JPediatr(RioJ).2014;90(6):529---532
www.jped.com.br
EDITORIAL
Growth,
bone
health,
and
later
outcomes
in
infants
born
preterm
夽
,
夽夽
Crescimento,
saúde
óssea
e
resultados
mais
recentes
em
neonatos
prematuros
Nicholas
Embleton
a,b,∗,
Claire
L.
Wood
aaNewcastleHospitals,NHSFoundationTrust,Newcastle,UnitedKingdom
bInstituteofHealthandSociety,NewcastleUniversity,Newcastle,UnitedKingdom
Oneintenbabiesworldwidearebornpretermeveryyear; over90%oftheseareborninlowandmiddle-income coun-tries such asBrazil.1 Improvements in neonatal intensive
careandincreasedsurvivalofpreterminfantshasledtoan increasingfocusonthelong-termimpactsofpretermbirth, specificallywithrespecttometabolicoutcomessuchasbone mineral density (BMD) and timing and extent of catch-up growth.
Metabolic
bone
disease
of
prematurity
Preterm infants are particularly susceptible to metabolic bonediseasefortwokeyreasons:Firstly,80%offetalbone mineral accumulation occurs during the last trimester of pregnancy, with a surge in placental transfer of calcium, magnesium, and phosphorus to the neonate.2 A preterm
infant ex-utero must accrete bone mineral during this period without the support of the regulatory placental
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2014.03.001
夽 Pleasecitethisarticleas:EmbletonN,WoodCL.Growth,bone
health, and later outcomes in infants born preterm. J Pediatr (RioJ).2014;90:529---32.
夽夽SeepaperbyQuintaletal.inpages556---62.
∗Correspondingauthor.
E-mail:Nicholas.embleton@ncl.ac.uk(N.Embleton).
environment, and almost all these infants will have sig-nificantly lower bone mineral content (BMC) than those bornatterm. Secondly,ex-uteroliving conditionsmakeit moredifficultforinfantstomoveandstresstheirbonesas theywouldhave donein-utero.3 Aswell asmineral
insuf-ficiency,lowerBMDis alsoaconsequenceof otherfactors suchasmedication(e.g.steroids,diuretics,etc.), respira-torycompromise,4andinfection,5whichmaydamagebone
trabeculae.Althoughmetabolicbonediseaseofprematurity isoftenasymptomaticanddescribedasself-limiting,6
con-cernremainsthatunder-mineralizationduringsuchacritical periodcouldincreasetheriskofchildhoodfracture.Perhaps moreimportantly,itmayresultinreducedpeakbonemass,7
whichisakeypredictorforriskofosteoporosisinadulthood.
Impact
of
preterm
birth
on
later
metabolic
bone
outcomes
In this issue of Jornal de Pediatria, Quintal et al.8 have
conducteda comprehensive longitudinal study, examining bonemineralizationandbodycompositionusingdualX-ray absorptiometry(DXA)in14preterminfantsoverthefirstsix postnatalmonths,andcomparedthemtoinfants bornfull term.Thisis important,asprevious researchstudieshave producedconflictingdata ontheeffectofprematurity on laterBMD. Consistent withdata from thisstudy, previous studiesinpreterminfantshaveshownalowerbonemass,9
http://dx.doi.org/10.1016/j.jped.2014.08.002
530 EmbletonN,WoodCL
BMD,7andBMC4atthecorrectedageofterm,aswellasa
lowerweightandponderalindex.7Severalstudies,however,
havefailedtodemonstrateanassociationbetweenpreterm birthandlaterbonestrength,5,10,11whilstothershaveshown
greaterBMCandBMDintermchildrencomparedtopreterm, atfollow-up.4,12Apossibleexplanationforthevariationin
study resultsmay be inthe timing of follow-up as catch-upinbonemineralizationmayoccurthroughout childhood andadolescence.13Ofnote,inQuintaletal.’sstudy,8
catch-upbone mineralization appearsto haveoccurred in early infancy;thus,datafrompretermandfull-terminfantswere comparableby6monthsofage.Thismaybeattributableto thepersistingbenefitsof growthfactorspresent inbreast milk,asQuintaletal.’scohortwereallbreastfed,compared tomuchofthepublisheddatafromformulafedbabies. Con-tinuedfollowupofthiscohortwithfurtherDXAscansinlater childhoodandadulthood wouldprovideadditionalinsights intotheirpeakbonemass.
