Vitamin D Pediatrics

DATE
VITAMIN D DEFICIENCY IN
CHILDREN: NOVEL
MANAGEMENT APPROACH
DR. NAME
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IND1174103

Vitamin D deficiency: Epidemiology
Vitamin D deficiency is increasingly
being recognized the world over as
also in India
Prevalence of vitamin D deficiency is
around 30-90% across all age groups
from neonates to adolescents as well
as pregnant and lactating mothers
Prevalence is similar across the country
and in rural and urban areas
Given that vitamin D and calcium are
both critical for musculoskeletal health
in growing years, addressing the issues
of their deficiency in the pediatric and
adolescent population is critical
Khadilkar A et al. Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines. Indian Pediatrics 2017; 54: 567-573

People at risk of Vitamin D deficiency
All pregnant and breastfeeding women, especially teenagers and young
women
Infants and young children under 5 years of age & Older people aged 65
years and over
People who have low or no exposure to the sun - covering their skin for
cultural reasons, housebound or confined indoors for long periods
People who have darker skin, for example people of African, African
Caribbean and south Asian origin
South Australian Paediatric Clinical Practice Guidelines Vitamin D Deficiency in Children available at
https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/resources/policies/vitamin+d+deficiency+in+children+-+sa+paediatric+clinical+guideline

Risk factors for
vitamin D
deficiency in
children
• Infant of vitamin D deficient mother
• Dietary deficiency (e.g. prolonged breastfeeding)
• Minimal vitamin D is available in the diet (breast
milk 25 units/L, milk formula 400units/L, oily
fish, eggs, butter, and margarine 50-
100units/day)
• Small bowel disorders (e.g. coeliac disease,
inflammatory bowel disease)
• Pancreatic insufficiency (e.g. cystic fibrosis);
Chronic liver/renal disease
• Medications (e.g. anticonvulsants, rifampicin,
isoniazid, chronic glucocorticoids)
• Obesity (reduces bioavailability of vitamin D)

Vitamin D
deficiency in
Infants &
Children
Indian studies have
shown significant
correlation of
serum 25 (OH) D
concentration
between mother-
infant pairs
Low vitamin D
levels in mother
result in low
vitamin D level in
cord blood and
new born
Exclusively
breastfed infants
continue to have
low 25 (OH) D
levels
Human milk
typically contains a
vitamin D
concentration of
25 IU per liter or
less
1. Mithal A et al Vitamin D deficiency in India. Recommendation for prevention & treatment: Endocrine society of India Expert group.
2. Khadilkar A et al. Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines. Indian
Pediatrics 2017; 54: 567-573

Case scenario
#1
A 12-day-old girl born in October presents to clinic with new-
onset focal seizures. In the previous 5 days, she has had right-
sided arm and leg twitching, left-sided head turning and lip
smacking. These episodes lasted for approximately 30 s, and
their frequency had increased to eight times per hour. There
is no history of fever, trauma, sick contacts or neonatal sepsis
risk factors. The baby is breastfed and supplemented with
formula. He is found to have hypocalcemia.
1. What is the relationship between an acute versus chronic
presentation of Vitamin D deficiency?
2. What are risk factors for Vitamin D deficiency?

What is the presentation?
Acute Vitamin Deficiency
Acute presentations occur in period of rapid growth with increased metabolic demand such
as neonatal period
• An un supplemented infant will reach deficient state more rapidly than infant whose
mother had adequate vitamin D state
Associated signs and symptoms:
• Hypocalcemia (including seizures)
- More likely in infants of diabetic or preeclamptic mother
- May occur in infants born to mothers with hyperparathyroidsm
• Lethargy
• Irritability
• Predisposition to respiratory infections in infancy
Wagner, C. and F. Greer. “Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents.” Pediatrics 122 (2008): 1142 - 1152.

What is the
presentation?
Chronic Vitamin D
deficiency
• State of deficiency occurs months
before findings are apparent on
physical exam
Rickets/ decreased bone
mineralization:
• Lab findings: normocalcemia or
asymptomatic hypocalcemia
• Rickets: peak incidence between
3 -18 months
Wagner, C. and F. Greer. “Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents.” Pediatrics 122 (2008):
1142 - 1152.

