Alimentacion Prematuro 2013 PDF

March 2013 Volume 162 Number 3 Supplement 1 Copyright 2013 by Mosby, Inc.
Global Neonatal Consensus Symposium:

Feeding the Preterm Infant
Guest Editors
Ricardo Uauy, MD, PhD
This Supplement is based on the Global Neonatal Consensus Symposium, Feeding the Preterm
Infant, which was held in Chicago, Illinois, October 13-15, 2010.
Sponsored by Mead Johnson Nutrition.
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March 2013 Volume 162 Number 3 Supplement 1 Copyright 2013 by Mosby, Inc.
Introduction to the Symposium on Nutrition of the Preterm Infant
Ricardo Uauy, MD, PhD and Carol Lynn Berseth, MD..................................................................................................................................... S1
Growth Curves: How to Best Measure Growth of the Preterm Infant
Jatinder Bhatia, MD, FAAP ................................................................................................................................................................................... S2
Feeding Preterm Infants Today for Later Metabolic and Cardiovascular Outcomes
Alexandre Lapillonne, MD, PhD and Ian J. Grifn, MD.................................................................................................................................... S7
Human Milk and the Nutritional Needs of Preterm Infants
David I. Tudehope, AM, MBBS, FRACP ............................................................................................................................................................. S17
Vitamin D, Vitamin A, Maternal-Perinatal Considerations: Old Concepts, New Insights,
New Questions
Teresa Murgua-Peniche, MD............................................................................................................................................................................... S26
Evaluation of Adequacy of Protein and Energy
Jatinder Bhatia, MD, FAAP, Patricia Mena, MD, Scott Denne, MD, and Cecilia Garca, MD....................................................................... S31
Lipid Needs of Preterm Infants: Updated Recommendations
Alexandre Lapillonne, MD, PhD, Sharon Groh-Wargo, PhD, LD, RD, Carlos H. Lozano Gonzalez, MD, MPH, and
Ricardo Uauy, MD, PhD ....................................................................................................................................................................................... S37
Selected Macro/Micronutrient Needs of the Routine Preterm Infant
Jatinder Bhatia, MD, FAAP, Ian Grifn, MD, Diane Anderson, PhD, RD, Neelam Kler, MD, and
Magnus Domell of, MD, PhD................................................................................................................................................................................ S48
Intestinal Mucosal Defense System, Part 1. Consensus Recommendations for Immunonutrients
Josef Neu, MD, Walter A. Mihatsch, MD, MBA, Jaime Zegarra, MD, Sarayut Supapannachart, MD, FAAP, MBA,
Zong-Yi Ding, MD, and Teresa Murgua-Peniche, MD..................................................................................................................................... S56
Intestinal Mucosal Defense System, Part 2. Probiotics and Prebiotics
Teresa Murgua-Peniche, MD, Walter A. Mihatsch, MD, MBA, Jaime Zegarra, MD, Sarayut Supapannachart, MD, FAAP, MBA,
Zong-Yi Ding, MD, and Josef Neu, MD.............................................................................................................................................................. S64
Nutritional Needs of the Micropreterm Infant
David Tudehope, AM, MBBS, FRACP, Mary Fewtrell, MD, Sudha Kashyap, MD, and Enrique Udaeta, MD ............................................ S72
Nutritional Requirements and Feeding Recommendations for Small for Gestational Age Infants
David Tudehope, AM, MBBS, FRACP, Maximo Vento, MD, PhD, Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD, and
Paulo Pachi, MD, PhD........................................................................................................................................................................................... S81
Nutritional Recommendations for the Late-Preterm Infant and the Preterm Infant after Hospital
Discharge
Alexandre Lapillonne, MD, PhD, Deborah L. OConnor, PhD, RD, Danhua Wang, MD, and Jacques Rigo, MD, PhD............................ S90
A3
Feeding the Preterm Infant: Opportunities and Challenges of Bringing Science to the Bedside
Josef Neu, MD, Cristine L. Bradley, MSc, RD, Zong-Yi Ding, MD, Hugh N. Tucker, PhD, FACN, CNS, and
Carol Lynn Berseth, MD......................................................................................................................................................................................S101
Nutritional Management of the Low Birth Weight/Preterm Infant in Community Settings:
A Perspective from the Developing World
Aamer Imdad, MBBS and Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD....................................................................................S107
Symposium Summary: Looking Back and Looking Forward
Carol Lynn Berseth, MD and Ricardo Uauy, MD, PhD...................................................................................................................................S115
A4 Vol. 162, No. 3, Supp. 1
Global Neonatal Consensus Symposium: Feeding the Preterm Infant
Guest Editors
Professor of Pediatrics
INTA U of Chile
Neonatology Division, Department of Pediatrics
Catholic University, Santiago, Chile
Faculty
Diane Anderson, PhD, RD
Associate Professor of Pediatrics
Baylor College of Medicine
Houston, Texas
Carol Lynn Berseth, MD
Medical Director for Global Innovation
Mead Johnson Nutrition
Evansville, Indiana
Jatinder Bhatia, MD, FAAP
Medical College of Georgia
Augusta, Georgia
Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD
Chair, Division of Women & Child Health
Aga Khan University
Karachi, Pakistan
Cristine L. Bradley, MSc, RD
Regulatory Sciences
Evansville, Indiana
Scott Denne, MD
Indiana University School of Medicine
Indianapolis, Indiana
Zong-Yi Ding, MD
Honor President
1st August Childrens Hospital
afliated with the General Hospital of Beijing Military Defense Area
Beijing, China
Magnus Domell of, MD, PhD
Associate Professor
Department of Clinical Sciences, Pediatrics
Umea University
Umea, Sweden
Mary Fewtrell, MD
Head of Nutrition, Physiology & Metabolism
University College London Institute of Child Health
London, United Kingdom
Cecilia Garca, MD
Director, Neonatal Intensive Care Unit
Hospital Sanatorio de la Trinidad Palermo
Buenos Aires, Argentina
Ian Grifn, MD
UC-Davis Medical Center
Sacramento, California
Sharon Groh-Wargo, PhD, LD, RD
Associate Professor
Case Western Reserve University
MetroHealth Medical Center
Cleveland, Ohio
Aamer Imdad, MBBS
Division of Women & Child Health
The Aga Khan University
Karachi, Pakistan
Sudha Kashyap, MD
Morgan Stanley Childrens Hospital
Columbia University Medical Center
New York, New York
Neelam Kler, MD
Head, Department of Neonatology
President of the National Neonatology Forum (NNF)
Sir Gangaram Hospital
New Delhi, India
Alexandre Lapillonne, MD, PhD
Paris Descartes University
APHP Necker Hospital
Paris, France
CNRC, Baylor College of Medicine
Houston, Texas
Carlos H. Lozano Gonzalez, MD, MPH
Professor of Neonatology
Academia Mexicana de Pediatra
Pediatra Medicina Perinatal
Monterrey, N.L. Mexico
March 2013 A5
Patricia Mena, MD
Ponticia Universidad Cat olica de Chile
Director of Newborn Unit
Dr Sotero del Rio Hospital
Santiago, Chile
Walter A. Mihatsch, MD, MBA
Head of the Department of Pediatrics Harlaching
Munich Municipal Hospitals
Munich, Germany
Teresa Murgua-Peniche, MD
Infancy Area Director, National Center for Child and
Adolescent Health, CeNSIA
Secretary of Health, Mexico City
Foege Fellow, Rollins School of Public Health
Hubert Department of Global Health
Emory University
Atlanta, Georgia
Josef Neu, MD
University of Florida
Gainesville, Florida
Deborah OConnor, PhD, RD
Associate Professor
Department of Nutritional Sciences, University of Toronto
Director, Clinical Dietetics, Hospital for Sick Children
Toronto, Canada
Paulo Pachi, MD, PhD
Santa Casa de Misericordia de S~ao Paulo
S~ao Paulo, Brazil
Jacques Rigo, MD, PhD
Professor of Neonatology and Nutrition
Department of Neonatology
University of Liege
CHR Citadelle
Liege, Belgium
Sarayut Supapannachart, MD, FAAP, MBA
Ramathibodi Hospital School
of Medicine
Mahidol University
Bangkok, Thailand
Hugh N. Tucker, PhD, FACN, CNS
Distinguished Research Fellow
Evansville, Indiana
David Tudehope, AM, MBBS, FRACP
Professor of Paediatics and Child Health
University of Queensland
Queensland, Australia
Enrique Udaeta, MD
Chief, Division of Pediatrics
Hospital Infantil de Mexico
Mexico City, Mexico
Maximo Vento, MD, PhD
Hospital Universitario y Politecnico La Fe
Valencia, Spain
Danhua Wang, MD
Peking Union Medical College Hospital
Beijing, P.R. China
Jaime Zegarra, MD
Pediatrician
Hospital Nacional Cayetano Heredia
Lima, Peru
A6 Vol. 162, No. 3, Suppl. 1
Faculty Disclosures
The authors who contributed to this publication have disclosed the following industry relationships:
Diane Anderson, PhD, RD, received an honorarium from
Mead Johnson Nutrition for attendance, presentation, and
manuscript preparation.
Jatinder Bhatia, MD, FAAP, received an honorarium from
Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD,
received an honorarium from Mead Johnson Nutrition for
attendance, presentation, and manuscript preparation.
Carol Lynn Berseth, MD, is the Medical Director for Global
Innovation at Mead Johnson Nutrition. She organized and
facilitated the Symposium on Nutrition of the Preterm
Infant, and received an honorarium from Mead Johnson
Nutrition for attendance, presentation, and manuscript
preparation.
Cristine L. Bradley, MSc, RD, is an employee of the sponsor,
Mead Johnson Nutrition, and received an honorarium from
Scott Denne, MD, received an honorarium from Mead
Johnson Nutrition for attendance, presentation, and
Zong-Yi Ding, MD, received an honorarium from Mead
Magnus Domell of, MD, PhD, received an honorarium from
Mary Fewtrell, MD, received an honorarium from Mead
Cecilia Garcia, MD, received an honorarium from Mead
Ian Grifn, MD, received an honorarium from Mead
Sharon Groh-Wargo, MD, LD, RD, received an honorarium
from Mead Johnson Nutrition for attendance, presentation,
and manuscript preparation.
Aamer Imdad, MBBS, received an honorarium from Mead
Sudha Kashyap, MD, serves as an advisor to Mead Johnson
Nutritionals, and received an honorarium from Mead
Neelam Kler, MD, received an honorarium from Mead
Alexandre Lapillonne, MD, PhD, received an honorarium
Carlos H. Lozano Gonzalez, MD, MPH, received an
honorarium from Mead Johnson Nutrition for attendance,
presentation, and manuscript preparation.
Patricia Mena, MD, received an honorarium from Mead
Walter A. Mihatsch, MD, MBA, is a recipient of a
research grant from Mead Johnson Nutrition, and
received an honorarium from Mead Johnson Nutrition
for attendance, presentation, and manuscript preparation.
In the past, he has acted as a scientic consultant to several
infant formula companies.
Teresa Murgua-Peniche, MD, received an honorarium
Josef Neu, MD, has received a research grant and honoraria
for speaking from Mead Johnson Nutrition, is currently on
its Scientic Advisory Committee, and received an
Deborah L. OConnor, PhD, RD, received an honorarium
Paulo Pachi, MD, PhD, received an honorarium from
Mead Johnson Nutrition for attendance, presentation,
March 2013 A7
Jacques Rigo, MD, PhD, received an honorarium from
Mead Johnson Nutrition for attendance, presentation,
Sarayut Supapannachart, MD, FAAP, MBA, received an
Hugh N. Tucker, PhD, FACN, CNS, is an employee of Mead
Johnson Nutrition, and received an honorarium from Mead
David Tudehope, AM, MBBS, FRACP, received an
Enrique Udaeta, MD, is a consultant for Mead Johnson
Nutrition, and received an honorarium from Mead Johnson
preparation.
Ricardo Uauy, MD, PhD, chaired the Symposium on
Nutrition of the Preterm Infant. Mead Johnson
Nutrition paid his travel expenses. He also received
an honorarium to compensate his time for
contributing to, organizing and chairing the meeting
and for his contribution to the nal editing of the
supplement.
Maximo Vento, MD, PhD, received an honorarium from
Danhua Wang, MD, received an honorarium from Mead
Jaime A. Zegarra, MD, is a recipient of a research
grant from Mead Johnson Nutrition, and received
an honorarium from Mead Johnson Nutrition
for attendance, presentation, and manuscript
preparation.
A8 Vol. 162, No. 3, Suppl. 1
Introduction to the Symposium on Nutrition of the Preterm Infant
I
t has been nearly a decade since the publication of Nutri-
tion of the Preterm Infant, Second Edition.
1
Numerous
changes in neonatal care have occurred in the interim,
and the need to rene nutritional care of the preterm infant
is apparent. The science base indicates gaps in our knowledge
of appropriate nutritional support and the need to establish
new recommendations have evolved. Thus, we now have
a better understanding about the requirements for specic
nutrients and the need to address immaturity of host de-
fenses, nutrient metabolism, and tissue repair mechanisms
in preterm infants. Increasing numbers of infants survive
birth and beyond at ever-lower gestational ages. At the
same time, a broader range of the critical needs of the late
preterm infant has become increasingly apparent. The nutri-
tional requirements of very premature and late preterm in-
fants differ from those of other preterm infants. In some
geographic regions up to one-third of infants are classied
as small for gestational age (SGA). The nutritional needs of
this population also differ from those of appropriately sized
preterm infants. Finally, as the world becomes smaller, there
is a need to address health issues for all infants, and particu-
larly preterm infants, in a more universal and global manner.
This Supplement reports the deliberations and proceed-
ings of the Global Neonatal Consensus Symposium, Feeding
the Preterm Infant, held in Chicago, Illinois, on October 13-
15, 2010, which provided robust interactions among interna-
tional academic neonatal nutritional experts in reviewing and
updating the scientic literature concerning the needs of pre-
term infants. We identied 30 experts to participate in this
task. We established 4 areas of work: (1) updating nutrient
recommendations (protein, micronutrients, and lipids); (2)
reviewing new science about the immaturity of host defense
for the preterm infant; (3) recognizing the unique nutritional
needs of specic subpopulations of preterm infants (the mi-
cropreterm infant, the SGA infant, the late preterm infant,
and the postdischarge infant); and (4) identifying the chal-
lenges that prevent us from translating our understanding
of science to practical application.
Small teams were appointed to research each of these
topics throughout the year, culminating in a 3-day interactive
symposium where each teams work was reviewed and re-
ned by the entire group at large. To focus this work, we de-
ned: (1) micropreterm infant as one born at #27 weeks
gestation and, commonly, <800 g at birth; (2) SGA infant
as one born at $34 weeks gestation and weighing less than
the third percentile; (3) late preterm infant as one born at
34-38 weeks gestation; and (4) the postdischarge infant as
any preterm infant who survived to be discharged home,
typically at a corrected gestational age of $37 weeks.
The participating global experts developed consensus on
nutritional recommendations and statements available in the
current literature and identied a series of gaps in our knowl-
edge. They highlighted the multiple challenges external to the
science that limit our capacity totranslate science intopractical
application. They alsorecognizeda series of issues that apply to
all patient groups. These issues were highlightedseparately and
include the use of breast milk, identifying appropriate growth
curves, developing methodology to recommend nutrient in-
take, and a reconsideration of the importance of vitamin A
and vitamin D for immature infants. What emerged among
the participants as they progressed through the deliberations
was a sense of global commitment to this altruistic effort.
We anticipate the resulting synergy will help shape a global
consensus on neonatal nutrition practices in the future.
Author Disclosures
Ricardo Uauy, MD, PhD, chaired the Symposium on Nutri-
tion of the Preterm Infant. Mead Johnson Nutrition paid his
travel expenses. He also received an honorarium to compen-
sate his time for contributing to, organizing, and chairing the
meeting and for his contribution to the nal editing of the
Supplement. Carol Lynn Berseth, MD, is the Medical Director
for Global Innovation at Mead Johnson Nutrition. She orga-
nized and facilitated the Symposium on Nutrition of the Pre-
term Infant. R.U. wrote the rst draft of this manuscript. n
Instituto de Nutrici on y Tecnologia de los Alimentos
University of Chile
Neonatology Division
Department of Pediatrics
Catholic University
Santiago, Chile
Evansville, Indiana
Reprint requests: Ricardo Uauy, MD, PhD, Instituto de Nutrici on y Tecnologia
de los Alimentos, University of Chile, PO Box 138-11, Macul 5540, Santiago,
Chile. E-mail: uauy@inta.cl
Reference
1. Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the Preterm
Infant: Scientic Basis and Practical Guidelines. 2nd edition. Cincinnatti,
OH: Digital Educational Publishing, Inc; 2005.
Please see the Author Disclosures at the end of this article.
0022-3476/$ - see front matter. Copyright 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.046
SGA Small for gestational age
S1
Growth Curves: How to Best Measure Growth of the Preterm Infant
Birth weight is one of the most important anthropometric measures in the evaluation of an infant. For the full-term
infant, birth weight is compared with reference or standard growth curves that are constructed by plotting weight,
length, and head circumference against postnatal age. Following a similar approach for preterm infants is less ef-
fective for a variety of reasons. Birth weight and other anthropometric measures used to evaluate an infant at birth
are inuenced by various maternal characteristics, the intrauterine milieu, and duration of gestation. Second, the
causes of premature birth and their impact on birth weight are largely unknown. Third, gestational age is difcult
to determine with full certainty. One approach that has been used to circumvent these issues is to use intrauterine
growth reference curves. However, these curves do not really reect normal growth because they were con-
structed using cross-sectional data frominfants born prematurely and, as such, do not reect the normal condition.
Thus, there is a need to develop normative growth curves derived fromhealthy preterminfants that can be applied
to neonates born prematurely. These should be updated periodically to reect secular trends in maternal body
weight, height, and overall health. (J Pediatr 2013;162:S2-6).
G
rowth is a sensitive indicator of postnatal health. The commonly used clinical measures of growth compare
weight, length, and head circumference with postnatal age. Other measures of growth include mid-arm circum-
ference, skin fold measurements, assessment of body composition, and biochemical markers. These measures of
growth are used to dene nutritional strategies, educate caregivers, and enable early detection of growth alterations or
failure. It is particularly important to have reliable measures of growth for premature infants because extrauterine growth
restriction is common in small premature infants and is now recognized as a risk factor for poor neurodevelopmental
outcomes.
1,2
Two types of growth curves are used to monitor postnatal growth. A reference growth curve is based on a sample or pop-
ulation without exclusions or specifying the type of nutrition provided and describes how children actually grow. A standard
growth curve follows a prescriptive approach based on how children should grow. A good example of the latter is the World
Health Organization (WHO) Multicenter Growth Reference Study in which selection criteria includes predened, ideal ma-
ternal and environmental conditions; the resulting fetal and postnatal growth charts generated indicate how growth should
occur under these ideal conditions.
3
Growth Assessment of the Preterm Infant
The American Academy of Pediatrics and the Canadian Pediatric Society presently recommend that preterm infant growth
should approximate intrauterine growth after allowing for a brief cessation in growth in the early neonatal period. However,
the intrauterine environment differs markedly from the extrauterine environment. Postnatally, infants encounter temperature
stress, feeding intolerance, insensible water loss, infectious agents, and medical interventions that increase energy expenditure
and nutrient losses that affect measures of growth.
4,5
Ehrenkranz et al have demonstrated this in infants less than 1500 g at birth
(Figure 1).
6
To assess growth of the preterm infant, a variety of intrauterine growth curves have been constructed by plotting growth
measures at birth against gestational age. The rst birth weight per centile curves for gestational age were reported by Lub-
chenco et al.
7
Intrauterine growth was estimated from 5635 live-born Caucasian infants at 24-42 weeks of gestation. Curves
of the 10th, 25th, 50th, 75th, and 90th percentiles were compiled, smoothed and presented for male, female, and all infants.
These curves represent infants who were born alive and survived to a particular gestational age. These curves may not
represent normal growth rates because most of the infants were born prematurely and were likely affected by health con-
ditions that induced premature birth. Subsequently, birth weights within a given gestational age were subdivided to classify
infants as appropriate for gestational age, large for gestational age, and small for gestational age.
8
Lubchenco et al later
published curves that included measurements of length and head circumfer-
ence.
9
A number of investigators in other countries have constructed similar
curves that describe observed fetal growth.
10-19
From the Department of Pediatrics, Medical College of
Georgia, Georgia Health Sciences University, Augusta, GA
Please see the Author Disclosures at the end of this
article.
EFW Estimated fetal weight
WHO World Health Organization
S2
Limitations of Currently Available Growth
Estimates
The most common variable used to monitor growth of the
preterm infant is gestational age estimated from the date of
onset of the mothers last normal menstrual period. Errors
in gestational age appear to be magnied at lower gestational
ages. This is especially true if an obstetric estimate of gesta-
tional age is not available because an obstetricians estimate
is closer to actual age than a neonatologists estimate in the
delivery room.
20
Ultrasound imaging studies of the fetus coupled with good
maternal dating and history have been used to estimate ges-
tational age and weight in longitudinal and cross-sectional
studies.
21,22
Weights predicted by these methods, compared
with birth weights, place infants below the mean gestational
age-related estimated fetal weight (EFW). Further, the inci-
dence of fetal growth restriction based on EFW increases as
gestational age decreases. More recently, body weight and
EFW standards have been used to generate z-scores for
body weight and for EFW. The z-scores for body weight are
normally distributed around the mean whereas the z-scores
for EFW are skewed towards fetal growth restriction, demon-
strating signicant differences between the two approaches.
Ideally, one would have liked a comparison of the same in-
fants/fetuses studied using both methods.
Cooke et al concluded that EFW would give more accurate
information regarding fetal growth restriction.
23
The draw-
back of using EFW curves is that fetal ultrasound is not
very reliable in predicting birth weight. Ben-Haroush et al
EFW in 840 pregnant women and concluded that EFW was
correlated with birth weight but became less accurate at
low gestational ages, high birth weights, and young maternal
age.
24
Chauhan et al concluded that clinical and ultrasound
methods provide poor estimates of birth weight.
25
Hence, fe-
tal weight curves derived from currently available technology
may not be optimal guides to achieve target postnatal growth
goals. Moreover, given that almost all preterm infants less
than 29 weeks gestation have extrauterine growth restriction
(Figure 1), use of fetal weight-based curves would make the
infants appear to be more growth restricted. Because the
error of estimating gestational age remains the same, the
use of curves based on EFW does not appear to provide an
advantage over the use of curves based on actual birth weight.
Moreover, if there is a period of poor growth, subsequent
weight gain would need to be greater to catch up, and the
effects will be larger the later the growth alteration occurs.
In addition, recent data indicate that birth weight appears
to increase over time. Thus, it is appropriate to use updated
curves when available.
Growth rates have been estimated by a number of authors
(Table).
26
Although most practicing neonatologists aim for
the best growth possible to avoid adverse metabolic
effects, recent concerns about the late effects of early-
accelerated growth have raised some caution (see Lapillonne
and Grifn, in this supplement).
27
There are insufcient data to construct robust ethnic-
specic growth curves. Moreover, whenever this issue has
been explored using appropriate methodologies, as with the
Multicenter Growth Reference Study, the observed differ-
ences were found to be due to environmental conditions
rather than truly genetic or ethnic differences. Despite this,
some countries use area-specic growth charts to describe
their populations.
Recent Advances
We believe that growth curves need to be updated periodi-
cally. Toward this end, Olsen et al has published a new
growth curve.
28
The investigators used a large data set from
248 US hospitals in 33 states for births in 1998-2006. Exact
methods for measuring length and head circumference
were not described, although the large number of infants in
the data set may compensate for errors in measurements.
Figure 1. Extrauterine growth restriction. Extremely low birth
weight infants growpoorly after birth.
6
Average body weight is
plotted against postmenstrual age for infants born at 24-25
weeks (dotted line), 26-27 weeks (short dashes), and 28-29
weeks (long dashes). Reprinted with permission from Pediat-
rics.
6
Copyright 1999 by the American Academy of Pedriatics.
Table. Comparison of growth rates
Authors N
Daily weight
gain at 27-34
wk (g/kg) Population
Lubchenko et al 1963
7
5635 14.9 Caucasian
Hoffman et al 1974
32
1 164 871 11.2 African American
female
13.7 African American
male
15.4 Caucasian male
15.7 Caucasian female
Arbuckle et al 1993
16
1 087 629 16.3 Male
16.9 Female
Alexander et al 1996
18
3 134 879 20 Not specied
Adapted from Grifn IJ. Nutritional assessment in preterm infants. In: Cooke RJ, Vandenplas
Y, Wahn U, eds. Nutrition support for infants and children at risk. Nestle Nutr Workshop Ser
Pediatr Program. Nestec Ltd, Vevey/S. Karger, Basel 2007;59:177-92.
Vol. 162, No. 3, Suppl. 1 March 2013
Growth Curves: How to Best Measure Growth of the Preterm Infant S3
Gestational age was determined by neonatologist best esti-
mate using obstetric history, obstetric examinations, prenatal
ultrasound and postnatal physical examinations.
28
The au-
thors did not state whether a standardized scoring system
was used or how a discrepancy between the obstetricians
and neonatologists estimates was resolved. The nal sample
of 257 855 data points included 57.2% male infants and
50.6% white, 15.7% black, 24.4% Hispanic, and 9.3% other
infants, a distribution that is similar to US birth data. The
curves were validated as sex-specic groups by gestational
age. The sex-specic curves were then compared with the
Lubchenco curves. Surprisingly, even though the data were
obtained 3 decades later than Lubchencos and, presumably,
were obtained from places closer to sea level, the new curves
have lower birth weights at low gestational ages and higher
birth weights from 36 weeks onwards.
The most commonly used growth curves in neonatal units
internationally are the Fenton curves (Figure 2) that are
based on data from Nicklasson et al, Kramer et al, Beeby
et al, and the US Centers for Disease Control.
15,19,29,30
Fenton
conducted a systematic review and meta-analysis and im-
proved on the data of Babson and Benda.
31
Three large
Figure 2. Fetal-infant growth chart for preterm infants. The Fenton growth chart
31
can be used to monitor growth of preterm
infants from22 weeks gestation through 20 weeks post-term. Reprinted with permission from: 2003 Fenton; licensee BioMed
Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any
purpose, provided this notice is preserved along with the articles original URL. Available at: http://www.biomedcentral.com/
1471-2431/3/13.
THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 162, No. 3, Suppl. 1
S4 Bhatia
population-based surveys were identied. The data from dif-
ferent sources were averaged together to derive the per centi-
les and create a growth chart that combined both sexes. The
Centers for Disease Control and Prevention growth curves
were used to assess growth beyond 40 weeks corrected age.
If a hypothetical infant born at 1500 g and 30 weeks is plotted
on the Fenton and Olsen curves, it appears that for both boys
and girls weight-for-age would be higher in the Olsen curves
than in the Fenton curves. Figure 3 demonstrates the
differences between the Olsen and Fenton curves. Although
not apparent from Figure 3, the Olsen curves are sex-
specic (the curves for males are shown) and range from
the 3rd to the 97th percentile (similar to the Fenton
curves), but the curves deviate from each other at both the
lower and higher gestational ages (eg, the 3rd percentile on
the Olsen curves are lower than the 3rd percentile of the
Fenton curves throughout). The Fenton curves run
through 50 weeks postmenstrual age, and the Olsen curves
are limited to 41 weeks. More research and practical use are
needed before recommendations can be made on the use of
the new curves. Weights for an actual infant are plotted
with the Olsen and Fenton curves (Figure 3). This example
illustrates two issues of practical signicance. The
differences in assessing growth by the two curves are small,
and no demonstrable health consequences are suggested.
Moreover, there is no difference in the classication of
growth status. However, once growth falters after 37 weeks
post-menstrual age, the infant falls below or near the 3rd
percentile on both curves. Intrauterine growth curves
provide idealized guidelines to monitor the growth of
preterm infants. Preterm birth is not normal, and many
other variables related to preterm birth can affect growth.
Nonetheless, we suggest that postnatal growth be adjusted
by gestational age at birth, and all infants be followed using
the WHO international growth standard.
Two large population based international studies may pro-
vide more rened measures of fetal growth and truly interna-
tional normative standards. The International Fetal and
Newborn Growth Consortium for the 21st Century study
(available at: http://www.intergrowth21.org.uk) provides
normative data resulting from using a prescriptive ap-
proach that describes normal fetal growth, preterm growth,
and newborn nutritional status from 8 geographically diverse
populations and relates these standards to neonatal health
risk. The worldwide use of these tools should improve in-
fants healthcare and nutritional status. In addition, the IN-
TERBIO-21st study, an extension of the International Fetal
and Newborn Growth Consortium for the 21st Century pro-
ject (available at: http://www.obs-gyn.ox.ac.uk/omphi/
studies/interbio-21st) may improve the phenotypic charac-
terization of the intrauterine growth restriction/small for ges-
tational age and preterm birth syndromes.
Using Growth Curves to Manage Preterm
Infants
The positive and negative consequences of more aggressive
nutrition support need to be assessed over the short-and
long-term because apparent gains can be offset by long-
term adverse consequences. Equally, we should strive to
achieve normal growth for adjusted age commensurate
with feeding tolerance as soon as possible to support optimal
brain development and linear growth. Both are potentially
compromised if early feeding fails to deliver optimal
nutrition.
There remains uncertainty about the ideal growth and nu-
trient requirements of premature infants. Management of
these infants over the past 2 decades has changed as have
the nutrient preparations available for them. There is an in-
creased use of human milk, and growth patterns of human
milk-fed infants in the short term have been demonstrated
to be similar to formula-fed cohorts with appropriate human
milk fortication. We should strive to create reference
charts for exclusively human milk-fed infants as we do for
term infants and consider the relative gains and losses in
terms of long-term growth, development, and overall health.
Summary
Numerous growth curves based on EFW are available. The
utility of these curves is limited by our ability to determine
the accurate estimates of fetal weight and gestational age.
The errors associated with fetal weight-based curves are not
different from those associated with body weight-based
curves. It is unknown whether improved identication of
Figure 3. Olsen and Fenton curves. Lines indicate the 3rd,
50th, and 97th percentiles for weight of male infants born in
the US from 1998-2006 at 23-42 weeks of gestation, adapted
fromOlson et al.
28
The shaded area is bounded by the 3rd and
97th percentiles for weight of all infants described by Fen-
ton.
31
The closed circles represent the growth of an actual
infant born at 27 weeks gestation.
March 2013 SUPPLEMENT
Growth Curves: How to Best Measure Growth of the Preterm Infant S5
small-for-gestational age infants or fetal growth restriction at
birth would lead to better postnatal care. Until more data are
available, the use of currently published body weight charts,
such as the Fenton charts, appears appropriate. An idealized
population of preterm infants does not exist similar to the
prescriptive growth of term infants demonstrated in the
WHO infant-children curves and the recent fetal-infant
growth curves. These latter charts describe growth as it
should be, not as it actually occurs. n
Author Disclosure
Jatinder Bhatia, MD, FAAP, received an honorarium from
manuscript preparation. J.B. wrote this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Department of Pediatrics,
Medical College of Georgia, Georgia Health Sciences University, 1120 15th
Street, BIW 6033, Augusta, GA 30912-3740. E-mail: jatindeb@georgiahealth.
edu.
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S6 Bhatia
Feeding Preterm Infants Today for Later Metabolic and
Cardiovascular Outcomes
1,2
, and Ian J. Grifn, MD
3
Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neu-
rodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of
preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known
whether the inuence of infant and childhood growth rates and early nutrition on long-term outcomes is the
same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review
the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic out-
comes in preterm infants.
Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of develop-
ment have signicant adverse effects on later development. Our review suggests that growth between birth and
expected term and 12-18 months post-term has no signicant effect on later blood pressure and metabolic syn-
drome, whereas reduced growth during hospitalization signicantly impacts later neurodevelopment. In contrast,
growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular
well being, which suggests that nutritional interventions during this period are worthy of more study. Our reviewalso
highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hos-
pitalization and after discharge on development, the risk of developing hypertension, or insulin resistance. (J Pediatr
2013;162:S7-16).
A
dvances in perinatal and neonatal care have resulted in improved survival for very low birth weight (VLBW) and ex-
tremely low birth weight (ELBW) infants,
1,2
but preterm birth continues to contribute disproportionately to neonatal
morbidity and subsequent physical and neurodevelopmental disabilities.
2
Early nutrition is critical for brain develop-
ment,
3
and protein and energy undernutrition in preterm infants during the early neonatal period is associated with later def-
icits in cognitive function and brain development.
3
Low birth weight (LBW) status because of poor fetal growth increases the risk for hypertension and insulin resistance in
adults,
4,5
a concept known as fetal programming. When exposed to nutritional deprivation in utero, a fetus adapts to increase
its chance of survival, albeit at the cost of intrauterine growth restriction (IUGR). However, when nutrient supply is no longer
limited, these changes become maladaptative and can lead to an increased risk of insulin resistance, diabetes, and cardiovascular
disease.
4,5
It is tempting to extrapolate these observations to preterminfants as they, too, are usually born LBW (<2.5 kg). How-
ever, many preterm infants have normal or relatively normal growth prior to birth. Furthermore, most preterm infants have
extrauterine growth restriction (EUGR)
2
that might either mitigate or exacerbate the effects of IUGR, which occurs in 50% of
all preterm infants.
Most early epidemiologic studies used birth weight to identify infants and did not distinguish the effects of IUGR and pre-
term birth independently. Therefore, it is unclear whether or not LBW status because of preterm birth has the same metabolic
and cardiovascular consequences as LBW status resulting from poor fetal growth (IUGR).
As neonatal medicine advances, increasing numbers of preterm infants survive into adulthood. Thus, it is becoming crit-
ically important to dene the risk for abnormal cardiovascular and metabolic outcomes in this population. Issues that re-
quire clarication are: (1) the effect of neonatal, infant, and childhood growth on long-term metabolic and cardiovascular
outcomes in preterm infants; (2) the effects of macronutrient and micronutrient intake and feeding practices on long-term
metabolic and cardiovascular outcomes in preterm infants; and (3) whether nutritional and growth-related risk factors result
in adverse metabolic and cardiovascular outcomes differently between term LBW and preterm infants and between IUGR/
small for gestational age (SGA) preterm
From the
1
Department of Neonatology, APHP Necker
Hospital, Paris Descartes University, Paris, France;
2
CNRC, Baylor College of Medicine, Houston, TX; and
3
Department of Pediatrics, University of California-
Davis, Sacramento, CA
article.
AGA Appropriate for gestational age
BMI Body mass index
BP Blood pressure
DBP Diastolic blood pressure
ELBW Extremely low birth weight
EUGR Extrauterine growth restriction
HDL High-density lipoprotein
HOMA-IR Homeostasis Model of
Assessment-Insulin Resistance
IQ Intelligence quotient
IUGR Intrauterine growth restriction
LBW Low birth weight
LCPUFA Long-chain polyunsaturated fatty
acid
SBP Systolic blood pressure
VLBW Very low birth weight
S7
infants and appropriate for gestational age (AGA) preterm
infants.
We review the current knowledge on the effects of growth
and nutrition on neurodevelopmental, metabolic, and car-
diovascular outcomes of preterm infants in order to try to
clarify these issues.
Effects of Prematurity, IUGR, Postnatal
Growth, and Early Nutrition on
Neurodevelopment
Long-term outcome data indicate that preterm infants are at
increased risk for adverse neurodevelopmental outcomes,
even in the absence of neonatal morbidities such as intraven-
tricular hemorrhage and periventricular leukomalacia.
6,7
The
exact cause is not clear, but nutritional factors appear to be
critically important for growth and neurodevelopment in
the fetus and newborn.
8
Effects of IUGR
The risk for adverse outcomes is increased in IUGR (dened
as an abnormal rate of fetal growth or failure to reach ones
genetic potential) and SGA (dened by a birth weight
<10th percentile for age) premature infants compared with
their peers.
9-11
Our data from a population of 2846 live
births, demonstrate that SGA children born at 29-32 weeks
gestation have a higher risk for minor cognitive disabilities,
inattention/hyperactivity symptoms at 5 years of age, and
a higher risk for poor school performance at 8 years relative
to those born preterm but AGA.
12
Furthermore, mildly-SGA
infants (dened as those with births weights between the 10th
and 20th percentiles) also have an increased risk for minor
cognitive difculties and behavioral difculties.
12
Effects of Postnatal Growth
The majority of VLBW infants in the neonatal intensive care
unit nursery fail to approximate in utero growth rates. Body
size is typically below the 10th percentile by 36 weeks post-
conceptional age
13
and often remains low throughout child-
hood and even into adolescence.
14
This EUGR is attributable
in part to inadequate intakes of energy and protein in the rst
weeks of life.
15
The causes of inadequate intakes during this
period include acute neonatal illness and a clinicians concern
for tolerance of enteral feeding, tolerance of parenteral mac-
ronutrient intake, and a desire to minimize morbidities, such
as chronic lung disease, patent ductus arteriosus, and necro-
tizing enterocolitis. Macronutrients tend to be introduced
slowly and increased cautiously out of concern for gastroin-
testinal or metabolic intolerance.
16
Such concerns often lead
to nutritional deciencies that, until recently, were consid-
ered to be inevitable.
15
Studies have demonstrated an association between re-
stricted postnatal growth and poor neurodevelopmental out-
come.
17-20
Lower developmental scores are associated with
weights below the 10th percentile at 2 years in high-risk
ELBW infants.
17
In-hospital growth is positively related to
neurodevelopmental outcome in ELBW infants.
18
Lower
rates of weight gain and head growth are associated signi-
cantly with the incidence of cerebral palsy, mental develop-
ment index <70, and neurodevelopmental impairment at
18 months corrected age. Gains in weight and body mass in-
dex (BMI) from birth to expected term are positively associ-
ated with neurodevelopment outcomes at 18 months in very
preterm infants.
19
Although considerable attention has focused on the effects
of growth from birth to expected term on later development,
less is knownabout the effects of postnatal growth after the due
date and psychomotor development. Latal-Hajnal et al
11
dem-
onstrated that Bayley psychomotor development scores of for-
mer VLBW infants measured at 2 years were more closely
related to postnatal growth than to the degree of growth retar-
dation at birth. SGA children whose weights remained <10th
percentile at age 2 years and AGA children whose weights
had fallen belowthe 10th percentile by 2 years had signicantly
lower psychomotor development indices and/or mental devel-
opment index than SGA children with catch-up growth and
AGA children with weights >10th percentile at age 2 years, re-
spectively. Alarge multicenter study demonstrated that greater
weight and length gain between expected term to 4 months
post-termwere positively, but modestly, related to neurodeve-
lopmental outcomes at 18 months.
19
However, increases in
weight disproportionate to length provided no additional ben-
et. Although there was no association between growth from
4-12 months and neurodevelopment outcomes at 18 months
in the entire population, there was an association between
BMI gain between 4-12 months and neurodevelopment at
18 months in the subgroup of SGA preterm infants. These
data suggest that promoting growth during the whole rst
year of life is important for SGA preterm infants. Moreover,
poor postnatal growth in preterm infants, especially poor
head growth, is associated with increased prevalence of motor
and cognitive impairment at 3 to 8 years
20-23
and a loss of 4.1
intelligence quotient (IQ) points in adults.
