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J Pediatr (Rio J). 2014;xxx(xx):xxx---xxx

www.jped.com.br

EDITORIAL

Growth, bone health, and later outcomes in infantsborn preterm�

Crescimento, saúde óssea e resultados mais recentes em neonatosprematuros

Nicholas Embletona,∗, Claire L. Woodb

a Newcastle Hospitals, NHS Foundation Trust, Newcastle, Reino Unidob Institute of Health and Society, Newcastle University, Newcastle, Reino Unido

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Received 28 July 2014; accepted 4 August 2014

One in ten babies worldwide are born preterm every year;over 90% of these are born in low and middle-incomecountries such as Brazil.1 Improvements in neonatal inten-sive care and increased survival of preterm infants has ledto an increasing focus on the long-term impacts of pretermbirth, specifically with respect to metabolic outcomes suchas bone mineral density (BMD) and timing and extent ofcatch-up growth.

Metabolic bone disease of prematurity

Preterm infants are particularly susceptible to metabolicbone disease for two key reasons: Firstly, 80% of fetal bonemineral accumulation occurs during the last trimester ofpregnancy, 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 periodwithout the support of the regulatory placental environ-ment, and almost all these infants will have significantly

DOI of original article:http://dx.doi.org/10.1016/j.jped.2014.03.001

� Please cite this article as: Embleton N, Wood CL. Growth, bonehealth, and later outcomes in infants born preterm. J Pediatr(Rio J). 2014. http://dx.doi.org/10.1016/j.jped.2014.08.002

∗ Corresponding author.E-mail: Nicholas.embleton@ncl.ac.uk (N. Embleton).

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http://dx.doi.org/10.1016/j.jped.2014.08.0020021-7557/© 2014 Sociedade Brasileira de Pediatria. Published by Elsevi

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ower bone mineral content (BMC) than those born at term.econdly, ex-utero living conditions make it more diffi-ult for infants to move and stress their bones as theyould have done in-utero.3 As well as mineral insufficiency,

ower BMD is also a consequence of other factors suchs medication (e.g. steroids, diuretics, etc.), respiratoryompromise,4 and infection,5 which may damage bone tra-eculae. Although metabolic bone disease of prematuritys often asymptomatic and described as self-limiting,6 con-ern remains that under-mineralization during such a criticaleriod could increase the risk of childhood fracture. Perhapsore importantly, it may result in reduced peak bone mass,7

hich is a key predictor for risk of osteoporosis in adulthood.

mpact of preterm birth on later metabolicone outcomes

n this issue of Jornal de Pediatria, Quintal et al.8 haveonducted a comprehensive longitudinal study, examiningone mineralization and body composition using dual X-raybsorptiometry (DXA) in 14 preterm infants over the first sixostnatal months, and compared them to infants born fullerm. This is important, as previous research studies have

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roduced conflicting data on the effect of prematurity onater BMD. Consistent with data from this study, previoustudies in preterm infants have shown a lower bone mass,9

MD,7 and BMC4 at the corrected age of term, as well as a

er Editora Ltda. All rights reserved.

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ower weight and ponderal index.7 Several studies, however,ave failed to demonstrate an association between pretermirth and later bone strength,5,10,11 whilst others have shownreater BMC and BMD in term children compared to preterm,t follow-up.4,12 A possible explanation for the variation intudy results may be in the timing of follow-up as catch-p in bone mineralization may occur throughout childhoodnd adolescence.13 Of note, in Quintal et al.’s study,8 catch-p bone mineralization appears to have occurred in earlynfancy; thus, data from preterm and full-term infants wereomparable by 6 months of age. This may be attributable tohe persisting benefits of growth factors present in breastilk, as Quintal et al.’s cohort were all breastfed, compared

o much of the published data from formula fed babies. Con-inued follow up of this cohort with further DXA scans in laterhildhood and adulthood would provide additional insightsnto their peak bone mass.