Vitamin D
Deficiency:
Stages and
Clinical Signs
Wagner, C. and F. Greer. “Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents.” Pediatrics 122 (2008):
1142 - 1152.

Vitamin D deficiency: Clinical manifestations
Rickets in a neonate resulting from maternal vitamin D deficiency may result in hypocalcemic
seizures and rarely cardiomyopathy
Approximately 40-50% of total skeletal mass is accumulated during childhood and adolescence.
Severe vitamin D deficiency: 25 (OH)D level < 5.0 ng/mL, results in
Rickets in an infant or
adolescent
Osteomalacia and muscle
weakness in an older
child/adolescent
Negative impact on the
peak bone mass
Low bone mineral density
in childhood, which may
subsequently result in
osteoporosis in adulthood
2. Khadilkar A et al. Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines. Indian Pediatrics 2017; 54: 567-573

SPINE
Kyphoscoliosis
PELVIS
Pelvic deformities
coxa vara
CHEST
Rachitic rosary
Harrison’s groove
LIMBS
Wrist widening
Genu valgum, Genu varum
Windswept deformity
Ankle widening
Double malleolus
Clinical features of Rickets
2. Vitamin D supplementation: CDSCO. Available on : https://www.cdc.gov/breastfeeding/recommendations/vitamin_d.htm access on : 22/01/17.
SKULL
Frontoparietal bossing
Wide open fontanelle (AF)
Delated closure of AF
Craniotabes
Symptoms
& signs due to
deformities

Other features of Rickets
Hypotonia
• Proximal weakness
• Delay in gross motor
milestones
• Protuberant abdomen
• Visceroptosis
Dental abnormalities
• Delayed dentition
• Enamel hypoplasia
• Dental caries
Repeated infections
• Impaired phagocytosis
• Repeated chest infection
due to ciliary dysfunction
• Respiratory muscle
weakness
• Compliant chest

Differential diagnosis for rickets and
hypocalcaemia: laboratory results

Extra skeletal effects of Vitamin D
Vitamin D and immune system
• Vitamin D receptors(VDRs) are present all over the body including antigen-
presenting cells, with known direct effects on innate and adaptive immunity
• Vitamin D metabolizing enzymes(1-α-hydroxylase) are present in many cell
types including various immune cells such as antigen-presenting-cells, T cells,
B cells and monocytes.
• Vitamin D also increases the production of some anti-inflammatory cytokines
and reduces the release of some pro-inflammatory cytokines
Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013 Jul;5(7):2502-21.

Postulated Mechanisms by which Vitamin D act
as an Immunomodulator
• Physical Barrier: Vitamin D helps maintain tight junctions, gap junctions,
and adherens junctions (e.g., by E-cadherin). Several articles discussed how
viruses disturb junction integrity, increasing infection by the virus and
other microorganisms
• Vitamin D is a modulator of adaptive immunity; 1,25(OH)2D3 suppresses
responses mediated by the T helper cell type 1 (Th1), by primarily
repressing production of inflammatory cytokines IL-2 and interferon
gamma (INFγ)
Rondanelli M et al. Self-care for common colds. Evidence-Based Complementary and Alternative Medicine. 2018 Oct;2018
Cantorna M.T. Mechanisms underlying the effect of vitamin D on the immune system. Proc. Nutr. Soc. 2010;69:286–289. doi: 10.1017/S0029665110001722.

Postulated Mechanisms by which Vitamin D act
as an Immunomodulator
• Vitamin D enhances cellular innate immunity partly through the induction
of antimicrobial peptides, including human cathelicidin, by 1,25-
dihdroxyvitamin D, and defensins.
• Cathelicidins exhibit direct antimicrobial activities against a spectrum of
microbes, including Gram-positive and Gram-negative bacteria, enveloped
and nonenveloped viruses, and fungi
Youssef DA, Miller CW, El-Abbassi AM, Cutchins DC, Cutchins C, Grant WB, Peiris AN. Antimicrobial implications of vitamin D. Dermato-endocrinology. 2011 Oct 1;3(4):220-9

EFFECTS OF
1,25(OH)2D3
ON IMMUNE
CELLS
Skrobot A, Demkow U, Wachowska M. Immunomodulatory role of vitamin D: a review. InCurrent Trends in Immunity and Respiratory Infections 2018 (pp. 13-23). Springer, Cham.