24
Effects of Postnatal Nutrition
VLBW infants routinely receive parenteral nutrition; this
may have a signicant effect on the neurodevelopmental out-
come of VLBW infants in subsequent years. Brandt et al stud-
ied 46 preterm infants
25
and found that mean energy intake/
kg body weight per day correlated signicantly with develop-
mental and IQs from 18 months to 6 years. Stephens et al
26
demonstrated that energy and protein intakes during the rst
week of life were strongly associated with developmental out-
comes at 18 months in ELBW infants. Furthermore, we
found a signicant association between the cumulative intake
of lipids during the rst 2 weeks of life and the development
quotient at 1 year corrected age in preterm infants who were
born before 28 weeks of gestation and given adequate protein
intake.
27
All together, these ndings demonstrate that opti-
mizing early nutrition by providing adequate parenteral nu-
trition during the rst weeks of life may limit the negative
consequences of undernutrition on early neurodevelopment.
Feeding mothers milk has a benecial effect on neurode-
velopment, as assessed by developmental scores, in preterm
S8 Lapillonne and Grifn
infants. Furthermore, the benets of breastfeeding on devel-
opment seem to extend beyond the rst 2 years of life and
into adolescence. Unfortunately, studies of the effect of
mothers milk cannot be carried out as randomized trials
and, thus are, affected by confounding variables that inde-
pendently affect the supply of mothers milk and the outcome
of the infant. In contrast, studies of donor human milk can be
carried out as controlled studies. The few studies that have
examined the effect of donor human milk on developmental
outcome and neurologic impairment have failed to demon-
strate a signicant effect of donor human milk.
28
A detailed
discussion about the benets of breast milk, breastfeeding,
and supplements are presented in the chapter on human
milk by Tudehope in this supplement.
29
Early enteral intake and neurodevelopmental outcome
vary with type of supplemented formulas. In large preterm
infants, Lucas et al demonstrated higher cognitive and motor
scores at 18 months corrected age and higher verbal IQs and
lower rates of cerebral palsy at 7.5-8.0 years of age in preterm
infants (<1850 g) fed preterm versus term formula.
29,30
The
follow-up of a subgroup of this cohort showed a persistent
benet of using preterm versus term formula on verbal IQ
up to adolescence.
32
Furthermore, subsequent magnetic res-
onance imaging studies showed that infants fed preterm for-
mula had signicantly larger caudate volumes.
33
In contrast,
the use of an enriched formula or multinutrient-fortied hu-
man breast milk after hospital discharge does not seem to
provide any additional benets on later development
34,35
(see Lapillonne et al in this supplement).
36
Effects of Prematurity, IUGR, Postnatal
Growth, and Early Nutrition on
Cardiovascular Health, and the Metabolic
Syndrome
The Model of the LBW Term Infant is Likely
Inapropriate
Most studies that have examined the relationship between
early growth and adult chronic diseases have shown that be-
ing born LBW increases the risk of subsequent chronic dis-
ease. In many cases, the association between birth weight
and later outcomes becomes clearly evident when adult size
is included in the statistical analysis.
4
Poor fetal and acceler-
ated postnatal growth rates appear act in synergy. The worst
outcome is often found in babies born small who subse-
quently become large.
4
Growth during fetal life and infancy appear to inuence
body composition later in life. LBW infants usually have
the fastest rate of infant growth and gain proportionately
more fat than lean body mass relative to AGA infants when
a sufcient amount of energy is provided. This prole indi-
cates that LBW infants respond to an energy-rich diet differ-
ently than normal preterm infants. Recent studies indicate
that birth weight is strongly predictive of lean mass and has
less of an impact on fat mass later in life.
37
The rate of post-
natal weight gain, particularly during childhood, appears es-
pecially important in the etiology of central adiposity, which
is linked to metabolic responses that lead to insulin resistance
and corresponding changes in glucose and lipid metabolism.
A faster trajectory of childhood growth has also been linked
with increased risk of adult chronic disease.
38
These mecha-
nisms could, together, explain why the risk of cardiovascular
disease is greatest in those born small who subsequently be-
come overweight; these infants are less able to adapt to
a high metabolic burden.
37
From a nutritional point of view, promoting catch-up
growth in LBWterminfants by providing an enriched formula
similar to preterm formulas has not been shown to improve
growth and neurodevelopment and may, in fact, be equivalent
to overfeeding. In contrast, providing the preterm infant with
a pretermformula is a very different situation. Pretermformu-
las are designed to maintain fetal growth rates, which are con-
sidered to be optimal for such infants.
39
Therefore, feeding
a preterm formula to preterm infants is appropriate when hu-
manmilkis unavailable. Furthermore, once preterminfants are
fed ad libitumand have some control over their nutritional in-
take, the use of preterm formulas does not seem to lead to in-
creased energy intakes compared with other formulas. Instead,
they provide greater amounts of specic nutrients (protein and
calcium) and micronutrients (eg, zinc, iron and copper) with-
out exceeding overall energy intake.
40
Data from preterm infants and term infants born with
IUGR should not be expected to be comparable because their
stages of maturity, growth, and nutritional needs are very dif-
ferent, despite their similarities in birth weights. Whether or
not poor growth, accelerated growth (ie, catch-up growth),
and early nutrition produce similar effects in preterm and
term IUGR infants remains unclear.
To unravel this uncertainty, we analyzed the literature for
preterm infants separately from LBW infants. We included
only studies published after 2000, thereby including the pe-
riod when modern methods of neonatal nutritional care
were in place, as well as those of preterm or VLBW (<1500
g) infants. This approach excluded data from LBW term in-
fants.
Cardiovascular Health of Preterm Infants
Effects of Prematurity. Numerous follow-up studies of
blood pressure (BP) in children born prematurely exist.
41
Prepubertal children who were born prematurely have simi-
lar or slightly elevated (0-4 mm Hg) mean systolic blood
pressure (SBP) compared with those born at term.
42
In a pop-
ulation based study including preterm infants born before 26
weeks of gestation, SBP and diastolic blood pressure (DBP)
are lower by 2.3 mm Hg and 2.4 mm Hg, respectively, in ex-
tremely preterm children compared with term children, but
these differences are explained by differences in height and
BMI. When current height and BMI are taken into account,
extremely preterm infants have SBPs and DBPs similar to
their term classmates,
43
even though they had experienced
substantial postnatal growth restriction. This may not hold
true at later ages. Teenagers and young adults born prema-
turely exhibit a more marked increase in SBP of 5 to 6 mm
Feeding Preterm Infants Today for Later Metabolic and Cardiovascular Outcomes S9
Hg compared with those born at term.
42
The shorter the ges-
tation (ie, the more preterm the infant), the higher the BP is
at adult age.
44,45
Infants born prematurely or VLBW infants
have a greater risk of hypertension compared with those
born at term.
45-48
Effects of IUGR. The effect of fetal growth on childhood or
adult BP remains controversial. Some studies suggest that
children born prematurely and SGA have an increased SBP
and pulse wave velocity, a measure of arterial stiffness,
49
whereas others found no effect of IUGR on BP during child-
hood.
50
Most studies of adults born prematurely do not sup-
port the hypothesis that IUGR increases the risk of high BP
later in life (Table).
44-48,51
Effects of Postnatal Growth. Fewer studies report associ-
ations between postnatal growth and BP.
44,47,48,52
In a follow-
up study of 19-year-old adults born as preterm infants, the
incidence of hypertension was higher in the preterm group
(gestational age <32 weeks and/or birth weight <1500 g)
than in the general population of term infants. However, nei-
ther BP nor lipid proles in the former preterm infants were
affected by birth weight, gestational age at birth, or early pat-
terns of growth.
51
Irving et al have shown that neither weight of preterm in-
fants at 44 weeks post-menstrual age nor weight gain over
any subsequent 4-week period up to 1 year of age was asso-
ciated with adult BP.
44
Similarly, Finken et al
53
found no as-
sociation between the carotid intima-media thickness in
young adults born preterm and weight gain during the rst
year of life.
Hack et al
47
found signicant correlations of adult SBP and
DBP with length and weight z-scores in VLBW individuals at
20 months, 8 and 20 years, but not earlier (ie, 40 weeks and 8
months). Rotteveel et al
51
showed that former preterm in-
fants, the quartile with the highest adult SBP had a higher
height SDS at 3 months of age and at ages 2, 5, 10, 19, and
21 years and a higher weight SDS at ages 1, 2, 5, 10, 19, and
21 years than those in the lowest SBP quartile, but not a higher
weight SDS at 3 and 6 months. Finally, Hovi et al
48
demon-
strated that among all VLBW subjects, birth-weight z-score
and weight z-score at term (40 weeks of postmenstrual age)
were unrelated to 24-hour BPs in the adult. Interestingly,
they found that a 1-unit decrease in z-score from birth to
term was associated with a 1.9 mm Hg higher (0.0-3.7) 24-
hour SBP and a similarly higher DBP. Although this effect
was attenuated when data were adjusted for gestational age
at birth, these data indicate that poor early extrauterine
growth may affect BP in the long term. Only one study de-
scribes a 4% lower ow-mediated endothelium dependent
dilation in adolescents when the highest rate of weight gain
in the rst 2 weeks after birth was compared with the lowest
rate.
54
The authors concluded that the accelerated neonatal
growth may negatively affect long-term cardiovascular
Table. Effects of IUGR, postnatal growth, and postnatal nutrition on metabolic and cardiovascular outcomes of adults
born preterm*
Does IUGR affect the BP, the glucose tolerance, or the lipid prole of adults born preterm?
References BP Glucose tolerance Lipid prole
Irving et al 2000
44
No No No
Doyle et al 2003
46
No - -
Hack et al 2005
47
Questionable - -
Hovi et al 2010
48
No - -
Johansson et al 2005
45
Yes - -
Mikkola et al 2007
50
No - -
Keijzer-Veen et al 2005
51
No No No
Hofman et al 2004
66
- No No
Dalziel et al 2007
67
- No No
Rotteveel et al 2008
71
No - -
Hovi et al 2009
76
Yes - -
Does postnatal growth affect the BP, the glucose tolerance, or the lipid prole of adults born preterm?
Irving et al 2000
44
No No No
Hack et al 2005
47
No for growth <8 mo of age - -
Yes for growth $8 mo of age
Hovi et al 2010
48
No for growth <20 mo of age - -
Yes for growth $20 mo of age
Keijzer-Veen et al 2005
51
No for growth <12 mo of age No for growth <12 mo of age -
Yes for growth $12 mo of age Yes for growth $12 mo of age
Dalziel et al 2007
67
No -
Does postnatal nutrition affect the BP, the glucose tolerance, or the lipid prole of adults born preterm?
No study available No study available No study available
*A study was included if: (1) published between 2000 and 2010, thereby demarcating the period of emerging modern methods of neonatal intensive care; (2) the study concerned young adults born
preterm, AGA-LBW infants, and/or VLBW (<1500 g) infant to estimate the maximal impact of prematurity and VLBW and to avoid to include SGA (ie, LBW infants) term infants; (3) studies including
a control group of normal weight term infants; and (4) the mean age at assessment was between 18 and 30 years.
health, but whether or not the ow-mediated endothelium
dependent dilation in adolescence is predictive of later car-
diovascular health remains uncertain.
The majority of studies (Table) do not, therefore, suggest
that early postnatal growth has a signicant effect on BP in
the adult. However, growth in later childhood and
adolescence might affect BP.
Effects of Early Nutrition. Very few studies have re-
ported the inuence of nutrition per se on BP. Breastfeeding
is not associated with BP at the age of 7.5-8 years, but is at the
age of 13-16 years.
55,56
Two randomized, controlled trials ex-
amined this issue. One compared banked human milk with
a preterm formula, and the other compared term with pre-
term formula. A 10% increase in human milk consumption
decreased mean arterial BP by 0.3 mm Hg. Consistent with
these ndings, data for term infants show that breastfeeding
reduces BP in later life.
57
It should be pointed out, however,
that the data suggest feeding in infancy has, at most, only
a modest effect on BP either in term or in preterm infants.
Thus, the effect has limited clinical or public health signi-
cance. Feeding an enriched formula versus a term formula
does not alter long-term BP.
56
The role of long-chain polyunsaturated fatty acids (LCPU-
FAs) on BP is also uncertain. Kennedy et al
58
found no signif-
icant effect of LCPUFA supplementation during infancy in
preterm infants on body composition and BP measured at
10 years. However, mean BP, SBP, and skin fold thickness
were higher in girls who received LCPUFA supplementation.
These data indicate that LCPUFA supplementation may have
negative long term effects.
59
However, because no adjust-
ment for current height was made, no denite conclusion
can be drawn from this study.
60
Furthermore, these results
are discordant with previous data for term infants showing
that dietary supplementation with LCPUFAs during infancy
is associated with lower BP in childhood.
61
Metabolic Syndrome in Preterm Infants
Effects of Prematurity. Insulin resistance or glucose
intolerance may develop in VLBW patients during child-
hood,
62-66
but is more likely observed during adult-
hood.
52,67-69
Although differences in fasting serum glucose
concentration or fasting insulin concentration are used as
outcomes in some studies,
44,68
more precise insulin resis-
tance tests have been used in others.
52,67-70
Hovi et al
68
showed a 40% increase in the 2-hour insulin concentration
(17.5-66.8) and a 19% increase in the insulin-resistance index
(5.7-33.7), as determined by Homeostasis Model of Assess-
ment - Insulin Resistance (HOMA-IR), in VLBW young
adults compared with controls. Rotteveel et al
52,71
used the
more precise hyperinsulinemic euglycemic clamp and con-
rmed that VLBW young adults had a signicantly greater
insulin resistance that remained signicant even after adjust-
ing for current weight, height, or indices of fat mass.
An abnormal lipid prole is one feature of the metabolic
syndrome. Indeed, elevated triglycerides may be the rst
sign of metabolic syndrome. Studies show no signicant as-
sociation between fasting plasma triglycerides, total choles-
terol, or high-density lipoprotein (HDL) cholesterol and
preterm birth or VLBW.
44,67,68,70,72,73
In fact, a favorable
lipid prole with a reduced circulating apolipoprotein- I level
has been reported in preterm infants.
74
Being overweight or obese also is a characteristic of the
metabolic syndrome. However, young adults born prema-
turely have a similar or lower BMI than their counterparts
born at term.
44,52,68,71
Fewer VLBW males, but not females,
were overweight or obese relative to term infants.
14
In
children, prematurity is associated with reduced body
fatness.
75
Total and central fat mass, assessed by bioelectric
impedance, dual X-ray absorptiometry, and skin fold thick-
ness, are similar in young adults born prematurely and at
term.
48,52,68,70,72,76
Very few data support the hypothesis
that preterm infants have a higher risk of increased trunk
fat mass.
77
Although a recent study of young adults supports
an association between preterm birth and greater total fat
mass and trunk fat mass, limb fat mass and total lean mass
were also elevated, which suggests that relative body fat pro-
portions were not altered.
74
Effects of IUGR in Preterm Infants. Although a few
studies suggest a relationship,
65
in most studies, long-term
insulin sensitivity, lipid prole, and body fat mass are not af-
fected by IUGR in VLBW patients (Table).
44,52,53,68,78
Hav-
ing had IUGR does not signicantly affect indices of
glucose intolerance and insulin resistance of former preterm
infants in adulthood.
44,68
Insulin sensitivity, measured by the
hyperinsulinemic euglycemic clamp method in young adults,
is the same in SGA and AGA VLBW groups.
52
In most studies of preterm infants, IUGR does not affect
fasting serum concentrations of triglycerides, total choles-
terol or HDL cholesterol.
52,67,68,70,72-74
Postprandial hyper-
triglyceridemia is observed in the metabolic syndrome and
may be related to the development of cardiovascular dis-
ease. In one study, a standardized mixed meal test per-
formed in SGA VLBW patients showed that IUGR men
had a higher triglyceride levels than controls.
71
This pattern
was not seen in SGA VLBW women or AGA VLBW patients.
These data suggest that IUGR might induce specically
a higher risk of cardiovascular disease in men born very pre-
maturely. Finally, having IUGR when born preterm does
not appear to increase the risk for increased adiposity in
the adult.
52,70,74
Effects of Postnatal Growth. Some studies have shown
an association between later but not early growth and in-
sulin resistance during childhood and adulthood (Table).
Insulin concentrations at 9-12 years of age are associated
with childhood weight gain, but not with weight gain
before 18 months of age.
65
Similarly, Irving et al
44
showed
that weight at 44 weeks after the mothers last menstrual
period and weights measured during any 4-week period for
up to 1 year were not associated with later insulin sensitivity.
Neither the SDS for weight at term nor the change in score
from birth to term is related to either the glucose or insulin
concentrations or the HOMA-IR index.
68
Finally, weight
gain from birth to 40 weeks gestation is not associated
with increased insulin sensitivity in children aged 4-10 years
born prematurely.
79
In contrast, weight gain from expected
term through childhood is signicantly associated with insu-
lin sensitivity.
79
Another study also suggests that rapid weight
gain from birth to 3 months of age is a poor predictor of in-
sulin resistance at adult age.
78
Fewtrell et al
65
measured fasting blood glucose and insulin
in former preterm infants at 9-12 years of age. Growth during
the immediate postnatal period was unrelated to later glucose
or insulin. Furthermore, once current body size was taken
into account, insulin, proinsulin, and split proinsulin con-
centrations were negatively correlated with weight SDS at
18 months of age. In other words, preterm infants who
were relatively heavier at 18 months of age were less likely
to have elevated insulin levels at 9-12 years of age than their
relatively lighter peers. This nding does not support a rela-
tionship between more rapid weight gain in preterm infants
during the rst 18 months of life and later risk of insulin
resistance. In contrast, late weight gain and adult fat accumu-
lation strongly predicts insulin resistance.
78
Growth patterns
during infancy and childhood are of great importance to
insulin sensitivity in later life.
52
Increased height gain be-
tween 1 and 5 years of age and increased weight gain between
2 and 21 years of age are strongly associated with lower insu-
lin sensitivity whereas increased weight gain between birth
and 1 year are not.
52
The few studies that sought an association between early
growth and later lipid prole do not support the hypothesis
that early growth in AGA preterm infants may be detrimen-
tal.
53,68,74
In particular, Hovi et al demonstrated that neither
the weight SDS at term nor the change in the score from birth
to term was related to the glucose or insulin concentrations
or the HOMA-IR index.
68
Similarly, Finken et al
53
found
no association between the lipid prole in young adults
born preterm and weight gain during the rst year of life.
We have examined the effect of weight gain in preterm in-
fants during the rst year of life on body composition over
the same period.
80
The quartile of preterm infants with the
most rapid weight gain during this period had a greater per-
centage whole body adiposity than the quartile with the slow-
est growth. However, even the faster growing quartile had
a lower percentage whole body adiposity than the reference
term infant.
Effects of Early Nutrition. Very few studies have assessed
the effect of nutrient supply on long-term metabolic out-
comes. Regan et al
79
showed no signicant association
between macronutrient or energy intakes and insulin sensi-
tivity in preterm infants at 4-10 years. It should be pointed
out that when a narrow range of intakes are compared, as
in this study, it may be difcult to nd a relationship between
early nutrition and long-term outcomes.
79
Singhal et al examined the effect of various diets and
growth rate on subsequent measures of insulin resistance
in 2 randomized controlled studies. Contrary to what they
observed for BP and for lipid proles, breastfeeding was
not signicantly associated with any indices of insulin resis-
tance.
81
There was also no difference between the term ver-
sus preterm formula fed groups. In further analysis, the
authors pooled the data into groups of infants assigned to
a nutrient enriched diet (enriched formula) versus a diet
lower in nutrients (human milk or standard formula).
81
When the studies were combined, split
32-33
proinsulin was
signicantly lower in the slow-growing groups. However,
there are a number of important caveats with this study:
(1) diets were given for only 2 weeks; and (2) growth was
very poor in all infants. The average change in weight of
the combined groups over a 2-week period was a loss of
56 g. These investigators also published similar data for a ref-
erence cohort of term infants. They show that the more rap-
idly growing cohorts had split
32-33
proinsulin levels similar
to term infants, and the slower growing cohort had split
32-
33
proinsulin levels less than the term infants (Figure).
Taken on face value this would suggest that preterm birth
followed by substantial postnatal growth failure produces
more favorable long-term metabolic consequences that nor-
mal termbirth. Even if this conclusion is correct, it would be
untenable and unethical to attempt to replicate this growth
pattern in preterm infants given the clear impact of early
growth on long-term neurodevelopmental outcomes. Fur-
thermore, whether or not the proinsulin concentration
values during adolescence are predictive of later insulin re-
sistance also remains to be determined. These investigators
also examined the effects of these diets on lipid prole at 13-
16 years.
82
Preterm infants who received human milk for
just 4 weeks showed marked benets in their lipid prole
and a reduction of 14% in the low-density lipoprotein:HDL
cholesterol compared with those who received preterm for-
mula, attributable largely to a decrease in low-density lipo-
protein cholesterol and related to the volume of breast milk
Figure. Early diet and fasting 32-33 split proinsulin
concentrations in adolescents born preterm fed either
a higher-nutrient versus lower-nutrient neonatal diet (data
from Singhal
81
). Normative values observed in adolescents
born at term are shown as a shaded band.
consumed.
82
The effects of term formula and preterm for-
mula were similar.
Early Growth Is Not a Perfect Surrogate of
Nutritional Status in Preterm Infants
Monitoring growth is an essential component of good clini-
cal care that easily indicates health and nutritional status. In
pediatrics, research and clinical practice have focused almost
exclusively on achieving adequate growth and preventing
growth failure. Deviations in growth, especially decreases in
growth, are associated with an increased risk of diseases in
the short- and long-term. Different organs grow at very dif-
ferent rates. The brain and head circumference grow mainly
during the rst 2 years of life. Fat mass, expressed as percent
of body weight, increases from birth to about 6-9 months, de-
creases for about 5-6 years, then increases again. Many factors
inuence growth. Genetic inuences play an important role
and can be modied by environmental factors. Nutrition,
a marker of environmental inuences, has a marked inu-
ence on growth.
In preterm infants, growth, and particularly weight gain,
has been widely used as a marker of adequate nutritional
support. However, the relationship among growth, nutrition,
and human milk feeding is complex in very preterm infants.
Enhanced postnatal growth and increases in head circum-
ference, in particular, are associated with improved neuro-
developmental outcomes.
23,83
Interestingly, head growth
catch-up occurs more often with breast milk feeding during
hospitalization
84
even though breastfed preterm infants
exhibit slower rates of growth than formula fed preterm in-
fants. Furthermore, preterm infants whose mothers choose
to breastfeed reach a higher development or IQ even though
they have slow rates of growth early in life.
85,86
The studies by Lucas et al
31,32,54,56,81,82
are puzzling be-
cause, on one hand, they show that human milk feeding
has benecial effects not only on neurodevelopment but
also on later BP, and lipid prole and may improve some in-
dices of insulin resistance. On the other hand, they also show
that preterm formula feeding improves growth and neurode-
velopment
33,34
but may not confer any benets with regards
to cardiovascular health and metabolic outcomes. Lucas
et al
65
have shown no signicant association between early
growth and cardiovascular health or insulin resistance. This
suggests that nutrition may affect development, brain, and
organ growth independently of total body growth. If energy
and protein intake affect development and are also main de-
terminants of growth, weight gain, and body composition,
other nutrients such as LCPUFAs, iron, zinc, copper, iodine,
selenium, vitamin A, choline, and folate may affect develop-
ment with limited or no effect on growth variables.
3
Although poor early growth is associated with adverse
neurodevelopmental outcomes, it is not reasonable to as-
sume that rapid growth provides neurodevelopmental ad-
vantages. The utility of growth as the sole or principal
indicator of nutrition status in the preterm infant is limited
because we do not know what denes optimal growth. We
only know, or suspect, that there are problems at both ends
of the spectrum, as poor and rapid early growth result in un-
favorable health outcomes. The current data indicate that
growth measures, especially weight gain, are not perfect sur-
rogates for nutritional status in preterm infants; they should
not be the only measures used to dene optimal nutritional
intakes.
Clinical Implications
Preterm infants are exposed to extrauterine life during a pe-
riod that normally is characterized by rapid intrauterine
growth. EUGR is a frequent clinical feature of very preterm
infants, which results from several factors that include in-
creased metabolic demand, poor early metabolic intolerance,
poor feeding tolerance, infections, respiratory distress, phar-
macologic effects (eg, of glucocorticoids), and inadequate
nutritional supply.
16,87,88
The picture is often complicated
by maternal conditions such as preeclampsia that may cause
IUGR.
The preterm infant is born during a critical period for
brain growth. The data cited above indicate that even brief
periods of relative undernutrition during a sensitive period
of development may have signicant adverse effects on later
development. The effect of early nutrition on subsequent IQ
and verbal IQ can be signicant (reaching 6-15 IQ points in
some studies), clinically relevant, and likely to have a large
population impact. A lot of attention has focused on the
role of the early protein and energy decit because it alters
brain development and weight gain, an easily accessible mea-
sure. However, efforts should continue to focus on improv-
ing nutritional care because deciencies of other nutrients,
which may not affect the growth trajectory, are likely.
Adults born prematurely have a signicantly greater risk of
developing hypertension and insulin resistance than those
born at term. In contrast to adults born IUGR or LBW at
term, adults born prematurely do not have an increased pro-
pensity for developing the other features of metabolic syn-
drome (ie, dyslipidemia and obesity). These differences are
not attributable to body size or composition or to fat distribu-
tion. Furthermore, fetal growth does not seemto play a signif-
icant role in the later risk of hypertension or insulin resistance
in VLBW infants as it does in term infants. Very interestingly,
current data suggest that growth velocity between birth and
expected term and/or before 12-18 months post-term has
no signicant effect on later BP and metabolic syndrome,
and reduced growth during hospitalization or during the rst
4 months of life impacts later development signicantly. In
contrast, growth during late infancy and childhood appears
to be major determinant of later health, suggesting a nutri-
tional intervention during this period would be effective.
Our review also highlights the paucity of data on the ef-
fects of nutrition during hospitalization or after discharge
on the risk of hypertension or insulin resistance. Therefore,
at present, no data support the hypothesis that interven-
tions aimed at discouraging weight gain during hospitaliza-
tion and after discharge would improve adult body
composition and reduce the chance of developing hyperten-
sion or type 2 diabetes. It is, therefore, vital that preterm
infants receive sufcient nutrients to prevent EUGR and
impaired neurodevelopment.
Nutritional protocols and current practices do not always
follow current guidelines.
16,79,87,88
Provision of inadequate
amounts of energy and protein are frequently noted, as dis-
cussed in other chapters of this issue. Alterations of dietary
intake during the perinatal period affect metabolic program-
ming and growth outcomes. In view of the documented ef-
fects of transient undernutrition on brain development and
on metabolic outcomes, we encourage physicians to follow
the most recent guidelines for preterm infants, which review
and synthesize the best available nutritional knowledge.
We strongly endorse human milk feeding as the preferred
method to nourish preterm infants during hospitalization
and after discharge. When human milk is not available,
products designed to support growth rates similar to the in-
trauterine rate are recommended. Furthermore, we recom-
mend that the term aggressive nutrition, a term coined
to characterize nutrition support that follows guidelines
but implies a potentially dangerous policy, should no longer
be used. We believe that aggressive nutrition is the stan-
dard of care, and anything less is inadequate. To reect
this, we suggest that the term adequate nutrition be used
in place of the misnomer aggressive nutrition.
Future Directions
We emphasize strongly that preterm infants be considered
distinct from LBW term infants because they have unique
medical vulnerabilities, states of maturation, and nutritional
needs that predispose them to high rates of morbidity and al-
terations in development and long-term health. Further-
more, the nutritional decits of preterm infants are very
specic and often iatrogenic. Extrauterine undernutrition
of preterm infants can be confused with intrauterine malnu-
trition of IUGR term infants because both results in a similar
early phenotype, but they differ quantitatively and qualita-
tively in many signicant ways. Therefore, we recommend
that future studies in this area distinguish infants by weight
and gestational age and not just by birth weight.
Current nutritional practices applied to the preterm infant
commonly result in undernutrition and poor growth. Future
research should focus on the potential link between early nu-
trition and long-term neurologic and developmental out-
comes and incidence of hypertension and type 2 diabetes in
individuals born prematurely.
Early growth appears frequently in the literature without
denition and has been used to dene a wide spectrum that
spans the rst 2 weeks to the rst 2 years of life. There is no
agreement on the denitions of early growth and later
growth for preterminfants and these terms should no longer
be used. For clarity and ease of comparison among studies,
we propose to clearly specify the period examined as follows:
birth to term for the period between birth and the due date;
term-6 mo growth for the period from expected term to 6
months post-term; 1-5 y growth for the period from 1-5
years; and so on.
Finally, we recommend that future studies be designed to
assess and dene growth in multiple time periods. The
available data suggest that undernutrition or reduced
growth during relatively short time frames can have signif-
icant impact on later development and health. Time periods
are also clinically important because nutrition is adminis-
tered by different routes (ie, intravenously, enterally, orally);
in different forms (ie, parenteral nutrition, human milk,
preterm formula, post-discharge formula, term formula,
solid food); in different doses (xed dose when enterally
fed, ad libitum when bottle fed or breastfed); and moni-
tored by a variety of individuals (physicians in neonatal in-
tensive care unit, general practitioners or primary care
pediatricians after discharge) during critically-important
periods in development. n
The authors thank the Association pour la Recherche et la Formation
en Neonatologie (ARFEN) for providing technical assistance.
Author Disclosures
Alexandre Lapillonne, MD, PhD and Ian Grifn, MD,
received an honorarium from Mead Johnson Nutrition for
attendance, presentation, and manuscript preparation. All
authors have participated to the review of the available data
and to the writing of the manuscript.
Reprint requests: Alexandre Lapillonne, MD, PhD, Department of
Neonatology, Necker Hospital, 149 rue de Sevres, 75015 Paris, France.
E-mail: alexandre.lapillonne@nck.aphp.fr.
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Human Milk and the Nutritional Needs of Preterm Infants
David I. Tudehope, AM, MBBS, FRACP
Key principles underpinning feeding guidelines for preterm infants include support for developmental care,
breastfeeding, milk expression, and creating feeding plans. Early trophic feeding with colostrum and transitional
milk improves immune protection and promotes gut maturation. Studies of preterm infants demonstrate that
feeding mothers milk (MM) decreases the incidence of infection and necrotizing enterocolitis and improves neu-
rodevelopmental outcome but may decrease ponderal and linear growth. Standard practice in neonatal units is
to promote mothers own milk as the feed of choice for all infants. However, it is not feasible or prudent to do so
for all preterm infants. Mothers of preterm infants have lower rates of successful breastfeeding compared with
those of term infants. MM can contain harmful bacterial or viral pathogens. Although preterm human milk (HM)
contains higher concentrations of protein, sodium, zinc, and calcium than mature HM, it falls short of supplying
adequate quantities of nutrients required by preterm infants. Therefore, HM supplemented with nutrients is rec-
ommended for all infants born before 32 weeks gestation and for certain infants born at 32-36 weeks of gesta-
tion. HM is the preferred feed, but preterm formula is an appropriate option when there is an inadequate supply
of MM. (J Pediatr 2013;162:S17-25).
T
he American Academy of Pediatrics, World Health Organization (WHO), and United Nations Childrens Fund recom-
mend that human milk (HM) be the exclusive nutritional source for full-term infants for the rst 6 months of postnatal
life and provided in combination with complementary foods for at least 1 year.
1-3
Breastfeeding and use of HM have
many advantages for infants, mothers, families, and society.
2-4
The role of HM in preterm infants is less well dened. Mothers of preterm infants encounter a variety of unique challenges
that result in lowrates of breastfeeding. Many of their infants are unable to breastfeed effectively for days, weeks, or even months
after birth. These mothers must learn to establish and maintain milk production by expression and require support in the hos-
pital and post-discharge to achieve and sustain exclusive breastfeeding. In the US, even though 69%of terminfants and mothers
initiate either partial or exclusive breastfeeding, the average rate of breastfeeding for preterminfants is 50%at hospital discharge
and even lower if the infant is <1500 g birth weight.
5
When lactation can be established, mothers preterm milk alone may not provide adequate nutrition. The estimated nutri-
tional requirements of the preterm infant have been dened as those needed to support the rates of growth and nutrient ac-
cretion of the third trimester fetus. The amount of protein, sodium, phosphate, and calcium in preterm HM falls short of
these needs.
6
Therefore, it may be necessary to fortify mothers preterm milk with additional nutrients to meet requirements.
1
Although HM is the preferred feed for premature infants, preterm formula is an appropriate option, especially if there is an
inadequate supply of mothers milk (MM).
HM
HM is not a discreet entity, but one that varies with time after delivery, length of gestation, length of each lactation
episode, and method of expression and collection. Colostrum is a pre-milk uid rich in immunoglobulins and immune
cells that is produced during the rst 24-48 hours postpartum. Transitional milk is produced during the 3rd-14th day
postpartum; it is rich in fat, lactose, and vitamins. Mature milk is produced after around 2 weeks postpartum. Mature
milk is less concentrated than transitional milk, and its lower nutrient density is maintained throughout the rst post-
partum year. The composition of HM varies with the length of gestation. Preterm breast milk, especially transitional
milk, contains higher levels of protein, sodium, chloride, calcium, zinc, copper, and folate than term breast milk
(Table).
7
From the Mater Medical Research Institute and the
School of Medicine, The University of Queensland,
Queensland, Australia
article.
CMV Cytomegalovirus
DBM Donor breast milk
EBM Expressed breast milk
HM Human milk
ICU Intensive care unit
IQ Intelligence quotient
NEC Necrotizing enterocolitis
MM Mothers milk
NICU Neonatal intensive care unit
RCT Randomized controlled trial
TPN Total parenteral nutrition
S17
Composition of HM
The composition of HM varies with the time during each
lactation episode. Foremilk is released initially. After
about 2-3 minutes, hindmilk is produced. Hindmilk
has a higher fat and energy content than foremilk
8
and, thus, promotes weight gain better than foremilk
or regular breast milk. Drip milk is the milk that drips
from the opposite breast during breastfeeding. It was
used extensively in the 1980s for feeding preterm infants
until it was realized that drip milk had a low fat and en-
ergy content, similar to foremilk. The composition and
volume of expressed breast milk (EBM) vary with the
method used for expression. For example, sodium con-
centrations may be higher with hand pumping than me-
chanical pumping.
7
Protein and Amino Acids
HM contains a heterogenous mixture of bioavailable pro-
teins and peptides that matches the needs of the developing
infant. Colostrum is whey-dominant and contains high
concentrations of growth and immune protective factors.
As time from delivery increases, the abundance of these
factors decreases, and mature milk has more casein as
a source of amino acids. HM has a low protein level of
only 0.9-1.2 g/100 mL, 70% of which is whey and 30% is
casein.
9
The whey protein in HM is predominantly a-lact-
albumin, which is digested easily by the preterm infant and
acts to promote gastric emptying. Human whey protein
also contains lactoferrin, lysozyme, and secretory IgA that
inuence host resistance of the preterm infant.
Lipids and Fatty Acids
Lipids in HM provide about 50% of the energy needs of the
preterminfant. The lipids in HMinclude the long chain poly-
unsaturated fatty acids and gangliosides. The composition of
fatty acids on the triglyceride molecule and the presence of
bile salt-stimulated lipase allow the low birth weight (LBW)
infant to absorb greater amounts of fat compared with for-
mula,
10
but only if the milk is not pasteurized.
Carbohydrates
Carbohydrates in HM include lactose and oligosaccharides.
LBW infants absorb >90% of the lactose in HM. The nonab-
sorbed lactose remains in the gastrointestinal tract to soften
stool, improve absorption of minerals, and support the growth
of benecial intestinal ora. Approximately 10%-15% of the
carbohydrate in HM are oligosaccharides, which also remain
in the gastrointestinal tract and act as prebiotics that facilitate
growth of bacteria such as Bidus spp. Oligosaccharides
prevent bacterial attachment to the host mucosa and contrib-
ute in preventing systemic infection and necrotizing enteroco-
litis (NEC) in very lowbirth weight (VLBW) infants.
11
Inositol
is a component of membrane phospholipids, and compounds
containing inositol are important in signal transduction.
Breast milk, particularly colostrum, contains high concentra-
tions of inositol (about 1.8 mmol/L).
Other Components
HM contains many trophic factors (insulin-like growth
factor-1, epidermal growth factor, and transforming growth
factor-a) that are believed to enhance development of the
gastrointestinal tract.
12
HM also contains numerous enzymes
such as lipase, which improves lipolysis and fat absorption in
the gut.
Term and preterm HM contains a number of cells (macro-
phages, polymorphonuclear leucocytes, T and B lympho-
cytes), antimicrobial factors (secretory IgA, lactoferrin,
lysozyme, B12 and folate-binding proteins, complement, -
bronectin, and mucin), and antiviral factors
13
that confer lo-
cal immunologic protection to an infants gastrointestinal
tract.
Methods Used to Meet the Nutritional Needs
of the Preterm Infant
It is widely appreciated that breastfeeding provides a number
of benets to a mother and her infant. However, initiating
breastfeeding at the birth of a preterm infant is not always
feasible, and MM may not be available in adequate amounts.
There are other ways to meet the nutritional needs of preterm
infants.
Donor Breast Milk
Donor breast milk (DBM) derives from donor milk banks,
services that collect, screen, process, and dispense HM
Table. Composition of preterm transitional, mature
preterm, and term mature milk
Nutrient (units/L)
Preterm*
transitional
6-10 d
Preterm
mature
22-30 d
Term
mature
$30 d
Macronutrient
Total protein, g 19 0.5 15 1 12 1.5
Energy, kcal 660 60 690 50 640 80
Fat, g 34 6 36 4 34 4
Carbohydrate, g 63 5 67 4 67 5
Minerals
Calcium, mmol 8.0 1.8 7.2 1.3 6.5 1.5
Phosphorus, mmol 4.9 1.4 3.0 0.8 4.8 0.8
Magnesium, mmol 1.1 0.2 1.0 0.3 1.3 0.3
Sodium, mmol 11.6 6.0 8.8 2.0 9.0 4.1
Chloride, mmol 21.3 2.2 14.8 2.1 12.8 1.5
Potassium, mmol 13.5 2.2 12.5 3.2 13 2.0
Trace elements
Iron, mg 23 22 22
Zinc, mmol 58 13 33 14 15-46
Copper, mmol 9.2 2.1 8.0 3.1 3.2-6.3
Manganese, mmol 6 8.9 7.3 6.6 3-6
Iodine, mmol - 1.25 -
Vitamins
Vitamin A, IU 500-4000 500-4000 600-2000
Vitamin D, IU 40 40 -
Vitamin E, mg 2.9-14.5 2.9-14.5 2-3
Vitamin K, mg 0.7-5.3 0.7-5.3 1.2-9.2
Folate, mg 33 33 1.8
*Values are mean SD.
Adapted from Schanler RJ and Atkinson SA in Tsang et al.