TheexactinfluenceofbirthweightonlaterBMDremains unclear.Somestudies have foundthat, although preterm-borninfantswerelighterduringchildhoodthantheirterm counterparts, their BMD was appropriate for size. Adults whowerebornpretermremainonaverageslightlyshorter thantheirterm-born peers.Assomestudiesmaynothave madeappropriateadjustmentsfor current size,itmaybe difficulttodetermine whether BMD isappropriate ornot. Thereis also evidencethat very lowbirth weight (VLBW) infants,whetherpretermornot,attainasub-optimalpeak bonemassin partduetotheirsmallsize,but alsodue to theirsubnormalskeletalmineralisation.5TheHertfordshire
cohortstudy(whichformedthebasisforseveralofBarker’s studies)showedthatbirthweightwasindependently asso-ciatedwith bone density at 60-75 years of age. Although anotherstudyfoundnoassociationwithpretermbirthand peakbone mass,14 aneffectofbeingsmallfor gestational
agewasapparent,suggestingthataproportionoflaterbone massisdeterminedbyinuteroevents,suchasfetalgrowth.
The
challenges
of
optimizing
neonatal
nutrition
The use of fortified breast milk in this study and exclu-sivebreastfeedingpost-dischargeiscommendable.Maternal breastmilkisassociatedwitharangeofbenefitsbothinthe short-term(e.g.reduction inthe incidenceof necrotizing enterocolitis)andlong-term (e.g.improvedcognitive out-come.)AstudybyFewtrellatal.15showedthatthevariable
withthegreatesteffectonadultBMDwastheproportionof breastmilkintake.Giventhatbreastmilkhasamuchlower mineralcontentthanformula,andrequiresfortificationto meet nutrient requirements, the data of Fewtrell et al. suggestsapossiblebeneficialrolefornon-nutrient compo-nentssuchasgrowthfactors.The cohortofQuintaletal.8
highlightsthechallengesofprovidingadequatenutritionto enablegrowthinpreterminfants.Althoughmanyunitsnow strivetostartearlyfeeds,parenteralnutrition(PN)isnow commonplaceinmostNICUsandprovidesnutrientswhilst enteraltoleranceisachieved:inthisstudy,althoughenteral feedswerestartedsoonafterbirth,mostreceivedPN sup-portwithanaveragePNdurationof12days.
Preterminfantsmissoutontheimportantphaseof min-eralaccretioninthethirdtrimesterandarethereforeeven morevulnerabletotheeffectsofinadequatemineral pro-vision inthe postnatalperiod.Although PNsolutionshave improveddramaticallysincethefirstreportsofneonataluse inthelate1960’s,problemswithrespecttomineral provi-sionexistbecausecalciumandphosphate areinsoluble in high concentrations. The increased availability of organic salts,suchassodiumglycerophosphate,hasimproved sol-ubility (and therefore mineral provision), and increased intakesofaminoacidsarebothlikelytoresultinhigherlean massandbonemassaccretionthaninthepast,butPN pro-visioncontinuestolackastrongevidencebaseandseveral concerns persist.16 In particular, aluminiumcontamination
remainsaverycommonproblem,andisindependently asso-ciatedwithreducedBMCinlaterchildhood.15
Bonemineral andother growth deficitsaccrued whilst enteralnutritionisestablishedoftenincrease duringNICU stay.Mineraluptakeiscompromisedthroughthelowcontent inun-fortifiedbreastmilk(especiallyphosphate)and ineffi-cientabsorptionduetoanunder-developedgastrointestinal tract.6 This results in a greater loss of long bone
den-sity than observed in term infants and further increases the risk of metabolic bone disease. There is compelling evidence thatoptimizing early growth throughnutritional interventionsgeneratespositiveandlastingeffectsonbone mineralization,10 which may partially counteract preterm
bone deficits. A systematic review by Kusckel and Hard-ingin2009showedthatfortifyingthenutritionofpreterm babies improves growth and bone mineral aggregation.17
International guidelines from groups such as ESPGHAN recommend that those receiving unfortified breast milk shouldreceivemultivitamin,iron,folicacid,phosphate,and sodiumsupplementation.18
Severalstudieshaveemphasizedtheimportanceofearly growthonlaterbonehealth,2soitisencouragingtoobserve
in this study that the preterm infants demonstrated sig-nificant catch-upgrowthwithan increasein meanweight Z-score from-2.58 at40 weeksto-0.49at 6months,and an increasein meanlengthZ-scorefrom-2.22to-0.59at the 6-month follow-up. In a study by Cooperetal, those whowere lightest at 1 year of age hadthe lowest BMC.2