Vitamin D and Immunomodulation
High levels of vitamin D:
1. Potent inhibition of dendritic cell maturation and
2. Lower expression of major histocompatibility complex (MHC) class II
molecules
3. Down-regulation of costimulatory molecules and
4. Lower production of proinflammatory cytokines such as IL-2, IL-12, IFN-y
and IL-23
Skrobot A, Demkow U, Wachowska M. Immunomodulatory role of vitamin D: a review. InCurrent Trends in Immunity and Respiratory Infections 2018 (pp. 13-23). Springer, Cham.

Vitamin D &
Respiratory
Infections
• A prospective trial by Camargo found an inverse
association between cord-blood 25(OH)D level
and the risk of developing upper respiratory
tract infection by 3 months and wheezing at 15
months of age
• Newborns born with 25(OH)D < 20 ng/mL had
six-fold higher risk of respiratory syncytial
virus-related bronchiolitis at 1 year old
compared with those of 25(OH)D > 30 ng/mL
• A recent meta-analysis of 25 trials in 2017
showed reducing incidence of acute
respiratory tract infection after vitamin D
supplementation, which is more significant in
patients with severe vitamin D deficiency
(<10 ng/mL)
Chang SW, Lee HC. Vitamin D and health-The missing vitamin in humans. Pediatrics & Neonatology. 2019 Jun 1;60(3):237-44.

Metanalysis:
Vitamin D
supplementation
& proportion of
participants
experiencing at
least one acute
respiratory tract
infection (ARTI).
Adrian R Martineau et al. BMJ 2017;356:bmj.i6583

Vitamin D &
Bronchial
Asthma
• Maternal vitamin D intake during pregnancy
may be associated with children's risk of
developing wheezing episodes thereafter
• In a cross-sectional study vitamin D
concentration was directly correlated with
forced exploratory volume/forced vital capacity
(FEV1/FVC) ratio and predicted FEV1, meaning
that lower 25(OH)D level was more
significantly associated with asthmatic status
• A Cochrane systematic review in 2016
documented that vitamin D supplementation
had benefits on reducing risk of asthma
exacerbation requiring systemic glucocorticoids,
requiring emergency department visit or
hospitalization or both

Vitamin D &
Atopic
dermatitis
• A meta-analysis by Kim et al. demonstrated
that serum 25(OH)D level was lower in
patients with AD
• A small randomized clinical trial also found
beneficial effects of vitamin D
supplementation in children with winter-
related AD
• On the contrary, another systematic review
in 2012 did not show a significant benefit in
clinical outcomes after vitamin D
intervention

Vitamin D
and other
systemic
effects
• Observational studies demonstrated the
association between vitamin D deficiency
and the risk of
• Hypertension or cardiovascular
events, higher incidence of cancers,
more musculoskeletal pain or
migraine, and neuropsychiatric
disorders such as schizophrenia,
dementia or depression
• Current evidence for vitamin D
intervention in treating or preventing
these diseases is emerging

Indication for 25 (OH) D testing in children
• Late onset hypocalcemic seizures in infancy
• Idiopathic dilated cardiomyopathy in infancy especially if hypocalcemia has
been documented
• It is desirable (but not mandatory in case it is not financially feasible) to check
baseline 25 (OH) D levels in case of nutritional rickets.
• However, all cases of rickets who have failed to respond to one course of vitamin D
supplementation must have their 25 (OH) D levels checked.
• Cases of suspected osteomalacia in adolescence

Indication for 25 (OH) D testing in children
• Children having disease or medications increasing the risk of osteoporosis includes
but not limited to:
• Children on antitubercular, antiepileptic, antiretroviral medications
• Children on long-term/ intermittent high dose steroids
• Childhood cancer
• Malabsorption – celiac disease, inflammatory disease
• Recipients of organ transplant
• Chronic liver and kidney disease
• Chronic inflammatory rheumatic disease –
Juvenile Idiopathic Arthritis (JIA), Ankylosing spondylitis

Methods use to assess vitamin D
• 25 (OH) D level is preferred Because
• Longer half life of about 3 weeks
• Stronger affinity to D-binding proteins
• Higher blood concentration than other metabolites
• Represent convergence of all forms of vitamin D
Methods for testing Vitamin D
• Immunoassays like Radioimmunoassay (RIA) or Chemiluminescence (CLIA) - commonly used in
India; Can’t differentiate between D2 and D3
• HPLC – good accuracy with lower cost.
• LC/MS/MS (Liquid chromatography / Mass spectrometry) - gold standard, but Not available widely

Case Scenario
#2
• A young mother in your practice presents for the
2 week newborn exam for her second child whom
she is breastfeeding. She would like to breastfeed
exclusively until she returns to work at which time
she would like to start supplementing with formula.
1. What is the MOST appropriate advice to give
this mother about her child’s nutrition?