6
S18 Tudehope
donated by nursing mothers who are not related to the recip-
ient infant. Guidelines for the establishment and operation of
HM banks are available.
14
Donors are required to be in good
health, nonusers of drugs, alcohol, and cigarettes, and
screened for HIV-1, hepatitis B and C, and syphilis. DBM
is identied as being collected following a term or preterm
delivery and < or $30 days from date of delivery. DBM is
subjected to pasteurization, which removes potentially harm-
ful bacteria but also lipase, lymphocytes, and other important
components of HM.
Nutritional Supplements
Preterm infants fed solely preterm HM have poor rates of
growth and nutritional decits. The nutritional decits of pre-
termHMcan be corrected by adding nutrients such as glucose
polymers, medium-chain fatty acids, vitamins (vitamin A,
vitamin D, thiamine, riboavin, pyridoxine, nicotinamide,
and ascorbic acid), or minerals (iron, zinc, calcium, and phos-
phate). Alternatively, HM fortiers that contain multiple
components (macronutrients as well as minerals calcium,
phosphorus, sodium, and vitamins A, D, E, K, riboavin, folic
acid, and zinc) can be used. These fortiers are available in
powdered or liquid form and must be prepared with care. It
is important to mix powdered fortiers in HM thoroughly
sothat the nutrients canbe absorbedeasily. It shouldbe appre-
ciated that fortiers dilute HM, including nutrients, growth
factors, and anti-infective agents, even though they provide
adequate quantities of other types of essential nutrients.
Formula
When a mother cannot produce sufcient amounts of milk
or her infant is not growing appropriately, preterm formula-
tions are available to help meet the nutritional needs of a pre-
term infant. Preterm formulas are designed to provide
nutrient intakes to match intrauterine accretion rates and
are enriched with energy, typically 80-82 kcal/100 mL, pro-
tein, minerals, and trace elements.
Benets of HM and Breastfeeding for
Preterm Infants
Feeding HM to term infants provides nutritional, gastroin-
testinal, immunologic, developmental, and psychological
benets that may impact their long-term growth and devel-
opment. HM provides nutrients and energy as well as a range
of substances that promote growth and development, protect
the infant during its vulnerable early life, and prevent disease
as an adult. These benets are likely to also apply to preterm
infants, although less information is available about this pop-
ulation.
Gastrointestinal Tract
HM provides a number of benets to the developing gastro-
intestinal tract. HM promotes more rapid gastric emptying,
improves gut motility, and usually results in more frequent
stooling.
15
Preterm infants fed HM tolerate full enteral feeds
more rapidly and require less parenteral nutrition than those
fed formula. Preterm infants have reduced pancreatic and
lingual lipase activities, a reduced bile pool and, therefore,
decreased fat absorption and more steatorrhea relative to
term infants. Providing HM to preterm infants increases fat
absorption because it contains many enzymes, including li-
pase, that enhance intestinal lipolysis. In addition, HM con-
tains hormones, peptides, amino acids, nucleotides, growth
factors, and inhibitors of proinammatory cytokines
15
that
enhance maturation of the mucosal barrier and protects pre-
term infants from foreign proteins.
Several randomized controlled trials (RCTs) that compare
feeding HMor formula to preterminfants have reported a de-
crease in transient gastrointestinal intolerance, transient ces-
sation of feeds, and NEC in HM-fed infants, but only when
fed MM. In contrast, one meta-analysis found no signicant
difference between the effects of unsupplemented, termDBM
and formula on feed intolerance in preterm infants.
16
Colonization of the gastrointestinal tract commences im-
mediately after birth with the initiation of enteral feeding
and becomes well established within a fewdays. Bidobacteria
and Lactobacilli predominate in infants fed MM; other enteric
organisms appear less frequently. Coliforms, Enterococci,
and Bacteroides spp predominate in formula-fed infants. Pre-
term infants are susceptible to abnormal colonization be-
cause enteral feeds are often delayed and preterm infants
are exposed to broad spectrum antibiotics and endemic
organisms within the neonatal intensive care unit (NICU) en-
vironment.
17
Infectious Diseases and NEC
Preterm infants fed HM have lower incidence of late onset
sepsis, urinary tract infection, diarrhea, and upper respira-
tory tract infection than those fed formula.
18
Providing
HMresults in less pathogenic fecal ora and, importantly, of-
fers the potential to reduce the quantity of fecal pathogens ac-
quired in the nursery. Preterm infants fed MM have lower
rates of NEC, diarrhea, and urinary tract infection than those
fed term formula.
19
Feeding MM signicantly decreases the
incidence of systemic or local infections and NEC in LBW
infants.
7
Neurodevelopmental Outcomes
Children classied as VLBW have poorer cognitive function
and academic performance than those who have normal
birth weights. Several studies indicate that feeding HM has
a positive effect on neurodevelopmental outcomes in LBW
infants. One prospective, nonrandomized study of 300 in-
fants <1850 g birth weight compared intelligence quotient
(IQ) scores at 7.5-8 years of age between those receiving
DBM or formula.
20
After correcting for social and educa-
tional factors, there was an 8.3 point IQ advantage for those
receiving DBM and a dose-dependent relationship between
proportion of DBM and IQ score. Breastfeeding was associ-
ated with signicantly higher IQ scores than formula feeding
in a meta-analysis of 3 studies of LBW infants.
21
The results from other studies are not as clear. A multicen-
ter study of 463 preterm infants <33 weeks gestational age
Human Milk and the Nutritional Needs of Preterm Infants S19
found no difference in IQ scores between groups fed supple-
mented HM or formula from birth to term chronological
age.
22
However, at 12 months chronological age, the duration
of feeding supplemented MM was shown to be positively as-
sociated with Bayley Mental Development Index. In two
other studies, LBW infants were randomized to receive un-
supplemented drip donor term milk or calorie-enriched pre-
term formula from birth until hospital discharge. In one
study, there was no difference in neurodevelopment at 18
months.
23
In contrast, the other study reported higher scores
at 37 weeks gestational age on the Neonatal Behavioral As-
sessment Scales for infants who received standard infant for-
mula.
24
More work needs to be done to delineate the effects
of HM on neurodevelopment.
Other Benets
Breastfeeding has a protective effect against atopic disease for
up to 4 years of age, but only when there is a high risk of at-
opy.
25
HM fed infants have a decreased incidence and sever-
ity of retinopathy of prematurity compared with infants fed
preterm formula.
26
The ability to provide breast milk may
be an important psychological benet for a mother who is
able to provide little or none of the care needed by her criti-
cally ill preterm infant. Mothers who breastfeed are reported
as having strong feelings of attachment, maternal empower-
ment, and self-condence and esteem.
27
Potential Disadvantages of HM for Preterm
Infants
Transmission of Infection via HM
HM has been recognized as a source of transmission of sev-
eral pathogens, including bacteria, viruses, and possibly par-
asites. Nonetheless, there are few infectious pathogens that
pose risks to the newborn that outweigh the potential benets
of breast milk. Maternal infection with HIV, tumor viruses,
active tuberculosis, and untreated maternal bacteremia with
a virulent pathogen are notable exceptions in the industrial-
ized world.
Holder pasteurization effectively removes cytomegalovi-
rus (CMV) infectivity and should be used for DBM samples.
Early studies indicated that freezing may be an effective
technique, but late viral RNA and viral infectivity was shown
to persist after freezing at 20
C for up to 10 days.
28
Although not an ideal approach, a mother who is known
to be infected with CMV may consider freezing her own
milk to decrease the rate of CMV transmission. Although
Herpes simplex types 1 and 2, Varicella zoster, and
Epstein-Barr viruses have been detected in preterm breast
milk, feeding with HM has not been shown to be a signi-
cant route of transmission.
29
Nutritional Gaps with Feeding Mothers
Unfortied Preterm Breast Milk
Preterm infants fed exclusively unfortied HM have poor
rates of growth and nutritional decits during and after hos-
pitalization. There are many reasons to explain these decits.
The concentrations of protein and fat in preterm milk vary
widely. Protein content decreases throughout lactation. Se-
rum albumin and blood urea nitrogen concentrations may
decline in preterm infants as a result of inadequate dietary
protein intake. Fat content varies from early to late lactation,
throughout the day, from mother to mother, and within
a single expression (eg, hind milk can contain up to 3 times
as much fat as foremilk). Further variations in fat content
can occur with collecting, mixing, storing, and mode of en-
teral feeding. Healthy preterm infants usually tolerate 160-
180 mL/kg/d of milk, whereas infants with chronic neonatal
lung disease might only tolerate 120-140 mL/kg/d yet have
higher energy requirements because of the increased work
of breathing.
Nutritional Supplements
Specic nutrient deciencies of pretermHMcan be corrected
through appropriate supplementation with fortiers. The
Cochrane Systematic Review of HM protein supplementa-
tion with approximately 1.5 g/kg/d evaluated a total of 90
VLBW infants in 4 RCTs (3 trials using HM protein and 1 us-
ing bovine casein). Protein-supplemented infants grew better
by 3.6 g/kg/d weight gain, 0.18 cm/wk length, and 0.15 cm/wk
head circumference compared with unsupplemented infants,
but no outcomes past term were recorded.
30
A separate Cochrane Systematic Review of studies con-
cluded that multicomponent fortication of HMis associated
with short-term improvements in weight gain (2.3 g/kg/d),
linear growth (0.12 cm/wk), and head growth (0.12 cm/wk)
in the short term.
31
However, the sample size was too small
to determine whether multicomponent fortication of HM
provided long-termbenet in growth or neurodevelopmental
outcome or deleterious effects such as NECor gastrointestinal
intolerance. The authors concluded that it is unlikely that fur-
ther studies evaluating fortication of HMversus no fortica-
tion will be performed and that further research should
compare different proprietary preparations and evaluate
short- and long-term outcomes, in search of the optimal
composition of fortiers. It should be cautioned that adding
a fortier that contains large amounts of calcium to preterm
EBM has the potential to adversely affect fat absorption and
the intrinsic host resistant properties of the milk. Some stud-
ies have demonstrated signicantly lower fat absorption, and
therefore lower energy, and lower growth rates in infants fed
fortied HM compared with preterm formula.
Summary of Evidence
Data frommeta-analyses and RCTs indicate that feeding with
DBM rather than preterm or term formula may reduce the
incidence of NEC. There are insufcient data to conclude
whether there are neurodevelopmental advantages associated
with DBMcompared with pretermformula, although there is
some evidence that DBM is better than term formula.
Growth is slower in the short term in infants fed DBM
than those fed formula. There are insufcient data to assess
S20 Tudehope
the effects on long-term growth outcomes or feed intolerance
in VLBW infants, and there are no data available on specic
nutrient deciencies. All trials were small, unblinded, and
most used term drip milk, which has a lower calorie density
than hindmilk. Further, all but one of the studies was initi-
ated over 20 years ago. Since that time, formula and nutrient
fortiers for HM have been adapted to meet the special needs
of preterm infants. Overall, however, the available evidence
suggests that providing LBW infants with DBM rather than
formula, particularly term formula, may result in some ad-
vantages to the infant.
Feeding Plan for Preterm Infants
Availability of Breast Milk
Mothers are usually very anxious and often unwell after pre-
term delivery, especially if the infant requires intensive care.
Although feeding may not be seen as an immediate priority
after admission, mothers must be educated that the provision
of breast milk is a most important part of their infants care.
For most mothers, breast milk is not available in large quan-
tities until a few days after birth. Mothers need to be encour-
aged to continue with breast expression regularly as this may
increase supply. Often only small amounts of colostrum are
available in rst 1-5 days from a sick mother who has expe-
rienced a complex delivery. Even small amounts of colostrum
are important to the preterm infant and must be fed. DBM
can be used to supplement colostrum.
After normal birth, initiation of lactation can take a few
days. Enteral feeds should be started in preterm infants
within 48 hours of birth, although they may be held for up
to 72 hours after birth while waiting for breast milk to be-
come available if the mother wishes. Milk volumes are low
initially, and healthy, term babies receive little milk for the
rst few days of life. Milk transfer rates have been reported
to be 6-10 mL/kg on day 1 and 13-25 mL/kg on day 2. These
rates are low relative to current uid management protocols,
which recommend provision of up to 60-80 mL/kg on day 1.
To create a feeding plan for late preterm infants, one should
consider the low uid intake of healthy term infants and plan
to monitor blood glucose. If breast milk is not available in
sufcient quantity to provide an infants nutritional require-
ment, provision of supplementary intravenous uids or pre-
term formula should be discussed with the mother.
Strategies to Increase Breast Milk Supply
Mothers need to express frequently over the 24-hour day and
cumulatively for more than 100 minutes per day for optimal
milk production.
32
Mothers need to be advised, shortly after
delivery, about the benets of colostrum for their infant and
be provided with written information. An electric breast
pump is far quicker and more efcient than hand expression
or a manual breast pump and should be made available with
disposable items. Simultaneous pumping of both breasts is
time-efcient for some women. Skin-to-skin contact (kanga-
roo care) can contribute to bonding, enhanced milk produc-
tion, and successful exclusive breastfeeding.
32
Breast massage
assists the removal of breast milk. Early non-nutritive suck-
ing from about 32 weeks postmenstrual age accelerates the
transition from enteral feeding to full suck feeding. The use
of galactogogues, such as the antidopaminergic drugs, meto-
clopramide, or domperidone, can be effective when milk sup-
ply dwindles. Domperidone is considered the ideal
galactogogue because of its efcacy, lack of pediatric con-
cerns, and only rare, mild side effects in lactating women.
33
Major technological advances based on the pioneering
work of lactation researcher Peter Hartmann have recently
occurred in design and function of breast pumps that more
nearly mimic the sucking of a mature infant on the breast.
The latest innovation is a hospital-grade electric double
pump with 2-phase expression pumping, which results in re-
duced pumping time through faster let-down and milk ow
and has been proven to remove as much milk as a breastfeed-
ing infant.
34
Create a Protocol for Storing Breast Milk
To ensure that an infant receives her MM, strict guidelines
need to be established and followed. The protocol used at
Mater Mothers Hospital is shown in the Figure. Milk
should be collected in either glass or rigid plastic containers
and not in plastic bags because milk stored in plastic bags
may lose immune components or become contaminated.
The mother is provided with computer printed labels to be
used on every container of EBM including date and time of
expression. Parents are not permitted to access refrigerator/
freezer for storage or retrieval of milk. Before feeding EBM
to an infant, two authorized personnel must check the
labeled storage container of EBM against the identication
label on the feed chart and one of the infants attached
identication tags to ensure appropriate matching.
Establish a DBM Bank
Given the many benets of providing HM to preterm infants,
it makes sense to establish HM banks to serve mothers who
are unable to provide sufcient amounts of milk to their in-
fants. HM banking, popularized in the 1980s, received a ma-
jor blow with the global reports of transmission of infectious
diseases such as HIV, CMV, and tumor virus via breast milk.
The WHO/United Nations Childrens Fund Global Baby-
Friendly Hospital Initiative subsequently led to a revival of
interest in donor milk banks.
2,3
A DBM bank is a service
that collects, screens, processes, and dispenses HM donated
by nursing mothers who are not related to the recipient
infant. Breast milk banks are housed in hospitals or are
free-standing. Guidelines and accreditation for HM banking
established by state or local regulating agencies cover solicit-
ing, donors, collecting, processing, and distributing the milk.
Donors are healthy, nonusers of drugs, alcohol, and ciga-
rettes, and are screened for HIV-1, hepatitis B and C, and
syphilis. Donors, who are not paid, are separated into term
or preterm delivery and < or $30 days from date of delivery.
Each batch is tested for bacterial colony counts before and af-
ter Holder pasteurization. DBM is dispensed according to
prescription by physician. Preterm infants are the most
Figure. Storage, defrosting, verication, and administration of EBM and articial baby milk. Used with permission from Mater
Health Services, South Brisbane, Australia. (Continues)
S22 Tudehope
Figure. Continued.
frequent recipients of DBM, but term infants with gastroin-
testinal disorders and babies for adoption may have access
to DBM, often at their parents expense.
Monitor the Nutritional Adequacy of PretermBreast
Milk
Preterm infants can require considerable medical care and
have metabolic needs that exceed those of a normal term in-
fant. When a nutrition plan is dened, it is necessary to mon-
itor its effectiveness in maintaining appropriate rates and
types of growth. The assessment of growth and nutrition of
preterm infants, biochemical measures of growth, and post-
discharge care strategies are discussed elsewhere in this issue.
Case Study
A secundagravid woman with mild hypertension of preg-
nancy has a very large painful, antepartum hemorrhage at
28 weeks gestation. Fetal monitoring shows non-reassuring
fetal heart rate and an emergency cesarean delivery is per-
formed under general anesthesia. Postoperatively mother
continues to have bleeding because of a coagulopathy and re-
quires several liters of blood transfusion and supportive me-
chanical ventilation in adult intensive care unit (ICU). The
girl is born at 28 weeks gestation (1135 g [50th percentile
on Fenton chart]) and is depressed at birth with Apgar scores
2 and 6 at 1 and 5 minutes, respectively (umbilical artery cord
blood pH 7.14). She is resuscitated with intubation, positive
pressure ventilation, and endotracheal surfactant and admit-
ted to NICU where umbilical catheters were inserted and an-
tibiotics gentamicin and amoxicillin commenced. She
received 10% dextrose with electrolytes for 48 hours. She
was weaned off mechanical ventilation at 60 hours and com-
menced on nasal continuous positive airway pressure at 8 cm
H
2
O. Mother remained in ICU for 48 hours before being
transferred to the postnatal ward, at which time she was
seen by a lactation consultant. First colostrum was available
on day 3 but discarded because of her antibiotic therapy.
On day 5, she expressed 15 mL with aid of an electric breast
pump, which was the rst milk fed to baby. Baby received
starter solution of total parenteral nutrition (TPN) (protein
15 g/L) at 80 mL/kg on day 3, which was increased by 20
mL/kg/d and changed to maintenance TPN solution (protein
20g/L) on day 5. Fat emulsion was commenced on day 4 at 1
g/kg/d and increased by .05 g/kg/d up to 3 g/kg/d. Starter
TPN solution (protein 15 g/L) was commenced at 100 mL/
kg on day 3 and increased by 20 mL/kg/d. On day 5 TPN
was changed to maintenance (protein 20 g/L) and fat infu-
sion reached maximum of 3 g/kg/d. Enteral feeds with
mothers EBM were increased by increments of 10 mL/kg/
d from day 5. On day 7, baby was re-intubated and ventilated
for increasing apnoea and coagulase negative Staphylococcus
blood stream infection. Umbilical catheters were removed
because of infection and replaced with a long peripheral can-
nula into superior vena cava for supplemental TPN. Feeds
were withheld for 36 hours because of increase in light green
aspirates. Feeds were recommenced at 20 mL/kg/d and nally
reached full enteral feeding at 150 mL/kg on day 20. EBM was
half fortied with HM fortier on day 20 and fully fortied
on day 24. Babys weight dropped to 965 g on day 9 and re-
gained birth weight on day 18. On day 28 (32 weeks corrected
age), baby weighed 1300 g (<10th centile) and on day 42 was
1585 g (5th centile). Babys rst suck feed was at 35 weeks
corrected age and transition to full suck feeds took 21 days.
She was discharged home fully breastfeeding at 38 weeks
post-menstrual age with a weight of 2414 g (3rd percentile
for corrected age).
Observations of Case Study
The hospital had a strong culture of breastfeeding VLBW in-
fants and waited until MM milk was available and free of an-
tibiotics before enteral feeding baby on day 5. This is not the
best practice because the baby should have received trophic
feeding on day 1or 2. Maternal antibiotics are rarely a contra-
indication for feeding colostrum to baby but if mother was
too unwell to express her breasts or provide milk, a breast
milk substitute, DBM if available or preterm formula, should
have been offered to provide trophic benets. The lactation
consultant should have interviewed mother in ICUbefore be-
ing transfered to the postnatal ward.
Considering the mothers ill health post-cesarean delivery,
an individualized feeding plan developed between staff in
ICU and NICU most likely would have avoided much of de-
lay in initiation and transitioning of breast milk feeding.
Overall, a more aggressive approach to feeding and nutrition
was required.
Mother will need ongoing support in the community to
continue exclusive breastfeeding for the undisputed long-
termhealth benets for her VLBW infant. Careful monitoring
of growth using the WHO chart is recommended and follow-
up with a pediatrician and child health clinic with nursing
staff familiar with extremely preterm infants. If babys weight
does not exhibit catch up or falls below 3rd percentile, health
professionals have a dilemma and nutritional options need to
be discussed with mother. Again, a more aggressive approach
to the introduction and advancement of enteral feeding may
have provided better growth for this baby. n
Author Disclosures
David Tudehope, AM, MBBS, FRACP, received an hono-
rarium from Mead Johnson Nutrition for attendance, pre-
sentation, and manuscript preparation. D. T. wrote this
manuscript.
Reprint requests: David Tudehope, AM, MBBS, FRACP, Mater Medical
Research Institute, Level 3 Quarters Building, Annerley Rd, Wooloongabba
4102, Queensland, Australia. E-mail: david.tudehope@mater.org.au.
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Vitamin D, Vitamin A, Maternal-Perinatal Considerations: Old Concepts,
New Insights, New Questions
Teresa Murgu
a-Peniche, MD
Vitamins A and Dare essential nutrients that play important roles in growth and development. Pretermand lowbirth
weight infants have low levels of these nutrients and are at risk for developing detrimental health consequences
associated with vitamin A and vitamin D deciencies. Preliminary data suggest that vitamin A and D supplementa-
tion is needed to prevent deciency. More work is needed to dene optimal doses, timing, and modes of adminis-
tration to ensure that an adequate supply of these vitamins is available to meet the critical needs during pregnancy
and in high-risk neonates. (J Pediatr 2013;162:S26-30).
T
he fat-soluble vitamins A and D play important roles in perinatal growth and development. Maternal concentrations
of these vitamins directly affect concentrations in the fetus and neonate. Preterm infants have low stores and are at
risk for vitamin deciency. Worldwide there is a silent epidemic of vitamin D deciency. This is an important public
health problem that not only relates to bone disease in the population, but also may increase the risk of developing a wide
range of common chronic diseases in adult life. Although vitamin A deciency is rarely seen in the US and other industri-
alized countries, it is a major nutritional concern in developing countries and is the leading cause of preventable childhood
blindness.
1
Vitamin D
Denition and Functions
The term vitamin D refers to either vitamin D2 (ergocalciferol) or D3 (cholecalciferol). The major source of vitamin D3 is
through the action of UV radiation from the sun on 7-dehydrocholesterol to form cholecalciferol in the dermal layers of the
skin. Cholecalciferol is then enzymatically converted to 25-hydroxycholecalciferol [25(OH)D, or calcidiol]. The primary active
form of vitamin D is 1,25-dihydroxycholecalciferol (calcitriol), which is formed from 25(OH)D by 1a-hydroxylase. Final
activation of calcitriol occurs in the kidneys and in many other tissues throughout the body. Calcitriol circulates bound to
a vitamin Dbinding protein to reach different organs. Calcitriol is also synthesized in or adjacent to regulated cellular targets,
acting in an autocrine and paracrine fashion as well.
2
Traditionally, the primary hormonal function of calcitriol is in controlling blood calcium concentrations by regulating the
expression of genes involved in the intestinal absorption, renal excretion, and bone movement of this mineral. Many other
functions of calcitriol have been identied as well, including immunomodulatory activity, insulin secretion, neuroprotective
functions, and others.
Maternal Vitamin D Status
The best indicator of maternal vitamin D status is serum 25(OH)D concentration. New denitions of vitamin D sufciency
have evolved based on functional biomarkers, and an optimal 25(OH)D level has not yet been determined. The Institute of
Medicine has recently proposed the following denitions
3
: (1) Sufciency: 25(OH)D levels of at least 50 nmol/L (20 ng/
mL); however, serum 25(OH)D concentrations >75 nmol/L (>30 ng/mL) are not consistently associated with increased benet;
(2) Risk of deciency: serum 25(OH)D level <30 nmol/L (<12 ng/mL); and (3) Potential risk for inadequacy: serum 25(OH)D
level 30-50 nmol/L (12-20 ng/mL).
Vitamin D deciency is highly prevalent in pregnant and lactating women and produces adverse consequences
in these women, their fetuses and, ultimately, their growing infants and children.
4,5
Several factors are responsible
for this epidemic, including increased awareness of the injuries associated with sun exposure, insufcient vitamin D
intake, and the rising prevalence of obesity. Adult obesity is associated with low 25(OH)D levels; whether vitamin
D insufciency is a risk factor for increased body fat or body fat is a risk factor for vitamin D insufciency is not
well understood.
6
From the National Center for Child and Adolescent
Health (CeNSIA), Mexico City, Mexico
article.
25(OH)D 25-hydroxycholecalciferol
NbVAS Newborn vitamin A supplementation
ROP Retinopathy of prematurity
S26
Data from the US National Health and Nutrition Exami-
nation Survey (2001-2006) revealed hypovitaminosis D (de-
ned as a serum 25(OH)D level <50 nmol/L) in 80% of
African American and 13% of white American women of re-
productive age.
5
Vitamin D deciency is widely prevalent in pregnant
women, and mothers with vitamin D deciency mothers re-
main decient during lactation. In a study of American
women at time of delivery, vitamin D deciency [dened
as 25(OH)D of <37.5 nmol/L] and insufciency [dened as
25(OH)D of 37.5-80 nmol/L] were detected in 29.2% and
54.1% of black women, 45.6% and 46.8% of black neonates,
5.0% and 42.1% of white women, and 9.7% and 56.4% of
white neonates. As recommended, 90% of mothers in the
study had prenatal vitamin D intake of 400 IU/day.
7
Similar
results were reported in a study from northern India, where
low levels of 25(OH)D (<22.5 ng/mL) were observed in
>80% of women and >95% of infants.
8
These studies high-
light the high prevalence of vitamin D deciency in pregnant
women and their neonates.
Maternal Consequences of Vitamin D Deciency
during Pregnancy
Vitamin D deciency has been linked to bone disease (ie,
rickets and osteomalacia). In malnourished populations, os-
teomalacia in mothers and abnormal skeletal metabolism in
fetuses and infants have been reported.
9
Nonclassical conse-
quences of vitamin D deciency have been detected in preg-
nant women; experimental and observational studies have
suggested that vitamin D deciency may be associated with
increased risk of preeclampsia, insulin resistance, and gesta-
tional diabetes.
10,11
Whether this association suggests causal-
ity cannot be determined based on the available data.
Maternal Vitamin D Status and the Fetus
There is a strong relationship between maternal and fetal (cord
blood) 25(OH)Dconcentrations. 25(OH)Dreadily crosses the
placenta and is metabolized to 1,25-dihydroxycholecalciferol
by the fetal kidney as early as 24 weeks gestation. At birth, neo-
natal serum 25(OH)D concentration is 50%-70% of maternal
serum25(OH)Dconcentration.
12
The signicance of maternal
deciency during pregnancy is that the fetus develops in a state
of hypovitaminosis D, which likely has short-term and long-
term detrimental effects.
Vitamin D deciency in newborns is associated with hypo-
calcemia and osteopenia, especially in preterm infants. These
effects on bone are long-lasting. In a longitudinal study of 198
children followed up at age 9 years, Javaid et al
13
concluded
that low maternal vitamin D concentration during the third
trimester of gestation was associated with reduced whole-
body and lumbar spine bone mineral content.
Different studies have suggested that vitamin D deciency
also may be associated with an increased risk of nonbone dis-
eases and/or abnormal development in the fetus. Vitamin D
has critical functions that affect organs other than bone.
Vitamin D receptors and 1-alpha hydroxylase have been
detected in the developing brain. Calcitriol target gene prod-
ucts, including neurotrophins NGF, NT3, and NT4/5, which
are critical for neurogenesis, have been identied.
2
Epidemi-
ologic data have conrmed associations between schizophre-
nia and winter birth and northern latitudes, which might
result from low 25(OH)D levels.
14
It remains to be seen
whether vitamin D deciency can be shown to negatively
impact cognitive or behavioral endpoints in experimental
or epidemiologic studies.
Whether vitamin D deciency in infants is associated with
long-term risk of diabetes should be considered as well. Aret-
rospective study of a birth cohort of 10 366 children sug-
gested that postnatal vitamin D supplementation (2000 IU/
day) was associated with an 8-fold reduction in the incidence
of type 1 diabetes mellitus.
15
More studies are needed to
analyze the role of hypovitaminosis D in the development
of this public health problem.
Vitamin D deciency also has been associated with an
increased risk of autoimmune diseases, such as rheumatoid
arthritis, allergy, multiple sclerosis, type 1 diabetes, and
certain cancers.
13
Evidence of causal relationships between
vitamin D status and a disease or health outcome other
than bone health remains elusive, however, owing to the mul-
tifactorial etiology of chronic diseases and the difculty of
isolating the effects of a single nutrient from other confound-
ing effects.
Interventions to Improve Vitamin D in Pregnant
Women
Although vitamin D supplementation is effective in prevent-
ing vitamin D deciency, the optimal vitamin D require-
ment in women remains unknown. Studies evaluating
plasma vitamin D status have shown that vitamin D supple-
mentation of <2000 IU/day is not effective in achieving suf-
ciency.
16
The standard recommended daily allowance for
vitamin D supplementation in adults is 400 IU/day; the
same dose is recommended during pregnancy. However,
studies in adults suggest that a daily dietary allowance of
1000-2000 IU/day is needed to achieve a target circulating
25(OH)D value of at least 75 nmol/L.
17
In another study
of lactating women, intake of 6400 IU/day postpartum re-
sulted in signicantly higher levels of circulating vitamin D
compared with controls.
18
Higher amounts of vitamin D
may be necessary, although the precise dose needed remains
unknown.
Previous studies have explored the role of vitamin D sup-
plementation on perinatal outcomes. A study of 23 423
nulliparous Norwegian pregnant women found a 27% reduc-
tion in the risk of preclampsia in women receiving 10-15 mg/
day (600-800 IU/day) of vitamin Dcomparedwith women re-
ceiving no supplements.
19
Another study suggested that
vitamin Dsupplementation during pregnancy improved neo-
natal birth weight.
20
There is an urgent need to determine the optimal dose of
vitamin D to maintain vitamin D sufciency in pregnant
women when sun exposure is inadequate or skin color limits
the amount of vitamin D formed from UV radiation. Vita-
min D deciency during pregnancy not only may impair
Vitamin D, Vitamin A, Maternal-Perinatal Considerations: Old Concepts, New Insights, New Questions S27
maternal and fetal skeletal formation, but also may play
a role in epigenetic imprinting that can affect other, extra-
skeletal functions later in life and even inuence reproduc-
tive outcomes.
Vitamin A
Functions
Vitamin A is involved in regulating and promoting growth
and cell differentiation and in maintaining the integrity of re-
spiratory epithelial cells. Vitamin A is also part of the photo-
sensitive visual pigment complex in the retina and plays a role
in reproductive functions and immunocompetence. Carot-
enoids, dietary precursors of vitamin A, have potent antiox-
idant properties.
21
Prenatal Considerations
The mechanism of vitamin A transport across the placenta
and its regulation are not fully understood. The estimated ra-
tio of maternal to fetal plasma vitamin A concentrations in
healthy pregnancies is roughly 2:1.
22
Trials in women of reproductive age conducted in coun-
tries with a high prevalence of vitamin A deciency have
reported conicting results in relation to outcomes associ-
ated with vitamin A supplementation. A study in Nepal
found that supplementation with vitamin A or its precursor
(b carotene) in women of reproductive age reduced
pregnancy-related mortality by 44% (95% CI, 16%-63%).
23
In contrast, a large-scale, randomized study performed in
Ghana with more than 200 000 women of reproductive age
found no improvement in perinatal or infant survival with
vitamin A supplementation.
24
The different outcomes in
these two studies may be related to the higher incidence of
severe vitamin A deciency in Nepalese women, as mani-
fested by eye disease, compared with Ghanaian women. Large
studies are needed to examine the role of vitamin A supple-
mentation on reproductive outcomes.
It is important to emphasize that an oversupply of vitamin
A can be toxic. Excess retinoic acid in the rst trimester of
pregnancy is reportedly teratogenic, leading to spontaneous
abortions and fetal malformations, including microcephaly
and cardiac anomalies.
25
Postnatal Considerations: Prematurity and Vitamin A
An adequate concentration of plasma vitamin A in very
low birth weight (VLBW) infants has not yet been dened.
Plasma concentration is not necessarily a good index of vi-
tamin A status. Plasma concentrations can be normal even
when tissue (liver, lungs, and other organs) stores are low.
Nonetheless, a concentration <200 mg/L (0.70 mmol/L) is
considered decient, and a concentration <100 mg/L (0.35
mmol/L) indicates severe deciency and depleted liver
stores.
1
Preterm infants have lower plasma concentrations of ret-
inol and retinol-binding protein compared with their term
counterparts. This decit is more severe in smaller babies,
thus, in a multicenter study in extremely low birth weight
infants, 54% of extremely low birth weight infants who did
not receive intramuscular vitamin A had a plasma retinol
concentration <0.70 mmol/L at 28 days.
26
Role in Lung Development
Vitamin A is required in the fetal lung for cellular differenti-
ation and surfactant synthesis. Vitamin A and steroid hor-
mones have similar effects on prenatal and postnatal lung
development, operate through similar cell receptors, and
may be interdependent.
Administration of antenatal steroids may contribute to
higher plasma vitamin A values measured soon after birth
in the most immature preterm infants. In addition, postmor-
tem studies have found larger lung and hepatic vitamin A
stores in extremely low birth weight infants who received ste-
roids. Indeed, the benecial pulmonary response to steroids
may be mediated in part by vitamin A. Werkman et al
27
re-
ported a higher retinol:retinol-binding protein, reecting
poorer vitamin A status, in preterm infants who later devel-
oped bronchopulmonary dysplasia compared with those
who did not.
Results from a meta-analysis of 8 eligible trials suggested
that supplementation with vitamin A in VLBW infants was
benecial in reducing the combined effect of death or oxygen
requirement at age 1 month. Three studies reported outcomes
at 36 weeks gestational age and showed a lower need for
oxygen in infants who received vitamin A supplements.
This benecial outcome was observed only in infants with
a birth weight <1000 g.
28
The lungs of the preterminfant may be decient in vitamin
A at birth, but whether this can be modied by supplemen-
tation of either the mother or newborn infant is unknown.
How lung concentrations of vitamin A relate (if at all) to
plasma retinol is unclear. It is unknown whether providing
the mother vitamin A in late pregnancy can decrease the
risk of bronchopulmonary dysplasia and/or respiratory dis-
tress syndrome in newborns, or act as an effective adjunct
to postnatal preventive therapy for respiratory morbidities.
Role in Visual Development
Low plasma vitamin A concentrations in preterm infants
have been associated with the development of retinopathy
of prematurity (ROP). However, there is insufcient evi-
dence to support routine vitamin A supplementation to pre-
vent ROP in preterm infants.
28
Additional studies are needed
to dene whether vitamin A supplementation might be ben-
ecial in preventing ROP in preterm infants and, if so, to es-
tablish the optimum dosing and timing of supplementation.
Immune Function and Vitamin A
There is an urgent need for vitamin A supplementation to
improve survival from infectious diseases in children in
countries where vitamin A deciency is prevalent. In these
settings, the World Health Organization recommends peri-
odic vitamin A supplementation in infants aged 6-59
months.
29
Routine newborn vitamin A supplementation
(NbVAS) has yielded controversial results, however. In
S28 Murgua-Peniche
Indian children, administration of NbVAS (24 000 IU on
days 1 and 2) reduced infant mortality at 6 months by almost
25%, with the greatest effect observed in infants with low
birth weight. The prevalence of severe diarrhea and septice-
mia was lower in the infants who received vitamin A.
30
In
a study performed in Indonesia, a single dose of 50 000 IU
given orally to term infants at birth reduced infant mortality
at age 1 year by 64%. In contrast to the Indian study, the
greatest impact was observed in infants with birth weight
>2500 g; the prevalence of severe respiratory infections com-
pared with placebo was also lower.
31
Other studies have not
conrmed these encouraging results, however, and system-
atic analyses of several trials have not documented any benet
from NbVAS.
32
Thus, at present, the World Health Organi-
zation does not recommend routine NbVAS to reduce infant
morbidity or mortality as a public health intervention.
33
More studies are needed to explore vitamin A status and neo-
natal outcomes in infants who receive vitamin A supplemen-
tation. Discrepancies among studies could be related to
differences in the prevalence and severity of maternal vitamin
A deciency, in the timing and mode of vitamin A adminis-
tration, in the dose of vitamin A administered, or other as yet
unexplored reasons.
Role of Vitamin A in VLBW Infants
There is a need to further analyze the role of vitamin A
supplementation in decreasing the incidence and severity
of infectious diseases in sick VLBW infants. Pooled data
from 2 studies (n = 807) in VLBW infants who received in-
tramuscular vitamin A supplementation showed a nonsig-
nicant trend towards a reduced prevalence of sepsis in
these infants (typical risk ratio, 0.89; 95% CI, 0.76-
1.05).
31
Trials to specically address this issue are still
needed. In VLBW infants, the best results from vitamin
A supplementation reported to date have been with intra-
muscular administration. One trial compared different in-
tramuscular dosing regimens (5000 IU 3 times weekly for 4
weeks, 10 000 IU 3 times weekly for 4 weeks, or 15 000 IU
weekly for 4 weeks) in infants weighing <1000 g. The op-
timal dose appeared to be 5000 IU 3 times weekly for 4
weeks; however, even with this dose, more than 25% of
the infants had evidence of vitamin A deciency.
33,34
Higher doses or a better mode of delivery may be needed.
Other routes of administration have proven less effective.
Vitamin A administered intravenous degrades in light
and adheres to tubing. Administration via the enteral route
also is not optimal. Administration by inhalation appears
feasible, but more study is needed.
In the future, it will be helpful to understand whether com-
bining antenatal vitamin A supplementation of the mother
with postnatal supplementation of the newborn can better
prevent neonatal morbidity compared with postnatal supple-
mentation alone. Moreover, it will be important to dene
whether vitamin A supplementation in lactating women im-
proves vitamin A status in their infants and, if so, to identify
the optimal dosage for this effect. For these approaches to be
effective, it will be necessary to identify appropriate bio-
markers for vitamin A concentrations at the sites where bio-
logically active vitamin A is stored.
Conclusion
Vitamin D deciency is a worldwide public health problem
that can affect pregnant women and their children. Hypovi-
taminosis D has acute and long-term negative effects on bone
health, and growing evidence suggests a possible association
with chronic disorders and adverse reproductive outcomes.
Many gaps remain in the knowledge of vitamin Ds modes
of action, requirements, and appropriate levels.
Vitamin A deciency is prevalent in developing countries.
This nutrient is essential for normal development of the eye
and immune system and apparently plays a role in lung func-
tion and maturation that is particularly important in preterm
infants. Questions remain related to appropriate measures of
sufciency and optimum dosages to promote health in preg-
nant women and preterm and term infants. Research to
address these questions is urgently needed. n
Author Disclosures
Teresa Murgua-Peniche has received an honorarium from
manuscript preparation. T. M.-P. wrote this manuscript.
