PERAN VITAMIN D PADA

KESEHATAN TULANG BAYI

BERAT LAHIR SANGAT RENDAH
TUNJUNG WIBOWO
DIVISI NEONATOLOGI, DEPARTEMEN ILMU KESEHATAN
ANAK, FKKMK UGM/RSUP DR. SARDJITO
Kesehatan tulang pada BBLSR
• Bayi kurang bulan berisiko menderita osteopenia
• Diperlukan intake yg adekuat: kalsium, fosfat dan vitamin D
• Monitor ketat osteopenia sngt diperlukan
• Faktor yg mempengaruhi Kesehatan tulang bayi kurang bulan
• Tumbuh cepat: perlu banyak kalsium dan fosfor
• Usia gestasi yg pendek: kehilangan waktu akresi kalsium dan fosfor
• Ekskresi dan absorbsi ginjal: terjadi ketidak seimbangan
• Absorbsi di usus: dipengaruhi vitamin D
• Kesehatan tulang bayi premature berpengaruh sampai dewasa
Bone health saat dewasa yg lahir term vs
L.F. Xie et al. Bone Reports 10 (2019) 100189

preterm
Table 2
Bone health in young adults born preterm versus term.
N pairs Very preterm Term Unadjusted mean difference (95% CI) Adjusted mean difference (95% CI)#

Lumbar spine
BMC, g 95 49.9 (47.6, 52.1) 54.6 (52.3, 56.8) −4.7 (−7.2, −2.1)⁎ −3.2 (−6.0, −0.4)⁎ BMC, aBMD and aBMD z-
Bone area, cm2
aBMD, g/cm2
95
95
43.6 (41.5, 45.8)
1.16 (1.13, 1.18)
44.7 (43.2, 46.2)
1.21 (1.19, 1.24)
−1.1 (−3.3, 1.1)
−0.06 (−0.09, −0.03)⁎
−1.1 (−3.5, 1.3)
−0.03 (−0.06, 0.00) scores scr signifikan lbh
aBMD Z-score
BMDvol, g/cm3
95
95
−0.6 (−0.8, −0.4)
0.36 (0.35, 0.37)
−0.2 (−0.4, 0.0)
0.37 (0.35, 0.38)
−0.4 (−0.7, −0.2)⁎
0 (−0.02, 0.01)
−0.2 (−0.4, 0.1)
–
rendah pada orang dewasa
Femoral neck dng Riwayat lahir kurang
BMC, g 87 4.5 (4.3, 4.8) 5.2 (5.0, 5.4) −0.7 (−0.9, −0.5)⁎ −0.2 (−0.4, −0.1)⁎
Bone area, cm2 87 4.5 (4.4, 4.7) 4.8 (4.6, 4.9) −0.2 (−0.4, −0.1) 0.0 (−0.4, 0.1) bulan pada semua
aBMD, g/cm2 −0.09 (−0.13, −0.05)⁎ −0.05 (−0.08, −0.01)⁎
aBMD Z-score
87
87
1.00 (0.97, 1.03)
−0.5 (−0.7, −0.3)
1.09 (1.06, 1.12)
0.1 (0.0, 0.3) −0.6 (−0.9, −0.4)⁎ −0.3 (−0.6, −0.0)⁎ pengukuran
Whole body
BMC, g 94 2476 (2375, 2577) 2788 (2689, 2887) −311 (−422, −199)⁎ −27 (−113, 58)
aBMD, g/cm2 94 1.14 (1.13, 1.16) 1.19 (1.17, 1.21) −0.05 (−0.07, −0.02)⁎ −0.01 (−0.03, 0.01)
aBMD Z-score 94 −0.3 (−0.5, 0.0) 0.3 (0.1, 0.5) −0.6 (−0.8, −0.3)⁎ −0.2 (−0.4, 0.1)

aBMD Z-score ≤ −1, n (%)

Lumbar spine 95 36 (38) 24 (25)
Femoral neck 87 32 (34)⁎⁎ 14 (16)
Whole body 94 23 (25) 10 (11)
Any of the 3 regions 95 50 (53) 27 (28)