The exact influence of birth weight on later BMD remainsnclear. Some studies have found that, although preterm-orn infants were lighter during childhood than their termounterparts, their BMD was appropriate for size. Adultsho were born preterm remain on average slightly shorter

han their term-born peers. As some studies may not haveade appropriate adjustments for current size, it may beifficult to determine whether BMD is appropriate or not.here is also evidence that very low birth weight (VLBW)

nfants, whether preterm or not, attain a sub-optimal peakone mass in part due to their small size, but also due toheir subnormal skeletal mineralisation.5 The Hertfordshireohort study (which formed the basis for several of Barker’studies) showed that birth weight was independently asso-iated with bone density at 60-75 years of age. Althoughnother study found no association with preterm birth andeak bone mass,14 an effect of being small for gestationalge was apparent, suggesting that a proportion of laterone mass is determined by in utero events, such as fetalrowth.

he challenges of optimizing neonatalutrition

he use of fortified breast milk in this study and exclu-ive breastfeeding post-discharge is commendable. Maternalreast milk is associated with a range of benefits both inhe short-term (e.g. reduction in the incidence of necro-izing enterocolitis) and long-term (e.g. improved cognitiveutcome.) A study by Fewtrell at al.15 showed that theariable with the greatest effect on adult BMD was the pro-ortion of breast milk intake. Given that breast milk has

much lower mineral content than formula, and requiresortification to meet nutrient requirements, the data ofewtrell et al. suggests a possible beneficial role for non-utrient components such as growth factors. The cohortf Quintal et al.8 highlights the challenges of providingdequate nutrition to enable growth in preterm infants.lthough many units now strive to start early feeds, par-nteral nutrition (PN) is now common place in most NICUs

nd provides nutrients whilst enteral tolerance is achieved:n this study, although enteral feeds were started soon afterirth, most received PN support with an average PN durationf 12 days.

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PRESSEmbleton N, Wood CL

Preterm infants miss out on the important phase ofineral accretion in the third trimester and are there-

ore even more vulnerable to the effects of inadequateineral provision in the postnatal period. Although PN solu-

ions have improved dramatically since the first reportsf neonatal use in the late 1960’s, problems with respecto mineral provision exist because calcium and phosphatere insoluble in high concentrations. The increased avail-bility of organic salts, such as sodium glycerophosphate,as improved solubility (and therefore mineral provision),nd increased intakes of amino acids are both likely toesult in higher lean mass and bone mass accretion thann the past, but PN provision continues to lack a strongvidence base and several concerns persist.16 In particular,luminium contamination remains a very common problem,nd is independently associated with reduced BMC in laterhildhood.15

Bone mineral and other growth deficits accrued whilstnteral nutrition is established often increase during NICUtay. Mineral uptake is compromised through the low contentn un-fortified breast milk (especially phosphate) and ineffi-ient absorption due to an under-developed gastrointestinalract.6 This results in a greater loss of long bone den-ity than observed in term infants and further increaseshe risk of metabolic bone disease. There is compellingvidence that optimizing early growth through nutritionalnterventions generates positive and lasting effects on boneineralization,10 which may partially counteract pretermone deficits. A systematic review by Kusckel and Hardingn 2009 showed that fortifying the nutrition of pretermabies improves growth and bone mineral aggregation.17

nternational guidelines from groups such as ESPGHANecommend that those receiving unfortified breast milkhould receive multivitamin, iron, folic acid, phosphate, andodium supplementation.18