Reprint requests: Teresa Murgua-Peniche, MD, Rollins School of Public
Health, Hubert Department of Global Health, 1518 Clifton Road, Mail Stop
1518-002-7BB, Atlanta, GA 30322. E-mail: teresamurguiap@gmail.com.
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S30 Murgua-Peniche
Evaluation of Adequacy of Protein and Energy
1
, Patricia Mena, MD
2
, Scott Denne, MD
3
, and Cecilia Garc
a, MD
4
Growth assessment is the most common measure of nutritional adequacy in pediatrics, especially when evaluating
nutrition of preterm neonates. The American Academy of Pediatrics denes postnatal nutrient intake to promote
growth as one that approximates the rate of growth.for a normal fetus of the same post-menstrual age.
1
It is
known that in the fetus, fat and lean body mass are accreted progressively as gestation progresses, whereas post-
natal growth and observed accretion of fat and lean body mass differ. This review discusses anthropometric mea-
sures used to assess growth, biochemical markers used to monitor nutritional sufciency, and the effect of growth
trajectory in preterm infants on health outcomes later in life. (J Pediatr 2013;162:S31-6).
G
rowth is the most common measure of nutritional status in newborns, particularly in preterm infants. Growth is char-
acterized by orderly short- and long-term coordinated changes in body size and tissue composition. The American
Academy of Pediatrics recommends that postnatal nutrient intake in the preterm infant be designed to provide nu-
trients to approximate the rate of growth and composition of weight gain for a normal fetus of the same post-menstrual age,
and to maintain normal concentrations of blood and tissue nutrients.
1
It is unclear whether this goal is achievable or even
desirable if we are unable to assess the short- and long-term consequences of specic growth rates in terms of survival and
long-term health.
It is known that the late gestation fetus accretes fat at a higher rate than earlier in gestation. The optimal composition of
growth for preterm infants after birth is uncertain, however. The interpretation of growth-related variables depends strongly
on the estimation of developmental stage used for the assessment, given that such variables are determined by gestational age,
maturity, developmental processes, nutrient intake, programmed growth rate for each stage, and associated morbidities.
The appropriateness of nutritional intake for infants in routine clinical practice is commonly monitored by changes in an-
thropometric measurements. Such measurements are easy to obtain and have proven useful for tracking an infants progress
over time, but because they are assessed post hoc, their usefulness is limited. The opportunity to accomplish meaningful
changes occurs days to weeks after the institution of the initial nutritional management plan. The accurate measurement of
postnatal growth of very low birth weight (VLBW) infants is essential for both clinical care and research. The consequences
of poor or excessive growth during hospitalization may affect these infants both acutely and over the course of life.
Weight
Using the currently available fetal growth reference data, most VLBW infants (<1500 g) accrue a "weight decit" of 198-335 g
from birth until birth weight is regained at age 2-3 weeks.
2
Very preterm infants can lose up to 15%-20% of their birth weight.
3
Although this weight loss principally reects changes in hydration, up to one-half may be related to mobilization of lean tissue,
glycogen, and fat stores to compensate for inadequate nutrient intake in the rst few days after birth.
Weight growth velocity (GV; g/kg/day) summarizes infant weight gain over a specic time interval, smoothing the variability
inherent in daily weight measures. Changes in GV are much more sensitive for identifying changes in growth compared with
changes in absolute weight plotted on growth curves. Regular assessments of GV averaged over 5 or 10 days can help identify
growth failure early and monitor the response to nutritional interventions.
4
Calculated GVs vary based on the starting points
(eg, birth weight, nadir, time to regain birth weight) and time intervals (eg, birth to 28 days, birth to discharge, nadir to
discharge, time regained birth weight to discharge) used. Patel et al
5
proposed a mathematical exponential model for GV
assessment during the hospital stay that produced results comparable to a desirable growth rate, reported as 20 g/kg/day
for intrauterine weight gain and 12.0-21.2 g/kg/day for postnatal weight gain in a large VLBW infant population.
6
Kashyap et al
7
reported that lean mass accretion is related directly to protein intake, and that fat accretion is related primarily
to energy intake. The available preterm formulas and fortied human milk diets provide a protein intake of approximately
3.5-3.6 g/kg/day and an energy intake of approximately 120 kcal/kg/day when
From the
1
Medical College of Georgia, Georgia Health
Sciences University, Augusta, GA;
2
Hospital S otero del
Rio, Santiago, Chile;
3
Indiana University School of
Medicine, Indianapolis, IN; and
4
Sanatorio de la Trinidad,
Buenos Aires, Argentina
article.
BUN Blood urea nitrogen
DEXA Dual emission x-ray absorptiometry
GV Growth velocity
S31
fed at sufcient volume. These intakes support growth and
protein accretion at or slightly greater than intrauterine rates,
but lead to relatively increased fat deposition. Despite this,
however, many VLBW infants who consume these diets re-
main below the 10th percentile of intrauterine growth stan-
dard at discharge. There is clear evidence indicating that,
with respect to growth, VLBW infants are likely to benet
from a higher protein intake and from an energy intake not
exceeding 120-130 kcal/kg/day.
Global scientic societies, in support of the World Health
Organization and American Academy of Pediatrics, recom-
mend the use of human milk in all infants, including preterm
infants. In 2002, an expert panel convened by the Life Sci-
ences Research Ofce of the American Society for Nutritional
Sciences concluded that current scientic evidence is insuf-
cient to identify the optimal protein content for preterm in-
fant formulas.
8
Length
Weekly measurements of length are an excellent means of
tracking linear growth; they are also the most accurate indices
of lean body mass compared with weight or head circumfer-
ence. In addition, length measurements have proven useful as
components of a variety of indicators that compare body
weight and length (eg, body mass index, ponderal index). Eh-
renkranz et al
9
reported an average rate of length gain of
approximately 1 cm/week, signicantly greater than the
0.69-0.75 cm/week increase reported in term infants during
the rst 3 months of life in other studies.
Head Circumference
Like length, head circumference measurements should be re-
corded on a weekly basis. Head circumference increases at
a rate of 0.89-1.00 cm/week in VLBW infants.
9
The rate of
head circumference growth increases with postnatal age; in-
fants with the lowest birth weights have the steepest rates of
head circumference growth. Head circumference catch-up
growth, an index of brain growth, has been associated with
early, aggressive protein administration and better neuro-
logic outcomes.
6,10
Body Composition
In isolation, weight is an insensitive marker of growth unless
matched with concomitant assessment of body composition.
No good bedside measures of body composition are currently
available.
11
However, the advent of bedside whole-body air
displacement plethysmography (pea pod; www.bodpod.
com [Cosmed, Rome, Italy]) and possibly dual emission x-
ray absorptiometry (DEXA) in the future could make it pos-
sible to measure body composition in a relatively easy and
noninvasive fashion.
12
With plethysmography, analysis of
the whole-body density permits estimation of fat-free and
fat mass, and with DEXA, a whole-body scan produces
a pseudo3-compartment model of body composition incor-
porating bone minerals, body fat, and the remaining soft tis-
sues. Previous studies in term and preterm infants have
reported body composition reference ranges based mainly
on DEXA.
13
Biochemical Assessments
Serum measurements are of little use in assessing overall pro-
tein and energy status, but measurement of blood glucose,
blood urea nitrogen (BUN), and some plasma proteins are
clinically useful for identifying special conditions that require
adjustment of protein and/or mineral intake. Urea is the nal
end product of oxidation of amino acids and proteins and
represents the irreversible loss of nitrogen from the body.
BUN values in neonates are difcult to interpret, because
an excess of protein intake in relation to requirements and
an excess of ultimately oxidized amino acids lead to high
levels of urea synthesis. An elevated BUNvalue may represent
appropriate amino acid delivery, utilization, and subsequent
appropriate oxidation, or may represent amino acid intoler-
ance. However, considering that human milk is relatively low
in protein, the potential use of BUN to adjust the use of for-
tiers is a valid option. In a prospective randomized study,
Arslanoglu et al
14,15
showed that adjusting the fortication
of human milk using BUNconcentrations as a marker of pro-
tein tolerance resulted in increased weight gain and head cir-
cumference growth.
Visceral proteins, measured in the serum, are the product
of protein anabolism, with the major site of production in the
liver. Visceral protein synthesis and plasma levels depend on
amino acid availability. Albumin is synthesized in the liver
and is the most abundant plasma protein. Albumin concen-
trations are lowin fetuses and preterminfants compared with
term neonates. Once synthesized, approximately 40%-50%
of body albumin resides in the extravascular space. Given
its wide volume of distribution and a long half-life, albumin
levels are slow to respond to changes in nutritional manage-
ment or disease state. Transthyretin (prealbumin), along
with retinol-binding protein, serves as the serum transport
protein for vitamin A and thryoxine, and its synthesis in
the liver is highly sensitive to protein and/or energy intake.
Both prealbumin and retinol-binding protein have a shorter
half-life (2-3 days) than albumin, and respond to changes in
nutrient balance within 7 days. Prealbumin contains a high
concentration of tryptophan and one of the highest ratios
of essential to nonessential amino acids of any protein in
the body. The serum concentration of prealbumin increases
when more than 55% of assessed protein and energy needs
are met. In adults, when protein is kept constant and energy
is varied, prealbumin changes; if energy is maintained and
protein is varied, retinol-binding protein changes.
16
Several studies have included serial measurements of
plasma and urinary amino acids.
17-20
These measures may
be useful for evaluating the effects of the level of protein in-
take and protein quality (eg, differences in whey:casein ra-
tios), as well as the metabolic pathways involved in the
synthesis of nonessential amino acids. Plasma amino acid
S32 Bhatia et al
patterns of lowbirth weight (LBW) infants may be inuenced
not only by the quantity and quality of protein ingested, but
also by the energy supply, gestational age, rate of growth,
time of sampling with respect to feeding, and maturation
of enzymes that synthesize and metabolize amino acids.
The milk protein fractions whey and casein have different
solubilities in acid. Approximately 70% of the proteins in hu-
man milk are in the soluble whey fraction, and 30% are in the
insoluble casein fraction. The whey fraction provides lower
concentrations of phenylalanine, tyrosine, and methionine
and higher concentrations of taurine compared with the
casein fraction, and these amino acid patterns are reected
in blood concentrations. Preterm infants fed a whey:casein
protein ratio of 60:40 (similar to breast milk) have reasonably
well-balanced plasma amino acids and an adequate coef-
cient of protein utilization (protein gain:intake). Higher
proportions of casein cannot be handled with the same
efciency, as evidenced by the development of metabolic
acidosis and higher plasma tyrosine and phenylalanine con-
centrations reported with commercial formulas derived
from bovine milk with a 18:82 whey:casein.
17-19
Lactoferrin,
lysozyme, and secretory immunoglobulin are specic human
whey proteins involved in host defense; these proteins are es-
sentially absent in bovine milk.
20
Trajectory of Weight Gain and Later
Outcomes
Numerous studies have demonstrated that a suboptimal in-
trauterine environment, as well as undernutrition or overnu-
trition during the early neonatal period, has adverse affects
on later outcomes. The fetal origins of adult health and dis-
ease and catch-up growth hypotheses, for example, have
proposed that there are critical windows during growth
that may reect genetic/nutrient/environmental interactions
that translate to phenotype programming.
13
There is concern that aggressive feeding in an effort to pro-
duce catch-up growth also may contribute to later adverse
outcomes. Growth is a sensitive, but nonspecic, indicator
of aninfants overall health andwell being. Optimal growth,
based on a statistical approach, implies adherence to anthro-
pometric development of healthy infants, with specic sex
and age distributions as indicated by recommended reference
curves. A new challenge has been added to the term optimal
growtha pattern of early growth to prevent adverse out-
comes, such as cardio-metabolic diseases, later in life.
Nutritional conditions during key periods of develop-
ment are of profound importance in determining the subse-
quent life-long growth trajectory of an organism. A period of
nutritional decit can be followed by accelerated growth,
compensating for the initial deprivation. Although this com-
pensatory growth can bring quick benets, it is also associ-
ated with a number of unintended, potentially deleterious
consequences that often do not become evident until much
later in adult life.
21
The concept of programming states that events occur-
ring early in life during a period of critical sensitivity or
plasticity have a strong inuence on later, long-lasting var-
iability in phenotype. Postnatal weight gain is an important
component of the programming of adipose tissue growth
and insulin sensitivity, both of which have major potential
effects on the prevalence of adult chronic diseases.
22
For ex-
ample, the risk of metabolic syndrome is greatest in adults
who were born small and experienced a high rate of catch-
up growth. The precise patterns of growth leading to
obesity are unclear, with both infant size and infant growth
implicated.
23,24
Most infants born small for gestational age
(SGA) experience rapid catch-up growth during the rst
year of life. Fetal growth restriction followed by rapid
weight gain early in postnatal life is implicated in promot-
ing central adiposity, insulin resistance, type 2 diabetes, and
cardiovascular diseases.
Research studies have established that protein intake in ex-
cess of metabolic requirements may enhance the secretion of
insulin and insulin-like growth factor-1, favor growth during
the rst 2 years of life, and increase adipogenic activity and
adipocyte differentiation.
25,26
Meta-analyses of observational
studies indicate that breastfeeding, relative to feeding of stan-
dard infant formulas, reduces the risk for obesity in breastfed
infants owing to the lower protein content of breast milk (the
early protein hypothesis).
27
The relationship between early growth and later cardiovas-
cular and metabolic risks has not yet been studied extensively.
An observational study found that rapid weight gain during
the rst 3 months of life was associated with more central ad-
iposity, a higher percentage of body fat mass, and lower insu-
lin resistance, all of which are important determinants of
cardiovascular disease and type 2 diabetes later in life.
28
According to DEXA body composition analyses in children,
a predominant distribution of central fat rather than periph-
eral fat is associated with an unfavorable cardiovascular risk
prole,
29
although not all studies have supported this associ-
ation.
The SGA infant with catch-up growth presents a prole of
higher adiposity, especially visceral fat, and its related meta-
bolic differences of hyperinsulinemia and low adiponectin.
Overall ndings also suggest a diminished capacity to store
subcutaneous fat that may reect decits in skeletal muscle
in SGA infants at birth, resulting in reduced glucose utiliza-
tion, redirection of glucose to lipogenesis, and fat storage
in adipose tissue.
30
LBW is known to be associated with higher blood pres-
sure later in life, but the association between weight gain
in infancy and later blood pressure remains unclear. In
a large 5-country study, Adair et al
31
reported an increased
risk for elevated blood pressure associated with each period
of weight gain during infancy and childhood; however,
higher systolic pressure in adulthood was related mainly
to adult size.
A cohort trial conducted by Singhal et al
32
studied children
born SGA and randomly assigned at birth to receive either
a standard or a nutrient-enriched formula. Blood pressure
was measured at age 6-8 years in 51% of the randomized chil-
dren. Diastolic and mean arterial blood pressures were
Evaluation of Adequacy of Protein and Energy S33
signicantly lower in children assigned to the standard for-
mula group compared with the nutrient-enriched formula
group. Despite several limitations, that study suggested that
faster early growth can have negative effects on long-term
health.
Even though the underlying biological mechanisms are
still unclear, prematurity, fetal and neonatal growth restric-
tion, and catch-up growth are strongly associated with
increased risks of developing hypertension, insulin resis-
tance, and type 2 diabetesall components of the metabolic
syndrome. Various hypotheses to explain this association
have been proposed, pointing to a role of a detrimental fetal
environment, a genetic susceptibility, or an interaction be-
tween them, as well as to the particular dynamic changes in
adiposity that occur during catch-up growth.
In neonates born at term, the association between small
size at birth and impaired glucose regulation later in life is
well established. VLBW preterm and SGA births are also as-
sociated with insulin resistance in childhood. Current nutri-
tional strategies that promote catch-up growth should
include monitoring of weight-for-length and adiposity, and
the concept of healthy catch-up growth should be a goal
of future research.
33
Published studies have all tried to bal-
ance long-term side effects and potential benets resulting
from rapid recovery growth. Weight-for-age decits mark-
edly increase the risk of death in children aged <5 years.
34
Given our current knowledge of child health in developing
countries, as well as the risk of both poor growth and exces-
sive growth in the early neonatal period, it seems quite rea-
sonable to continue to promote growth of small infants
and young children to match normal growth based on inter-
national norms (eg, World Health Organization Multicenter
Growth Reference Study growth standards). A major prior-
ity, however, is to reanalyze existing datasets to assess the
full impact of catch-up growth on health in both the short
term and the long term.
Neurodevelopmental Outcome
Infants born preterm are at increased risk of developing cog-
nitive and motor impairments compared with infants born at
term. Several studies have demonstrated that inadequate
early nutrition exerts an adverse inuence on long-term
developmental outcome. Ultimate brain growth of preterm
infants is less than that of normal infants born at term.
35-37
Preterm birth during this critical stage with superimposed
perinatal undernutrition might result in adverse neurocogni-
tive function later in life. This reduced brain growth may be
improved by nutritional strategies during hospitalization and
the catch-up growth period.
10
The rst year of life may
provide an important opportunity for human somatic and
brain growth to compensate for earlier prenatal and postnatal
deprivation.
38
Concern has focused principally on outcomes in the more
vulnerable populations, such as extremely LBW infants; how-
ever, follow-up studies have also shown impairment in more
mature preterm infants as well as late preterm infants (34-36
weeks gestational age). Neurologic abnormalities, learning
difculties, poor scholastic achievement, and behavioral
problems have been reported.
39
The prevalence of cerebral
palsy is 3-fold greater in late preterm infants compared
with full-term infants.
40
Studies conducted over the last decade have indicated that
a high incidence of growth failure or catch-down growth
between birth and hospital discharge is associated with
poorer neurodevelopment in the long term. The term
catch-down growth was suggested by Ong et al
41
to dene
growth failure as a decrease in weight z score of >0.67 (ie,
>0.67 SD). Lathal-Hajnal et al
42
studied neurodevelopmental
outcome in relation to growth status at birth and to postnatal
growth in 219 VLBW infants. SGA children had a lower mean
Bayley Scales of Infant Development Psychomotor Develop-
ment Index score at age 2 years compared with SGA children
who experienced catch-up growth. Appropriate for gesta-
tional age children with catch-down growth were more likely
to have lower mean Bayley Psychomotor Development Index
and Mental Development Index scores than those who re-
mained at >10th percentile at age 2 years, and also had
a higher incidence of severe cerebral palsy (22.9% vs 1.2%;
P = .008).
Ehrenkranz et al
6
investigated the effect of growth rates
on neurodevelopmental outcomes in a cohort of VLBW in-
fants. In a subset of that study, extremely LBW infants were
divided into quartiles of in-hospital growth rate and evalu-
ated at 18-22 months corrected age. The mean rate of
weight gain in the rst and fourth quartiles was 12.0 g/
kg/day and 21.2 g/kg/day, respectively. Comparing the low-
est with the highest quartiles, the risk of cerebral palsy, Bay-
ley Psychomotor and Mental Developmental Index scores
<70, and neurodevelopmental impairment were signi-
cantly correlated with growth rate.
Current information indicates a clear relationship between
pre- and postnatal undernutrition and disturbed structural
and functional brain development.
43
Outcome studies have
documented impaired cognitive development in childhood
among SGA preterm infants,
44
and volumetric magnetic res-
onance imaging studies have found diminished overall brain
volume, as well as decreased cerebral cortical gray matter and
hippocampal volumes, in similar infants.
45,46
More than 2
decades age, Lucas et al
47
investigated neurodevelopmental
outcomes related to different nutritional approaches in
LBW preterm infants during hospitalization. The most valu-
able contribution of these studies was to open a new line of
evidence that strongly supports a favorable and differential
effect of human breast milk on neurodevelopment.
Clinical Evaluation of Feeding Strategies
Once the negative impact of postnatal growth failure on
neurodevelopment became evident, several studies were un-
dertaken in attempts to elucidate the optimal nutritional
strategy. The most recent evidence suggests that early high
protein intake may improve growth in VLBW infants. Ran-
domized controlled trials have suggested short-term safety
S34 Bhatia et al
and efcacy of starting parenteral amino acid infusions at
2.5-3.5 g/kg/day as soon as possible after birth
48-50
and
then advancing up to 4 g/kg/day. Although data evaluating
the longer-term effects of this strategy are limited, a large
observational study has demonstrated that preterm infants
receiving earlier and higher amounts of amino acids ex-
hibited improved growth in the neonatal intensive care
unit, lower rates of microcephaly in males at age 18-22
months, and neurodevelopmental outcomes similar to
those in infants receiving lower amounts of early amino
acids.
10
Another observational study showed that increased
protein intake during the rst week of life was associated
with higher Mental Developmental Index scores and lower
likelihood of length growth restrictions at age 18 months
in extremely LBW infants.
51
In contrast, a small random-
ized trial with limited follow-up suggested that higher early
amino acid intake may be associated with abnormal neuro-
cognitive outcome at age 18 months, but not at age 24
months.
52
Variation in nutritional practices, especially those involv-
ing the initiation and advancement of enteral nutrition,
largely explain the differences in growth reported in different
newborn intensive care units. From the standpoint of opti-
mizing growth, feeding preterm infants earlier and faster de-
creases the time to achieving full feeds and improves GV; as
the available evidence suggests, growth and catch-up from
birth to at least age 1 year are the primary variables related
to favorable neurodevelopmental outcomes. Numerous ben-
ecial effects of breast milk in term and near-term infants
have been demonstrated, including improved cognitive skills,
improved behavior ratings, and decreased rates of infection.
Improved neurodevelopment has been related to the pres-
ence of long-chain polyunsaturated fatty acids (eg, arachi-
donic acid, docosahexaenoic acid), found in human milk,
but not in bovine milk. Recent extensive and detailed analy-
ses of nutritional support and outcomes in preterm infants
have yielded the following recommendations
50,53
: (1) early,
aggressive parenteral nutrition; (2) early enteral nutrition;
(3) feeding of human milk with appropriate fortication, es-
pecially in VLBWinfants; and (4) feeding of premature infant
formula when human milk feeding is not possible.
Conclusions and Recommendations
The ideal nutritional management of preterm newborns em-
ulates intrauterine growth. Evaluating the appropriateness of
nutritional care remains an unresolved challenge. Many vari-
ables intervene in and interfere with theoretical calculations
during the postnatal period, and nutritional goals should
not be considered exclusively for the short term, but rather
should be projected into childhood and adult life. Although
the anthropometric components of growth (weight, height,
and head circumference) provide very limited information,
they remain the tools most commonly used to monitor
growth. New measures are needed that provide more com-
prehensive information about growth and development dur-
ing infancy, childhood, and beyond. n
Author Disclosures
All authors have received honoraria from Mead Johnson
preparation. P. M. and S. D. wrote the rst draft of this
manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Division of Neonatology,
Medical College of Georgia, Georgia Health Sciences University, BIW-6033,
Augusta, GA 30912. E-mail: jatindeb@georgiahealth.edu.
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S36 Bhatia et al
Lipid Needs of Preterm Infants: Updated Recommendations
1,2
, Sharon Groh-Wargo, PhD, LD, RD
3
, Carlos H. Lozano Gonzalez, MD, MPH
4
,
and Ricardo Uauy, MD, PhD
5
Long-chain polyunsaturated fatty acids (LCPUFAs) are of nutritional interest because they are crucial for normal de-
velopment of the central nervous system and have potential long-lasting effects that extend beyond the period of
dietary insufciency. Here we review the recent literature and current recommendations regarding LCPUFAs as
they pertain to preterm infant nutrition. In particular, ndings that relate to fetal accretion, LCPUFA absorption
and metabolism, effects on development, and current practices and recommendations have been used to update
recommendations for health care providers.
The amounts of long-chain polyunsaturated fatty acids (LCPUFAs) used in early studies were chosen to produce
the same concentrations as in term breast milk. This might not be a wise approach for preterm infants, however,
particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed
what is normally provided in the small volumes that they are able to tolerate. Recent studies have reported outcome
data in preterm infants fed milk with a docosahexaenoic acid (DHA) content 2-3 times higher than the current con-
centration in infant formulas. Overall, these studies show that providing larger amounts of DHA supplements, es-
pecially to the smallest infants, is associated with better neurologic outcomes in early life. We emphasize that
current nutritional management might not provide sufcient amounts of preformed DHA during the parenteral
and enteral nutrition periods and in very preterm/very low birth weight infants until their due date, and that greater
amounts than used routinely likely will be needed to compensate for intestinal malabsorption, DHA oxidation, and
early decit. Research should continue to address the gaps in knowledge and further rene adequate intake for
each group of preterm infants. (J Pediatr 2013;162:S37-47).
P
reterm infants are particularly susceptible to postnatal growth failure and nutrient deciencies. Dietary lipids provide
preterminfants with most of their energy needs. Recent interest has focused on the quality of dietary lipid supply early in
life as a major determinant of growth, infant development, and long-term health. In this regard, LCPUFAs are of con-
cern because they are crucial for normal development of the central nervous system development and have the potential for
long-lasting effects extending beyond the period of dietary insufciency.
1
Furthermore, LCPUFAs also have potentially signif-
icant modulatory effects on developmental processes that affect short-term and long-term health outcomes related to growth,
body composition, immune and allergic responses, and the prevalence of nutrition-related chronic diseases.
1
Recommendations for intake of total fat, essential fatty acids (EFAs), and medium-chain triglycerides (MCTs) have not var-
ied over the last decade, and to our knowledge, there are no new data that would cause us to modify the current recommen-
dations.
1
This is not to say that there have been no new developments in the area of LCPUFAs. Consequently, the aim of this
article is to review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant
nutrition. In particular, ndings related to fetal accretion, LCPUFA absorption and metabolism, effects on development,
and current practices and recommendations are used to update recommendations for health care providers.
LCPUFA Fetal Accretion Rate
When data on intrauterine accretion are available, the amount of nutrient required to attain the mean rate of accretion can be
used to estimate the minimum nutrient requirement for preterm infants. When there are adequate bioavailability data on the
relative absorption of a nutrient from human milk or infant formulas and on oxidation rate and/or losses, a recommendation
can be made regarding the minimum amount for absorption that will result in
a net retention rate similar to the intrauterine accretion rate.
From the
1
Paris Descartes University, Assistance
Publique H^ opitaux de Paris Necker Hospital, Paris,
France;
2
Childrens Nutrition Research Center, Baylor
College of Medicine, Houston, TX;
3
Case Western
Reserve University, MetroHealth Medical Center,
Cleveland,
OH;
4
Academia Mexicana de Pediatra, Pediatra
Medicina Perinatal, Monterrey, Mexico; and
5
Institute of
Nutrition and Food Technology, University of Chile,
Santiago, Chile
article.
ALA a-linolenic acid
ARA Arachidonic acid
DHA Docosahexaenoic acid
EFA Essential fatty acid
EPA Eicosapentaenoic acid
LA Linoleic acid
LCPUFA Long-chain polyunsaturated fatty acid
MCT Medium-chain triglyceride
MDI Mental Development Index
S37
Attention so far has focused mainly on DHA accumulation
in the central nervous system. Whether the brain is protected
when availability of DHAis limited is not known, but the ease
with which fetal brain DHA is altered by maternal dietary n-3
fatty acid intake suggests that the membrane lipid composi-
tion of the fetal brain is sensitive to changes in DHA supply.
2
Because most LCPUFAs accumulate in white adipose tissue
and, to a lesser extent, in lean mass and the liver,
3
it is impor-
tant to consider the accumulation of DHA and other LCPU-
FAs in all relevant organs.
Analyses of fetal autopsy tissue yielded the following esti-
mates of intrauterine accretion of LCPUFAs during the last
trimester: 106 mg/kg/day for linoleic acid (LA), 4 mg/kg/
day for a-linolenic acid (ALA), 212 mg/kg/day for arachi-
donic acid (ARA), and 43 mg/kg/day for DHA.
3
It is likely
that the accumulation of LCPUFAs is not linear over time
during the last trimester of gestation. Thus, using these num-
bers to calculate an average daily rate of fatty acid accumula-
tion will overestimate or underestimate tissue requirements
during specic periods of growth. A more precise estimate
of the fetal accretion rate cannot be determined until more
data become available.
The placenta selectively favors the transfer of DHA over
other fatty acids, including ARA, during the last trimester
of pregnancy.
4
It is generally thought that the fetus does
not synthesize LCPUFAs from their precursors at rates suf-
cient to support an adequate DHA accretion rate. However,
evidence from stable isotope studies in preterm infants sug-
gests that ARA and DHA synthesis occurs to some degree
at an age when the infant would normally be dependent on
placental transfer.
5
Tracer studies indicate that the rate of
ARA synthesis is signicantly greater than the rate of DHA
synthesis, suggesting that the fetus has a greater ability to reg-
ulate ARA supply by de novo synthesis or placental reuptake
compared with DHA supply.
4
Overall, these data suggest that
exogenous supply of DHA may be more critical than that of
ARA during the perinatal period.
LCPUFA Absorption and Metabolism
The fetus does not accumulate appreciable amounts of fat
until the last trimester of gestation. Thus, postnatally, adipose
tissue cannot be a signicant source of LCPUFAs for brain
growth of preterm infants as it is for term infants. The LCPU-
FAs used for organ growth, including brain growth, depend
on the amount of LCPUFAs supplied exogenously, intestinal
absorption of LCPUFAs, and, nally the capacity to synthe-
size and oxidize LCPUFAs.
Digestion and Absorption of LCPUFAs. Mechanisms
of fat absorption and digestion have been reviewed exten-
sively elsewhere.
1
MCTs and structured lipids (eg, synthetic
b-palmitate) do not fall within the scope of this review,
even though they may affect LCPUFA absorption and im-
prove overall fat absorption. Human milk fat is provided in
the form of a milk fat globule and consists mainly of triacyl-
glycerols (98%), phospholipids (1%), and cholesterol and
cholesterol esters (0.5%). In breast milk, LCPUFAs are
mainly triacylglycerols esteried at the sn-2 and sn-3 posi-
tions and can be part of the phospholipid fraction.
6
Human
milk contains bile salt-stimulated lipase and palmitic acid in
the b position of the triglyceride molecule. These unique
components increase the bioavailability of human milk fat
by improving absorption and digestion. However, human
milk for preterm infants is often pasteurized to suppress viral
and bacterial activity. Heat inactivates bile saltstimulated
lipase and changes the structure of the milk fat globule. These
actions may be the reason why feeding pasteurized milk is
associated with a 30%reduction in fat absorption and growth
rate.
7
Fortication of human milk, particularly with calcium,
may further impair LCPUFA absorption. Overall, only 70%-
80% of ARA and DHA from pasteurized breast milk is
absorbed by very preterm infants (Table I).
The recombinant form of human bile saltstimulated
lipase signicantly increases DHA and ARA absorption
when added to pasteurized human milk.
8
This approach
can be potentially benecial, but the safety, efcacy, and
cost-effectiveness of using recombinant human bile salt
stimulated lipase as an additive must be fully characterized
before routine use can be recommended.
LCPUFAs from sh oils or from single-cell algae are added
as triacylglycerols to the fat blend of preterm formulas. DHA
in algal oils has a weak positional specicity and contains
equal amounts of DHA in the sn-1, sn-2, and sn-3 positions,
unlike the DHA triacylglycerols present in breast milk. These
chemical differences may reduce absorption of DHA derived
from algal sources. Although sh oil provides DHA with
a bond located in the sn-2 position, it also contains eicosa-
pentaenoic acid (EPA), which has not yet been proven safe
in preterm infants (Table I).
Phospholipids are not a common source of LCPUFAs in
preterm formulas.
9,10
However, it can be speculated that
DHA derived from phospholipids offers potential advantages
because it: (1) is one of the forms found naturally in human
milk; (2) provides ARA and other LCPUFAs; and (3) may be
one way to promote brain DHA uptake.
11
LCPUFA Metabolism by Preterm Infants. Studies
using LCPUFA precursors labeled with stable isotopes have
demonstrated that LCPUFA synthesis occurs even in small
preterm infants.
1
Using the novel stable isotope natural
abundance approach, the estimated mean endogenous
synthesis of ARA was reported as 27 mg/kg/day at 1 month
and 12 mg/kg/day at 7 months, and that of DHA was
13 mg/kg/day at 1 month and 2 mg/kg/day at 7 months.
12
Thus, endogenously synthesized LCPUFAs are insufcient
to meet requirements dened by the fetal accretion rate.
Whether conversion in human milk-fed preterm infants is
similar to that in formula-fed preterm infants, or whether
conversion is affected by the supply of dietary EFAs or LCPU-
FAs, remains to be established.
Recent studies in adult populations have suggested that
variability in biochemical and functional central nervous sys-
tem responses to changes in diet are explained in part by
S38 Lapillonne et al
single nucleotide polymorphisms in genes responsible for
EFA desaturation. This nding adds complexity to dening
LCPUFA requirements and establishing the extent of the
effect of the intake other nutrients (eg, LCPUFA precursors,
n-3/n-6 fatty acid ratio) that affect endogenous LCPUFAsyn-
thesis.
13
These ndings explain much of the variance in ARA
blood levels, but no association between polymorphism desa-
turase and DHA levels has yet been identied, suggesting
a stronger role for the inuence of diet on DHA levels.
14,15
To our knowledge, there is no similar evidence for preterm
infants; however, because the conversion of EFA to LCPUFAs
is highly variable, it is likely that the single nucleotide poly-
morphisms that play a regulatory role in LCPUFA formation
may exist in preterm infants as well. In support of this con-
cept, a large interindividual variability in the rate of conver-
sion of EFAs to LCPUFAs has been measured in stable
isotope studies of infants.
16,17
The nal step in the synthesis of DHA is considerably
more complex than that for ARA. DHA synthesis requires
enzymes present in peroxisomes and the endoplasmic retic-
ulum, along with the coordinated movement of fatty acids
between these two organelles. A recent study of infants
born at term found that, compared with dietary EPA, con-
version of EPA to DHA is twice as efcient when EPA is
formed from dietary ALA.
16
Even though conversion of
EPA to DHA is less efcient with EPA from the diet com-
pared with EPA formed from ALA, EPA is present in the
human milk and relatively well absorbed (Table I). Thus,
when estimating ingested DHA equivalents, it may be
appropriate to include approximately 45% of dietary EPA
in the calculation.
16
None of the estimated retention gures reported to date
have taken into account DHA oxidation and endogenous
biosynthesis. Present evidence suggests that DHA oxidation
may occur in adults as well as in preterm infants. Signicant
b-oxidization of DHA in adults was reported recently.
18
In
addition, DHA in plasma phospholipids is decreased in pre-
term infants who receive 42 mg/kg/day of DHA (ie, a dose
similar to the theoretical fetal accretion rate) through a lipid
emulsion containing sh oil, suggesting that DHA oxidation
may be signicant.
19
Furthermore, some DHA oxidation
likely occurs in preterm infants, when energy intake does
not meet requirements, but the magnitude cannot be esti-
mated based on the available data.
Effects of LCPUFAs Supplementation in
Preterm Infants
Possible effects of LCPUFA supplementation include im-
proving neurologic and visual development. These effects
are numerous and signicant enough to serve in dening
the need for and dosage of LCPUFAs for preterm infants.
In contrast, effects on modulation of immune function in
preterm infants are too scarce to add sufcient information
for estimating requirements.
Data from Experimental Studies. LCPUFAs, particu-
larly DHA, play important roles in central nervous system
development. Complex neural functions affected by the com-
position of dietary fatty acid supply include neurogenesis,
photoreceptor differentiation, activation of the visual
pigment rhodopsin, protection from oxidative stress, synap-
togenesis, activities of multiple enzymes, function of ion
channels, neurotransmitter concentrations, and eicosanoid
metabolism.
20
In rodents and nonhuman primates, poor
accumulation of retinal and brain DHA leads to abnormal
retinal physiology, poor visual acuity, increased duration of
visual xation, and increased stereotyped behaviors and loco-
motor activity.
21
The evidence most relevant to the issue of
causality showed that control performance levels were
Table I. Comparison of intestinal absorption of fatty acids among formulas
Study I* Study II
Preterm breast milk Standard PTF1 PL PTF TG-MO PTF Fortied preterm breast milk Standard PTF2 TG-FO PTF
Intestinal absorption
(fatty acids, %)
18:2n-6 88.1 3.0 69.7 0.3 91.3 1.7 68.9 4.0 83.5 13 97.8 1.6 95.9 3.0
20:4n-6 81.1 3.6 NA 84.7 1.7 80.4 2.3 76.6 12 NA 75.9 10.2
18:3n-3 90.3 2.6 88.5 1.5 94.4 1.1 90.5 1.6 85.3 12 98.2 1.3 96.7 2.7
20:5n-3 57.0 6.9 NA 64.3 9.5 NA 81.0 25 NA 92.5 3.3
22:6n-3 78.4 4.0 NA 88.3 1.8 80.4 2.3 76.9 18 NA 94.8 4.2
Metabolizable intake (fatty
acids, mg/kg/day)
18:2n-6 608 61 585 29 601 13 575 38 453 231 906 213 878 152
20:4n-6 26.0 2.1 NA 16.4 0.4 40.0 1.4 20.1 6 NA 1.7 0.2
18:3n-3 35.2 3.8 64.5 1.2 51.0 0.8 64.7 1.8 29.9 9.0 80.9 18.0 54.2 6.9
20:5n-3 2.7 1.0 NA 1.4 0.4 NA 10.0 10.0 NA 4.6 1.0
22:6n-3 14.1 1.2 NA 12.0 0.3 30.6 1.1 15.9 7.0 NA 18.2 3.7
NA, not applicable; PTF, preterm formula; PL, LCPUFAs from phospholipids; TG-MO PTF, triacylglycerols from microorganisms; TG-FO PTF, triacyglycerols from sh oil.
Shown are intestinal absorption of fatty acids and metabolizable intake of fatty acids at age 4 weeks in preterm infants fed exclusively unfortied (study I) or fortied (study II) preterm breast milk,
standard preterm formula with no LCPUFAs added (standard PTF1; standard PTF2), preterm formula with LCPUFA TG-MO PTF or from TG-FO PTF, or preterm formula with LCPUFA phospholipids
from egg yolk (PL PTF).
*Study I: data from Carnielli et al.
9
Study II: balance study performed in a subset of 15 preterm infants from Lapillonne et al
53
; postnatal age 4 weeks, no signicant difference among groups for postnatal age, corrected age, and
weight at time of the balance study (Picaud JC et al, unpublished data 2012).
Lipid Needs of Preterm Infants: Updated Recommendations S39
restored when DHA was added to the diets of animals with
severely reduced brain DHA concentrations.
21
Nevertheless,
the magnitude of these effects is not large, despite the fact
that the studies were conducted under profound dietary re-
striction. The relevance of these ndings to human develop-
ment is unclear.
Supplementation with Standard Doses of LCPUFAs.
The effects of LCPUFAs on the developing brain have been
reported extensively,
22-27
and are not reviewed here. Overall,
studies in preterm humans indicate possible benets for ret-
inal and cognitive development, as suggested by greater sen-
sitivity to light on electroretinography, more mature visual
acuity, and short-term effects on global developmental out-
comes at 6-18 months after DHA supplementation of pre-
term infant formula. The effects in term infants are weaker
but supported by sufcient data to merit consideration of
enriching term formulas with LCPUFAs.