BMC, bone mineral content; aBMD, areal bone mineral density; BMDvol, volumetric BMD; CI, confidence interval.
# height Z-score, fat mass and lean mass in g.
⁎
Mean difference between very preterm and term (reference) significantly different from 0 at p < 0.05.
⁎⁎
Proportion between very preterm and term significantly different at p < 0.05 after adjusting for height Z-score, fat and lean mass.
Bone Rep. 2019 Jun; 10: 100189.
Table 3 strength at 17 years of age (Ireland et al., 2016). Given that preterm
Osteopenia of Prematurity
• Penurunan bone mineral content (BMC) pada bayi kurang bulan
• Istilah yg sering dipakai
• metabolic bone disease (MBD),
• osteopenia of prematurity (OOP),
• neonatal rickets or
• rickets of prematurity
EPIDEMIOLOGI Osteopenia of
Prematurity
• Kejadian
• BBL< 1000 g: 55%
• BBL< 1500 g: 23%
• By premature yg dapat ASI: 40%
• By premature yg dapat susu formula khusus dan suplementasi calsium dan
fosfat: 16%
• Dampak jangka Panjang:
• Usia 7 th BBL<1500g: mempunyai berat badan, Panjang badan, BMI dan
lumbal BMI dan BMD yg lbh rendah dari populasi
• Usia 5,7-8,3 th bayi dng UK 34 minggu mempunyai masa tulang yg lbh rendah
dibandingkan yg lhr cukup bulan
Italian Journal of Pediatrics 2009, 35:20
doi:10.1186/1824-7288-35-20
 Maternal and Neonatal Factors Affecting Bone Mineral Content of
Indonesian Term Newborns
Wibowo T et al, 2021. Front. Pediatr. 9:680869. doi: 10.3389/fped.2021.680869

• Cross-sectional
• Tujuan: menentukan BMC bayi cukup bulan dan factor yg
Bone Mineral Content Term Newborns

mempengaruhi
bjects (N = 45). TABLE 2 | Mean ± SD BMC of whole body, whole body except head, trunk and

• Sampel: 45 bayi cukup bulan

Bone Mineral Content Term Newborns
legs.
Mean ± SD or N (%)
Site Mean ± SD
bjects (N = 45).
• Pemeriksaan: dual-energy x-ray absorptiometry (Dxa)
32.1 ± 6.1
TABLE 2 | Mean ± SD BMC of whole body, whole body except head, trunk and
WB BMC (g)
legs. 33.2 ± 9.3
Mean ± SD or N (%)

• Hasil
WB BMC except head (g) 13.7 ± 5.0
Site Mean ± SD
18 (40.0%) Trunk BMC (g) 6.2 ± 2.7

27 (60.0%) LegsBMC
WB BMC(g)(g) 6.7±±9.3
33.2 7.0
32.1 ± 6.1
1.56 ± 0.05 WB BMC except head (g) 13.7 ± 5.0
BMC, bone mineral content; WB BMC, whole body BMC.
23.8±4.1
18 (40.0%) Trunk BMC (g) 6.2 ± 2.7

27 (60.0%) Legs BMC (g) 6.7 ± 7.0

TABLE 3 | Mean of bone mineral content according to determinant variables.
3 (6.7%)
1.56 ± 0.05 BMC, bone mineral content; WB BMC, whole body BMC.
27 (60.0%)
23.8±4.1 Characteristics WB BMC (mean ± SD) P-value
Di Negara maju:
11 (24.4%)
34 (6.7%)
(8.9%)
TABLE
Sex 3 | Mean of bone mineral content according to determinant variables. • Laki-laki: 68,8 g
27 (60.0%)
Male (23)
Characteristics
36.2 ± 9.3
WB BMC (mean ± SD)
0.028a
P-value • Perempuan: 65,9 g
Female (22) 30.2 ± 8.3
11
20 (24.4%)
(44.4%)
FAKTOR RISIKO Osteopenia of
Prematurity
ANTENATAL POSTNATAL

