PHOSPHO-CALCIUM METABOLISM

PRETERM

Luís Pereira-da-Silva

Hospital de Dona Estefânia, CHLC EPE

Faculdade de Ciências Médicas, UNL

Escola Superior de Tecnologias da Saúde de Lisboa, IPL

Course: Neonatal Nutrition

Braga, May12th 2012

PRETERM

METABOLIC BONE DISEASE

Neonatal Childhood

Metabolic Bone Disease

Vachharajani. NeoRev 2009

Osteopenia

Decrease in organic bone matrix (osteoid): thickness or number of

trabeculae or thickness of bone cortex

bone mineral content (BMC) (mass of mineral per unit length)

Osteomalacia

Decrease in mineralization of organic bone matrix accumulation of

nonmineralized bone matrix and softening of bones.

BMC plus bone mineral density (BMD) (ratio of BMC to bone area)

Osteopenia of Prematurity

Bozzetti. Ital J Pediatr 2009

Occurs at 10th–16th postnatal weeks, but it may remain silent until

severe demineralization

Affects 23% of VLBW and 55% of ELBW infants

PRENATAL

POSTNATAL - NICU

POSTNATAL - POSTDISCHARGE

PRENATAL

Cetin. Ann Nestle 2010

Nutrição óssea Intrauterine nutrition

3 compartment model

Bone nutrition last trimester

>24 weeks: mineral transference with peak of:

Ca (active transport) 120-150 mg/Kg/d (~ 13-16 ml/Kg/d of Ca

gluconate 10%)

P 60-75 mg/Kg/d

Mg 2.5-3.4 mg/Kg/d

Mineral transference - dependent on maternal Ca and vitamin D status

Vachharajani. NeoRev 2009, Velaphi. S Afr J Clin Nutr 2011

Bone nutrition last trimester

Maternal Ca intake

Low intakes (<600 mg/d) risk for lower bone mass in neonates

Koo. Obstet Gynecol 1999

Maternal Ca supplementation does not affect newborn bone

mineral mass in populations with adequate baseline intakes Prentice. J

Nutr 2003

Bone nutrition last trimester

Maternal vitamin D status

Prospective study on 424

pregnant women:

Maternal vitamin D insufficiency

can influence fetal femoral

development (high resolution

3D ultrasound) as early as 19

weeks’ gestation

Mahon. J Bone Miner Res 2010

Bone nutrition last trimester

Maternal vitamin D status

Cohort on 198 children born in UK, evaluated at age of 9 years:

Maternal use of vitamin D supplements associated with greater

childhood bone mineral mass

Very low maternal concentrations of serum 25-hydroxyvitamin D

associated with lower bone mineral mass in the offspring

Javaid . Lancet 2006

Bone nutrition last trimester

Cooper. Nestlé Nutr Workshop Ser 2008, Vachharajani. NeoRev 2009

Endocrine

environment

PTH / PTHrP

GH/IGF axis

T3

vit D3

Calcitonin

Estrogen

Endocrine environment

The fetus is maintained hypercalcemic in a high calcitonin and

estrogen environment promoting the modeling/ remodeling ratio

in favor of modeling increasing the endocortical bone

Rigo. J Pediatr 2006

Bone nutrition last trimester

Bone nutrition last trimester

Other factors

Mechanical stimulation – regular fetal kicks against the uterine wall

Rauch. Arch Dis Child F&N Ed 2002

Parental height Harvey. J Clin Endocrinol Metab 2008

Chorioamnionitis, preeclampsia Vachharajani. NeoRev 2009

Bone nutrition last trimester

Ossification

Intramembranous (skull,

face)

Endochondral (remaining

skeleton)

Cooper. Nestlé Nutr Workshop Ser 2008,

Velaphi. S Afr J Clin Nutr 2011

Bone nutrition last trimester

Cooper. Nestlé Nutr Workshop Ser 2008

Vachharajani. NeoRev 2009

Endochondral

The osteoblasts form the

primary trabeculae by

depositing an osteoid matrix

bone growth occurs by

replacement of the cartilaginous

core

POSTNATAL

NICU

Protein nutrition

of the matrix

Bone nutrition preterm infant

Rauch. Arch Dis Child F&N Ed 2002; Rigo. J Pediatr 2006

NUTRIENTS

Energy e protein: collagen of the matrix

Minerals: Ca, P, Mg

Vitamin D

Protein and Energy

I. At birth loss of transference

of nutrients in 3rd trimester

II. In NICU difficulty in providing

all the nutrients – by parenteral

and enteral routes

IUGR and EUGR

VLBW infants (<1500g)

II. Discharge

I. At birth

IUGR and EUGR

VLBW infants (<1500g)

At birth: ±18% with IUGR

At the end of neonatal period

and at discharge: ±75% with

EUGR Precoce

? Recuperação

Pós-alta

Ehrenkranz. Pediatrics 1999

Martin. Pediatrics 2009

Short term: AA + energy weight gain

RCT 125 neonates <1250g

Parenteral nutrition:

Group A: AA + lipids up

to 3.5g/Kg/d

Group B: AA up to

2.5g/Kg/d + lipids up to

2g/Kg/d

More aggressive PN

(early high doses)

weight gain

Wilson. Arch Dis Child F&N Ed 1997

RCT

PN ≥ D1 AA 3g/kg/dia

at 52h after birth:

nitrogen balance

(protein accretion)

Protein Balance

By Nitrogen Balance

-1

-0.5

0

0.5

1

1.5

1

AA Intake

Nit

rog

en

Bala

nce

(g/k

g/d

)

1 gm/kg/d3 gm/kg/d

p=0.010

Thureen. Pediar Res 2003

Short term: early high AA nitrogen balance

3 RCT Population N Intervention (I)

Control (C)

Outcome

Thureen.