28,29
Interestingly, two recent meta-analyses concluded that
the available randomized controlled trials do not show
clear benets of formula supplementation with LCPUFA
on neurodevelopment in preterm infants.
24,30
This nding
is somewhat surprising, given that many studies have
suggested that LCPUFAs play an important role in develop-
ment. Several factors may explain these apparent discrep-
ancies, as reviewed previously.
3
In brief, meta-analyses are
designed a priori to classify results as positive or negative
relative to a dened clinical issue of interest. In other
words, a treatment is deemed either to work and be recom-
mended or to not work and thus not be recommended.
This approach yields the most useful information when
a given treatment is well dened. With regard to randomized
controlled trials designed to assess the effects of DHA enrich-
ment in preterm formulas, there obviously is extreme vari-
ability in study design. The assessment schedule and
methodology, dose and source of fatty acid supplementation,
and composition of the control formula vary considerably
among studies.
Other potential explanations for the difculty in demon-
strating clinical benets of LCPUFA supplementation in pre-
term formulas by meta-analysis include variations in study
endpoints, selection of relatively mature and healthy preterm
infants, timing of the DHA decit as well as DHA provision,
genetic background, maternal DHA status, single versus mul-
tiple pregnancy, in utero growth and maturation, and the
ability of preterm infants to synthesize DHA from ALA or
EPA. It has been shown that the DHA equivalent, which
depends on the rate of conversion and amount of EFA in
the diet, has a greater impact than DHA intake on the mag-
nitude of visual acuity response at age 4 months.
23
Clearly,
the magnitude of these factors in modulating DHA status
and development in preterm infants is not known and war-
rants further research.
With regard to safety, adding LCPUFA to preterm for-
mulas has no signicant effect on the relative risks of sep-
sis, necrotizing enterocolitis, retinopathy of prematurity,
intraventricular hemorrhage, or bronchopulmonary dys-
plasia.
24,30
It has been 15 years since a sh oilenriched
formula was rst shown to reduce growth in preterm in-
fants. Since that time, very little new information has be-
come available to conrm or refute the nding that high
n-3 and low n-6 LCPUFA intake reduces growth in very
low birth weight infants.
24
However, it is likely that in
this specic group of infants, the balance between n-3
and n-6 LCPUFAs is critical for growth, and it is prudent
to minimize the decline of ARA status, which has been
associated with reduced growth. Supplementation with
n-3 and n-6 LCPUFAs has been shown to be safe and
possibly even benecial in preterm infants when
growth
24,31
and body composition
32
are used as the safety
parameters.
Supplementation with High Dosages of LCPUFAs.
The dosages of LCPUFAs used in early studies were chosen
to produce the same concentrations of ARA and DHA in for-
mula as seen in term breast milk. This might not be a wise
approach for preterm infants, particularly for very and ex-
tremely preterm infants, whose requirements for LCPUFAs
and other nutrients exceed what is normally provided in
the small volumes that they are able to tolerate during the
rst days or weeks of life. Because the amount of DHA pro-
vided by ingesting breast milk is well belowthe in utero accre-
tion rate, providing DHA at a dose higher than that of term
human milk might better fulll requirements and confer
health benets. Three studies report outcome data in preterm
infants fed milk with a DHA content exceeding 0.2%-0.4%
fatty acids, which are the levels most widely used in previous
studies
33-37
(Table II).
One study examining the effect of providing DHA supple-
mentation (0.5% of total fatty acids) for up to 9 months after
term reported that DHA improved growth in the entire co-
hort of preterm infants and improved mental development
in boys.
33
It should be noted that g-linoleic acid, not ARA,
was the n-6 PUFA source in the supplement used in that
study.
In another study, the objective was to evaluate effects on
neurologic development of supplementing human milk
with oils (DSM, Heerlen, The Netherlands) that provided
an extra 32 mg of DHA and ARA per day.
34
This interven-
tion started 1 week after birth and continued until hospital
discharge. Interestingly, DHA content of the control hu-
man milk was high (0.7% total fatty acids), probably re-
lated to the high sh consumption of the mothers.
Combined with the LCPUFAs in human milk, infants re-
ceived 59 mg/kg/day of DHA and 48 mg/kg/day of ARA.
At the 6-month follow-up evaluation, the intervention
group performed better than the control group in the
problem-solving subscore of the Ages and Stages Question-
naire. An electrophysiological assessment of event-related
potentials revealed that infants in the intervention group
also had signicantly lower responses to a standard image,
indicating better recognition memory. At 20 months post-
natal age, no differences in the mental and motor develop-
ment scores of the Ages and Stages Questionnaire or in the
Mental Development Index (MDI) score of the Bayley
Scales of Infant Development
38
were observed; however,
plasma DHA concentration at discharge was positively cor-
related with Bayley MDI score. The intervention group had
better results at 20 months in the free-play sessions, sug-
gesting positive effects from supplementation on functions
related to attention. Furthermore, plasma DHA concentra-
tion at discharge was positively correlated with sustained
attention.
38
The third study was designed to compare the effects of
a high versus a standard DHA intake (ie, 1% vs 0.35% total
fatty acids as DHA) with ARA intake kept constant. This
study included breastfed and formula-fed infants. Mothers
who provided breast milk took capsules containing 3 g of ei-
ther tuna oil (900 mg DHA) or soy oil (no DHA), resulting
in milk with either high or standard DHA content. A for-
mula with matching high versus standard DHA concentra-
tions was used for infants who required supplementary
feeds. The feeding regimen was started between days 2 and
5 after birth and maintained until expected term. All infants
received a standard term formula with DHA after the ex-
pected term. Visual acuity was signicantly improved at 4
months corrected age in the high-DHA group.
37
At 18
months there were no overall differences in the MDI or
the Bayley Psychomotor Developmental Index, but fewer in-
fants had an MDI score <70.
35
Infants who weighed <1250 g
and were fed the high-DHA diet had a higher MDI score
than controls (mean difference, 4.6; 95% CI, 0.1-9.0; P <
.05), but the difference was not signicant when gestational
age at delivery, sex, maternal education, and birth order
were taken into account. Girls fed a high-DHA diet had
higher MDI scores and were less likely to have mild or sig-
nicant developmental delay than control girls. This effect
was not seen in boys. Finally, the early advantage in visual
and cognitive functions did not translate into any clinically
meaningful change in language development or behavior
when assessed in early childhood.
39
Giving very low birth weight infants larger doses of DHA
appears to be safe and may provide further health benets
for functions beyond development. One trial found a reduced
incidence of oxygen treatment at 36 weeks in the high-DHA
group compared with the standard-DHA group,
35
which can
be interpreted as a short-term benet of high DHA doses.
Overall, the studies published to date indicate that greater
DHA supplementation is associated with better neurologic
outcomes. One study suggested that the smallest infants,
which are the most vulnerable to DHA deciency, are those
the most likely to reap the greatest benet from high-dose
supplementation.
35
The observation that a nonsignicant
difference in mean MDI translates to fewer infants with
a low MDI score suggests that low development score are
at least in part, due to early nutritional deciencies.
Table II. Visual acuity and development outcome results with DHA supplementation in preterm infants
Reference Site
Age,
weeks n Groups Duration Age Outcomes
Fewtrell et al (2004)
33
United
Kingdom
25-34 238 DHA 0.5% + g-LA versus
no LCPUFAs
Up to 9
months CA
18 months CA No overall difference in Bayley
MDI and Psychomotor
Development Index; higher
Bayley MDI in boys
Smithers et al (2008)
30
Australia 27-31 657 DHA 1% versus DHA 0.30%
(no difference in ARA)
Days 2-5 until
due date
2 and 4
months CA
No difference in visual acuity
at 2 months; higher visual
acuity at 4 months
Makrides et al (2009)
35
18 months CA No overall difference in Bayley
MDI and Psychomotor
Development Index; fewer
severe mental delay; higher
MDI in girls; higher MDI
(unadjusted analysis only)
and fewer mild mental delay
in infants with birth weight
<1250 g
39
26 months CA;
3-5 years CA
No difference in language
development; no difference
in behavior
Henricksen et al (2010)
34
Norway 141 DHA 59 mg/kg/day + ARA
45 mg/kg/day versus
DHA 32 mg/kg/day + ARA
22 mg/kg/day
1 week until
discharge
6 months CA Higher problem solving subscore
at the ages and stages
questionnaire; better
recognition memory at the
event-related potential test
Westerberg et al (2011)
38
20 months
postnatal age
No difference in Bayley MDI, but
signicant correlation between
plasma DHA concentration
at discharge and MDI; better
attention capacity at the
free-play session test
CA, corrected age.
Shown are results of visual acuity and development outcome assessments of randomized controlled trials using DHA supplementation in preterm infants at a dose exceeding 0.4% of total fatty
acids. DHA and ARA are expressed as % total fatty acids.
Although DHA supplementation beyond discharge and/or
expected term is recommended,
40
one of the trials did not use
such a strategy.
35
This may explain, high-dose versus
standard-dose DHA supplementation failed to signicantly
improve the development outcome of the whole cohort, par-
ticularly when the assessment was performed long after the
period of supplementation. It also should be noted that
none of the regimens studied prevented the early DHA decit
due to parenteral nutrition.
41
This early DHA decit during
the parenteral nutrition phase may have contributed to the
impaired developement at 18 months of age.
Assessment of Status and Current Practices
LCPUFA Composition: Human Milk
The fat and fatty acid content of human milk is known to be
highly variable. For example, fatty acid composition varies
among countries, from woman-to-woman, by duration of
gestation and stage of lactation, throughout the day, and dur-
ing a feeding. This variability may be of little signicance for
a healthy term infant, but it presents more of a risk to the pre-
term infant, whose feedings are delivered articially and con-
trolled by a medical team.
The fatty acid composition of human milk is known to
vary worldwide. Variability is greater for ALA and DHA
than for LA and ARA.
42,43
The LA content of human milk
ranges from 7.9% in the Philippines to 17.8% in Chile,
a <2.5-fold difference. ALA has a 5-fold disparity, ranging
from 0.43% in the Philippines to 2% in China. The world-
wide mean (SD) concentration of DHA in breast milk
(by weight) is 0.32% 0.22% (range, 0.06%-1.4%), and
that of ARA is 0.47% 0.13% (range, 0.24%-1%).
44
Mothers
who live in coastal areas or on islands produce milk with the
highest DHA levels. Mothers who live away from the coast
and/or in developed countries consume fewer marine foods
and produce milk relatively low in DHA. Human milk re-
sponds to changes in the maternal diet, and LCPUFA supple-
mentation increases DHA concentration in milk.
Fatty acid composition of human milk varies by stage of
lactation and duration of gestation. Total fat, LA, and ALA
increase and DHA and ARA decrease as milk transitions
from colostrum to mature milk. There are no important dif-
ferences between full-term and preterm human milk in terms
of total fat, most saturated and monounsaturated fatty acids,
or the EFAs LA and ALA.
45
Preterm milk may contain
a slightly higher proportion of medium- and intermediate-
chain fatty acids than term milk, which may be advantageous
for fat and calcium absorption in preterm infants. Composi-
tional differences in LCPUFA levels between term and
preterm milk are of interest. As in full-term milk, con-
centrations of both DHA and ARA in preterm milk decrease
over the rst 3-5 weeks of lactation. Some studies have re-
ported more ARA and/or DHA in preterm milk than in
full-term milk, whereas other studies have reported the op-
posite.
45
In terms of percent contribution to total fatty acids,
however, DHA is often higher in preterm milk than in full-
term milk.
45
The reported ranges of DHA and ARA values in preterm
human milk are summarized in Table III. Based on the
values presented in Table III, the estimated mean (SD)
concentration of DHA in preterm human milk (by weight)
is 0.33% 0.10% (range, 0.22%-0.55%), and that of ARA
is 0.55% 0.09% (range, 0.44%-0.69%). These values are
very similar to those reported in full-term human milk.
44
Banked human milk may be fed to preterm infants when
their mothers own milk is unavailable or insufcient. The es-
timated mean fat content in banked human milk is 3.2 g/100
mL, somewhat lower than the generally accepted value for
mature human milk.
46,47
This may be related to inadequate
emptying of the breast during pumping. The LCPUFA con-
tent of banked human milk appears to be similar to that of
mature milk. Pasteurization and storage of banked human
milk induces lipolysis, inactivates bile saltstimulated lipase
and lipoprotein lipase, reduces fats, and increases the abso-
lute amount of free fatty acids in pooled samples. These ef-
fects alter the integrity of human milk and may contribute
to slower growth in preterm infants fed banked milk versus
their mothers own milk.
7
LCPUFA Composition: Infant Formula Products
Commercial infant formulas marketed for preterm infants
vary in fat quantity and quality. Total fat ranges between
Table III. Composition of LCPUFA in milk from mothers of preterm infants
Reference Site Age, weeks n
% total fatty acids
Sampling time point(s) DHA ARA
36
Australia <33 21 0.26 0.45 Pooled; 26-40 weeks
Clandinin et al (1997)
54
Canada 28-34 25 0.3 0.54 <42 days of life
Jacobs et al (1996)
55
Netherlands 30-35 5 0.4 0.6 Third week of life
Carnielli et al (1998)
9
Netherlands 27-33 20 0.26 0.48 28 days of life
Beijers and Schaafsma (1996)
56
Netherlands 26-36 65 0.32 0.49 Mean colostrum, 1 week; transitional,
2 weeks; mature, >2 weeks
Bitman et al (1983)
57
US 26-36 46 0.22 0.56 42 days of life
Luukkainen et al (1995)
58
Finland 25-33 23 0.4 0.44 Mean, 5 samplings over 3 months
Genzel-Boroviczeny et al (1997)
59
Germany 24-33 19 0.32 0.59 Mean, 4 samplings over 1 month
Rueda et al (1998)
60
Spain 33-36 6 0.55 0.69 Mean colostrum, 1 week; transitional,
2 weeks; mature, >2 weeks
Kovacs et al (2005)
61
Hungary 23-33 8 0.27 0.66 Mean, 5 samplings over 3 weeks
3.8 and 4.2 g/dL, provided by a combination of long-chain
triglycerides and MCTs. Up to 40%-50% of total fat may
come from MCTs. Preterm infant formula is routinely sup-
plemented with commercially available sources of LCPUFA,
so that the fatty acid composition resembles that of human
milk. Most of the LCPUFA oils added to infant formulas
are derived frommicroorganisms; however, some are derived
from a combination of low-EPA sh oil as a source of DHA
and oil from microorganisms as a source of ARA.
LCPUFA Intake from Infant Feedings
The estimated DHAaccretion rate is 45 mg/kg/day during the
last trimester of gestation.
3
Most contemporary intravenous
lipid emulsions provide little if any LCPUFAs. Human milk
and formulas designed for preterm infants contain DHA
and ARA, but arguably in insufcient amounts to compensate
for an accumulated decit. Consequently, preterm infants
who receive many weeks of parenteral nutrition followed by
human milk and/or commercial preterm formula may accu-
mulate a DHAdecit of up to 50%of the normal rate.
41
Table
IV compares DHA and ARA intakes from selected enteral
feedings given to preterm infants. Assuming an average fat
content of 3.9 g fat/dL in human milk, milk with 0.2%-
0.4% fatty acids as DHA would provide a 1-kg preterm
infant fed at full enteral feeds of 180 mL/day with only 14-
28 mg DHA/kg/day, an amount clearly below the in utero
accretion rate of 45 mg/kg/day.
LCPUFA Status: Insights from Studies with High
Doses of DHA
The effect of milk DHA on preterm infant plasma or erythro-
cyte DHA depends largely on dose.
36
Milk that contains
0.8% DHA provides an intake of 45 mg/kg/day, assuming
a human milk fat content of 3.7% and a volume intake of
150 mL/kg/day. In the study by Smithers et al,
36
milk DHA
content ranged from 0.2% to 1.25% of total fatty acids
(assumed to represent 11-67 mg/kg/day), and there was a di-
rect relationship between milk DHA content and erythrocyte
DHA content. At a milk DHA content of >0.8% of fatty acids
(45 mg/kg/day), none of the infants had an erythrocyte
DHA concentration <6% at expected term, but at a milk
DHA content of 1% (54 mg/kg/day), the erythrocyte
DHA concentration ranged between 6.5% and 9%, within
the range expected in term infants at birth.
2,3
The DHA in-
take of the control infants (ie, 32 mg/kg/day) in the study
of Henriksen et al
34
did not prevent a decline in plasma
DHA concentrations, conrming that intake below the fetal
accretion rate is inadequate to maintain normal DHA status
in preterm infants.
34
In the intervention group of the same
study, preterm infants received 59 mg DHA/kg/day, which
increased plasma DHA concentration by 12% from the
time of study inclusion to hospital discharge. Assuming
a DHA intestinal absorption rate of 80%, DHA intake be-
tween 55 and 60 mg/kg/day provides DHA at a rate match-
ing the fetal accretion rate.
In terms of ARA intake, the aforementioned studies dif-
fered greatly. In one study, ARA supplementation was given
at a dose similar to that of DHA,
34
whereas in another study
no ARA supplementation was given.
36
Consequently,
changes in ARA status during the DHA supplementation
period differed between these studies. A dramatic decline
in ARA status was observed when milk ARA content was
0.5% of total fatty acids
36
; in contrast, ARA status was sta-
ble when similar doses of ARA and DHA were used.
34
Ad-
ditional studies are needed to determine the potential
effects of these changes on ARA status, but because no de-
crease in ARA status is observed during fetal life, such bio-
logical effects in preterm infants probably should be
avoided. Because the DHA:ARA ratio varies widely in
term milk
44
and preterm milk,
48
future research should fo-
cus on dening individual DHA and ARA needs rather than
an optimal DHA:ARA ratio.
Finally, the studies cited here provide clues on how to
increase LCPUFA intake in human milk-fed preterm
Table IV. Estimated LCPUFA intake at 120 kcal/kg/day from various forms of human milk and preterm infant formulas*
Total fat, g/100 mL
LCPUFA, % total fatty acids LCPUFA, mg/100 mL LCPUFA intake, mg/kg/day LCPUFA absorbed, mg/kg/day
DHA ARA DHA ARA DHA ARA DHA ARA

Human milk
Full-term 4.2
z
0.32
x
0.47
x
13.4 19.7 24.2 35.5 19 28
Preterm 3.9
z
0.33
{
0.55
{
12.9 21.4 23.2 38.6 18 31
Banked 3.2** 0.32
0.47
10.2 15.0 18.4 27.1 15 22

Fortied 4.4
zz
0.33
xx
0.55
xx
12.9 21.4 19.3 32.2 15 26
Formula
Standard
{{
3.6 0.24 0.52 8.6 18.7 15.6 33.7 12 27
Preterm
{{
4.2 0.3 0.55 12.6 23.1 18.9 34.6 15 28
*Full-term, preterm, and banked human milk and standard formula assume 20 kcal/oz and 180 mL/kg/day; fortied and preterm formula assume 24 kcal/oz and 150 mL/kg/day.
Intestinal absorption, 80%.
9
zData from Lawrence (1995).
62
xData from Brenna et al (2007).
44
{See Table I.
**Data from Wojcik et al (2009).
46
Assuming fatty acid concentrations of full-term milk.
63
zzAssuming the fat content of preterm milk
62
plus 0.5 g fat/100 mL from non-LCPUFA-containing fortier
xxAssuming fatty acid concentrations of preterm milk.
{{Mean of preterm formula products available in the US.
infants. In one study, sh oil was given to lactating
mothers to increase the DHA content of their milk. Sup-
plementing mothers with the appropriate amount of tuna
oil increased human milk DHA concentrations to the de-
sired level with only a small increase in EPA and no
change in ARA levels.
48
However, despite its physiological
basis, this strategy leads to large variations in the DHA
content of human milk, with values as low as 0.3% and
as high as 2.5% observed. Furthermore, this strategy
does not allow supplementation with both ARA and
DHA concomitantly. Adding DHA with or without ARA
directly into the feeding is likely to be the most reliable
technique for delivering adequate amounts of DHA to
preterm infants.
Previous LCPUFA Recommendations
Various regulatory bodies, professional organizations, and
expert panels have issued recommendations and consensus
statements on LCPUFA intake for preterm infants. These rec-
ommendations rely on the composition of human milk and
the results of decades of research related to LCPUFA intake
and blood and tissue levels, anthropometric parameters,
and visual and neurocognitive outcomes. Evidence supports
the superiority of human milk and the safety of supplement-
ing formulas with DHA and ARA in amounts similar to those
found in human milk.
49
Table V summarizes Previous recommendations.
Interestingly, in 2002 the Expert Panel of the Life Sciences
Research Organization did not recognize a need for
LCPUFAs and did not recommend a minimum content of
ARA, DHA, or EPA for preterm infant formulas at that
time. Just 3 years later, Koletzko and Innis
1
recognized the
essentiality of ARA and DHA and proposed a minimum
value for the requirements of preterm infants. More
recently, the European Society for Pediatric Gastro-
enterology, Hepatology, and Nutrition did not change the
recommendations, but rather expressed them as mg/kg/day
instead of percentage of total fatty acids.
50
Updated Recommendations for LCPUFA
Intake in Preterm Infants
Breastfeeding
In agreement with other reports, we strongly endorse human
milk as the preferred food source for preterminfants. We em-
phasize, however, that fortiers and supplements must be
used appropriately to meet the specic needs of preterm in-
fants, especially very preterm infants. The DHA content in
human milk is highly variable, mainly because of variations
of maternal diets. Nutritional counseling during the lactation
period is recommended to ensure optimal mothers intake of
omega-3 fatty acids.
Fat, EFA, and MCT Intake
There are no new data since the recommendations of 2010 to
modify the recommendations for total fat intake, EFAs, and
MCTs for preterm infants.
1
DHA
Given the limited and highly variable formation of DHA
from ALA, and the critical role of DHA in normal retinal
and brain development in humans, DHA should be consid-
ered conditionally essential during early development. Early
deprivation of DHA should be identied early and treated
aggressively, because it is not known denitively if
Table V. Recommendations for enteral LCPUFA in preterm infants
Life Sciences Research
Organization, 2002* Koletzko and Innis, 2005
European Society for Pediatric Gastroenterology,

Hepatology, and Nutrition, 2010
z
Current
LA (C18:3n-3)
% total energy - 3.2-12.8 3.2-12.8 3.2-12.8
mg/100 kcal 352-1425 352-1425 350-1400 350-1400
mg/kg/day - 600-1680 385-1540 385-1540
% total fatty acids 8-25 8-25 - -
ALA (C18:2n-6)
% total energy - 0.7-2.1 $0.45 $0.45
mg/100 kcal 77-228 77-228 $50 $50
mg/kg/day - - $55 $55
% total fatty acids 1.75-4 1.75-4 $0.9 $0.9
LA:ALA 6-16:1 6-16:1 5-15:1 5-15:1
ARA (C20:4n-6)
mg/100 kcal - - 16-39 -
mg/kg/day - - 18-42 18-45
% total fatty acids #0.6 0.3-0.7 - -
DHA (C22:6n-3)
mg/100 kcal - - 11-27 -
mg/kg/day - - 12-30 12-60
% total fatty acids #0.35 0.2-0.5 - -
ARA:DHA 1.5-2:1 1.2-2:1 1-2:1 -
EPA (C20:5n-3) #30% DHA #30% DHA #30% DHA #20 mg/kg/day
*Klein (2002).
64
Koletzko and Innis (2005).
1
zAgostoni et al (2010).
50
a transient decit can be compensated for with regard to
central nervous system growth and maturation. We empha-
size that current nutritional management does not provide
sufcient amounts of preformed DHA during the paren-
teral and enteral nutrition periods and in very preterm/
very low birth weight infants until the due date. Nutrient
recommendations should be expressed as absolute amount
per kg/day rather than as a proportion of total fatty acids,
because the latter applies only if full enteral feeding is
reached. The fetal accretion rate of DHA is approximately
45 mg/kg/day. Greater amounts may be needed to compen-
sate for intestinal malabsorption, DHA oxidation, and early
decit. On the other hand, the amount of DHA that can be
synthesized endogenously by preterm infants is unclear.
DHA intakes of 55-60 mg/kg/day from the time of preterm
birth to expected term have been tested and appear to be
safe, to promote normal DHA status, and to improve vi-
sual and neurocognitive functions. These values are likely
to represent an adequate intake for very preterm infants,
but further research is needed to conrm that they repre-
sent adequate intake for all infant groups (ie, extremely,
very, and moderately preterm infants, with or without in-
trauterine growth restriction, and males and females). Be-
cause the maximum DHA content of human milk is
>1.5% of fatty acids (equivalent to 84 mg/kg/day),
51
and
because no studies with such a high intake in preterm
infants have been reported, no upper limit can be set
with certainty.
ARA
Preformed ARA should be provided to ensure adequate ARA
levels during the period of DHA supplementation. Limited
data are available to dene the necessary ARA dose with cer-
tainty. When a high dose of DHA is provided, 45 mg/kg/day
of ARA has been shown to support growth and normal ARA
status.
EPA
Limited data are available to identify whether there is any
benet to including EPA in the diet of preterm infants.
Thus, we recommend an EPA intake not exceeding 20 mg/
kg/day, which is the mean + 1 SD amount of EPA provided
daily by human milk when fed at 180 ml/kg/day.
48
Duration of Supplementation
The recommendations for DHA, ARA, and EPA specied
above should be continued until the infant reaches the
expected due date. After the expected due date, recommen-
dations for term infants should be applied.
52
Research is
needed to examine whether LCPUFA supplementation after
the due date may provide additional benets.
Gaps in Knowledge and Recommendations
for Future Research
Future research should consider short- and long-term ef-
fects of LCPUFA status of preterm infants before and after
the due date according to interindividual differences, such
as genetic variations in fatty acid desaturase activities or
sex. Investigators are encouraged to address subgroups
that have specic needs and benets, such as extremely
preterm infants and preterm infants with intrauterine
growth retardation, extrauterine growth retardation, bron-
chopulmonary dysplasia, or prolonged parenteral nutri-
tion. Supplementation studies should be designed to
examine growth, body composition, visual and cognitive
development, attention and behavioral disorders, and ef-
fects on immune outcomes and cardiovascular function.
Studies evaluating the effects of different amounts of
LCPUFAs and the specic effects of ARA supply, with suf-
cient duration of intake, adequate sample sizes, and stan-
dardized methodology for outcome measurements,
warrant careful consideration. Future studies should evalu-
ate various DHA levels to dene dose-response relation-
ships and elucidate potential immediate and long-term
benets and safety issues. The most effective mode of de-
livering LCPUFAs (ie, through supplementation of the
mother, supplements mixed in milk, and/or enriched for-
tiers) also merit further evaluation. n
We thank Mrs Gretchen Duenas and the Association pour la
Recherche et la Formation en Neonatologie (ARFEN) for providing
technical assistance and Professors Jean-Charles Picaud, MD, PhD,
and Bernard Salle, MD, for providing additional balance study
data.
Author Disclosures
Ricardo Uauy, MD, PhD, chaired the Symposium on Nutri-
tion of the Preterm Infant. Mead Johnson Nutrition paid his
travel expenses and provided an honorarium for contribut-
ing to, organizing, and chairing the meeting and for his assist-
ing with the nal editing of the supplement. All authors
received honoraria from Mead Johnson Nutrition for atten-
dance, presentation, and manuscript preparation. A. L. wrote
the rst draft of this manuscript.
Reprint requests: Alexandre Lapillonne, MD, PhD, Professor of Pediatrics,
Department of Neonatology, Necker Hospital, 149 rue de Sevres, 75015 Paris,
France. E-mail: alexandre.lapillonne@nck.aphp.fr.
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2002;132:1395S-577S.
Selected Macro/Micronutrient Needs of the Routine Preterm Infant
1
, Ian Grifn, MD
2
, Diane Anderson, PhD, RD
3
, Neelam Kler, MD
4
, and Magnus Domell
of, MD, PhD

5
Requirements for optimal nutrition, especially for micronutrients, are not well dened for premature infants. The ref-
erence fetus, developed by Ziegler et al,
1
has served as a model to dene nutritional needs and studies designed to
determine nutrient requirements. Revision of nutrient requirements and provision of optimal nutrition may lead to
improved outcomes in preterm infants. Appropriate provision of nutrients also may help prevent nutritional disor-
ders, such as metabolic bone disease and anemia. In this review, we discuss calcium, phosphorus, magnesium,
vitamin D, iron, and copper, and dene optimal intakes based on the available published data. (J Pediatr
2013;162:S48-55).
O
ptimal micronutrient requirements for preterm infants are not well dened. Increasing numbers of these infants sur-
vive after birth at progressively lower gestational ages. It is important to dene micronutrient needs and provide
appropriate amounts of these nutrients to prevent nutritional disorders, such as metabolic bone disease and neonatal
anemias. In this article we reviewcurrent data frompreterminfants and recommend the micronutrient intake necessary to meet
the estimated requirements for calcium, phosphorus, magnesium, vitamin D, copper, and iron.
Calcium and phosphorus homeostasis and formation of bone matrix are complex processes that require an adequate supply
of protein and energy, as well as calcium, phosphorus, magnesium, and vitamin D. Vitamin D is important for bone miner-
alization, supports physiological processes that affect neuromuscular and immune functions, and plays a role in the heart, lung,
pancreas, and brain. Iron is the oxygen-binding moieity of hemoglobin and myoglobin, which are essential for oxygen trans-
port. It is also a cofactor for cytochrome C and other enzymes, which are necessary for cellular energy metabolism. Iron is crit-
ically important for normal brain development, including myelin formation and neurotransmitter synthesis. Zinc is essential
for multiple enzymes involved in gene expression, signal transduction, apoptosis, cellular proliferation, differentiation, and
growth. Copper is essential for enzymes in the electron transport chain and the antioxidant systems; anemia, neutropenia,
and osteoporosis may result from copper deciency.
Background: Calcium, Phosphorous, Magnesium, and Vitamin D
Physiology of Mineral Accretion and Bone Formation
The majority of fetal mineral accretion occurs during the third trimester.
1
Peak calciumaccretion rate, typically 120-160 mg/kg/
day (3-4 mmol/kg/day) in late gestation, is maintained through active transplacental calcium inux. Parathyroid hormone
(PTH), PTH-related peptide, and 25-hydroxy vitamin D [25(OH)D] play important roles in the transplacental transport of
calcium and bone remodeling.
2
After birth, dramatic physiological changes in bone metabolism result from disruption of
the maternal mineral supply, stimulation of calciotropic hormone secretion, changes in the hormonal environment, and a rel-
ative reduction in mechanical stress. These events stimulate the remodeling process, leading to increased bone resorption and
decreased bone density.
3
Calcium, Phosphorus, and Magnesium Intake
Low birth weight (LBW) infants, either preterm or infants with intrauterine growth restriction, have signicantly lower calcium
and phosphorus stores compared with infants who are born at termand appropriate for gestational age. This might be the result
of low total body mineral content at birth, which is subsequently worsened by a suboptimal postnatal dietary calcium supply,
transient hypoparathyroidism, lack of mechanical stimulation, and the use of diuretics and other calciuric drugs.
Estimated daily enteral calcium and phosphorus requirements in preterm infants are 120-230 and 60-140 mg/kg/day, respec-
tively. These values may be overestimates, however, because the unique postnatal environment of preterm infants might modify
their mineral needs. Bone accretion in early infancy is not likely to occur at rates observed during the third trimester in utero.
Furthermore, bone remodeling increases after birth, and released minerals be-
come available to the pool of precursors necessary for early postnatal bone
growth and turnover. Recent studies suggest that calcium retention in the range
From the
1
Medical College of Georgia, Georgia Health
Sciences University, Augusta, GA;
2
University of
California Davis Medical Center, Sacramento, CA;
3
Baylor College of Medicine, Houston, TX;
4
Sir
Gangaram Hospital, New Delhi, India; and
5
Department
of Clinical Sciences, Pediatrics, Umea University, Umea,
Sweden
article.
25(OH)D 25-hydroxy vitamin D
PTH Parathyroid hormone
S48
of 60-90 mg/kg/day ensures appropriate bone mineralization
in very low birth weight (VLBW) infants.
4
An enteral intake
of 120-140 mg/kg/day will support this level of calcium reten-
tion, given an estimated absorption rate of 50%-65%.
Phosphorus accretion is linked to calcium and nitrogen
retention. Phosphorus absorption is efcient (up to 90%)
in infants fed either human milk or formula. If calcium reten-
tion is 60-90 mg/kg/day and nitrogen retention is 350-450
mg/kg/day, then phosphorus intake sufcient to meet accre-
tion by bone and soft tissues can be achieved by an intake of
65-90 mg/kg/day of a highly absorbable phosphate source,
and the resultant calcium:phosphorus would be 1.5-2.0:1.
Similar to calcium, magnesium has a high accretion rate in
utero during the third trimester. Thus, preterm infants
have a higher magnesium requirement than term infant,
estimated as 8-15 mg/kg/day.
Requirement for Vitamin D
The ideal denition of optimal vitamin D levels would be
based on functional biomarkers, such as intestinal calcium
absorption, extent of bone mineralization, and PTH concen-
trations. Recent studies based on adult vitamin D physiology
indicate that a serum 25(OH)D concentration <50 nmol/L is
consistent with vitamin D deciency, and a concentration
50-80 nmol/L is consistent with vitamin D insufciency.
25(OH)D concentrations >80 nmol/L are considered suf-
cient. However, because no similar studies in preterm infants
are currently available, values from adult and pediatric pop-
ulations are extrapolated to neonates.
Low vitamin D level is not uncommon in neonates fed ei-
ther breast milk or infant formula. Preterm neonates are at
particular risk for metabolic bone disease, for reasons that
include: difculty achieving adequate enteral intake of cal-
cium, phosphorus, and vitamin D; relative immobility; de-
pendence on total parenteral nutrition; use of unfortied
human milk; and adverse effects of medications (ie, diuretics
and steroids) administered during hospitalization. Metabolic
bone disease may be present in >50% of extremely low birth
weight (ELBW) infants and in up to 25% of VLBW infants.
Impact of Vitamin D Supplementation in Preterm
and Term Infants
Total and free 25(OH)D concentrations in cord blood of
preterm and full-term neonates are lower than those in ma-
ternal blood. Early supplementation with vitamin D has
been studied in neonates. Salle et al
5
evaluated 25(OH)D
levels in 17 preterm infants who received 1000 IU of vita-
min D daily from birth. Mean levels increased from 20
nmol/L (range, 10-40 nmol/L) at birth to 92 nmol/L (range,
71-116 nmol/L) at 6 months. This dosage is sufcient to
raise vitamin D levels to the desired range when adminis-
tered for 6 months. Whether this leads to any functional
benets is unclear, however. Several other clinical studies
have evaluated the relationship between vitamin D3 intake
and 25(OH)D concentrations.
6-12
These ndings support
the consensus opinion that a vitamin D intake of 800-
1500 IU/day is necessary to increase 25(OH)D concentra-
tions to above 75 nmol/L in preterm infants of mothers
with vitamin D deciency. At best, 400 IU/day of vitamin
Dthe amount recommended for term infantsis pro-
vided in some US neonatal intensive care units.
13
It is likely
that an intake far lower than this is currently provided,
given that clear criteria for vitamin D sufciency in preterm
infants have not yet been established.
Evidence from Randomized Controlled Trials
A randomized controlled trial investigating the effect of vita-
min D supplementation on bone density and biochemical
indices in preterm infants has demonstrated that doses of
200-400 IU/kg body weight/day is sufcient to maintain nor-
mal vitamin D status.
14
However, a more recent trial that
compared 3 doses (200, 400, or 800 IU/kg/day) led the au-
thors to conclude that higher doses might accelerate bone
turnover.
15
Although vitamin D provides clear short-term
benets to preterm infants, the benets of increased vitamin
Dintake on bone mineral status in preterm-born children are
no longer evident at age 9-11 years.
16
Factors Affecting Enteral Absorption of Calcium
and Phosphorus
Intestinal absorption of calcium and bone accretion are
affected by numerous factors. Calcium phosphate has low
solubility compared with calcium chloride, citrate, and car-
bonate. Organic calcium salts, such as calcium gluconate
and glycerophosphate, are more soluble and readibly
absorbed. Ahigh palmitate content in fat reduces calcium ab-
sorption, secondary to the formation of insoluble calcium
soaps.
Supplementation of human milk with phosphorus im-
proves calcium retention and reduces calciuria in infants.
Human milk has an excellent calcium:phosphorus and,
thus, high bioavailability; however, it is relatively low in
calcium and phosphorus and requires fortication to
achieve adequate mineralization in preterm infants. When
human milk fortier is provided with adequate amounts
of calcium and phosphorus, calcium retention reaches 60
mg/kg/day. The use of human milk fortiers containing
highly soluble calcium glycerophosphate improves calcium
retention by up to 90 mg/kg/day in formula-fed infants, al-
though the percentage of net calcium absorption is less
than that seen with human milk. Because the poor bio-
availability of preterm formula is compensated for by
a higher calcium and phosphorus content, routine mineral
supplementation is not required in infants fed preterm in-
fant formula.
The reported effects of vitamin D supplementation on cal-
cium absorption have been inconsistent due to differences in
study design. Bronner et al
17
showed that calcium absorption
in LBW infants was directly proportional to daily calcium in-
take and independent of vitamin D supplementation. In con-
trast, Senterre et al
18
reported that calcium absorption in
preterm infants increased from 50% to 71% when human
milk was supplemented with 1200 IU/day of vitamin D3
with no additional calcium. This latter result suggests that
Selected Macro/Micronutrient Needs of the Routine Preterm Infant S49
vitamin D supplementation supports calcium absorption.
Calcium absorption increases in a relatively low-pH environ-
ment and with a high-lactose, high-casein formula.
Assessment of Bone Mineralization
Biochemical Markers. Plasma calcium and phosphorus,
serum alkaline phosphatase, and serum osteocalcin concen-
trations and urinary excretion of pyridium cross-links of col-
lagen are used to screen for metabolic bone disease in
preterm infants; however, these markers have limitations
and cannot be considered diagnostic of osteopenia. Never-
theless, elevated serum osteocalcin concentration, coupled
with high serum alkaline phosphatase activity and increased
excretion of cross-linked collagen, has been proposed as
a marker of osteopenia in preterm infants.
Radiologic Markers. Conventional radiologic evaluation
is an insensitive method for evaluating metabolic bone dis-
ease in preterm infants givens the variations in X-ray expo-
sure, as well as quantication. Bone mineral loss must be
signicant before it can be appreciated radiologically. Efforts
to dene bone density objectively on standard radiography
using a scoring system
19
have been followed by more accurate
estimations of bone mineral content by bone absorptiometry.
Dual X-ray absorptiometry has been proven to provide the
most accurate determination of bone mineral content in pre-
term and term infants, and numerous studies have estab-
lished normative data.