• Placental insufficiency • Prolonged TPN > 4 weeks

• Preeclampsia • Bronchopulmonary dysplasia
• Chorioamnionitis • Necrotizing enterocolitis
• Genetic polymorphisms (vitamin • Liver disease Renal disease
D receptor, estrogen, collagen • Medications (loop diuretics,
alpha I) methylxanthines,
• Male gender glucocorticoids)
DIAGNOSIS Osteopenia of Prematurity
• Gold standard pemeriksaan bone mineral density (BMD): Dual energy X-ray
absorptiometry (DEXA)
• Tidak semua center tdk punya alat
• Pelaksanaan tidak mudah
• Pemeriksaan radiologi-->Koo’s score:
• Grade 1: terdapat bone rarefaction (penipisan tulang)
• Grade 2: terdapat penipisan tulang yg berhubungan dengan perubahan
metaphyseal, bayangan dan pembentukan tulang subperiosteal
• Grade 3: terdapat fraktur spontan
• Manifestasi klinis biasanya baru nampak pada fase akhir penyakit dan sngt sulit
terdeteksi
• Skrining sngt perlu dilakukan
• Pemeriksaan marker biokimia pd serum pd minggu ke-3 kehidupan bisa membantu Dx
• Marker biokimia: calcium, phosphate, alkaline phosphatase (ALP), PTH, dan vitamin Dà
tidak ada yg spesifik
Peranan vitamin D pada Kesehatan
tulang BBLSR
• Berperan dalam absorbsi kalsium di usus
• Resorbsi tulang
• Penurunan ekskresi kalsium dan fosfat
• Pd bayi kurang bulan
• Minggu pertama absorsi kalsium di usus pasif
• Selanjutnya akan merupakan transport aktif yg akan dipengaruhi vit D
 Metabolisme Vit D
A Review on Vitamin D Deficiency Treatment in Pediatric Patients

detrimental bone effects of vitamin

rapid decreases in calcium may p
seizure, further complicating the cl
(e.g., etiology of seizures). Valproic
it is an inhibitor of the enzyme syste
bone turnover through increasin
activity and therefore tilting the bal
formation and bone resorption.17,18
Recommendations have been ma
tients on an AED to receive a preve
of vitamin D 400 to 2000 units per
characteristics such as baseline calc
tration, polypharmacy, and sun exp
help guide vitamin D therapy as w
diagnosed with AED-induced osteo
need larger doses of vitamin D repla
apy to correct biochemical abnorm
Misra M, Pacaud D, Petryk A et al. Vitamin D deficiency in children and its management: review of87 calcium,
current knowledge and recommendations. Pediatrics. and phosphorus).18 Calcidi
2008;122(2):398–417
 Kadar vitamin D pada neonatus
• Kadar 25 (OH)D normal/adekuat atau defisien tidak konsisten antar literatur
• APP dan IOM
• kadar normal: >= 20 ng/ml (utk bayi cukup bulan/kurang bulan)
• Toksik: > 100 ng/ml
• Kadar inadekuat: 12-20ng/mlà kadang blm berhubungan dng defisiensi vit D yg
menyebabkan gangguan absorbs kalsium atau ricket
• Ricket biasanya manifes bila kadar< 12 ng/ml
• low 12 ng/mL, although this is dependent on calcium intake as well as vitamin D
status1
• Kesimpulan klasifikasi kadar vit D2
• Vitamin D sufficiency: 21 to 100 ng/mL • Excess: 101-149 ng/ml
• Vitamin D insufficiency: 16 to 20 ng/mL • Intoxication: >150 ng/ml
• Mild to moderate deficiency: 5-15 ng/ml
• SevereVitamin D deficiency: <5 ng/mL
1Ann Nutr Metab 2020;76(suppl 2):6–14
2Misra M, Pacaud D, Petryk A et al. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417
Kadar Vit D pd BBLSR di Indonesia:
Maternal and perinatal factors affected vitamin D status on very low
birth weight infants (Wibowo T et al, DRAFT for Publication)
• cross-sectional
• Tujuan: utk mengetahui prevalensi dan factor risiko defisiensi vit D
pada BBLSR
• Tempat: RSUP Dr. Sardjito
• Sampel: 133 BBLSR
• Waktu pemeriksaan vit D: saat fullfeed (±14 hari)
• Hasil Parametrics Mean ± SD or N(%)
Vitamin D level (ng/ml) 10.7 ± 6.2
Vitamin D status
Normal 11 (8.2)
Insufficiency 17 (12.8)
Deficiency 71 (53.4)
Severe deficiency 34 (25.6)
 Faktor yg meningkatkan risiko def vit D pd bayi
kurang bulan