Inafurtherstudy,weightgainduringthefirsttwoyearsof lifepredictedBMDatage9-14.19 Fewtrelletal.suggested
thatpreterminfants withthemost substantialincrease in height (length) between birth and follow-up showed the greatestbonemassatfollow-up.12Theyalsodemonstrated
thatbirthlengthalonewasastrongpredictoroflaterbone mass,suggestingthatoptimizinglineargrowthearlymaybe beneficialtolaterbonehealth.However,themeanweight Z-scoreattermof-2.58inQuintaletal.’sstudy8highlights
Growth,bonehealth,andlateroutcomesininfantsbornpreterm 531
The
use
of
DXA
scanning
as
an
adjunct
to
biochemistry
in
the
detection
of
metabolic
bone
disease
Quintaletal.demonstrate thatDXAscanningisareliable andwell-validatedtechniquetoestimateBMCandBMD. It is well tolerated due toitsnon-invasive natureand short scantimes,andtheradiationlevelsinvolvedarelowerthan backgroundlevels.ThenewerDXAmachineswithenhanced image resolution enable accurate calculation of fat and leanmassindices,althoughtheycannotreliablydetermine adipose tissue partitioning. Plain radiographs in preterm infants on NICU frequently demonstrate osteopenia, but areinsensitivemarkers of BMD. Biochemicalmarkers may helpdeterminethepresenceofmetabolicbonedisease;for example, high levels of alkaline phosphatase can be use-ful asaprompt tocheckserumcalciumandphosphate.20
However,thecomplexityofprocessesinvolvedinmetabolic bone disease of prematuritymean that biochemical mea-suresaresimilarlyinsensitive.Thekeytomanagementisto focuseffortsthatminimizeitsoccurrenceasmuchasis fea-sibleinbusyNICUsettings,ratherthanperfectingsensitive detectionmethods.Thiscanbedonebyencouragingtheuse of aluminium-free, high qualitymineral supplemented PN solutionswithadequateamountsofaminoacids,combined withtheearlyandsustaineduseofbreastmilk,and supple-mentedbytheroutineuseoffortifiersthatmeet nutrient requirements.
Epigenetics
and
bone
metabolism
Many of the long-term effects on bone health may be duetoprogramming andmodulatedby epigenetic mecha-nisms---mitotically-heritablealterationsingeneexpression potentialthatarenotcausedbychangesinDNAsequence. The classic examples are DNA methylation and histone acetylation21 and resultin differences in gene expression
andtranscription,butmayalsoinvolvepost-transcriptional effectsonotherprocessessuchasproteintranslation.Early lifegrowthandnutritionalexposuresappeartoaffect cellu-larmemoryandresultinvariationinlaterlifephenotypes. Muchofthisworkispreliminary,butinitialdatasuggestthat epigeneticmechanismsmayunderlietheprocessof devel-opmentalplasticityanditseffectontheriskofosteoporosis. One of the models that has been postulated is the role ofmaternal vitamin Dstatus andpostnatalcalcium trans-fer.EarlyworkonmethylationandvitaminDreceptorsand placentalcalciumtransporterssuggeststhatepigenetic reg-ulationmightexplainhowmaternalvitaminDlevelsaffect bonemineralizationintheneonate.21 Muchofthecurrent
research is in animal models, but if the changes can be replicatedinhumans,epigeneticorother biomarkersmay providerisk assessmenttoolstoenabletargeted interven-tiontothoseatgreatestriskofosteoporosis.
Future
clinical
and
research
priorities
Longitudinal studies with minimal attritional losses, and especially those conducted within randomized controlled trial settings are needed if we are to improve health
outcomesofpreterminfantsacrosstheglobe.Thisresearch needstobehighqualityandconductedinlow-,middle-,and high-incomecountriessogeneralizabilitycanbemaximized. Risk benefit ratios of medical interventions are sensitive to the individual and the healthcare context. Neverthe-less, the importance of early bone and body growth on thelaterdevelopmentofmetabolicdiseasessuchas osteo-porosismeansthatoptimizingnutritionbothpre-and post-hospital discharge must remain a clinical priority. Impor-tantly,greatereffortsmustbeappliedtosupportresearch and quality improvements initiatives within and between countries---weneedtoimproveourcollaborativeworking!
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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