Previous Guidelines
Early guidelines recommended a vitamin D dose of 200 IU/
day for : (1) all breastfed infants unless they are weaned to
at least 500 mL/day of vitamin D-fortied formula or milk;
(2) all non-breastfed infants who ingest <500 mL/day of vita-
min D-fortied formula or milk; and (3) children and adoles-
cents who do not get regular sunlight exposure, do not ingest
at least 500 mL/day of vitamin Dfortied milk, or do not
take a daily multivitamin supplement containing at least
200 IU of vitamin D
20
(Table I). These recommendations
were based on data from the US, Norway, and China that
showed an intake of vitamin D of 200 IU/day prevents
physical signs of vitamin D deciency and maintains serum
25(OH)D concentrations at 27.5 nmol/L. In contrast, in
some parts of Europe there have been reports of low cord
blood levels of 25(OH) D (<10 mg/mL) in preterm infants,
suggesting a higher required daily intake of up to 1000 IU.
The American Academy of Pediatrics guidelines, revised
in 2008, recommend an increased minimal supplementation
of 400 IU/day to mantain serum 25(OH)D levels at >50
nmol/L.
13
However, this dose might not be sufcient in
parts of world where dietary supplementation with vitamin
D is not routine, and the prevalence of vitamin D deciency
is higher. Considering the prevalence of vitamin D de-
ciency in pregnant mothers, the European Society of Pediat-
ric Gastroenterology, Hepatology, and Nutrition guidelines
issued in 2009 state that higher vitamin D supply in preterm
infants could be necessary to correct rapidly the low fetal
level.
21
A vitamin D intake of 800-1000 IU/day during the
rst months of life is recommended, as this dose may help
achieve vitamin D sufciency without risk of toxicity. These
guidelines were based on several reports that documented
vitamin D doses in sufcient ranges with supplementation
of 800-1000 IU/day.
Gaps in Knowledge
Few studies have dened vitamin D requirements objectively
in neonates, particularly in preterm neonates. Future studies
are needed to dene the threshold for adequate vitamin D
levels in neonates based on physiological functions. Guide-
lines for optimal vitamin D intake in preterm infants should
take into account maternal vitamin D intake and status, as
well as geographic, racial, and other constraints.
Copper
In Utero Copper Accretion
Factorial analysis suggests a net requirement of 30 mg cop-
per/kg/day in preterminfants is adequate to maintain normal
growth.
22
Postnatal Copper Metabolism
Concentration of copper is high in early milk and declines
with lactation.
23
Copper deciency at 5 weeks to 8 months
postnatally has been reported in preterm infants.
23-31
It is
notable, however, that most of these case reports are of in-
fants who received copper-free parenteral nutrition; there is
a paucity of similar recent reports.
Assessment of Copper Status
Copper status is estimated by measuring the plasma con-
centration of copper or ceruloplasmin, the main copper-
binding protein in plasma. Both of these indicators are
decreased in severe copper deciency but are relatively
insensitive to marginal copper deciency. The activity of
the enzyme copper-zinc superoxide dismutase in erythro-
cytes may be a more sensitive indicator of copper de-
ciency. The main clinical features of copper deciency
are anemia, thrombocytopenia, neutropenia, apnea, osteo-
porosis and other, characteristic changes in bone.
24-31
Se-
rum copper concentrations are normally <35 mg/dL, and
Table I. Recommended vitamin D supplement for
preterm infants by feeding method
Early breast
milk only
Early breast milk
with human milk
fortier (4 g/100 mL)
Preterm
formula
Suggested
intake
20-70 IU/L 903 IU/L 400-800 IU/L 400-1000 IU/day
Standard term formula in the US is supplemented with 400 IU/L of vitamin D. A term infant with
formula consumption of 1 L/day will meet the daily requirement and needs no additional
supplementation. A breastfed term infant should be supplemented with a liquid preparation of
vitamin D at a dose of 400 IU/day. A preterm infant will not be able to achieve such a high daily
intake even with preterm formula containing more than 1000 IU/L of vitamin D until he or she
weighs more than 2 kg and achieves a daily enteral intake of 160 mL/kg. Thus, a preterm
infant, whether breastfed or formula-fed, will require vitamin D supplementation in the form of
an oral liquid preparation.
S50 Bhatia et al
the ceruloplasmin concentration is <15 mg/dL in copper
deciency.
24,27,28
Previous Guidelines
The currently recommended enteral copper intake is 120-150
mg/kg/day.
21,32-34
In a comprehensive review of the nutrient
composition of preterm infant formulas, Klein
22
recommen-
ded a copper concentration of 100-250 mg/100 kcal. At an
energy intake is 120 kcal/kg/day, this recommendation is
equivalent to 120-300 mg/kg/day.
Newer Guidelines
The 9 published studies of copper balance in preterm infants
present summary data for 28 different groups of preterm
infants.
35-43
Copper intake (mean SD) was 162 128
mg/kg/day (range, 54-528 mg/kg/day), zinc intake was 1226
653 mg/kg/day (range, 511-2360 mg/kg/day), and the zinc:-
copper ratio (mg/mg) was 8.62 3.14 (range, 3.9-16.9).
To assess the effect of zinc intake on copper retention, we
performed a multiple regression analysis, weighted by the
number of subjects in each of the 28 groups. Copper reten-
tion was positively related to copper intake (P < .0001), neg-
atively related to zinc intake (P < .0001) and postnatal age
(P = .0012), and unaffected by feeding type (human milk
vs formula; P = .83). Zinc and copper intake accounted for
most of the variability in copper retention (R
2
= 0.776), as
did the full model (R
2
= 0.787). Our analysis yielded the fol-
lowing equation:
Copper retention (mg/kg/day) = 7.8148 + [0.5871
copper intake (mg/kg/day)] [0.0508 zinc intake (mg/
kg/day)].
From this model, the copper intake required to produce
copper retention of 30 mg/kg/day increases linearly with in-
creasing zinc intake (Figure 1). This retention would be
expected at a copper intake of 210 mg/kg/day if zinc intake
were 2000 mg/kg/day, and at a copper intake of 232 mg/kg/
day if zinc intake were 2250 mg/kg/day.
Gaps in Knowledge
The main gaps in our current knowledge regarding copper
requirements for preterm infants involve the effects of copper
retention from diets containing a higher zinc intake (>1.5-2
mg/kg/day) and high intake of enteral copper on liver func-
tion and serum transaminase levels in preterm infants with
and without cholestasis.
Zinc
Zinc is essential for a multitude of enzymes and plays an
important role in cellular growth and differentiation. Zinc
deciency leads to stunted growth (poor length gain),
increased risk for infection, skin rash, and possibly poor neu-
rodevelopment.
44
Assessment of Status
Marginal zinc deciency is notoriously difcult to diag-
nose, owing to the lack of a reliable biomarker.
44
Even
though serum or plasma zinc is the most commonly used
biomarker, it is not a sensitive indicator of marginal zinc
deciency.
44
Current Recommendations
Most studies of zinc requirements in preterm infants have
recommended intakes in the range of 1-2 mg/kg/day.
21,32
For formulas, these intakes are equivalent to a minimum
zinc content of 1.1 mg
22
to 1.2 mg/100 kcal,
21
and a maxi-
mum content of 1.5
22
to 1.8 mg/100 kcal.
21
Intakes as high
as 3 mg/kg/day are sometimes recommended,
23
especially
for infants who weigh <1000 g.
32
There are concerns about
higher zinc intake because of the potential adverse effect of
zinc on copper absorption, however,
44
and a zinc:copper of
<20:1 is recommended for preterm infants.
21
Gaps in Knowledge
There remain large gaps in our knowledge of zinc require-
ments in preterm infants. Areas of uncertainty include:
(1) the in utero zinc accretion rate in the fetus; (2) the opti-
mal accretion rate in postnatal preterm infants; (3) bioavail-
ability and retention of zinc contained in human milk
fortied with modern human milk fortiers and in modern
formulas; (4) effects of zinc intake on the absorption of other
minerals (eg, iron and copper) in preterm infants; (5) effect
of other minerals (eg, iron, copper) on the absorption of
zinc intake in preterm infants; and (6) effect of fat absorption
on zinc absorption in preterm infants.
In Utero Zinc Accretion
In a comprehensive appraisal of nutrient requirements in
preterm infants, Klein
22
estimated zinc requirements in
preterm infants using a factorial method. The requirement
for retained zinc (ie, the amount by which that zinc ab-
sorption must exceed zinc losses) was estimated to be
Figure 1. Interrelationship of copper and zinc intake. The
copper intake (mean and 2 SD) required to achieve a copper
retention of 30 mg/kg/day is shown for different zinc intakes.
Also shown are the current range of intakes recommended
by Tsang et al,
32
Agostoni et al,
21
and Klein.
22
approximately 400 mg/kg at 1500-2500 g (30-32 weeks of
postconceptional age).
22
Metabolic Balance Studies
The 14 reports on zinc balance in preterm infants published
to date
35-43,45-49
present summary data for a total of 35 dif-
ferent groups from studies examining infants at several dis-
tinct time points or with several different diets. When the
analysis is weighed for the number of individuals in each
group, zinc retention is positively correlated with zinc in-
take (P = .0401), is greater in formula-fed infants compared
with human milk-fed infants (P = .0085), and is unaffected
by either gestational age (P = .44) or postnatal age (P = .30)
(Figure 2).
If we assume that a zinc retention of 400 mg/kg/day is
optimal, based on Kleins data for infants weighing 1500-
2500 g, then a zinc intake of 2200 mg/kg/day is required in
formula-fed infants and an intake of 2025 mg/kg/day is
required in human milk-fed infants to meet that requirement
for absorbed zinc. These intakes are equivalent to 1.7-1.9 mg/
100 kcal. Assuming an energy intake of 120 kcal/kg/day, this
is equal to 1.3-1.5 mg/100 mL of an 80-kcal/100 mL formula
or 1.1-1.3 mg/100 mL of a 67-kcal/oz formula.
Supplementation Trials
Fewstudies have examined the effect of zinc supplementation
in preterm infants (Table II).
50-54
The most relevant of these
is the study by Friel et al,
54
who randomized 52 VLBW infants
to receive 66 kcal/100 mL of formula containing either 0.67
or 1.1 mg/100 mL zinc starting at 1 month before discharge
and continuing until 6 months after discharge. These formu-
las would be expected to provide approximately 1.2 or 2.0
mg/kg/day zinc (assuming an energy intake of 120 kcal/kg/
day). The group with the higher zinc intake demonstrated
improved linear growth (but no differences in weight gain
or head circumference increase), higher motor scores, and
(at some time points) higher plasma zinc concentrations.
54
These results suggest that the higher zinc intake (in line
with our estimate from metabolic balance data) is preferred
over a lower zinc intake.
Safety of Higher Zinc Doses
Zinc is a relatively nontoxic mineral.
44
The Institute of Med-
icine reviewed dietary reference intakes and identied the
potential adverse effect of oral zinc on copper absorption
as the most likely adverse effect of high zinc intake.
44
Based
on data from balance studies,
35-43,45-49
we conclude that
a zinc intake of 2.0-2.25 mg/kg/day is required to ensure an
adequate zinc retention of 400 mg/kg/day.
Iron
Preterm and LBW infants are at high risk for iron deciency.
Iron is necessary for brain development, and iron deciency
anemia in infants is associated with poor neurodevelopment.
In contrast to most other nutrients, however, there is no
mechanism for excretion of iron from the human body.
Excessive iron supplementation may increase the risk of in-
fections, cause poor growth, and interact with absorption
and metabolism of other minerals. Furthermore, iron is a po-
tent pro-oxidant, and iron overload may lead to free radical
disorders. Thus, it is important to avoid both iron deciency
and iron overload in preterm infants.
Estimated Iron Requirements
Owing to the physiological shift of iron from hemoglobin
into iron stores that occurs in newborns, a healthy term in-
fant is initially independent of exogenous iron and is able to
double its birth weight before iron stores are depleted.
Preterm and LBW infants have higher iron requirements
because of more rapid postnatal growth; small preterm in-
fants double their birth weight at 6-8 weeks, whereas term
infants do not achieve this until approximately 4-6 months
of age.
Figure 2. Relationship between zinc intake and zinc reten-
tion. Mean zinc intake (mg/kg/day) and zinc retention (mg/
kg/day) reported in previous studies.
35-43,45-49
For formula-
fed infants, y = 0.1358x + 100.6 (R
2
= 0.12); for human milk-
fed infants, y = 0.450x 510.2 (R
2
= 0.12).
Table II. Summary of signicant ndings from zinc
supplementation trials in preterm infants
Reference
Low zinc
intake,
mg/kg/day
High zinc
intake,
mg/kg/day
Signicant
differences,
high versus
low intake
Haschke et al (1985)
51
0.17* 0.48* \ serum zinc
Loui et al (2004)
52
0.3-0.4
0.6
None
Diaz-Gomez
et al (2003)
53
0.55-0.71 0.94-1.43 \ serum zinc
\ red cell zinc
\ linear growth
Friel et al (1993)
54
1.1-1.2
1.9-2.2
\ serum zinc
\ linear growth
\ motor scores
Trials are ranked in increasing order of zinc intake in the high-zinc group.
*Assuming calorie intake of 120 kcal/kg/day.
At 6 weeks and at 3 weeks.
At 3 months and at the start of the study.
S52 Bhatia et al
Using a factorial approach, estimated iron requirements
for preterm infants with a birth weight of 1 kg are 1.4-2
mg/kg/day during the rst year of life. However, these esti-
mates do not consider blood losses and blood transfusions,
which greatly inuence iron status and iron requirements
in small preterm infants. Delayed umbilical cord clamping
causes blood to ow from the placenta to the newborn and
is associated with fewer blood transfusions and reduced inci-
dence of intraventricular hemorrhage in preterm infants.
Local practice regarding umbilical cord clamping, blood
sampling, blood transfusions, and erythropoietin treatment
greatly inuences iron requirements of preterm infants dur-
ing the rst months of postnatal life.
Iron Absorption
Preterm infants absorb 25%-40% of iron from iron supple-
ments given between feedings and 11%-27% of iron from
iron-fortied preterm formula, rates exceeding those seen
in term infants. Studies on iron bioavailability from
multinutrient-fortied human milk are lacking.
Randomized Controlled Trials
Relatively few randomized studies comparing different doses
of iron supplements or fortication of human milk or for-
mula given to preterm or LBW infants have been published
to date.
Iron versus Placebo. A meta-analysis of studies pub-
lished before 1992 showed that prophylactic iron given as
a supplement or in iron-fortied formula leads to signi-
cantly reduced incidence of anemia at 6 months in preterm
infants.
55
An enteral iron dose of 2 mg/kg/day was used in
that study. In a recent randomized controlled, blinded trial
(n = 285), Berglund et al
56
showed that iron supplements of
2 mg/kg/day given from 6 weeks of age reduced the risk of
iron deciency anemia at age 6 months in marginally LBW
infants (2000-2500 g). No adverse effects with regard to
infant growth, infection, or other morbidity were reported.
A recent follow-up of these children found that those sup-
plemented with 1-2 mg of iron per kg/day up to age
6 months exhibited signicantly fewer behavioral problems
at age 3 years.
57
Different Iron Doses. Several randomized controlled tri-
als have investigated the effects of preterm formulas contain-
ing different amounts of iron. All of these trials included
preterm infants with an average birth weight of 1.4-1.5 kg.
In one trial, an iron intake of 1.3 mg/kg/day resulted in higher
iron stores compared with an intake of 0.3 mg/kg/day, even
though the incidence of iron deciency (dened as serumfer-
ritin <19 mg/L) at 2 months postdischarge was similar in both
groups (32%).
58
A similar study found no difference in iron
status between preterminfants receiving 0.9 mg/kg/day or 1.2
mg/kg/day, and there were no cases of iron deciency anemia
at age 6 months.
59
In another study, the 2 intervention
groups (high-iron and low-iron) had iron intakes of 5.9
and 3.0 mg/kg/day, respectively, at discharge and approxi-
mately 3 and 2 mg/kg/day, respectively, at age 3-9 months.
That study found no difference in neurodevelopment or in
the prevalence of anemia at age 12 months, but the high-
iron group had higher glutathione peroxidase concentrations
(a marker of oxidative stress), lower plasma zinc and copper
levels, and a higher rate of respiratory tract infections, sug-
gesting possible adverse effects of the higher iron concentra-
tions.
60
In an iron supplementation trial in LBW infants (average
birth weight 2000 g), iron intake ranged from 1.0-1.6 mg/
kg/day to 3.6-6.8 mg/kg/day. Serum ferritin level was higher
at 20 weeks, but erythrocyte superoxide dismutase activity
was reduced in the high-iron group, suggesting that high
iron intake could alter copper metabolism. Furthermore,
there was no signicant difference in hemoglobin concentra-
tion between the groups at 20 weeks.
61
The study by Berglund et al
56
found signicant differ-
ences in iron status at 6 months between marginally
LBW infants (2000-2500 g) who had received 1 or 2 mg/
kg/day of iron between 6 weeks and 6 months of life. How-
ever, there were no signicant differences in the proportion
of infants with iron deciency or iron deciency anemia in
the 2 groups. Furthermore, a secondary analysis taking
compliance and diet into account showed that an actual
dietary iron intake of 1 mg/kg/day effectively prevented
iron deciency.
Timing of Iron Supplementation. Older studies have
shown that early iron supplementation does not improve
early anemia of prematurity (before 2 months), which is
believed to be caused by immature erythropoiesis rather
than by iron deciency.
55
However, 2 recent studies
have suggested that initiation of iron supplementation
or fortication at age 2 weeks, compared with 6-8 weeks,
leads to a reduced need for blood transfusions in VLBW
infants.
62,63
Previous Guidelines
In 2002, Klein
22
recommended an iron intake of 2-3.6 mg/kg/
day (1.7-3.0 mg/100 kcal based on 120 kcal/kg/day). In 2005,
Tsang et al
32
recommended an intake of 2-4 mg/kg/day (1.3-
3.1 mg/100 kcal based on 130 kcal/kg/day for ELBW infants
and 1.5-3.6 mg/100 kcal based on 110 kcal/kg/day for
VLBW infants). In 2010, European Society of Pediatric Gas-
troenterology, Hepatology, and Nutrition recommended an
intake of 2-3 mg/kg/day (1.8-2.7 mg/100 kcal based on 110
kcal/kg/day) for infants with a birth weight <1800 g.
21
The
World Health Organization recommends 2-4 mg/kg/day
for all LBW infants aged 2-24 months,
64
and the American
Academy of Pediatrics recommends 2 mg/kg/day at age
1-12 months for all LBW infants.
65
Gaps in Knowledge
To date, no studies have examined the effects of different
doses of iron supplementation or fortication in ELBW in-
fants, even though these infants are likely to be at increased
risk for iron deciency and iron overload. In addition, there
are no data on the long-term health consequences of different
dietary iron intakes in preterm and LBW infants.
Recommended Intakes for Preterm and
VLBW Infants
Calcium: 120-160 mg/kg/day; phosphorus: 60-90 mg/kg/day;
magnesium: 8-15 mg/kg/day; vitamin D: 400-1000 IU/day;
copper: 150-200 mg/kg/day; zinc: 2-2.25 mg/kg/day; iron:
2-3 mg/kg/day (birth weight < 1500 g); 2 mg/kg/day (birth
weight 1500-2500 g).
Conclusion
Traditionally, the high calcium and phosphorus require-
ments of preterm neonates have been proposed to match
the intrauterine accretion rate in the third trimester. How-
ever, recent studies suggest that a lower postnatal mineral
accretion (enteral calcium intake of 120-140 mg/kg/day and
phosphorus intake of 60-90 mg/kg/day) is sufcient to main-
tain adequate retention of these minerals. The goal of vitamin
D supplementation should be to achieve an intake of 400-
1000 IU/day. In countries and geographical areas with
a higher risk and/or prevalence of vitamin D deciency, in-
take should be targeted at the higher end of the range, and
populations at low risk for vitamin D deciency should re-
ceive vitamin D at the lower end of the range.
We recommend a dietary iron intake of 2 mg/kg/day for
infants with a birth weight of 1500-2500 g and 2-3 mg/kg/
day for infants with a birth weight of <1500 g. Prophylactic
iron should be started at age 2-6 weeks (at 2 weeks in
VLBW infants). Infants receiving erythropoietin treatment
and those with signicant, uncompensated blood losses will
need a higher dose initially, requiring a separate iron supple-
ment in addition to pretermformula or fortied human milk.
A prolonged dietary iron intake of >3 mg/kg/day should be
avoided in most cases because of possible adverse effects. In
infants who have received multiple blood transfusions, serum
ferritin concentration should be determined before starting
iron supplementation/fortication, and prophylactic iron
should not be given while serum ferritin is above normal
levels for newborns.
66
Iron supplements or intake of iron-
fortied formula in the recommended doses should be
continued after discharge, at least until age 6-12 months,
depending on diet. Hemoglobin and serum ferritin should
be checked at follow-up visits, taking the physiological
changes of iron status during infancy into consideration. n
Author Disclosures
All authors received honoraria fromMead Johnson Nutrition
I. G. wrote the rst draft of this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Division of Neonatology,
Medical College of Georgia, Georgia Health Sciences University, BIW-6033,
Augusta, GA 30912. E-mail: jatindeb@georgiahealth.edu.
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Intestinal Mucosal Defense System, Part 1. Consensus Recommendations
for Immunonutrients
Josef Neu, MD
1
, Walter A. Mihatsch, MD, MBA
2
, Jaime Zegarra, MD
3
, Sarayut Supapannachart, MD, FAAP, MBA
4
,
Zong-Yi Ding, MD
5
, and Teresa Murgu
a-Peniche, MD
6
When microbial communities colonize in the developing intestinal tract after birth, microrganisms interact with specic
apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inam-
matorycytokines, thusprovidingprotectionfrompathogen-inducedmucosal damage. Multipleimmunemodulatoryfac-
tors in human milk and innate humoral factors also control inammatory responses, providing additional protective
effects. Our understandingof theroleof theluminal microbial communitiesor microbiotaisgrowingrapidlyasnovel tech-
nologies provide new insights into their taxonomy, function during early development, and impact on life-long health.
Multiple studies have evaluated the effects of the specic nutrients, glutamine, arginine, nucleotides, polyunsaturated
fatty acids, andlactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to mod-
ulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial
translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is
yet known to design specic clinical care practices that support a healthy microbiota. (J Pediatr 2013;162:S56-63).
T
he mucosa of the small intestine is an interface between the external environment and the internal milieu and the site of
selective assimilation of certain nutrients and molecules and exclusion of others. The rst line of host defense is the
innate immune system, which is present at birth. It works in association with the adaptive immune system, which de-
velops postnatally following exposure to various antigens and the microbiome to modulate the immune response.
Infants, particularly those who are undernourished, may be at increased risk of harm caused by microbial pathogens and
dietary antigens. Potentially harmful bacteria proliferate and facilitate bacterial translocation and/or mucosal invasion. Several
factors promote the creation of a hostile gastrointestinal (GI) environment and predispose the preterm infant to disease.
1
These
include the use of feeding tubes, routine use of broad-spectrum antibiotics, and the subsequent proliferation of antibiotic-
resistant pathogens, colonization of the gut with multi-resistant commensal local ora in the neonatal intensive care unit,
and poor nutrition status secondary to the functional immaturity of an infants GI tract.
This paper reviews several aspects of host defenses in the newborn and external factors affecting the intestinal mucosa such as
type of feeding, the role of the intestinal microbiome, physical and chemical factors in the intestine, and the immune system,
particularly the innate immune system.
Human Milk
Human milk protects the intestinal tract from infection and damage induced by dietary antigens. It also contains protective
agents, including immunoglobulins, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and various cell types.
2
Biologically-active antibodies appear in human milk as the result of maternal exposure to antigens and confer protection to
her infant.
3
This is particularly relevant because the mothers fecal bacteria commonly colonize the infant at birth and, thus,
generate a shared microbiome specic to the maternal-infant dyad.
4
Physical and Chemical Protective Factors
Intestinal motility can be a critical factor in clearing antigens presented to the mucosa. The time available for transport to the
brush border and absorption depends on the rate at which luminal contents ow through the GI tract. Migratory motor
From the
1
University of Florida, Gainesville, FL;
2
Munich
Municipal Hospitals, Munich, Germany;
3
Hospital
Nacional Cayetano Heredia, Lima, Peru;
4
Ramathibodi
Hospital School of Medicine, Mahidol University,
Bangkok, Thailand;
5
1st August Childrens Hospital,
Afliated with the General Hospital of Beijing Military
Defense Area, Beijing, China; and
6
National Center for
Child and Adolescent Health (CeNSIA), Mexico City,
Mexico
article.
GI Gastrointestinal
IL Interleukin
LA Linoleic acid
LCPUFA Long chain polyunsaturated fatty acid
PUFA Polyunsaturated fatty acid
TPN Total parenteral nutrition
S56
complexes act as housekeepers to propel luminal contents
caudally through the intestinal tract. In preterm infants,
motility is immature because coordinated motor complexes
that are important for digestion and absorption are not
mature until 34 to 35 weeks gestational age.
5
Immature
motility promotes bacterial overgrowth and, thus, reduces
absorption of key dietary nutrients.
Gastric acid secretion increases in preterm infants during the
rst weeks after birth.
6
Normal gastric acid and pancreaticobili-
ary secretions decrease the amount of viable microorganisms
andintact dietary proteinantigens that reachthe small intestine.
Pancreatic insufciency in the preterm infant can last through-
out the rst year of life. Low gastric acid and pancreaticobiliary
secretions, coupled with the common use of histamine-blockers
to prevent gastric ulcers, allow a greater bacterial or antigenic
load to reach the distal intestine and colon, thus predisposing
the infant to sepsis and necrotizing enterocolitis (NEC).
7
Intestinal mucus plays a signicant role in intestinal de-
fense.
8
Mucus is a complex viscous gel that covers the surface
of the villous epithelium. It is mainly composed of water and
electrolytes, but it also contains mucins, glycoproteins, im-
munoglobulins, glycolipids, and albumin. Bioactive factors,
such as lactoferrin, lysozyme, and glycolipids from human
milk, may also be present within the mucus gel. Mucus is se-
creted into the lumen of the intestine fromstorage vacuoles in
goblet cells that are interspersed among enterocytes along the
villus-to-crypt axis. Once secreted, mucus envelops foreign
antigens, which helps propel them caudally within the lumen.
The intestine responds quickly to insults by secreting copious
amounts of mucin. Mucin from the small intestine of new-
born rats contains more protein than that of adult rats; carbo-
hydrate composition also changes with age. Newborn mucin
contains less fucose and N-acetyl-cysteine than adult mucin.
9
Developmental aspects of mucin in the human small intestine
remain poorly understood. Improved understanding of mu-
cin function in the future may lead to preventative actions
treatments designed to protect the developing GI tract.
Intestinal Epithelium
The enterocyte develops from the same undifferentiated stem
cell that gives rise to the goblet, enteroendocrine, and, prob-
ably, M cells in the intestine. Goblet cells are found through-
out the small and large intestine. Special tight junctions and
interdigitations join the intestinal epithelial cells and serve as
a permeability barrier between the external and internal mi-
lieus.
10
Intestinal permeability is controlled by the tight
junctions and altered by lack of enteral nutrition, various mi-
crobes and cytokines, cortisol, and stress. These intercellular
junctions are exquisitely sensitive to modulation by small
molecules, such as the short-chain fatty acid butyrate and
glutamine, which act to preserve them.
Subepithelial Cells
Follicular dendritic cells are important nonphagocytic
antigen-presenting cells. They reside in lymphoid follicles
and present antigens to CD 4
+
T cells and B cells. In response
to an antigen signal, naive T cells differentiate into effector or
regulatory (tolerance-inducing) T cells and, thereby, play
a central role in the maintenance of local immune homeosta-
sis. Peyer patches are aggregations of lymphoid tissue located
in the lamina propia and submucosa of the GI tract. They rst
appear at about 19 weeks of gestation, spread throughout the
jejunum and ileum from 24 to 40 weeks gestation, and re-
main prominent in the terminal ileum in the adult.
Innate Humoral Factors
Numerous innate humoral factors (lysozyme, peroxides, lac-
toferrin, trefoil peptides, other bioactive proteins, and glyco-
proteins) are secreted by exocrine glands and cover mucosal
surfaces. They contribute to mucosal protection in conjunc-
tion with phagocytes in the absence of specic antibodies.
These factors are present in mucosal secretions and act syn-
ergistically to protect from pathogens and other insults be-
fore the adaptive immune system has the opportunity to
mount an antigen-specic response. Although a complete re-
view of innate humoral factors is beyond the scope of this
paper, lactoferrin deserves special attention because it is in
relatively high concentrations in human milk and may pro-
vide some protection to the developing infant. Lactoferrin
is a multifunctional protein produced in neutrophils and
stored in an iron-free state. Anti-infective properties of lacto-
ferrin include bacteriostatic, bactericidal, antifungal, and an-
tiviral actions.
Inammatory Response Cells and Mediators:
Cytokines and Chemokines
The role of cytokines produced by intestinal epithelial cells is
presently being elucidated. Interleukin (IL)-6 has important
proinammatory functions such as inducing secretion of
acute-phase proteins by the liver and enhancing T-cell prolif-
eration and B-cell antibody secretion. Intestinal epithelial
cells also secrete various types of chemokines in response to
inammatory stimuli. The rst chemokine found to be pro-
duced by intestinal epithelial cells was IL-8, which is induced
by tumor necrosis factor-alpha. IL-8 is known to stimulate
leukocytic inltration of tissues. The most obvious function
of intestinal epithelial cells is to maintain a barrier to intesti-
nal luminal contents. The cytokine-related inammatory re-
sponse drastically reduces this barrier function. Interferon
gamma, another pro-inammatory cytokine, reduces the ep-
ithelial barrier function in cells grown in culture. Transform-
ing growth factor-beta, a mediator that participates in cell
restitution and wound healing, counteracts this action.
Immunomodulatory Nutrients
Glutamine
Glutamine, the most abundant amino acid in the human
body, plays a central role in inter-organ carbon and nitrogen
ux. Glutamine has not traditionally been used as
Intestinal Mucosal Defense System, Part 1. Consensus Recommendations for Immunonutrients S57
a nutritional supplement because it is synthesized endoge-
nously and considered a non-essential amino acid. How-
ever, glutamine supply can be depleted rapidly, particularly
in response to injury, infection, or chronic glucocorticoid
treatment. Glutamine also is an important fuel for rapidly di-
viding cells such as enterocytes and immune cells. The amide
nitrogen of glutamine is critical for the biosynthesis of nucle-
otides required for cell replication and hexosamines. Gluta-
mine and nucleotides act synergistically to promote
differentiation and proliferation of intestinal epithelial cells.
The key antioxidant peptide, glutathione, is also formed
from glutamine.
Glutamine is not currently contained in total parenteral
nutrition (TPN), and many premature infants do not feed
enterally for weeks. The sudden cessation of maternal gluta-
mine supply at birth may be detrimental to preterm infants
who are highly stressed and/or undergoing rapid growth.
Preterm infants may need exogenous glutamine for optimal
growth and normal development of the intestinal mucosa
and immune function, among other things. Premature neo-
nates who develop NEC have reduced plasma glutamine and
arginine concentrations.
11
Two large multicenter trials have
evaluated the safety and efcacy of glutamine supplementa-
tion. Parenteral glutamine supplementation was shown to
have no effects.
12
In contrast, enteral glutamine supplemen-
tation improved tolerance to enteral feedings.
13
In addition,
enteral supplementation also decreased the incidence of
intraventricular hemorrhage and periventricular leukomala-
cia.
13
These preliminary results indicate that glutamine sup-
plementation may be benecial, but additional large-scale
controlled studies are needed to provide more detailed infor-
mation about whether and how glutamine should be pro-
vided to preterm infants.
Arginine
Arginine is an essential amino acid for the fetus and neo-
nate and a conditionally essential nutrient for adults. L-ar-
ginine is a versatile and critical component of nutrition and
metabolism. It is a precursor for the synthesis of nitric
oxide, creatine, polyamines, urea, ornithine, proline, gluta-
mate, and other molecules with biologic importance. Argi-
nine also stimulates the secretion of insulin and growth
hormone.
A certain concentration of arginine may be necessary not
only for tissue growth but also for normal physiological func-
tion. Arginine concentrations can decrease when metabolic
demand increases or when endogenous synthesis decreases
or becomes limited. Premature infants who develop NEC
Table. Characteristics of Included Studies
Source n
Birth weight/
gestational age Prebiotics
Dosage and
duration
Primary
outcome
Amin, 2002
25
152 #1250 g
#32 wk
Parenteral L-arginine 1.5 mmoL/kg/d
(26 mg/kg/d) during
the rst 28 d of life
Incidence of NEC all
stages
Costalos, 2003
26
87 28-32 wk Saccharomyces
boulardii and
polyamine
2 10
9
/kg and 2 340
mmoL/kg/d from rst
feed to 30 d
Gut function and stool
colonization
Neu, 1997
27
68 500-1250 g
24-32 wk
Enteral glutamine
in premature
formula
0.08 mg/k/d initially to
0.31 mg/k/d by day
13 of life
Nosocomial sepsis,
tolerance to subsequent
feeding and length of
hospitalization
Van den Berg, 2005
28
102 #1500 g
<32 wk
Enteral glutamine 0.3 g/k/d from d 3 to d
30 of life
Time to achieve $120
mL/k/d of enteral
feeding
Vaughn, 2003
13
649 500-1250 g Enteral glutamine 0.3 g/k/d during the
rst 28 d
Incidence of culture-proven
nosocomial sepsis
Bober-Olesinska, 2002
29
55 580-1250 g
26-32 wk
Parenteral glutamine Solution with 20% of
total amount of amino
acids from d 4 to d
14 of life
Incidence of NEC all stages,
nosocomial sepsis, and
length of hospitalization
Poindexter, 2004
30
721 401-1000 g Parenteral glutamine Solution 20% of total
amount of amino acids
from d 3 to d 120 of life,
death, or discharge
Death or late onset sepsis
Thompson, 2003
31
35 <1000 g and <1500 g
who required O
2
>40%
or ventilated within 24 h
Parenteral glutamine 2.5% L-glutamine solution,
16% of total amount of
amino acids. Amino acids
started on rst d of life at
1 g/kg/d and increased
by 0.5 g/kg/d to a maximum
of 3 g/kg/d
Time to establish full enteral
feeding
Manzoni, 2009
24
472 #1500 g Oral BLF alone or in
combination
with LGG
BLF 100 mg/d alone or in
combination with
LGG 6 10
9
CFU/d from
birth to d 30 of life
(d 45 for ELBW)
Incidence of late onset
sepsis
BLF, bovine lactoferrin; CFU, colony forming units; ELBW, extremely low birth weight; O
2
, fraction of inspired oxygen; LGG, Lactobacilus GG.
S58 Neu et al
have signicantly lower plasma concentrations of arginine
than infants who do not.
11,14
Low concentrations of arginine
in premature infants may reduce the formation of nitric
oxide, a critical mediator that regulates intestinal blood
ow in response to inammation or injury.
Hypoargininemia (plasma arginine <32 mol/L) is associ-
ated with increased severity of respiratory distress syndrome
and hypoxemia in preterm infants who are dependent upon
TPN.
15
Enteral nutrition is essential for maintaining mucosal
mass and integrity, and infants on TPN fail to synthesize cit-
rulline and arginine from glutamine, glutamate, and proline
in the small intestine. Several investigators are exploring the
differences between enteral versus TPN feeding on endoge-
nous arginine synthesis.
Nucleotides
Nucleotides, nucleosides, and nucleobases are compo-
nents of the non-protein nitrogen fraction in human
milk. Nucleotides, derived from endogenous biochemical
sources, de novo synthesis, the salvage pathway, or
from the diet, provide purines and pyrimidines for nu-
cleic acid synthesis. Many recent studies have suggested
that nucleotides may be conditionally essential nutri-
ents for the GI tract under conditions of stress (eg, in-
fection, post-intestinal resection, or trauma). There is
a strong interaction between glutamine and nucleotides
in the intestinal epithelium.
16
A study of 311 full-term
healthy infants showed that term formula fortied with
nucleotides enhanced infant immunity, as indicated by
Haemophilus inuenzae and diphtheria humoral antibody
responses. Nucleotide-supplemented formula was also as-
sociated with a reduction in the number of infants with
diarrhea; however, this outcome was not assessed in all
study infants.
17
Omega-3 Polyunsaturated Fatty Acids
Dietary fatty acids such as linoleic acid (LA) (18:2n-6)
and a-linolenic acid (18:3n-3) of the n-6 and n-3 series
of polyunsaturated fatty acid (PUFA), respectively, are
considered to be essential because they are not formed
endogenously. Once ingested, essential fatty acids are
converted to longer-chain, highly unsaturated fatty acids,
including arachidonic acid (ARA) from LA and eicosa-
pentaenoic acid and docosahexaenoic acid (DHA) from
a-linolenic acid. Modulation of immune and inamma-
tory responses is related to the balance between omega-
6 and omega-3 PUFAs; a high omega-6:omega-3 is
pro-inammatory. A systematic review of randomized
controlled trials in premature newborn infants who re-
ceived infant formula supplemented with DHA or control
formula found no difference in incidence of sepsis or
NEC between the groups. The incidence of retinopathy
of prematurity and bronchopulmonary dysplasia was
also similar in both groups. However, the sample sizes
were small, and the effect of DHA doses was not clearly
demonstrated.
18
DHA and other n-3 long chain polyunsaturated fatty
acid (LCPUFA) may play signicant roles in anti-
w
e
b
4
C
=
F
P
O
Figure 1. LCPUFA supplementation versus control. Outcome: neonatal sepsis.
w
e
b
4
C
=
F
P
O
Figure 2. LCPUFA supplementation versus control. Outcome: neonatal NEC.
inammatory processes and have long-term positive effects
on allergic illnesses. One study evaluated 1342 newborn in-
fants enrolled in a multicenter, prospective, open-label,
trial. Infants who received formula supplemented with
DHA and ARA had a lower incidence of bronchiolitis in
the rst year of life.
19
Another study found similar out-
comes in a randomized controlled trial in infants receiving
formula supplemented with DHA and ARA or placebo.
20
The infants who received formula with DHA early in life
had a lower incidence of upper respiratory infection,
wheezing/asthma, and allergies up to 3 years of age com-
pared with the control group. Manley et al showed that
preterm infants who received a high DHA supplement
had a signicantly lower incidence of chronic lung disease
than those who did not.
21
Additionally, Martin et al have
shown that healthy preterm infants have signicantly better
DHA status than their counterparts who have chronic lung
disease.
22
Fish oil-based intravenous lipid emulsions are now be-
ing used to treat parenteral nutrition-associated liver dis-
ease, a severe inammation of the liver that occurs
following prolonged TPN. It is a serious complication in
premature infants and in children with short bowel syn-
drome who receive prolonged parenteral nutrition. Infants
w
e
b
4
C
=
F
P
O
Figure 3. Supplementation with other immunonutrients versus control. Outcome: neonatal sepsis.
S60 Neu et al
who receive sh oil-based intravenous lipid emulsions
have lower rates of death and liver transplantation com-
pared with infants who receive a soybean-based product
that contain more n-6 LCPUFA and no preformed n-3
LCPUFA.
23
Further, infants who receive sh oil-based in-
travenous lipid emulsions recover from cholestasis 6 times
faster than control infants. No adverse side effects were
found.