• Nutrisi yg tidak adekuat

• Kurangnya paparan sinar matahari
• Waktu gestasi yang pendek: transfer vitamin D intrauterine terbatas
• Peningkatan kebutuhan vitamin D

UpToDate, Vitamin D insufficiency and deficiency in children and adolescents, 2022

 KEBUTUHAN VITAMIN D PADA BBLSR

Gomella, T. lacy, Eyal, F.G., Bany-Mohammed, F.

2020. Gomella’s Neonatology:
Management, Procedures, On-Call
Problems, Diseases, and Drugs. 8th ed.
McGraw-Hill Education.
VITAMIN D di ASI

Gomella, T. lacy, Eyal, F.G., Bany-Mohammed, F.

2020. Gomella’s Neonatology: Management,
Procedures, On-Call Problems, Diseases, and
Drugs. 8th ed. McGraw-Hill Education.
 Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [2]. However,

Recommendations for significant differences remain in the recommended target goals for 25(OH)D levels and in the
recommended doses for specific neonatal populations from these expert bodies (Table 1). The

vitamin D supplementation
IOM recommends a 25(OH)D level of 50 nmol/l based on bone health and mineralization.
This recommendation is based, in part, off of work by Priemel et al evaluating bone

Table 1. Recommendations for vitamin D supplementation.

Recommending Body Patient Age Recommended Recommended Target Comments Year of
Supplementation Serum Level Publication
American Academy of Healthy infants 400 IU daily 50 nmol/l (targeting *Begin soon after birth, in the first 2008[5]
Pediatrics—Section of birth– 12 months of bone health) few days of life. *All breastfeed
Breastfeeding and age and partially breastfed infants.
Committee on Nutrition *Formula fed infants taking 1 liter
of formula
AAP—committee on Preterm Infants 200–400 IU 50 nmol/l (targeting Discharge vitamin D 2013[6]
nutrition VLBW bone health) recommended for breastfed
infants 400 IU, for formula fed
200–400 IU
AAP—committee on Preterm 400–1000 IU 50 nmol/l (targeting Tolerating Full Enteral Feeds 2013[6]
nutrition infants 1500g bone health)
World Health Organization Preterm Infants 400–1000 IU Low and Middle-income countries WHO[7]
Institute of Medicine Infants 0–6 months 400 IU 50 nmol/l (targeting Under assumption of minimal 2011[8]
bone health) sunlight
ESPHAGAN Preterm Infants 800–1000 IU 80 nmol/L Stable Growing, 1000 to 1800 2010[4]
grams
Pediatric Endocrine Breastfed Infants, 400 IU 50 nmol/l (desire 800 IU for high risk populations i.e. 2008[2]
Society or those taking additional studies to preterm infants
1Lformula/day determine if 80 nmol/L
is optimal)
Endocrine Society Healthy Infants 0–1 400–1000 IU 75 nmol/l (for non- 0–1 vitamin D deficient ( 50 nmol/ 2011[9]
year skeletal benefits) l) 2000 IU/D for 6 weeks followed
by maintenance dosing
Randomized trial of two doses of vitamin D3 in preterm
infants <32 weeks: Dose impact on achieving desired serum
25(OH)D3 in a NICU population
Anderson-Berry A, Thoene M, Wagner J, Lyden E, Jones G, Kaufmann M, et al. (2017) PLoS ONE 12(10): e0185950.
https:// doi.org/10.1371/journal.pone.0185950