Recommendations for Vitamin D Supplementation in
Breastfed and Partially Breastfed Infants
• The American Academy of Pediatrics (AAP)/ Indian academy of pediatrics
(IAP) recommends a daily intake of vitamin D of 400 IU/day for all infants
and children beginning in the first few days of life
• Human milk typically contains a vitamin D concentration of 25 IU per liter
or less.
• When maternal vitamin D status is deficient, particularly in winter, the
unsupplemented infant 25-OH-D concentration is very low

How are we
doing/ current
clinical
practice?
• A minority of breastfed infants receive vitamin D
supplementation
• Vitamin D use is strongly linked to physician
recommendations
• Many parents believe breastmilk has all the
needed nutrition.
• Educational efforts directed at physicians and
parents are needed to increase compliance with
Vitamin D supplementation guidelines.

Guidelines for treating & preventing
vitamin D deficiency

Treatment of Vitamin D deficiency in children
Indian Academy of Pediatric guidelines: July 2017
AGE GROUP PREVENTION TOLERABLE UPPER LIMIT TREATMENT TREATMENT WITH LARGE
DOSE (ORAL ROUTE
PREFERRED)
Premature
neonates
400 IU/day 1000 IU/day 1000 IU/day NA
Neonates 400 IU/day 1000 IU/day 2000 IU/day NA
1-12 months 400 IU/day 1000-1500 IU/day 2000 IU/day 60,000 IU weekly for 6
weeks (over 3 months of
age)
1-18 years 600 IU/day 3000 IU/day till 9 years,
4000 IU/day from 9-18
years
3000-6000 IU/day 60,000 IU weekly for 6
weeks
At risk groups 400-1000 IU/day As per age group As per age group As per age group

Treatment of Vitamin D Deficiency in children
Endocrine society of India expert group recommendation
AGE GROUP DAILY REGIMEN INTERMITTENT DOSING SINGLE DOSE
<1 year 1000-2000 IU/day for
8-12 weeks
Not recommended Not recommended
1-12 years 2000-4000 IU/day for
8-12 weeks
60,000 IU once in 2
weeks for 8-12 weeks
1,50,000 IU stat dose,
repeat after 6 weeks if
necessary
12-18 years 4000 – 6000 IU/day for
8-12 weeks
60,000 IU once a weeks
for 6-8 weeks
3,00,000 IU stat dose,
repeat after 6 weeks if
necessary

Treatment of
Vitamin D
Deficiency in
children
Healing of rickets should be confirmed by
Estimation of calcuim, phosphrous
and alkaline phosphatase and
Confirmation of radiologic healing
on radiographs of hands / knee
done after
4-6 weeks of treatment
Adequate calcium intake of 30-75 mg/kg/day
of elemental calcium must be ensured during
treatment

Treatment of Hypocalcemic Emergencies
(Seizures and cardiac failure)
• IV calcium gluconate (10%, 100 mg/mL, elemental calcium 9
mg/mL) to be given as 1-2 ml/kg diluted in equal amount of
normal saline and given slow i.v. over 10-20 minutes
• Calcitriol – 20-100 ng/kg/day in 2-3 divided doses till
normalization of serum calcium
• Elemental calcium – 100 mg/kg/day
• Supplement vitamin D as per age group
• High dose or IM injection of vitamin D do not give any
additional benefit for emergency treatment and can be
potentially harmful