Lactoferrin
In addition to being an innate humoral protein, the iron-
binding protein lactoferrin is the most abundant whey pro-
tein in human milk. As implied by its name, lactoferrin was
rst isolated from milk. Subsequently, it was found to be in
most exocrine uids such as saliva, bile, pancreatic secretions,
and tears. Lactoferrin also is in plasma. Bovine lactoferrin has
been shown to decrease late onset sepsis in premature in-
fants.
24
Clinical Strategies to Enhance Intestinal
Immunity and Host Defense: Evidence-Based
Clinical Practices
Numerous studies have evaluated the effects of immunonu-
trients on outcomes in premature and low birth weight
infants. Characteristics of relevant clinical trials from the
w
e
b
4
C
=
F
P
O
Figure 4. Supplementation with other immunonutrients versus control. Outcome: neonatal necrotizing enterocolitis.
US National Medical Library Medline database (through
February 2010) are shown in the Table. The role of specic
immunonutrients on the incidence of NEC and sepsis
is summarized in Figures 1-4. Based on these studies,
no conclusions and recommendations can be made on
the use of immunonutrients such as glutamine, arginine,
nucleotides, omega-3 PUFA, and lactoferrin, in preterm
infants.
There is convincing and exciting preclinical evidence that
immunonutrients have the capability to improve host de-
fense and the possibility to prevent diseases such as NEC,
bronchopulmonary dysplasia, and hospital-acquired sepsis.
Encouraging data from one randomized controlled trial
suggest that lactoferrin may prevent neonatal sepsis or
NEC. There are insufcient data available to recommend
the routine use of glutamine, arginine, nucleotides,
omega-3 LCPUFA, or lactoferrin for improvement of host
defense in preterm infants. Well-designed, randomized,
controlled clinical studies with sound scientic basis (eg,
those based on animal studies and other experimental
models) are needed. n
Author Disclosures
T. M. in the past has acted as scientic consultant of one
formula company. Josef Neu, MD has received a research
grant and honoraria for speaking from Mead Johnson
Nutrition and is currently on its Scientic Advisory
Committee. Walter A. Mihatsch, MD, MBA, is a recipient
of a research grant from Mead Johnson Nutrition. In the
past, he has acted as a scientic consultant to several
infant formula companies. Jaime Zegarra, MD, is a recip-
ient of a research grant from Mead Johnson Nutrition.
All authors received an honorarium from Mead Johnson
preparation. Teresa Murgua-Peniche, MD, in the past,
has acted as a scientic consultant for an infant formula
company. J. N. wrote the rst draft of this manuscript.
Reprint requests: Teresa Murgua-Peniche, MD, Foege Fellow, Rollins School
of Public Health, Hubert Department of Global Health, 1518 Clifton Road, Mail
Stop 1518-002-7BB, Atlanta, GA 30322. E-mail: teresamurguiap@gmail.com.
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Intestinal Mucosal Defense System, Part 2. Probiotics and Prebiotics
Teresa Murgu
a-Peniche, MD
1
, Walter A. Mihatsch, MD, MBA
2
, Jaime Zegarra, MD
3
,
Sarayut Supapannachart, MD, FAAP, MBA
4
, Zong-Yi Ding, MD
5
, and Josef Neu, MD
6
The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional
and clinical outcomes that result from the specic interactions among microbial communities, their products,
and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingre-
dients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from in-
testinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm
infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance.
Fewwell-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingre-
dients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufcient
evidence to recommend the routine use of these ingredients in all preterm infants. (J Pediatr 2013;162:S64-71).
C
ommensal microbes in the gastrointestinal tract play an important role in nutrition, angiogenesis, and mucosal immu-
nity. The interaction of luminal microbes with cells of the intestinal epithelium also inuence the balance of mucosal
inammatory and anti-inammatory processes, which play a signicant role in gastrointestinal illness and health sta-
tus. Gut colonization starts immediately after birth, and the pattern of microbial colonization differs between formula-fed and
breastfed infants. Preterm infants are particularly susceptible to abnormal colonization for many reasons, including delayed
feeds, antibiotic use, and others. Provision of probiotics or prebiotics may change this abnormal pattern and confer health ben-
ets through different mechanisms. On the other hand, use of probiotics and prebiotics may introduce and/or stimulate in-
nappropriate colonization of microbes at an inopportune time and, thereby, negatively affect the microbial ecology and
immune system of an individual for a lifetime. Herein, we describe the most relevant modes of action of probiotics and the
primary results reported for their use in preterm infants.
The Intestinal Microbial Environment
Current understanding of intestinal colonization in neonates is derived largely from studies using culture-based techniques.
Recent studies suggest that many preterm infants are exposed to microbes in utero via the amniotic uid, even those without
a history of rupture of membranes or culture-positive chorioamnionitis.
1
Thus, the conceptual framework that the intestine is
sterile at birth and the possibility that intestinal microorganisms play a role in intestinal development, especially in regards to
mucosal immunology, may need to be reevaluated.
With regard to initial postnatal colonization, studies using ribosomal DNA and RNA microarray-based assays showed that
the patterns of microbial communities vary widely over time in healthy term infants, which suggests that the current denition
of healthy colonization is too narrow.
2
By 1 year of age, the prole of microbial communities in the infant changes to resemble
that of the adult. Further, the composition and temporal patterns of intestinal microbial development in fraternal twins is strik-
ingly similar, which suggests that genetic factors of the host contribute in shaping this development. Strikingly, Bidobacteria
are not detected in these infants. This nding may have far-reaching implications because most studies of probiotic and pre-
biotic agents have targeted the propagation of these organisms, believed to be benecial for the developing intestinal tract.
A few studies of microbial ecology in premature infants have used non-culture-based techniques to characterize the micro-
biota. Recently, microbial DNA has been detected in meconium. This indicates that microbiota have an intrauterine origin and
that the intrauterine environment is not sterile.
3
Lower microbial diversity has been detected in infants whose mothers had
intended to breastfeed and in infants born at <30 weeks gestation. The implica-
tions of these ndings remain unclear. Fecal samples taken from infants diag-
nosed with necrotizing enterocolitis (NEC) have reduced diversity, increased
abundance of gammaproteobacteria, and decreased numbers of other bacterial
species.
4
Of note, infants who receive antibiotics prior to the onset of NEC for
a higher mean number of days have decreased microbial diversity. Whether these
differences in diversity and bacterial strains relate to predisposition to NEC
From the
1
National Center for Child and Adolescent
Health (CeNSIA), Mexico City, Mexico;
2
Munich
Municipal Hospitals, Munich, Germany;
3
Hospital
Nacional Cayetano Heredia, Lima, Peru;
4
Ramathibodi
Hospital School of Medicine, Mahidol University,
Bangkok, Thailand;
5
1st August Childrens Hospital,
afliated with General Hospital of Beijing Military Defense
Area, Beijing, China; and
6
University of Florida,
Gainesville, FL
article.
S64
requires further research. The evaluation of the microbiota
and its interaction with the gut mucosa during development,
in both health and disease conditions, could yield informa-
tion that might revolutionize our current thinking and lead
to a more rational, mechanistically based approach to the
use of pre- and probiotics.
Probiotics
It has been proposed that probiotics protect the host not only
from intestinal diseases, but also from allergic disorders, liver
inamation, and other systemic conditions.
5,6
Probiotics or
their metabolites interact with the host and with microbes,
as do benecial commensal intestinal microbes, which makes
the study of their mode of action unique and complex.
Mode of Action
Little is known about whether probiotics exert a benecial ef-
fect only in the presence of preexisting commensal intestinal
microbiota. Commensal microbes in the intestinal tract pro-
vide a number of benets for the host. Probiotics act in syn-
ergy to exert similar effects. Probiotics are also thought to
simulate commensal microbes. They compete for nutrient
binding sites to provide a protective barrier against incoming
bacteria and have, in some cases, antimicrobial action. Probi-
otics may also interfere with the adherence of pathogenic
bacteria, increase the physical and immunological barrier
function of the intestine, increase mucus production, de-
crease ischemic injury through nitric oxide production, and
modulate the inamatory response. In addition, there is
some evidence linking probiotic use with improved intestinal
motility.
7
Adherence
Experimental evidence has shown that different strains of
probiotics interfere with the adherence of pathogenic bacte-
ria. There is now evidence that this effect may be mediated by
soluble molecules secreted by probiotic strains.
8
Immunomodulation
There is evidence that probiotics have immunomodulatory
actions, which may be benecial for diseases with high pro-
inamatory activity in the bowel such as inammatory bowel
disease and NEC. The immunomodulatory effect may be me-
diated by strengthening the intestinal barrier, whereby bacte-
rial translocation across the epithelium and activation of the
secondary inammatory cascade are reduced. In addition,
there is a specic immune stimulation by probiotics through
processes involving dendritic cells that present antigens to
undifferentiated T-cells, directing their differentiation to ef-
fector versus regulatory phenotypes. Dendritic cells also sam-
ple commensal organisms, incorporate them, and transport
them to mesenteric lymph nodes where they induce a local
immune response by activating specic B-cells to produce
specic secretory IgA.
9
It has also been demonstrated that a combination of
probiotic organisms and toll receptor agonists derived from
microbes can decrease nuclear factor kB activation to pre-
serve the inhibitor, IkB.
10
This function is important because
high nuclear factor kB activity has been associated with devel-
opment of NEC.
11
The small intestine contains the major part of the gut-
associated lymphoid tissue, which interacts with intestinal
microbes to mediate responses in the small intestine to these
microbes. Within the large intestine, probiotics ferment car-
bohydrates to produce short chain fatty acids, which act to
alter innate immunity.
12
Immunomodulatory effects associated with probiotics
may also confer protection to the liver, specically by pre-
venting production and/or uptake of lipopolysaccharides
in the gut and thereby reducing levels of low-grade in-
ammation.
6
Other
Antiviral activity has been demonstrated in the culture uid
of probiotics. This raises interest in the role of probiotics
against viral infections such as enteroviruses.
13
Also, cytopro-
tective effects of probiotics have been suggested through ac-
tivation of heat shock protein.
10
Safety of Probiotics
Infection
The most important area of concern with probiotic use is the
risk of sepsis. Probiotic therapy has been associated occasion-
ally with adverse effects, including bacteremia, sepsis, or
endocarditis in a select subset of patients who were immuno-
compromised or severely debilitated.
10,14-16
Sepsis related to
probiotic use in children has also been reported. In many
cases, strain homology has been detected by molecular typing.
There are now several reports of Lactobacillus bacteremia and
Saccharomyces boulardii fungemia related to probiotic use in
children with underlying risk factors such as short gut
syndrome, immune deciency, complex cardiac diseases,
or antibiotic-related diarrhea.
17,18
Probiotic nosocomial
Saccharomyces cerevisiae sepsis and, more recently, a case of
Bidobacterium breve sepsis, thought to have low pathogenic
potential, have beenreported as well.
19,20
The bacteremia/fun-
gemia most likely originates fromthe probiotic strain through
translocation and may be attributable to gut ischemia due to
poor cardiac function and/or catheter contamination.
18
Boyle et al have proposed the following risk factors for pro-
biotic sepsis
21
: immune compromise, prematurity, catheter
in place, impaired intestinal barrier, jejunostomy (gastric
acid bypass), concomitant administration of broad spectrum
antibiotics to which probiotics are resistant, probiotics of
high mucosal adhesion, and cardiac valvular disease. It is
clear that sick, premature infants are at increased risk.
Metabolic Activities
The intestinal microbiota play an important role in many
metabolic activities, including digestion of complex carbohy-
drates, lipid metabolism, and glucose homeostasis. Mice col-
onized with microbiota store more fat than those not exposed
Intestinal Mucosal Defense System, Part 2. Probiotics and Prebiotics S65
to microrganisms.
22
Although improved energy storage may
be benecial in selected populations such as low birthweight
infants, the ability of probiotics to promote weight gain is
controversial at this time. Luoto et al
23
demonstrated that
early gut microbiota modulation with probiotics modied
the growth pattern and restrained excessive weight gain dur-
ing the rst years of life in a selected group of children. Exces-
sive weight gain during the rst months of life may be
a consequence of failure to establish anti-inammatory and
tolerance responses to the initial environmental challenge
presented by indigenous gut microbes, thus creating a low-
grade inammatory state characteristic of obesity and meta-
bolic disorders.
24
Modulation of this phenomenon through
external interventions may explain, in part, the results of
these studies.
The importance of these experimental ndings remains to
be substantiated by future results of well-designed clinical
studies, particularly as we face a global obesity epidemic. It
is possible that only microbes with specic metabolic and im-
munomodulatory activities may be benecial. Thus, care
needs to be taken to nd the most effective and safe strains.
Immune Activities of Probiotics. Potential Risk?
Intestinal microbiota are necessary for a range of immune
functions, including antibody production, development
and persistence of oral tolerance to food antigens, and forma-
tion of germinal centers within lymphoid follicles.
25,26
Ma-
nipulations of the microbiota in newborns may have
signicant immunomodulatory effects. The long-term effects
of these manipulations are difcult to predict but particularly
important because there is potential risk of modifying im-
mune responses in the adult.
Microbial Resistance
Another potential risk is the transfer of antimicrobial resis-
tance from probiotic strains to pathogenic bacteria present
in the intestinal microbiota. Many Lactobacillus strains are
resistant to vancomycin, for example; this resistance could
be transferred potentially to staphylococci or enterococci.
Despite this concern, conjugation studies have not found
the vancomycin-resistant genes of lactobacilli to be transfer-
able to other genera.
27
Delivery Risks
The mode of probiotic delivery must be designed to ensure
that microbes maintain probiotic activity and stability with-
out compromising infant formula safety. Warming formula
containing probiotics to temperatures above 40
C will
change the natural balance of the culture. This is in contrast
to World Health Organization recommendations to mix in-
fant formula with hot water (>70
C) to minimize the risk of

potentially deadly infections caused by Enterobacter sakaza-
kii, which has been found in powdered infant formula.
28
Monitoring
If probiotics are to be used in newborns, the incidence of sep-
sis secondary to probiotic translocation and antibiotic resis-
tance; changes in growth, development, immune function,
and allergic diseases and long-term changes must be moni-
tored. Further, to document possible associations between
the supplemented probiotic and sepsis, it will be important
to use molecular probes to identify infectious agents because
they are more sensitive and strain-specic than culture-based
methods and may be less prone to bias.
Evidence-Based Clinical Practices: Clinical
Strategies to Enhance Intestinal Immunity or
Host Defense with Probiotics, Prebiotics,
and Synbiotics
Extensive research using a variety of approaches has been con-
ducted thoughout the world in relation to the supplementa-
tion of preterm infant feedings with probiotics. This review
provides information from the US National Medical Library
Medline database through February 2010. With regard to
host defense, 13 randomized controlled trials (RCTs) report
on the effect on sepsis or NEC incidence, although the meth-
odological quality of these studies varies. A summary of the
most relevant studies is presented in the Table. There is no
convincing evidence of a benecial effect with regard to
sepsis incidence. Most of the studies showed no effect, one
presented an increased risk, and one showed a decreased
risk. Individual results and references are presented in
Figure 1. In contrast, some of the available RCTs support
the hypothesis that certain probiotics prevent NEC
(Figure 2). Because the majority of probiotic-containing
products have been evaluated in single sites, independent
replication of these results in adequately powered, large,
multicenter trials is essential before a particular product can
be recommended for routine use in preterm infants.
Prebiotics
Prebiotics are selectively fermented ingredients that allow
changes in the composition in the gastrointestinal micro-
ora, that confer benets upon host well-being. Prebiotics
are not fully digested in the small intestine and, thus, can
act in the lower intestinal tract to preferentially promote
the growth of non-pathogenic organisms such as bidobac-
teria and lactobacilli. Human milk contains considerable
amounts of a variety of different oligosaccharides, which
are fermented, in part, in the infants colon. The concentra-
tion of oligosaccharides changes with the duration of lacta-
tion. Levels are highest in colostrum at 20-23 g/L then
decline to about 20 g/L on day 4 of lactation and to 9 g/L
on day 120 of lactation.
29
Some absorption of intact human
milk oligosaccharides occurs in preterminfants, but most ol-
igosaccharides resist digestion in the small intestine and un-
dergo fermentation in the colon.
30
Oligosaccharides are
implicated in maintaining normal gut ora and inhibiting
growth of pathogenic bacteria. Their fermentation products,
short-chain fatty acids, provide nutrition and energy for co-
lonocytes and for the body following absorption. Other ev-
idence suggests that human milk oligosaccharides may
S66 Murgua-Peniche et al
Table. Characteristics of included studies
Source n
Birthweight/gestational
age Probiotics Dosage and duration Primary outcome
Kitajima, 1997
41
91 <1500 g Bidobacterium breve 0.5 10
9
organisms once daily from rst feed for 28 d Gut colonization by Bidobacterium breve
Bin Nun, 2005
42
145 <1500 g Bidobacterium infantisStreptococcus
thermophylusLactobacillus acidophilus
0.35 10
9
CFU of each from rst feed to 36 wk
corrected age
NEC all stages
Samanta, 2009
43
186 <1500 g and <32 wk Bidobacterium bidusBidobacterium
lactisBidobacterium infantisLactobacillus
acidophilus
2 2.5 10
9
CFU/d until discharge NEC, sepsis, death, and hospital stay
Lin, 2008
44
434 <1500 g <34 wk Bidobacterium bidusLactobacillus
acidophilus
125 mg/k/do twice daily for 6 wk NEC $ stage II
Lin, 2005
45
367 <1500 g Lactobacillus acidophilus Bidobacterium
infantis
125 mg/k/do twice daily from d 7 until discharge Death or NEC $ stage II
Mihatsch, 2010
46
183 <1500 g and <30 wk Bidobacterium lactis 6 2 10
9
CFU/kg/d (12 billion CFU/kg/d) for rst 6 wk Nosocomial infections
Mohan, 2006
47
69 <37 wk Bidobacterium lactis 1.6 10
9
CFU once daily from d 1 to d 3; 4.8 10
9
CFU
once daily
from d 4 to d 21
Gut colonization by Bidobacterium lactis and enteric
pathogens
Mohan, 2008
48
69 <37 wk Bidobacterium lactis 1.6 10
9
CFU once daily from d 1 to d 3; 4.8 10
9
CFU
once daily from d 4 to d 21
Weight gain, fecal pH, fecal calprotectin, lactate, IgA
Stratiki, 2007
49
80 27-36 wk Bidobacterium lactis Preterm formula 2 10
7
CFU/g formula powder started
within 48 h, for 30 d
Intestinal permeability (lactulose/mannitol ratio)
Rouge, 2009
50
94 <1500 g and <32 wk Bidobacterium longum Lactobacillus GG Each 2 2.5 10
9
CFU/d until discharge Percent of infants with >50% enteral feed intake
at d 14
Dani, 2002
51
585 <1500 g or <33 wk Lactobacillus GG 6 10
9
CFU once daily from rst feed until discharge Urinary tract infections, sepsis, NEC $ stage II after
7 d of probiotics
Manzoni, 2006
52
80 <1500 g Lactobacillus casein sp. rhamnosus 6 10
9
CFU once daily from d 3 to 6 wk or discharge
from NICU
Gut colonization by Candida species
Millar, 1993
53
20 800-2560 g and <33 wk Lactobacillus GG 2 10
8
/d for 2 wk Fecal colonization, pathogenic ora, clinical symptoms
CFU, colony forming unit; IgA, immunoglobulin A; NICU, neonatal intensive care unit.
Data derived from references: [41-53].
M
a
r
c
h
2
0
1
3
S
U
P
P
L
E
M
E
N
T
I
n
t
e
s
t
i
n
a
l
M
u
c
o
s
a
l
D
e
f
e
n
s
e
S
y
s
t
e
m
,
P
a
r
t
2
.
P
r
o
b
i
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i
c
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P
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e
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o
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i
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S
6
7
have anti-infective roles in the intestinal, respiratory, and
urinary tracts. Finally, sialic acid is a structural and func-
tional component of brain gangliosides and could play
a role in neurotransmission and memory. Animal data sug-
gest that early supplementation with sialic acid increases
brain ganglioside sialic acid concentration and improves
learning ability.
31
Techniques to synthesize human milk oligosaccharides
in quantities sufcient to supplement infant formula are
not available currently. A variety of prebiotics that are
thought to mimic clinical effects attributed to human
milk oligosaccharides have been studied in preterm infants.
These include fructo-oligosaccharides from plants, galacto-
oligosaccharides, acidic oligosaccharides from carrots, and
w
e
b
4
C
=
F
P
O
Figure 1. Inuence of probiotics on the incidence of culture-proven sepsis. References for Figure 1: [41-54].
lactulose.
32-39
Supplementation of pretem infant formula
with prebiotics did not have a signicant effect on fecal bi-
dobacteria counts, stool pH, stool viscosity, or gastroin-
testinal transport.
38,39
Early feeding tolerance in extremely
immature infants may be improved by prebiotics, although
conclusive evidence for this effect is lacking.
38,39
It has been
hypothesized that prebiotics increase host defense in pre-
term infants and, thereby, reduce the incidence of gastroin-
testinal complications (eg, NEC, reduce the incidence of
hospital-acquired infections, and improve long-term out-
come. However, clinical research is insufcient to conrm
these hypotheses. So far, no convincing effect on sepsis in-
cidence
32,35-37
or on the incidence of NEC
32,35,37,38
has
been found in RCTs. In summary, based on available
w
e
b
4
C
=
F
P
O
Figure 2. Inuence of probiotics on the incidence of NEC (Bell stage $2). References for Figure 2: [41-54].
data, routine use of prebiotics in all preterm infants can
not be recommended.
Synbiotics refer to nutritional supplements that contain
probiotics and prebiotics. The one preliminary RCT designed
to measure the effect of certain synbiotic products in preterm
infants on sepsis and NEC incidence was too underpowered
for sound conclusions.
40
Conclusions and Recommendations
Regarding Use of Prebiotics, Probiotics, and
Synbiotics in Preterm Infants
There is no conclusive evidence (Level of Evidence 1a) to rec-
ommend the routine use of probiotics, prebiotics, or synbiot-
ics in all preterm infants. There are encouraging preliminary
data (Level of Evidence 2b) that indicate specic probiotics
may be safe and effective where the incidence of NEC is
high. However, these studies need to be repeated in RCTs.
The available trials do not indicate that an optimal probiotic
or prebiotic strain, dosing regimen, or protocol have been
identied. The available evidence does not indicate whether
products that contain a single strain of probiotic are more
or less effective than those that contain multiple strains.
Safety and efcacy of each probiotic strain must be tested
separately. Data generated with one probiotic strain do not
necessarily apply to another strain. Outside of clinical studies,
clinicians should only use probiotics that have been shown to
be safe. Conrmation of efcacy and safety is required in
large, adequately-powered, multi-center, well-designed
RCTs in low- and very low-birthweight infants. The inci-
dence of severe NEC (Bell stage $2) and mortality should
be monitored as primary outcomes. n
Author Disclosures
Teresa Murgua-Peniche, MD, has acted, in the past, as scien-
tic consultant for one infant formula company. Walter A.
Mihatsch, MD, is a recipient of research grants from Mead
Johnson Nutrition. In the past, he has acted as a scientic
consultant to several infant formula companies. Jaime A. Ze-
garra, MD, is a recipient of research grants from Mead John-
son Nutrition. Josef Neu, MD, has received a research grant
and honoraria for speaking from Mead Johnson Nutrition
and is currently on its Scientic Advisory Committee. All au-
thors received an honorarium from Mead Johnson Nutrition
T.M.-P. wrote the rst draft of this manuscript.
Reprint requests: Teresa Murgua-Peniche, MD, Foege Fellow, Rollins
School of Public Health, Hubert Department of Global Health,
1518 Clifton Road, Mail Stop 1518-002-7BB, Atlanta, GA 30322. E-mail:
teresamurguiap@gmail.com.
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Nutritional Needs of the Micropreterm Infant
1
, Mary Fewtrell, MD
2
, Sudha Kashyap, MD
3
, and Enrique Udaeta, MD
4
We have used an expansive denition of a micropreterminfant as <30 weeks gestation to provide a global perspec-
tive to a high risk group of preterminfants for which there are little published data to guide nutritional management.
Consensus nutritional guidelines for preterm infants have been developed for infants >1000 g birth weight and >28
weeks gestational age. Micropreterm infants have greater nutritional decits at birth than more mature preterm in-
fants and accumulate greater postnatal decits. Nutritional guidelines based on the needs of preterm infants born
>28 weeks gestation are unlikely, on a theoretical basis, to meet nutritional requirements of micropreterm infants.
Unfortunately, very few good quality studies have addressed the nutritional requirements of this group specically;
this makes it difcult to formulate solid, evidence-based nutritional recommendations for these neonates. Nutri-
tional management of micropreterm infants is based on recommendations established for preterm infants, which
are adjusted after considering an infants gestational age, birth weight, and clinical status. Minimal enteral feeding
should commence on the rst or second day of life, with incremental advancement and fortication of human milk
when 100 mL/kg is tolerated. Early use of parenteral nutrition is recommended, ideally initiated within the rst hours
of life and enteral feeds are being established; this will help prevent the accumulation of nutritional decits and
incidence of growth failure. Fortied human milk should be given in order to meet nutritional requirements. When
human milk is not available in sufcient quantity, a preterm formula should be given. (J Pediatr 2013;162:S72-80).
A
lthough the more commonly accepted classications of preterm infants are extremely low birth weight (ELBW) and
extremely preterm(<28 weeks gestation), we dened micropretermas <30 weeks gestation. Asubset of this population
is small for gestational age (GA); these infants weigh <10
th
percentile at birth at <30 weeks gestation. This expanded
denition was selected to gain a global perspective of a high risk group of preterm infants. We were unable to locate substan-
tial information about this population. This discussion addresses the current state of knowledge and clinical practice on the
nutritional requirements of the micropreterm infant.
Developmental Physiology and Biology
The composition of weight gained by the fetus changes with GA. The difference in body composition between a micropreterm
and a more mature infant impact decisions about nutritional management. For example, body water as a percentage of body
weight decreases rapidly during the last trimester. Water comprises about 80% of weight gained between 24 and 28 weeks of
gestation but only 60% of weight gained between 36 and 40 weeks. The proportion of weight gained as fat increases markedly
from 8% at 24-28 weeks to nearly 20% near term.
1
The fetal intestine is capable of digesting and absorbing milk feeds by 25 weeks gestation, but not as well as that of a more
mature infant. Gastrointestinal motor activity develops later and may limit tolerance to enteral feeds. Motility is described as
being disorganized between 25 and 30 weeks of gestation. This can cause nutrients to remain in the intestine, especially if
digestion is suboptimal, and may increase the risk of necrotizing enterocolitis (NEC).
2
Antenatal steroids accelerate the mat-
uration of the gut and reduce the incidence of NEC (relative risk: 0.46; 95% CI 0.29-0.74).
3
Swallowing activity begins to develop during the second trimester, and enteral ingestion of amniotic uid contributes to fetal
nutrition and development of the gastrointestinal tract. Postnatally, ingestion of colostrum and milk plays an important role in
stimulating gut maturation. Accompanying the development of the gastrointestinal tract, there is also progressive development
of different enzymes throughout fetal life.
4
Gastric pepsin and brush-border enzymes, including sucrase, aminopeptidase, and
lactase, develop in parallel and are present in low concentrations in infants born prematurely. Lactase activity remains low
throughout fetal life but increases markedly with the rst enteral feed, regardless of age. Shulman et al
5
initiated feeds on
From the
1
Mater Medical Research Institute and the
School of Medicine, The University of Queensland,
Queensland, Australia;
2
University College London
Institute of Child Health, London, United Kingdom;
3
Morgan Stanley Childrens Hospital, Columbia
University Medical Center, New York, NY; and
4
Hospital
Infantil de Mexico, Mexico City, Mexico
article.
BW Birth weight
GA Gestational age
P:E Protein:energy
PDF Post-discharge formula
PTF Preterm formula
S72
Table I. Summary of theoretical concerns and available data from micropreterm infants for specic enteral nutrients
Nutrient Theoretical concerns Published data for micropreterm infants? Current recommendations New recommendations
Fluid Increased requirements due to immature skin
Vulnerable to uid overload with worsening cardiovascular
disease, patent ductus arteriosus
No
Intakes of 150-180 mL/kg/d tolerated in enteral studies
Range 135-200 mL/kg/d
12,13
Energy Low energy stores. Intake often inadequate due to
concomitant illness restricting supply
Concern regarding NEC
EE of 60-75 kcal/kg/d by indirect calorimetry and by doubly labeled
water in stable ELBW infants
30,31
Higher levels of EE of 88-96 kcal/kg/d by doubly labeled water
method in infants with sepsis
31
and chronic lung disease
31
130-150 kcal/kg/d
12
120-140 kcal/kg/d
Protein Increased requirement for growth, especially if decits
accumulate
Greater risk of overload, metabolic acidosis, increased BUN
and urea
Some amino acids conditionally essential
ELBW infants (generally >750 g) included as subjects along with
VLBW infants in enteral feeding studies dening protein
requirements.
Factorial method
33
ELBW infants randomized and treated for 7 days with IV amino
acids starting at 0.5 g/kg/d and increased by 0.5-3.0 or starting 2
g/kg/d and increased by 1.0-4.0 daily; infants receiving higher
amino acids in rst week had lower NDI at 18 mo [not 2 y] and
lower z-scores for weight, length, and head circumference at 2 y
34
Factorial approach
31
: 3.5-4.0
g/kg/d
Tsang et al
12
: 3.8-4.4 g/kg/d
(26-30 wk PCA)
ESPGHAN
13
: 4.0-4.5 g/kg/d
ELBW 3.8-4.4 g/kg/d VLBW
3.6-4.5 g/kg/d
Larger trials than Blanco,
et al.
34
necessary to assess
best IV amino acid ad-
vancement and dosage
P:E P:E 3.6 g/100 kcal with protein intake 4.6 g/kg/d tolerated for 1
wk
35
P:E 3.6 g/100 kcal with protein intake 4.3 g/kg/d for longer periods
reported some evidence of protein overload
36
Tsang et al
12
: 3.3-3.4 g/100
kcal
ESPGHAN
13
: 3.6-4.1 g/100 kcal
3.0-3.6 g/100 kcal
Carbohydrate Provides 40%-50% of calories
PTF has 23%-50% glucose polymers and some have Gos and
Fos oligosaccharides as prebiotics
24-31 weeks GA infants (n=20): Formula supplementation with
oligosaccharides reduced stool viscosity and accelerated GI transit
37
Tsang et al
12
: 9-20 g/kg/d for
enteral feeding of growing
ELBW infant
10.5-14 g/kg/d
Lipids May have increased requirements due to high energy needs
and restricted uid intake
Absorption may be reduced with resultant steatorrhoea
Provides 50% energy in human milk
No Tsang et al
12
: 6.2-8.4 g/kg/d for
enteral feeding of growing
ELBW infant, or 4.1-6.5 g fat/
100 kcal
5-7 g/kg/d for enteral
feeding of growing
micropreterm, or 4.4-6.0 g
fat/100 kcal
LCPUFA Greater decit at birth. LCPUFA oxidized if energy supply
insufcient
In a multicenter trial of infants <33 weeks maternal diet high in
DHA and infant DHA dose of 1% total fatty acids increased MDI of
females <1250 g
38
For infants <1250 g, supplementation was associated with higher
MDI in unadjusted, but not in adjusted, analyses
For males overall, and for all infants with bodyweight <1250 g the
risk of BPD was lower in supplemented infants
39
DHA: 20-62 mg/kg/d
ARA: 30-36 mg/kg/d
EPA: #23 mg/kg/d
Some evidence to suggest
higher intake of DHA (1% of
total fatty acids) might have
particular benets to
micropreterm infants
Sodium High fractional excretion of sodium in rst 10-14 d No 4-5 mmol/kg/d in rst
10-14 d and
2.5-3.0 mmol/kg/d
thereafter
Calcium and
phosphorus
Greater mineral decit at birth (majority of mineral accretion
occurs in last trimester). Greater risk of metabolic bone
disease.
Calcium absorption rate 50%-65%, phosphate absorption
90%
No Tsang et al
12
:
Calcium 100-220 mg/kg/d
Phosphorus 60-140 mg/kg/d
Calcium intake of 120-180
mg/kg/d
Phosphorus intake of 60-90
mg/kg/d; (maintain phos-
phorus levels $1.8 mmol/L)
(continued )
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day 4 or day 15 in 135 infants at 26-30 weeks gestation and
found that early feeding was associated with increased lactase
activity. Macronutrient transporters are present by the third
trimester.
2
Certain enzymes of amino acid metabolism de-
velop late in gestation, including those involved in: (1) the
synthesis of cysteine from methionine, taurine from cysteine,
and tyrosine from phenylalanine; (2) the degradation of tyro-
sine; and (3) the production of urea.
6
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vations, micropreterm infants might be expected to require
certain amino acids (eg, cysteine and taurine), which are
not essential later in life, and may be at risk for accumulating
excessive amounts of others (eg, phenylalanine, tyrosine, and
methionine). Enzymes used in gluconeogenesis such as phos-
phoenolpyruvate carboxykinase may not develop until just
before or just after term delivery. This is not surprising be-
cause the fetal liver stores glucose as glycogen, and there is
a steady ow of glucose to the fetal circulation via the pla-
centa. Immediately after birth, glycogen phosphorylase and
glucose 6-phosphatase act to release glucose from liver glyco-
gen. Gluconeogenesis is not necessary to maintain blood glu-
cose concentrations until 24-48 hours after birth. The
micropreterm neonate is born with low stores of liver glyco-
gen,
7
a reduced gluconeogenic ability, and is, thus, at partic-
ular risk for developing hypoglycemia.
Current Practice
Perhaps reecting the lack of specic data and nutritional rec-
ommendations, the nutritional management of micropreterm
infants varies markedly among neonatal units and countries.
In 2006, neonatal practitioners were surveyed and reported
that they provided parenteral and enteral nutrition sooner
and in larger volumes than they had previously, indicating
improved nutritional management as a result of increased
knowledge.
8
Regardless, postnatal growth failure is virtually
inevitable in micropreterm infants. It is important to act
promptly to secure an adequate nutrient supply because early
growth failure is associated with adverse neurodevelopmental
outcomes. In a review from the National Institute of Child
Health and Human Development that evaluated ELBW in-
fants, 89% of infants weighed <10
th
percentile for GA at 36
weeks post-menstrual age, and 40% of infants had weight,
length, and head circumference <10
th
percentile at 18-22
months corrected age.
9
The many causes of growth failure in-
clude complications of extreme prematurity; extended time to
meet recommended dietary intakes; and failure to provide ad-
equate nutrients for recovery or catch-up growth.
10
Evidence Base for Dening Nutritional and
Feeding Practices for Micropreterm Infants
Nutrient Requirements
Very few studies have examined the nutrient requirements of
micropreterm infants, and most published studies do not
stratify by birth weight (BW) or GA or include subgroup
analyses. The available data for specic nutrients are summa-
rized in Table I.
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.
S74 Tudehope et al
Table II. Preterm nutrient recommendations (per 100 kcal) by expert group
Nutrient Unit ESPGHAN, 2010
13
Tsang et al, 2005
12
<1000 g BW
Tsang et al, 2005
12
>1000 g BW
LSRO, 2002
11
(preterm)
WHO
>1000 g BW
(Birth to 7 d)*
WHO
>1000 g BW
(stabilization to term)*
WHO
>1000 g BW
(term to 1 y)*
Protein g 3.2-4.1
2.5-3.4 2.6-3.8 2.5-3.6 [1.3-4.0] [2.5-3.0] [2.0]

Fat g 4.4-6.0 4.1-6.5 4.1-6.5 4.4-5.7 [0.7-4.8] [3.8-5.7] [4.0-6.6]
Linoleic mg 350-1400 467-1292 462-1309 [350-1425]
z
NS NS NS
a-Linolenic mg >50 NS NS [77-228]
x
NS NS NS
LA:ALA 5-15 5-15 5-15 6-16 NS NS NS
ARA mg 16-39 $22 $22 [0-34]
{
NS NS NS
DHA mg 11-27 $16 $16 [0-20]
jj
NS NS NS
Carbohydrate g 10.5-12 6.0-15.4 5.4-15.5 9.6-12.5 [6.7-26.7] [6.3-12.9] [6.8-14.1]
Vitamin A IU [1199-2464] 467-1154 538-1364 [680-1270] [933-2000] [583-1250] [545-1273]
mg RE 360-740 [140-347] [162-410] 204-380 [280-601] [175-375] [164-382]
Vitamin D IU 800-1000** 100-308 115-364 75-270 [40-260]** [400-800]** [400]**
Vitamin E IU [3.0-14.9] 4.0-9.2 4.6-10.9 [3.0-11.9] [8.0-16.0] [5.0-10.0] [5.5-10.9]
mg a-TE 2-10 [2.7-6.2] [3.1-7.3] 2-8
[5.4-10.7] [3.4-6.7] [3.7-7.3]

Vitamin K mg 4-25 5.3-7.7 6.2-9.1 4-25 [10.7-13.3] [6.7-8.3] [7.3-9.1]
Thiamin mg 125-275 120-185 138-218 30-250 [53-67] [33-42] [45]
Riboavin mg 180-365 167-277 192-327 80-620 [480-613] [300-383] [45]
Vitamin B6 mg 41-273 100-162 115-191 30-250 [15]
zz
[15]
zz
[15]
zz
Vitamin B12 mg 0.08-0.7 0.20-0.23 0.23-0.27 0.08-0.7 [0.15]** [0.15]** [0.15]**
Niacin mg 345-5000 2400-3700 2800-4400 550-5000 [720] [720] [720]
Folic acid mg 32-90 17-38 19-45 30-45 [50]** [50]** [25]**
Pantothenic acid mg 300-1900 800-1300 900-1500 300-1900 [1067-1733] [667-1083] [727-1182]
Biotin mg 1.5-15 2.4-4.6 2.8-5.5 1.0-37 [2.0] [1.3] [1.4]
Vitamin C mg 10-42 12-18.5 13.8-21.8 8.3-37 [8-13] [5-8] [18]
Choline mg 7-50 9.6-21.5 11.1-25.5 7-23 NS NS NS
Inositol mg 4-48 21-62 25-74 4-44 NS NS NS
Taurine mg NS 3.0-6.9 3.5-8.2 5-12 NS NS NS
Carnitine mg NS 1.9-2.2 2.2-2.6 2-5.9 NS NS NS
Calcium mg 110-130 67-169 77-200 123-185 [80-107] [134-200] [253]
xx
Phosphorus mg 55-80 40-108 46-127 82-109 [41-62] [65-98] [105]
xx
Ca:P mg:mg NS NS NS 1.7-2.0:1 NS NS NS
Magnesium mg 7.5-13.6 5.3-11.5 6.1-13.6 6.8-17 [6.5-8.1] [4.1-8.1] [4.4-13.3]
Iron mg 1.8-2.7 1.333-3.077 1.538-3.636 1.7-3.0 0.0 [1.7-2.5] [1.8-2.7]
Zinc mg 1.0-1.8 0.667-2.308 0.769-2.727 1.1-1.5 [0.57] [0.42-0.67] [0.89]
Manganese mg 6.3-25 0.5-5.8 0.5-6.8 6.3-25 [0.7-1.5] [0.5-0.9] [0.5-1.0]
Copper mg 90-120 80-115 92-136 100-250 [93-161] [58-101] [64-110]
Iodine mg 10-50 6.7-46.2 7.7-54.5 6-35 [34] [26-53] [29-58]
Selenium mg 4.5-9 0.9-3.5 1.0-4.1 1.8-5.0 [4.2-6.3] [2.6-3.9] [2.9-4.3]
Sodium mg 63-105 46-88 53-105 39-63 [31-92] [48-77] [42-63]
Potassium mg 60-120 52-90 60-106 60-160 [130-182] [81-114] [89-124]
Chloride mg 95-161 71-192 82-226 60-160 [47-142] [74-118] [64-97]
Chromium mg 0.027-1.12 0.07-1.73 0.08-2.05 NS [0.07-0.13] [0.04-0.08] [0.05-0.09]
Molybdenum mg 0.27-4.5 0.20-0.23 0.23-0.27 NS [0.26-0.51] [0.16-0.32] [0.17-0.35]
Fluoride mg 1.4-55 NS NS 0-25 NS NS NS
Total Nucleotides mg #5 NS NS NS NS NS NS
AMP mg NS 0.23-0.62 0.27-0.73 NS NS NS NS
CMP mg NS 1.4-3.2 1.6-3.7 NS NS NS NS
(continued )
M
a
r
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h
2
0
1
3
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S
7
5
Recently, several expert groups have reviewed the avail-
able scientic evidence and formulated consensus guide-
lines for the nutritional management of preterm infants.