• Rancang bangun: RCT

• Tujuan: Evaluasi perubahan konsentrasi 25(OH) D3 stlh 4 minggu
diberikan suplementasi dng dosis 400 vs 800
• Populasi: 32 bayi kurang bulan (UK: 24-32 mgg)
• Intervensi: vitsmin D3 400 vs 800 IU
• Hasil:
Kadar Vit D BMD < percentil 10
Sebelum (nmol/l) Sesudah (nmol/l)
400 IU 41,9 84,6 56% #p=0,048
&p= 0,04
800 IU 42,9 105,3# 16% &
Efficacy and safety of early supplementation with 800
IU of vitamin D in very preterm infants followed by
underlying levels of vitamin D at birth
Cho et al. Italian Journal of Pediatrics (2017) 43:45

• Rancang bangun: cohort

• Tujuan: menentukan efikasi dan keamanan suplementasi vit D 800 IU
pd BBLSR
• Populasi: 66 BBLSR
• Intervensi
• Vit D 800 IU sejak 14 hari pasca natal
• HMF (vit D: 66 IU/100 ml)
• Total intake vit D< 900 IU
• Analisis: dibagi menjadi < 10 ng/ml dan >= 10 ng/ml
 Serum phosphorus, mg/dL 5.0 ± 1.4 4.8 ± 1.4 0.51

Hasil:Serum ALP, IU/L

32 ± 1 weeks PMA
205.6 ± 63.7 178.8 ± 49.1 0.10

Table 2 Vitamin D status

Serum calcium, mg/dL 9.7 ± 0.5 9.4 ± 0.7 0.86
Variable Cord 25(OH)D Cord 25(OH)D P
Serum phosphorus, mg/dL 5.9concentrations
± 0.9 5.2 ± 0.8
concentrations 0.13
Serum ALP, IU/L <10± ng/mL
366.5 102.3 ≥10 ng/mL
422.0 ± 138.5 0.05
At birthSerum PTH, pg/mL * 76.3 ± 50.1 74.2 ± 69.1 0.92
N Vitamin D excess (>80 ng/mL) 0 20 029 -
Serum
36 ± 125(OH)D levels
weeks PMA 8.3 ± 1.9 21.4 ± 8.5 <0.001
Vitamin D sufficiency
Serum (>30 ng/mL)
calcium, mg/dL 9.70± (0%)
0.4 5 (17%)
9.7 ± 0.6 0.07
0.51
32 ± 1 Serum
weeks phosphorus,
postmenstrual age
mg/dL 6.2 ± 0.6 5.7 ± 1.9 0.07
N Serum ALP, IU/L 13 ± 91.6
284.6 18 ± 127.1
338.8 0.11
Serum 25(OH)D
Vitamin levels(>80 ng/mL)
D excess 0/1715.3 ± 10.1 24.1 ± 9.3
3/26 0.05
0.27
Vitamin D sufficiency (>30 ng/mL)
UCa/Cr 0.133 ±(23%)
0.16 4 (22%)
0.19 ± 0.28 1.00
0.50
36 ± 1 UCa/Cr
weeks postmenstrual
>0.8 age 0 1 (3%) 1.00
N Nephrocalcinosis, n 17
1 (5%) 226(7%) 1.00
Serum 25(OH)D
Weight, g levels 43.1±±254.1
1881.1 20.3 57.7 ± ±21.9
1813.2 331.3 0.03
0.44
Vitamin D sufficiency
Length, cm (>30 ng/mL) 41.311± (65%)
1.5 23 (88%)
40.5 ± 2.2 0.12
0.19
Data are presented as n (%), median (range), or mean ± SD
Head circumference, cm 30.6 ± 1.2 29.6 ± 1.4 0.43
BMC, g† 2.6 ± 2.0 2.1 ± 1.7 0.44
Table 3 Secondary
†
outcome variables at 32 and 36 weeks postmenstrual age
BMD, g/cm 0.11 ± 0.02 0.10 ± 0.02 0.63
Variable Cord 25(OH)D Cord 25(OH)D P
 Serum 25(OH)D levels 43.1 ± 20.3 57.7 ± 21.9 0.03
At birth
Vitamin D sufficiency (>30 ng/mL) 11 (65%) 23 (88%) 0.12