Several studies have emphasized the importance of earlyrowth on later bone health,2 so it is encouraging to observen this study that the preterm infants demonstrated sig-ificant catch-up growth with an increase in mean weight-score from -2.58 at 40 weeks to -0.49 at 6 months, and anncrease in mean length Z-score from -2.22 to -0.59 at the-month follow-up. In a study by Cooper et al, those whoere lightest at 1 year of age had the lowest BMC.2 In a

urther study, weight gain during the first two years of liferedicted BMD at age 9-14.19 Fewtrell et al. suggested thatreterm infants with the most substantial increase in heightlength) between birth and follow-up showed the greatestone mass at follow-up.12 They also demonstrated that birthength alone was a strong predictor of later bone mass, sug-esting that optimizing linear growth early may be beneficialo later bone health. However, the mean weight Z-score aterm of -2.58 in Quintal et al.’s study8 highlights the majorhallenges of promoting adequate growth during NICU stay.ven though the infants showed impressive catch-up growthp to 6 months of age, the dramatic fall in growth cen-iles during NICU stay, followed by a period of rapid growthcceleration, represents a pattern that is very different tohat observed following normal pregnancies. Whether this

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ype of growth trajectory represents an independent riskor later adverse metabolic outcome requires further study,ut highlights that growth, rather than absolute size, is theey variable determining longer-term health.

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ARTICLEGrowth, bone health, and later outcomes in infants born pre

The use of DXA scanning as an adjunct tobiochemistry in the detection of metabolicbone disease

Quintal et al. demonstrate that DXA scanning is a reliableand well-validated technique to estimate BMC and BMD. Itis well tolerated due to its non-invasive nature and shortscan times, and the radiation levels involved are lower thanbackground levels. The newer DXA machines with enhancedimage resolution enable accurate calculation of fat andlean mass indices, although they cannot reliably determineadipose tissue partitioning. Plain radiographs in preterminfants on NICU frequently demonstrate osteopenia, butare insensitive markers of BMD. Biochemical markers mayhelp determine the presence of metabolic bone disease; forexample, high levels of alkaline phosphatase can be use-ful as a prompt to check serum calcium and phosphate.20

However, the complexity of processes involved in metabolicbone disease of prematurity mean that biochemical meas-ures are similarly insensitive. The key to management is tofocus efforts that minimize its occurrence as much as is fea-sible in busy NICU settings, rather than perfecting sensitivedetection methods. This can be done by encouraging the useof aluminium-free, high quality mineral supplemented PNsolutions with adequate amounts of amino acids, combinedwith the early and sustained use of breast milk, and supple-mented by the routine use of fortifiers that meet nutrientrequirements.

Epigenetics and bone metabolism

Many of the long-term effects on bone health may bedue to programming and modulated by epigenetic mecha-nisms --- mitotically-heritable alterations in gene expressionpotential that are not caused by changes in DNA sequence.The classic examples are DNA methylation and histoneacetylation21 and result in differences in gene expressionand transcription, but may also involve post-transcriptionaleffects on other processes such as protein translation. Earlylife growth and nutritional exposures appear to affect cellu-lar memory and result in variation in later life phenotypes.Much of this work is preliminary, but initial data suggestthat epigenetic mechanisms may underlie the process ofdevelopmental plasticity and its effect on the risk of osteo-porosis. One of the models that has been postulated isthe role of maternal vitamin D status and postnatal cal-cium transfer. Early work on methylation and vitamin Dreceptors and placental calcium transporters suggests thatepigenetic regulation might explain how maternal vitaminD levels affect bone mineralization in the neonate.21 Muchof the current research is in animal models, but if thechanges can be replicated in humans, epigenetic or otherbiomarkers may provide risk assessment tools to enabletargeted intervention to those at greatest risk of osteoporo-sis.

Future clinical and research priorities

Longitudinal studies with minimal attritional losses, andespecially those conducted within randomized controlled

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rial settings are needed if we are to improve health out-omes of preterm infants across the globe. This researcheeds to be high quality and conducted in low-, middle-, andigh-income countries so generalizability can be maximized.isk benefit ratios of medical interventions are sensitiveo the individual and the healthcare context. Neverthe-ess, the importance of early bone and body growth onhe later development of metabolic diseases such as osteo-orosis means that optimizing nutrition both pre- and post-ospital discharge must remain a clinical priority. Impor-antly, greater efforts must be applied to support researchnd quality improvements initiatives within and betweenountries --- we need to improve our collaborative working!

onflicts of interest

he authors declare no conflicts of interest.

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