Summary and
Recommendations
of Vitamin D
supplementation
• All infants should be supplemented with 400 IU of vitamin D per
day (IAP recommendation)
• Starting within first few days of birth and continued throughout
infancy
Infants
• Beyond infancy, Supplementation with 600-1000 IU should be
continued with limited sunlight exposure due to lifestyle,
disability or cultural reasons
• Alternatively, based on clinical experience, 60,000 IU once in 2-3
months (Depending on age of the child)
CHILDREN
• Supplementation with 1000 IU/day
• Obese children or children suffering with malabsorption
disorders should receive 2000 IU/day of vitamin D (or 60,000
IU/month)
ADOLESCENTS

Nanotechnology and its utilization
in drug delivery of vitamin D

Nanotechnology & Nanoparticles
use in medicine
• Nanoparticles: Colloidal particles that range in size from 10 to 1000 nm in
diameter
• Nanomedicine: Application of Nanotechnology to health.
• It exploits the improved and often novel physical, chemical, and biological
properties of materials at the nanometric scale.
Data on file

Nanoparticle NDDS: Key features
• A ‘first time in India’ - Novel Drug Delivery System
• (NDDS) based on a vitamin D3 nanoparticle delivery platform
• The NDDS contains Vitamin D pre-solubilized and encapsulated in a lipid nanoparticle
• The NDDS nanoparticles are less than 150nm in diameter
• A stable NDDS, even in harsh GI conditions
• Maintains its nanoparticle and structural integrity even in strongly acidic and bile media
(representing both fasting and fed states)
• ‘Ready to Absorb’ format.
• The NDDS does not depend on lipids & bile salts for its absorption.
Data on file

Vitamin D absorption as Bile-Fat complex
BS- Bile salts; PL-Phospholipid; CHOL- Cholesterol; MG- Monoglyceride; FA-fatty acid; EX-Excess
OIL DROPLET
Bile
BS + PL + CHOL
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL
DROPL
ET
OIL D
ROPLE
T
OIL
DROPL
ET
OIL
DROPL
ET
1. Physical Break up
2. Lingual & Gastric Lipases
3. Emulsification (Bile Salts)
4. Pancreatic Lipases
Smaller Lipid Droplets
Lipid droplets in chyme
Lipids (FA / CH / MG ) in Emulsion
5. Creative illustration of an Individual ‘Micelle’
Final step from which FA / MG /Cholesterol are absorbed by passive diffusion
5. Bile Salts aid in formation of ‘Micelles’ with Fatty Acids & Monoglycerides.
Data on file

Vitamin D in nanoparticle
‘Vitamin D encapsulated in lipid nanoparticle with hydrophilic surface’
Data on file

Not all oral solutions of Vitamin D contain Nanoparticles
Transmission Electron
Microscopy is necessary
to confirm the presence
of encapsulated Vitamin D
nanoparticles
Data on file

Nanoparticle NDDS: Data evidence for absorption
Hypothesis – Oral absorption
of conventional vitamin D3 is
approximately 50%. Data on
the uptake of vitamin D3 from
the NDDS through the
intestinal epithelium is not
documented.
Aim – To investigate the
absorption of nanoparticle
based NDDS of vitamin D3
Bothiraja C, Pawar A & Deshpande G. Ex vivo absorption study of a nanoparticle based novel drug delivery system of vitamin D3 using everted intestinal sac technique. J Pharma Investig. 2016;46(5):425-432.

Nanoparticle NDDS: Data evidence for absorption
Method : Everted rat intestinal sac technique
Result :
• Vitamin D3 in NDDS showed a nonspecific absorption through various segments of
rat small intestine, with high flux, permeability coefficient and percentage of
absorption (79.21 ± 0.23, 76.55 ± 0.24 and 77.73 ± 0.24 % for duodenum, jejunum
and ileum)
• Average absorption of Vitamin D3 in NDDS was 77.83 ± 0.24 % through rat small
intestine.
• The predicted human absorption may be more than 90%.
Conclusion: Absorption of Vitamin D3 in NDDS is > 90%, various segment of Intestine (Duodenum,
Jejunum & Ileum)
Bothiraja C, Pawar A & Deshpande G. Ex vivo absorption study of a nanoparticle based novel drug delivery system of vitamin D3(Arachitol Nano™) using everted intestinal sac technique. J Pharma Investig. 2016;46(5):425-432.

Proprietary and confidential — do not distribute
life. to the
fullest.
Thank
You
For the use of registered medical practitioner only
IND1174103

Vitamin D Pediatrics

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