Efek samping
Serum calcium, mg/dL 7.0 ± 0.7 7.3 ± 0.8 0.12
Data are presented as n (%), median (range), or mean ± SD
Serum phosphorus, mg/dL 5.0 ± 1.4 4.8 ± 1.4 0.51
Serum
Table 3 ALP, IU/L outcome variables at 32 and 36205.6
Secondary weeks± 63.7
postmenstrual age 178.8 ± 49.1 0.10
32 ± 1 weeks PMA
Variable Cord 25(OH)D Cord 25(OH)D P
concentrations concentrations
Serum calcium, mg/dL 9.7 ± 0.5 9.4 ± 0.7 0.86
<10 ng/mL (N = 20) ≥10 ng/mL (N = 29)
At Serum
birth phosphorus, mg/dL 5.9 ± 0.9 5.2 ± 0.8 0.13
Serum calcium,
Serum ALP, IU/Lmg/dL 366.5
7.0 ± 102.3
± 0.7 422.0
7.3 ± 138.5
± 0.8 0.05
0.12
Serum PTH, pg/mL *mg/dL
Serum phosphorus, 76.3± ±1.450.1
5.0 74.2±±1.4
4.8 69.1 0.92
0.51
VitaminALP,
Serum D excess
IU/L (>80 ng/mL) 0
205.6 ± 63.7 0
178.8 ± 49.1 -
0.10
36±±11 weeks
32 weeks PMA
PMA
Serum calcium,
Serum calcium, mg/dL
mg/dL 9.7 ±± 0.5
9.7 0.4 9.7 ±± 0.7
9.4 0.6 0.51
0.86
Serum phosphorus,
Serum phosphorus, mg/dL
mg/dL 6.2 ±± 0.9
5.9 0.6 5.7 ±± 0.8
5.2 1.9 0.07
0.13
Serum ALP,
Serum ALP, IU/L
IU/L 284.6 ±± 102.3
366.5 91.6 338.8 ±± 138.5
422.0 127.1 0.11
0.05
VitaminPTH,
Serum D excess
pg/mL(>80
* ng/mL) 0/17± 50.1
76.3 3/26± 69.1
74.2 0.27
0.92
UCa/Cr D excess (>80 ng/mL)
Vitamin 00.13 ± 0.16 00.19 ± 0.28 -0.50
UCa/Cr
36 ± >0.8
1 weeks PMA 0 1 (3%) 1.00
Nephrocalcinosis,
Serum n
calcium, mg/dL 1 (5%)
9.7 ± 0.4 2 (7%)
9.7 ± 0.6 1.00
0.51
Weight,phosphorus,
Serum g mg/dL 1881.1
6.2 ± 0.6± 254.1 1813.2
5.7 ± 1.9± 331.3 0.44
0.07
Length,ALP,
Serum cm IU/L 41.3 ±±1.5
284.6 91.6 40.5 ±±2.2
338.8 127.1 0.19
0.11
Head circumference,
Vitamin D excess (>80cm
ng/mL) 30.6 ± 1.2
0/17 29.6 ± 1.4
3/26 0.43
0.27
†
Rekomendasi Suplementasi Vit D pd BBLSR

• Bayi <1500 g: 200-400 IU/ hari

• Bila BB≥1500 g full enteral feeding: 400 IU (UpToDate, 2022)
• European guidelines: 800 to 1000 IU/hari selama perawatan/ 1 bln
pertama
• An international consensus group recommends (Koletzko et al): 400 -
1000/ hari
• Praktek yg kita lakukan
• < 1500 g: 400 IU
• >= 1500 g: 600 – 800 IU
 KESIMPULAN
• Kejadian osteopenia of prematurity pada bayi kurang bulan masih
tinggi
• Osteopenia of prematurity memberikan dampak pada Kesehatan
tulang saat dewasa
• Suplementasi vitamin D 400 – 800 IU pada bayi kurang bulan aman
dan meningkatkan Kesehatan tulang
Terimakasih
• Staf Divisi Neonatologi:
• Dr. dr. Ekawaty LH, MPH, SpAk
• Dr. Setya Wandita, M.Kes, SpAK
• Dr. Alifah A, MSc, SpAK
• Dr. Elysa N Safrida, MSc, SpA
• Asisten Peneliti
• Dr. Riyo
• Dr. Huda Amilina