Pediar Res

2003

BW

<1300g

28 I: PN (g/Kg/d) start AA = 3

C: PN (g/Kg/d) start AA = 1

I: protein accretion

(nitrogen balance) + better

aminoacidogram

Ibrahim. J

Perinatol

2004

BW

<1250g

32 I: PN (g/Kg/d) ≥ 1h after birth

AA = 3 + lipids = 3

C: PN (g/Kg/d) 0-48h after

birth AA+lipids = 0; ≥D3: AA 2

3.5 + lipids 0.5 3

I: early intake - better

nitrogen balance

te Braake. J

Pediatr 2005

BW

<1500g

135 I: PN (g/Kg/d) ≥D1 AA = 2.4

C: PN (g/Kg/d) D1 =0 D2

=1.2 ≥D3 =2.4

I: at D4: nitrogen balance

+ better aminoacidogram

Short term: early high AA + energy protein

accretion

Ca & P

In premature infants Ca absorption depends on the Ca

intake, whereas Ca retention is related to the P supply

Rigo. J Pediatr 2006

Bone nutrition neonatal period

Preterm after birth sudden interruption of placental transference of Ca

& P

D1-D2: factors promoting precipitation of calcium phosphate limits the

intake by PN:

Relatively concentrations of Ca & P due to fluid restriction

Concentrations of glucose and AA (?)

Environment temperature

Early: PN just after birth Ca & P

Allwod. Nutrition 1998

D1-D2 after birth possible provide by PN up to Ca 60 mg/dL and P 35

mg/dL; Ca:P (mg) 1.7:1 (Ca = 60 mg/ Kg/d and P = 35 mg/ Kg/d) Parikh.

Am J Health Syst Pharm 2005 ; Wong. J Am Coll Nutr 2006

Limitation: most phosphate salts contain Na (eg, 2 mEq/mL in sodium

glycerophosphate and in monosodium phosphate 27.5%)

Short term: PN Ca & P bone mineral content

RCT 24 neonates <1200g

Exclusive PN during >3 weeks (mg/100ml): Ca 68 + P 62 versus Ca 50 +

P 46.5

Higher dose bone mineral content (single-photon absortiometry),

up to 26 weeks after interrupting PN (programming?)

Prestidge. J Pediatr 1993

Quantitative Ultrasound

RCT - from D1 of PN:

High dose (HD) Ca 75; P 44 mg/Kg/d

Low dose(LD) Ca 45; P 26 mg/Kg/d

Ca:P ratio (mg:mg 1.7:1)

mg/Kg/d

LD

Ca 45; P 26

HD

Ca 75; P 44

Greater difference observed

at ±5 postnatal weeks, after

interruption of PN (at ±2 weeks)

Mineral nutrition preterm infants

Klein. J Nutr 2002, ESPGHAN. JPGN 2006, Abrams. AJCN 2007

Ca & P concentrations in human milk and formulas (mg/100ml)

Human milk (HM): Ca 26; P 14

Preterm Formula: Ca ±100; P ±50

Post-discharge Formula (PDF): ±76; P ±38

Infant Formula (term): Ca ±46; P ±23

Mineral deficiency may occur in VLBW infants:

Fed unfortified HM or term formulas versus preterm formulas Koo.

Bone Miner Res 1988, Hawthorne. Minerva Pediatr 2004

Fed unfortified fortified HM Lucas. Am J Clin Nutr 1996

Short term: enteral Ca & P Mineralization

Experimental FPT at discharge: bone mineral content (DEXA)

RCT 37 neonates 28-32

wks

PTF mineral (mg/100Kcal):

experimental PTF (Ca

123 + P 74) versus

regular PTF (Ca 99 + P

52) up to 3 M

Lapillonne. AJCN 2004

Short term: enteral Ca & P Mineralization

Vitamin D

Osteopenia of Prematurity is primarily a disease of

inadequate mineral intake, not vitamin D deficiency Abrams. Am

J Clin Nutr 2007

However…

Bone nutrition neonatal period

Vitamin D

Recommended: 800-1000 UI/d ESPGHAN. JPGN 2010

Physical stimulus

Preterm infants

Passive range-of-motion exercise

Bone mineral mass (DEXA) Moyer-Mileur. Pediatrics 2000

Bone strength (QUS) Litmanovitz. Calcif Tissue Int 2007

Metanalysis 6 RCT: “weak evidence of physical activity programs

promoting short-term bone mineralization in preterm infants; however:

trials with small samples, poor methodological and reporting quality”

