UK from The Health Improvement Network (THIN) database records shows similar results that vitamin D prescribing in children has increased 26 folds from 2008 to 2016 without consistent guideline’s recommendations in terms of the prescribed dose and inappropriate testing [33]. The main reasons for poor guideline adherence to vitamin D testing were due to unavailability of national guideline in government hospitals and physicians’ knowledge gap about standard vitamin D guidelines. In developing countries including Pakistan unavailability of proper laboratory facilities in government hospitals and the unavailability of vitamin D supplements are the main reasons for compromised treatment [32].

Vitamin D supplementation intake is recommended in pregnant and nursing women. In our study, most patients belonged to low socioeconomic class. The nutritional status of children and their mothers was compromised due to their low-income status. In this study, a significant association was found between economic status and mother’s vitamin D supplements during pregnancy (p = 0.003), vitamin D supplement during breastfeeding (p = 0.002) mother’s vitamin D rich diet in pregnancy (p = 0.005). Vitamin D supplements intake and vitamin D-rich diet during pregnancy and breast-feeding were affected due to low socioeconomic status, because most mothers did not know about the benefits of vitamin D supplementations during pregnancy. Vitamin D supplements are a little bit expensive and this socioeconomic class could not afford the vitamin D supplements. Low education level and cost were the core issues. A study conducted in India, showing similar results of the association between vitamin D supplements intake during pregnancy and low socioeconomic status in pregnant women (p < 0.001) [34]. In a lower socioeconomic class, the trend of breastfeeding was higher in this study. Most mothers (46%) breastfed their child for the complete 2 years. Meanwhile, only 2% of mothers had taken vitamin D supplementation during breastfeeding so, suspected chances of vitamin D deficiency were higher in these children because human milk has low vitamin D content [35]. According to the recommendation by standard guidelines pregnant and breastfeeding mothers should take 400 IU of vitamin D supplements in these conditions [18, 19, 21‐23].

In this study, low economic status has a significant association with consumption of vitamin D food fortification products and vitamin D rich diet (egg yolk, fish, liver, cheese, and beef) in children in this study (0.001). Food fortification products are expensive and low economic status affects its consumption in Pakistan as well as in developing countries as compared to developed countries. A study conducted in Saudi Arabia (children 378, age 2–20 years) contradicted with our results in which low socioeconomic status was not significantly associated with consumption of vitamin D rich diet and vitamin D fortified food [36]. A cross-sectional survey conducted in the USA by from National Health and Nutrition Examination Survey (NHANES) database on different ethnic groups (8214 children, age less than 19 years) showed vitamin D dietary intake was 3 times higher in high-income Hispanic families than low-income Hispanic group and non Hispanic blacks, results of this study are aligned with our study [37]. A meta-analysis of 20 randomized control trials conducted by Khalifah et al., suggests vitamin D food fortification effectively improves vitamin D status in children [38].

Overall low adherence to the standard guideline was found in terms of vitamin D level diagnosis and prescribing. Although, adjunctive vitamin D therapy was being prescribed in disease management but there was a lack of evidence-based prescribing. In comorbidities, vitamin D level testing and prescribed dose were not in compliance with guidelines. The patient’s nutrition status was compromised due to low socioeconomic status, low education status, and less awareness about the importance of vitamin D. Due to low socioeconomic status and lack of mother’s knowledge about vitamin D rich diet, mothers had not taken vitamin D rich diet and vitamin D supplementation during pregnancy and breastfeeding. It is recommended that evidence-based prescribing according to standard guidelines protocols should be adopted by health care professionals. Free approachable vitamin D testing facilities must be provided to the population at the government level to cope with increasing vitamin D deficiency. Provision of local guidelines in hospitals, interventional programs, and training must be conducted at regular intervals for health care professionals to emphasize the implementation of standard guidelines.

This study evaluated the diverse aspects of vitamin D as adjunctive therapy in various disease conditions in children concern to standard guideline. The novelty of this study was well demonstrated by the various aspects of vitamin D in disease management, comorbidities, feeding practices of children, mother’s consumption of vitamin D in pregnancy and breastfeeding, this study tried to cover every important aspect of vitamin D consumption as adjunctive therapy to treat various diseases. A diverse study population minimized predictability bias. Moreover, due to the small sample size and limited time frame, findings cannot be generalized to the whole population. Disease association to vitamin D level cannot be determined because laboratory data was insufficient to find any conclusion. Due to a cross-sectional study causal effect cannot be determined.