Schulzke. Cochrane 2007

Physical activity Mineralization

POSTNATAL

Postdischarge

RCT: 89 neonates (±1250g, ± 29 wks)

After discharge: “PDF” (+40% Ca, +11% P e +21% protein) versus Infant

Formula during 1 year

At 12 M: without significant difference in bone mineralization (DEXA)

Medium term: enteral Ca & P no advantage

Koo. Am J Clin Nutr 2006

Picaud. J Pediatr 2008

RCT: 49 neonates <33 wks

After discharge: PTF (+96% Ca, +89% P e +35% protein) versus Infant

Formula during 2M >2M all receiving Infant Formula

At 4M CA: same bone area, however bone mineral content (DEXA)

Medium term: NE Ca & P Mineralização

ESPGHAN. JPGN 2006

Post-Discharge Formulas (PDF): protein & energy +

minerals

PDF Infant formula >40-52 wks CA in AGA infants

Fewtrell. Bone 2009

RCT cohort

202 preterm infants – first months: HM versus PTF

At 20 years: DEXA identical peak bone mass and bone turnover–

independent of type of feeding

Group HN - total bone mass and bone mineral content

Ca & P concentration in LM << FPT influence of non-nutritive factors in

HM?

Long term: enteral Ca & P no advantage

Vitamin D

Vigantol® 1 drop = 800 UI; Protovit N® 10 drops = 375 UI

PDF 100ml 64 UI; If 2 Kg, and150 ml/Kg/d 192 UI/d

HM (non fortified) 100ml = 3 UI; If 2 Kg – even consuming 170

ml/Kg/d only 4.5 UI/d…

Suggestion: HM ou PDF + Protovit N® 10 drops/d + Vigantol® 1 drops

every other day = ±800-1000 UI/d

Recommended: 800-1000 UI/d ESPGHAN. JPGN 2010

I. Dual energy X-ray

absorptiometry (DEXA)

Measures bone size and

mineral content: total body

bone mineral content (BMC) +

bone density

Bone assessment

DEXA: high accuracy and precision in assessing BMC in neonates

gold-standard in preterms Bonkovitz. Pediatr Radiol 2007

II. Quantitative ultrasound (QUS)

Speed of sound measures Bone

Strength: density + cortical

thickness + elasticity +

microarchitecture

Convenient: portable, non-invasive,

non-ionising McDevitt. Neonatology

2009

Bone assessment

QUS cannot be used as a surrogate for DEXA; however, both methods

may complement each other in the assessment of bone health Giani.

Arch Dis Child F&N Ed 2008

NICU, Hospital D. Estefânia, 2006

III. X-ray

“Thin “ and “washed-

out” bones, healing

fractures, subperiosteal

new bone formation,

and enlargement of

epiphysis

Bone assessment

Bone mineralization needs to be decreased by ≥20–40% for changes to

be visible on a plain radiograph late indicator Giani. Arch Dis Child

F&N Ed 2008

IV. Blood analysis

Hypophosphatemia, hypocalcemia and high alkaline phosphatase –

poor correlation with BMC assessed by DEXA in preterm infants

Faerk. ADC Fetal Neonatal Ed 2002

However, in clinical practice – early indicator of osteopenia :

phosphatemia < 4-4.5 mg/dl and/or alkaline phosphatase >800

IU/L Abrams. Am J Clin Nutr 2007

Bone assessment

V. Urine analysis

Urinary excretion of Ca and P

Tubular rebsorption of phosphate (TRP) - good guide for phosphate

supplementation; if >95% inadequate supplementation

%TRP = 1 − (PU/CrU) x (CrU/Pp) x 100

P = phosphorus; Cr = creatinine; U = urine; p = plasma

Harrison. Acta Paediatr 2008

Bone assessment

V. Urine analysis

Urinary Ca and P : creatinine ratios

Reference values: 95th centile: CaU:CrU = 3.8 mmol/mmol; PU:CrU =

26.7 mmol/mmol Aladangady. Pediatr Nephrol 2004

Standard reference - limited usefulness: ratios highly depend on type

of feed (HM, formula…) and not validated (DEXA) Harrison. Acta

Paediatr 2008

Bone assessment

SUMMARY

PRENATAL

Maternal diet: enough protein and energy + enough Ca

and vitamin D

Endocrine environment: promotes the modeling/

remodeling ratio in favor of modeling, increasing the

endocortical bone

SUMMARY

IN NICU

PN: early high Ca + P plus Mg, vit D, Zn *

Enteral: HM fortified HM; or Preterm formula; vit D

supplement *

Early passive range-of-motion exercise *

Steroids and diuretics – adverse effects

* sufficient for preventing osteopenia

SUMMARY

POST DISCHARGE

Breastfeeding; or breastfeeding complemented with PDF

or exclusive PDF Infant formula (>40-52 weeks CA)

Vit D 800-1000 UI/d

Thank you