In 2002, the Life Sciences Research Ofce of the American
Society for Nutritional Sciences made recommendations
for the nutrient content of formulas for preterm-low
BW infants based on current scientic knowledge and ex-
pert opinion. The examples and sample calculations were
based on a 1000 g preterm infant and dened for different
stages of postnatal life (transition, stable growing, and
post-discharge stages). The Life Sciences Research Ofce
pointed out that it was not known whether these recom-
mendations would meet the needs of infants weighing less
750 g because so few data concerning their nutritional re-
quirements were available.
11
Tsang et al
12
dened reason-
able nutrient intakes for ELBW and VLBW infants and for
different stages of postnatal life: day 0; transition (the pe-
riod of metabolic and physiologic instability after birth);
and the stable, growing period. The authors highlighted
the vulnerability of ELBW infants, who are likely to
have greater needs for many nutrients, be more suscepti-
ble to excess, and be a more heterogeneous population in
terms of their clinical status than other infants. The
authors noted that almost no data relate directly to this
sub-group. In 2010, the European Society of Paediatric
Gastroenterology, Hepatology and Nutrition Committee
on Nutrition published updated guidelines on enteral nu-
trition supply for preterm infants.
13
No specic recom-
mendations were provided for infants with BWs below
1000 g because only data for protein were available. De-
spite the lack of data for ELBW infants, all expert groups
recognized the importance of supplying sufcient protein
and energy to compensate for the accumulated decits
seen in almost all ELBW/micropreterm infants during
the early postnatal period. Recommended intakes by the
three expert groups are listed in Table II.
Use of Human Milk for Micropreterm Infants
Although human milk is accepted as the gold standard for
feeding healthy term infants, it cannot be assumed that this
is the case for micropreterm infants who have higher re-
quirements for most nutrients. Hence, it is important to
critically evaluate the nutritional adequacy and health ef-
fects of human milk for this specic population in order
to make evidence-based recommendations for optimal nu-
trition. A detailed discussion of the use of human milk for
preterm infants is provided elsewhere (see the discussion of
human milk by Tudehope et al, in this supplement); the
discussion here focuses specically on data relevant to the
use of human milk and infant formulas in the micropre-
term infant.
14
Term infant formulas are not suitable for
feeding preterm infants and are certainly inappropriate
for micropreterm infants.
Unmodied human milk is unlikely to meet the nutri-
tional requirements of micropreterm infants for several key
nutrients, including protein and energy (especially when ma-
ture donor milk is used), sodium, calcium, phosphorus,
T
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S76 Tudehope et al
magnesium, trace elements, and certain vitamins. However,
human milk does have theoretical advantages compared
with formulas, including the composition and absorbability
of its fats and the bioavailability of certain trace metals. Hu-
man milk also has a lower renal solute load than formulas de-
signed to meet the needs of preterm infants and contains
specic components that enhance mucosal maturation, pro-
vide protection from bacteria, and modulate gut inamma-
tion and motility.
Health Effects of Human Milk in
Micropreterm Infants
Few studies have examined the benets to health pro-
vided by human milk in micropreterm infants. Many of
the longer-term benets reported with human milk in
preterm infants, (eg, improved developmental outcome,
cardiovascular health, and bone health) might be antici-
pated to be greater in micropreterm infants who have
a greater risk for sub-optimal, long-term outcomes, but
no specic data are available to conrm or refute this
hypothesis.
Growth and Brain Development
A number of studies have reported slower growth, in both
weight and length, in preterm infants <32 weeks gestation
who were fed unsupplemented breast milk before hospital
discharge, compared with those who were fed formula.
15,16
An observational study reported that infants <30 weeks
GA who were fed fortied human milk had slower weight
gain (22 vs 26 g/kg/d), smaller length increments, and
lower discharge weights (2428 g vs 2998 g) than those
fed preterm formula (PTF) but were discharged home ear-
lier [22 vs 26 days].
15
However, ELBW infants who were
fed human milk shortly after birth had higher mental de-
velopment scores at 30 months than did infants who were
not.
16
An observational trial compared outcomes for pre-
term infants <30 weeks gestation who were fed mothers
milk exclusively with those who received supplemental do-
nor breast milk (DBM) or PTF as a supplement to mater-
nal milk when volume was inadequate
15
Those who
received only mothers milk had fewer episodes of late on-
set sepsis [23% vs 36%, OR 0.47 (0.25-0.7)] and total
infection-related events; shorter durations of hospital
stay (73 vs 88 days); fewer gram-negative organisms iso-
lated from blood cultures; but the same incidence of
NEC (6% vs 9%) compared with those who needed to
be supplemented. The addition of DBM to mothers
milk when volume was inadequate offered limited short-
term advantages over PTF.
15
Infection and NEC
A recent study compared a complete human milk-based diet
with a diet of DBM fortied with bovine milk fortier or PTF
and found that infants with BWs of 500-1250 g who received
a complete human milk-based diet had a signicant reduc-
tion in NEC (P < .02) and, especially, NEC requiring surgical
intervention. There were no differences among groups in
growth or rates of late-onset sepsis.
18
Use of DBM in the Micropreterm Infant
To make appropriate choices about the use of DBM in the
micropreterm infant, it is important to consider the relative
advantages and disadvantages. A recent Cochrane systematic
review
19
compared outcomes in preterm infants fed DBM or
formula. None of the 8 studies analyzed focused specically
on micropreterm infants, and most were 20-30 years old
and from an era when DBM was fed without fortication
or mineral supplements, often as the sole diet. Only 1 study
compared the effects of nutrient-fortied DBM versus PTF
as a supplement to mothers breast milk in micropreterm in-
fants.
20
This study was unable to establish any short-term
benet for DBM over PTF.
Fortication of Human Milk for the
Micropreterm Infant
A recent Cochrane review concluded that the use of multinu-
trient fortiers in infants weighing <1500 g is associated with
short-term improvements in weight gain, linear growth, head
growth, nitrogen retention, and blood urea levels.
21
The re-
view did not consider micropreterm infants separately. A
small randomized controlled trial
22
showed that adjustable
fortication of human milk (based on the infants blood urea
concentration) resulted in greater weight and head circum-
ference gains, which were signicantly correlated with pro-
tein intake compared with standard fortication.
Consensus Position on Feeding
Micropreterm Infants
What to Give: Nutrient Requirements
Because so few studies have focused specically on the micro-
preterm infant, evidence-based guidelines cannot be formu-
lated for the majority of nutrients for this group. Our
consensus position is that the recommendations for preterm
infants should be applied to micropreterm infants for most
nutrients. Although the reasonable nutrient intakes provide
an indication of nutrient requirements, they cannot and
should not be followed rigidly. Each infants nutrient require-
ments should be determined on an individual basis after con-
sidering GA, BW, presence or absence of growth restriction,
and clinical factors. Absorption and bioavailability of nutri-
ents from different types of milk vary widely and generally
are higher when human milk is used rather than infant for-
mula or other breast milk substitutes. Furthermore, nutrient
requirements change over time; micropreterm infants, in
particular, accumulate nutritional decits during rst few
weeks of life. Thus, nutritional management of these infants
should include requirements for catch-up growth.
Available Enteral Feedings
In practice, the main options for enteral feeds are human
milk or PTF. There is strong and convincing evidence that
Nutritional Needs of the Micropreterm Infant S77
feeding human milk to preterm infants has benecial effects
for short-term (risk of infection and NEC, feed tolerance)
and longer-term (neurodevelopmental outcome, cardiovas-
cular risk, bone health) outcomes. Given the generally poorer
outcomes for micropreterm infants, it is reasonable to hy-
pothesize that this group may gain even greater benets
from human milk than other preterminfants. However, feed-
ing unsupplemented human milk is associated with slower
ponderal and linear growth, higher risk of metabolic bone
disease, and deciencies of micronutrients; these concerns
are likely to be greater in micropreterminfants, who generally
have higher nutrient requirements. Thus, although human
milk is preferred over formula feeding, supplementation or
fortication of human milk is required for this group of in-
fants. When mothers breast milk is unavailable or in short
supply, DBM or PTF can be used. The short-term use of
breast milk substitutes for pretermbabies has not been shown
to have demonstrable adverse effects on risks of allergy, bowel
microora, duration of breastfeeding, or childhood or adult
diseases. PTFs are designed to meet the estimated nutrient re-
quirements for routine preterminfants but may not necessar-
ily meet the requirements for micropreterm infants. For
example, when volumes sufcient to provide an energy in-
take of 120 kcal/kg/d are fed, the available preterm infant for-
mulas and fortied human milk diets provide protein intakes
of approximately 3.2-3.6 g/kg/d, which are below the recom-
mended higher protein intakes for micropreterm infants
(especially ELBW infants). When higher energy intakes of
130-140 kcal/kg/d are provided, some PTFs will support
the recommended protein intakes for these infants, but the
higher energy intakes might result in increased fat deposition.
The more immature the infant, the greater is the need for en-
teral feeding regimens with a higher protein:energy (P:E) to
meet the goal of greater protein gain relative to fat. Supple-
mentation of current PTF (P:E 2.7-3.0 g/100 kcal) with pro-
tein will increase the P:E and result in more lean mass and
relatively less fat deposition. Recently PTFs with P:E of 3.3-
3.6 g/100 kcal have become available in several countries. A
PTF with relatively high P:E may be desirable for the micro-
preterm infant. However, at present, safety and efcacy of
formulas with higher P:E (>3.6/100 kcal) for micropreterm
infants are not known and need to be studied.
Feeding Schedules
The objectives of feeding right after birth are to stimulate gut
maturation and hormone release and test gut motility. Tro-
phic feeding or minimal enteral feeding, dened as <24
mL/kg/d, should commence on day 1 if possible or day 2 at
the latest. Gastric residues should not be allowed to interfere
with feeding. Feeding volumes of 1-2 mL/feed should be pro-
vided every 3-6 hours for infants <30 weeks gestation on
days 1-2. When these feeds are tolerated and the infant is
well, volumes can be increased by about 20 mL/kg/d. How-
ever, this approach may not be reasonable for all infants.
For example, infants who have no or reversed end diastolic
blood ow before delivery may be more likely to develop
NEC, especially when they are growth-restricted. These in-
fants may have abnormalities in splanchnic blood ow before
and after birth that may become less marked during the rst
week of life. In these infants, there may be justication for
a delayed and careful introduction of enteral feeding, prefer-
ably with colostrum.
One of the goals of providing postnatal nutrition for mi-
cropreterm infants is to ensure that the transfer of nutrients
to the fetus and neonate is maintained. Because immaturity
of the gastrointestinal tract precludes provision of substantial
nutritional support via the enteral route, nearly all micropre-
term and very low BW infants receive parenteral nutrition.
This liberal approach to parenteral nutrition, adopted over
the last decade, has markedly improved nutritional intakes
of ELBW infants. However, parenteral nutrition is associated
with risks, mainly sepsis and metabolic complications, and
the risk-benet ratio must be considered. Parenteral nutri-
tion must be started early to maintain a continuous nutrient
supply during the transition from the fetus in utero to the
preterm infant ex utero, preferably within the rst 24 hours
of life, for micropreterm infants. Many neonatal intensive
care units now have the ability to place central lines and ini-
tiate total parenteral nutrition.
Post-Discharge Feeding
It is unlikely that unsupplemented breast milk meets the nu-
tritional requirements of micropreterm infants after dis-
charge. Although the proportion of these infants who are
breastfed exclusively after discharge varies in different set-
tings and is sometimes low, the majority of infants receive
some breast milk for at least the rst few weeks after dis-
charge. There are various possible methods to increase nutri-
ent (and particularly protein) intake of micropreterm infants
who breastfeed after discharge, although none has been for-
mally evaluated. Mothers can mix expressed breast milk
with fortiers for each feed, or a number of breast feeds
can be replaced with a preterm or post-discharge formula
(PDF). Both strategies are likely to increase nutrient intakes,
but they may interfere to some degree with breastfeeding and
increase the risk of infection. However, these risks must be
weighed against the risks of malnutrition and poor growth.
The timely introduction of foods rich in energy, protein,
iron, and zinc should be encouraged in this group of infants.
Ideally, micropreterm infants who are fed formula after
discharge should receive a nutritionally enriched PDF. These
formulas are considered as stepping-stones between preterm
and term formulas. They have an energy content of 71-74
kcal/100 mL and are enriched with more protein, minerals,
vitamins, and trace minerals per 100 kcal than term formula.
A 2012 Cochrane systematic review (including 10 random-
ized controlled trials of good methodological quality and
762 infants) was limited because the measured outcomes dif-
fered.
23
No subgroup analyses were conducted for micropre-
term infants, and most studies enrolled preterm infants
under 1850 g. Infants fed PDF consumed less formula, the
same amount of energy, but more protein, calcium, and
phosphorus than those fed term formula. A meta-analysis
of 4 trials reported a signicant difference in weight and
S78 Tudehope et al
length but not head circumference at 9 months corrected age.
In 2001, Lucas reported no difference in Bayley Mental De-
velopment Index and Psychomotor Development Index
scores at 18 months in the two groups.
24
Four trials reported
no difference in bone mineralization. The review concluded
that available data did not provide strong evidence that feed-
ing preterm infants with nutrient-enriched formula follow-
ing hospital discharge affects growth rates or development
up to 18 months post-term compared with standard term
formula.
24
However, this conclusion was criticized for the
limited ability to combine the summary data available in
the published manuscripts.
26
Cooke pointed out that in
studies with adequate sample size and duration of 6-12
months, infants fed PTF or PDF (particularly males) had en-
hanced growth.
Monitoring of Nutritional Practices and
Status
Growth
Growth monitoring is an integral part of the medical and nu-
tritional assessment and management of micropreterm in-
fants, who are at high risk for intrauterine and extrauterine
growth restriction. The ideal postnatal growth rate for micro-
preterm infants is not known. Lean body mass gain (nitrogen
retention) could be measured in addition to weight gain to
derive better estimates of macronutrient requirements, but
this approach is difcult to apply outside of research set-
tings.
27
Without a universally-accepted growth standard for
monitoring longitudinal growth of preterm infants in hospi-
tal, the goal is to replicate the fetal growth rate of at least 15-
20 g/kg/d. The International Fetal and Newborn Growth
Consortium [INTERGROWTH-21] study currently is mon-
itoring longitudinal growth in a cohort of preterminfants 23-
36 weeks gestation to provide new growth standard curves.
28
The World Health Organization Multi-Center Growth Refer-
ence Group created sex-specic growth curves,
29
which
should be used to plot longitudinal growth for micropreterm
infants from the expected date of delivery.
Discussion
Future research should focus either on micropreterm/ELBW
infants or stratify subjects by GA or BW to allow balanced
sub-group analyses. Ideally, a standard denition should be
used (based on GA or BW) so data across studies can be com-
pared. It is important to dene optimal protein and energy
intakes and P:E, and measure lean mass, not just weight
gain, as an outcome. The specic nutritional needs of micro-
preterm infants with postnatal growth restriction before and
after discharge need to be dened.
Micropreterm infants have greater nutritional decits at
birth than more mature preterm infants and accumulate
greater postnatal decits. Recommendations for routine
preterm infants are not likely on a theoretical basis to meet
requirements for micropreterm infants. Only a few
good-quality studies have addressed this group specically,
making it impossible to formulate evidence-based recom-
mendations for most nutrients. Nutritional management of
micropreterm infants should be based on existing recom-
mended intakes for preterminfants, individualized according
to an infants GA, BW, and clinical status. Early use of paren-
teral nutrition is recommended while establishing enteral
feeds to avoid the accumulation of nutrient decits and
growth failure. Human milk should be used when available
but should be fortied to meet requirements, ideally based
on measurement of milk composition. When human milk
is not available in sufcient quantities, a PTF should be
used. n
Author Disclosures
Mary Fewtrell, MD, has received research funding and per-
formed advisory or consultant work Philips Advent and
Pzer. Sudha Kashyap, MD, has served on an advisory board
for Mead Johnson Nutrition. He has also, in the past, served
on advisory boards as a consultant for Abbott and Baxter.
Enrique Udaeta, MD, is a consultant for Nestle and Mead
Johnson Nutrition and is an academic speaker for Mead
Johnson Nutrition. All authors received an honorarium
and manuscript preparation. D. T. wrote the rst draft of
this manuscript.
Research Institute, Level 3, Quarters Building, Annerley Rd., Wooloongabba,
Queensland 4102, Australia. E-mail: david.tudehope@mater.org.au.
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S80 Tudehope et al
Nutritional Requirements and Feeding Recommendations for
Small for Gestational Age Infants
1,2
, Maximo Vento, MD, PhD
3
,
Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD
4
, and Paulo Pachi, MD, PhD
5
We dene the small for gestational age (SGA) infant as an infant born $35 weeks gestation and <10th percentile on
the Fenton Growth Chart. Policy statements from many organizations recommend mothers own milk for SGA in-
fants because it meets most of their nutritional requirements and provides short- and long-term benets. Several
distinct patterns of intrauterine growth restriction are identied among the heterogeneous grouping of SGA infants;
each varies with regard to neonatal morbidities, requirements for neonatal management, postnatal growth veloci-
ties, neurodevelopmental progress, and adult health outcomes. There is much we do not know about nutritional
management of the SGA infant. We need to identify and dene: infants who have true growth restriction and
are at high risk for adverse metabolic outcomes in later life; optimal growth velocity and catch-up growth rates
that are conducive with life-long health and well being; global approaches to management of hypoglycemia; and
an optimal model for postdischarge care. Large, rigorously conducted trials are required to determine whether ag-
gressive feeding of SGA infants results in improved nutritional rehabilitation, growth, and neurodevelopmental out-
comes. Before birth, maternal supplementation with specic nutrients reduces the rate and severity of growth
restriction and may prevent nutrient deciency states if infants are born SGA. After birth, the generally accepted
goal is to provide enough nutrients to achieve postnatal growth similar to that of a normal fetus. In addition, we rec-
ommend SGA infants be allowed to room in with their mothers to promote breastfeeding, motherinfant attach-
ment, and skin-to-skin contact to assist with thermoregulation. (J Pediatr 2013;162:S81-9).
S
mall for gestational age (SGA) newborns have a birth weight lower than expected for a given duration of gestation re-
gardless of its cause. Newborns with intrauterine growth restriction (IUGR) have a birth weight less than a predeter-
mined cut-off value due to nutritional restrictions during pregnancy. Low birth weight (LBW) newborns have
a birth weight <2500 g.
The SGA infant is dened as $35 weeks gestation and <10th percentile on the Fenton Growth Chart.
1
Technological ad-
vances in industrialized countries enable obstetricians to detect growth-restricted fetuses antenatally. Babies who are SGA
may be constitutionally small and at no greater risk than normally sized babies or small due to IUGR. SGA infants can be
term or preterm; for the latter category, the combination of SGA and prematurity signicantly increases the risk of neonatal
and infant mortality.
2
Infants with IUGR receive reduced amounts of critical nutrients in utero, which results in chronic growth
failure. This vulnerable group of infants with IUGR is at high risk for perinatal morbidity and mortality and constitutes 50% of
perinatal deaths occurring preterm and 20% of deaths at term.
3
Each year, more than 20 million infants worldwide are born with LBW. The global average incidence is 16% of all births,
varying between 7% in industrialized countries, 16% in developing countries, and 19% in the least developed countries.
4
This incidence is likely to be an underestimate because two-thirds of infants born in many parts of Africa, Asia, and Latin Amer-
ica are not reported or not weighed at birth.
5
Because of uncertainties with the assessment of gestational age in many countries,
it is difcult to be sure of the true proportion of LBW that are preterm and SGA, but the World Health Organization (WHO)
estimates that 69% of all LBW infants have IUGR. Low maternal socioeconomic status is predictive of infant growth restriction
at birth; commonly associated and interrelated factors include poverty, high parity, malnutrition, smoking, poor personal and
sexual hygiene, and maternal drug use. The likelihood of IUGRincreases when pregnancy is complicated by an underlying med-
ical condition that imposes stress on the fetus such as restricted umbilical artery ow, microvascular thrombi, and reduced
uterine perfusion. Constitutional growth restriction relates to parental stature and racial or ethnic factors. Typically, these
infants have symmetrical growth restriction at birth, do not reach normal growth
From the
1
Mater Medical Research Institute, South
Brisbane;
2
School of Medicine, University of
Queensland, Brisbane, Queensland, Australia;
3
Hospital
Universitario y Polit ecnico La F e, Valencia, Spain;
4
Aga
Khan University, Karachi, Pakistan; and
5
Santa Casa de
Misericordia de S~ ao Paulo, S~ ao Paulo, Brazil
Please see the Author Disclosures at the end of this ar-
ticle.
AGA Appropriate for gestational age
BMI Body mass index
IV Intravenous
PI Ponderal index
RR Relative risk
UNIMAP United Nations Multiple
Micronutrient Preparation
S81
percentiles postnatally, are not prone to metabolic disorders,
and should receive normal newborn care.
Several factors are involved in other forms of IUGR, in-
cluding racial/ethnic backgrounds, maternal age (<18
or >40 years), maternal height, weight at booking, socioeco-
nomic and marital status, altitude of residence, poverty,
parity, malnutrition, smoking, poor personal and sexual hy-
giene, maternal drug use, and complications of pregnancy.
Follow-up of these children indicates that they display high
rates of school failure, behavioral problems, attention decit,
language delay, subtle neurological decits, and sudden in-
fant death syndrome. SGA infants have reduced linear
growth in infancy and excess abdominal fat gain in child-
hood. This growth pattern is associated with increased rates
of cardiovascular disease, hypertension, and insulin resis-
tance later in adult life.
6-9
Determinants of Nutritional Requirements of
SGA Infants
Fetal Adaptation and Maladaptation to
Uteroplacental Failure
When intrauterine nutrient supply is compromised, the fe-
tus responds in a characteristic manner that increases the
chances of survival: (1) overall size is decreased; (2) brain
growth is spared; (3) lung maturation is accelerated; and
(4) red blood cell production increases. Blood ow is selec-
tively redistributed from less vital structures such as the
splanchnic bed, musculoskeletal structures, and pulmonary
and urogenital systems to more vital organs such as the
brain, heart, adrenal glands, and placenta. The relative hyp-
oxemia to which growth-restricted fetuses are exposed stim-
ulates erythropoiesis as a compensatory response that
increases hematocrit and the appearance of nucleated red
blood cells.
10
One-half of all infants with IUGR have a ve-
nous hematocrit > 60%; in 17% of infants, it is >65%. The
increased red cell mass increases energy and glucose con-
sumption. These adaptations can become pathologic if dep-
rivation is severe. Chronic hypoxemia can lead to metabolic
acidosis, which is commonly present in the growth-
restricted fetus before the onset of labor. Transient reduc-
tions in maternal blood ow during labor can further
decrease oxygen supply. The fetus becomes dependent on
anaerobic glycolysis and lactic acid accumulates, further
compromising potential for survival. Antenatal detection
of fetal growth restriction often is associated with abnormal
Doppler ow studies that reveal high resistance in umbilical
vessels and low resistance in cerebral vessels. Further re-
search in the pre- and postnatal periods is required to iden-
tify markers of blood ow redistribution and characterize
the related metabolic complications in IUGR infants.
Customized Fetal/Birth Weight Models
Customized fetal birth weight models derived from combin-
ing data from populations in several countries improves
identication of SGA infants at increased risk for adverse
outcomes.
3,10
All customized growth charts are remarkably
consistent in dening the variables that should be included
in the adjustment (ie, maternal height, weight, ethnicity,
and parity). There is evidence that SGA infants dened using
the corrected growth reference are truly at greater risk in
terms of morbidity and mortality than those dened by
growth references for the normal population. The use of cus-
tomized growth standards in high- and low-risk populations
has been shown to improve the prediction of abnormal 5-
minute Apgar scores, length of hospital stay, admission to
the neonatal intensive care unit, hypoglycemia, need for re-
suscitation, and perinatal death. Consequently, the Royal
College of Obstetricians and Gynaecologists in the United
Kingdom recommended the use of customized interpreta-
tion of birth weight adequacy in the identication and man-
agement of SGA fetuses.
11,12
Classication of SGA Infants
The commonly used classications focus on the timing of the
prenatal insult. In infants with proportionate growth restric-
tion, all anthropometric variables (weight, length, head cir-
cumference) are below the 10th percentile, whereas in those
with disproportionate growth restriction head circumference
is preserved, length is somewhat affected, and weight is com-
promised to a greater degree.
13
Miller and Hassanein
14
rst
described the use of Rohrers Ponderal Index (PI, equal to
mass/height
3
) in 1971. A normal PI is $2.41 and equates
to no length sparing and chronic IUGR, whereas a low PI
(<2.41) represents length sparing and acute or subacute
IUGR.
14
The classication of SGA as intrinsic implies onset
of IUGR at the time of conception or in rst trimester; clas-
sication as extrinsic implies later onset of IUGR. Early-
onset growth restriction, which tends to give rise to an SGA
infant who is proportionate, symmetrical, hypoplastic, and
has a normal PI, is more likely to have an intrinsic cause of
growth restriction such as poor maternal nutritional status,
chromosomal anomalies, and exposure to teratogens. Late-
onset growth restriction can result from disorders of the pla-
centa or from maternal problems that impair delivery of
oxygen and nutrients to the placenta. The infant with late-
onset growth restriction (extrinsic type) has disproportionate
growth that affects weight more than length and much more
than head circumference.
Patterns of Growth Restriction at Birth
Several distinct patterns of IUGR are identied among the
heterogeneous grouping of SGA infants with different neona-
tal morbidities, requirements for neonatal management,
growth velocities in childhood, neurodevelopment, and adult
health outcomes.
A mild decrease in fetal growth, 3rd to 10th percentile for
gestational age, represents the lower end of the normal distri-
bution of growth for gestational age, with growth restriction
usually attributed to constitutional factors. A moderate de-
crease in fetal growth, <3rd percentile for gestational age, is
usually of late onset. These infants often exhibit maladapta-
tion after birth, with catch-up growth in the rst 6 months,
although as a group these infants remain below the 50th
S82 Tudehope et al
percentile and are at risk of metabolic syndrome. A severe in-
trauterine growth failure indicates weights less than 3 SDs be-
low the mean for gestational age or <60% of expected weight.
Infants with early-onset growth restriction have high risks for
perinatal mortality, continued growth failure, and impaired
neurodevelopment.
Composition and Metabolism of SGA Compared
with Appropriate for Gestational Age Infants
The mainnutrients for the healthy fetus are glucose, lactate, ke-
tone bodies, and amino acids. The growth-restricted fetus re-
ceives fewer of these nutrients, which reduces lean mass,
body fat, bone mineral content, and glycogen stores and in-
creases the risk of hypoglycemia.
15
Growth-restricted neonates
have less body fat and greater proportions of body water than
their gestational-age matched peers. Neonatal water turnover
increases with the clinical degree of IUGR; this test has been
used as a putative measure of true growth restriction and sus-
ceptibility to postnatal morbidities. The meager reserves of en-
ergy in these infants can become exhausted during a stressful
labor and delivery. Protein turnover in SGA infants compared
with their appropriate for gestational age (AGA) peers range
from 2% to 30% greater to 20% lesser. Oxygen consumption
and energy expenditure in SGA infants are high, secondary
to a large brain:body and the need for catch-up growth. Fat
and protein absorption is 11%-14% lower in SGA infants
than AGA infants. Major problems in interpreting studies
and drawing conclusions about metabolism of SGA infants
are the heterogeneous groups studied, inconsistency in selec-
tion of controls (whether gestational age or birth weight),
and variability in feeding schedules.
15
Maternal Nutrition and IUGR
The associations between maternal undernutrition, chronic
energy decits, and micronutrient deciencies with IUGR
and SGA births are well recognized. Maternal undernutrition
(body mass index [BMI] <18.5 kg/m
2
) ranges from 10% to
19% in most low-income countries.
16
The nutritional status
of a woman before and during pregnancy is important for
a healthy pregnancy, and low maternal BMI is associated
with IUGR.
17
The exact comparative risks associated with
low maternal BMI, poor weight gain in pregnancy, and ma-
ternal micronutrient deciencies and the occurrence and se-
verity of IUGR are poorly quantied; however, there is
a growing body of evidence that supports the importance
of maternal nutrition before conception. Thus, interventions
to ameliorate IUGR/SGA should focus on malnourished ad-
olescent girls, especially those likely to become pregnant.
A meta-analysis of studies indicate that balanced protein
energy supplementation in pregnancy is associated with
a 31% reduction in risk of giving birth to SGA infants (rela-
tive risk [RR] 0.69; 95% CI 0.56-0.85).
18
Given the high prev-
alence of multiple micronutrient deciencies in pregnancy in
most developing countries,
19
the administration of a multiple
micronutrient supplement (eg, United Nations Multiple Mi-
cronutrient Preparation [UNIMAP]) during early pregnancy
is proposed as being superior to traditional iron-folic acid
combinations.
19,20
Compared with iron-folate supplementa-
tion, multiple micronutrient supplementation has compara-
ble effects on maternal anemia in the third trimester (RR
1.03; 95% CI 0.87-1.22) but is associated with a 9% reduction
in the risk of SGA births (RR 0.91; 95% CI 0.86-0.96).
21
UNIMAP Nutrient Content
The UNIMAP formulation contains 30 mg of iron, 400 mg of
folic acid, 15 mg of zinc, 2 mg of copper, 65 mg of selenium,
800 mg of retinal equivalents vitamin A, 1.4 mg of vitamin B1,
1.4 mg of vitamin B2, 18 mg of niacin, 1.9 mg of vitamin B6,
2.6 mg of vitamin B12, 70 mg of vitamin C, 5 mg of vitamin D,
10 mg of vitamin E, and 150 mg of iodine.
Feeding SGA Infants: Balancing Benets and
Risks
In supplying postnatal nutrient supply to SGA infants, one
must consider the balance of risks associated with under-
and overfeeding. The global epidemic of metabolic syndrome
in adults, especially in low-income countries in which the
prevalence of IUGR is high, demands a more careful ap-
proach in which the risks and benets of nutritional practices
are assessed adequately with both short- and long-term con-
sequences in mind. There is clearly no gain from iatrogenic
malnutrition and insufcient catch-up growth induced by
inadequate nutrient supply; consequences on brain develop-
ment and later educational performance are well dened.
There is also no gainand potential long-term consequences
on adult healthby promoting fat tissue gain, especially if
abdominal fat is being laid down.
Specic Nutritional Requirements for SGA Infants
$35 Weeks
The generally accepted goal is to provide sufcient nutrients
to achieve postnatal growth similar to that of a normal fetus
because specic requirements of most nutrients for SGA in-
fants are unknown. In 2006, WHO evaluated studies of in-
fants with birth weights <2500 g or gestation lengths <37
weeks from developing and developed countries.
13
Infants
were classied into 3 groups; birth weight <1500 g or gesta-
tion <32 weeks; birth weight 1500-1999 g or 32-36 weeks; and
term infants <2500 g. The nutritional requirements for AGA
preterm infants were not distinguished from those for SGA
infants. The Recommended Nutrient Intakes have been cal-
culated from fetal accretion rates, factorial equations, and
published values (Canada Paediatric Society Nutrition in
1995,
22
American Academy of Pediatrics Committee on Nu-
trition in 1985,
23
and European Society for Paediatric Gastro-
enterology, Hepatology, and Nutrition in 1987
24
). These
recommendations are summarized in the Table.
13,20,24-33
Which Milk Should Be Fed to the SGA Infant?
Breastfeeding is recommended as the optimal feeding method
and nutrition for all infants but is particularly important for
Nutritional Requirements and Feeding Recommendations for Small for Gestational Age Infants S83
Table. Summary of theoretical concerns and available evidence for special nutritional needs of SGA infants
Nutrient Theoretical issues
Published data and/or previous
recommendations Monitoring/outcomes
Recommendation based on
birth weight
Fluid Increased proportion of total body water; clinical
comorbidities such as polycythemia and hypoglycemia
RCT: infants fed 200 mL/kg on day 2
regained birth weight faster and had
more rapid weight gain than those fed
170 mL/kg on day 7
25
Edema, excessive weight gain, urine
output and specic gravity, serum
electrolytes
60 mL/kg [>2000 g]- 80 mL/kg [<2000 g]
on day 1 and increase to
160-200 mL/kg/d
13
Energy Reduced energy stores, especially fat and glycogen;
depletion of catecholamines; increased O
2
consumption
and total energy expenditure
None
110-135 kcal/kg/d
24
Anthropometric data, PI, skin folds
Research: Body composition
110-135 kcal/kg/d
24
Protein Reduced muscle mass and increased catabolism from
catecholamines; increased losses in stools (11%-14%)
compared with AGA infants; increased amino acid
turnover and more efcient protein synthesis
None
3.0-3.6 g/kg/d
13
Weight, length, head circumference
skinfolds, BUN, creatinine,
albumin
3.0-3.6 g/kg/d provides 12-15 kcal/kg/d
or 9%-13% of calories
13
P:E 2.2-3.3 g/100 kcal
Carbohydrate Decreased glycogen stores in liver and muscle and
in fat stores increases vulnerability for hypothermia
and hypoglycemia (<2.6 mmol/L), especially in
late-onset IUGR; insulin levels may be high or low
None
5-20 g/kg/d
13
Blood glucose levels as necessary 10-12 g/kg/d (40-48 kcal/kg/d) or 40%-45%
of energy; 6-10 mg/kg/minimum
Calculated from macronutrients
Lipids Decreased deposition in subcutaneous tissue/brown
fat; use and -oxidation; attenuated ketone bodies;
decreased absorption (11%-14%) compared with
AGA infants
None
4.5-6.8 g/kg/d
13
Anthropometric data, skin folds, PI
Research: Body composition studies
4.4-6.0 g/kg/d (40%-54% of energy based
on energy provided by macronutrients)
LCPUFA Depleted stores at birth due to impaired placental
transfer
DHA 1% of total fat for LBW
26
DHA 1% of total fat for LBW
26
; Preterm
not SGA studies
Sodium Increased compared with gestational age peer group None
1-3 mmol/kg/d
13
Serum sodium levels as necessary 63 mg/100 kcal (2.7 mmol/100 kcal;
maximum 86 mg/100 kcal
[4.6 mmol/100 kcal])
27
Calcium/phosphorus Low phosphate levels at birth; breast milk may
not meet needs but breast milk may adapt to needs
25
Decreased whole-body density and content compared
with AGA infants
Calcium 60-90 mg/kg accretion
Phosphorus supplementation
adjusted to nitrogen and calcium
supplementation
28
Calcium 120-160 mg/kg/d
Phosphorus 60-90 mg/kg/d
Vitamins Vitamin D
29
Vitamin A (1 mg3.33 IU)
29
800-1000 IU/day
400-1000 IU/day
Multivitamin supplementation
recommendations by many countries
Multivitamin supplementation for
breastfed SGA infants
Iron Normal serum iron but low stores at birth
High cord blood hematocrit and hemoglobin, but
ferritin <10 m/L
RCT: 0, 1, or 2 mg/kg/d iron for
2000-2500 g infants
30
RCT: 2-3 mg/kg/d
31
FBCs with reticulocytes before starting
iron; ferritin and transferrin to assess
iron stores (if available)
Supplementation with 2 mg/kg/d from 8
weeks and continue to 1
year or until iron-fortied food intake
Zinc Deciencies at birth due to maternal deciency
and decrease placental transfer; cumulative decit
due to low levels in mature human milk but adequate
levels in transitional milk
32
RCT of 5 mg in SGA >36 weeks, no
benet
33
Mortality, infection, cognitive outcomes Use of liquid multiple micronutrient
mixture
20
BUN, blood urea nitrogen; DHA, docosahexaenoic acid; FBC, full blood count; LCPUFA, long chain polyunsaturated fatty acids; P:E, protein to energy ratio.
T
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LBW infants, as research shows increased cognitive develop-
ment in this population with feeding human milk.
34
Mothers
breast milk is the rst choice of feed for SGAinfants because it
meets most of their nutritional requirements and provides
short- and long-term benets. Breastfeeding and expressed
breast milk reduce the incidence and/or severity of a wide
range of infectious diseases, including necrotizing enterocoli-
tis (NEC), bacterial meningitis, bacteremia, gastroenteritis,
respiratory tract infection, otitis media, and urinary tract in-
fection.
34,35
Breastfeeding decreases the rate of sudden infant
death syndrome/sudden unexpected death in infancy in the
rst year of life, and the incidence of insulin-dependent
(type 1) and noninsulin-dependent (type 2) diabetes mellitus,
obesity, certain cancers, hypertension, hypercholesterolemia,
and asthma in older children and adults.
34
Breastfeeding is
also associated with better speech and jaw development and
improved visual acuity.
25
Despite methodologic difculties and challenges, the use
of breast milk substitutes for growth-restricted neonates is as-
sociated with increased short- and long-term adverse out-
comes, including mortality and serious morbidity.
Epidemiologic studies
25,26
and randomized controlled trials
(RCTs)
36,37
in high-risk environments have found that the
incidence of invasive infection is greater in LBW infants
who are fed formula. A meta-analysis of RCTs
38
has shown
that formula-fed LBW infants have 5 times the risk of
NEC, a condition associated with a mortality of approxi-
mately 20% and signicant long-term health care costs
among survivors.
39,40
In a meta-analysis, formula feeding re-
sulted in later transition than breast milk in LBW infants.
38
It
should be noted, however, that all trials cited were performed
in the 1980s and 1990s with the use of standard term formu-
las lacking the immunological advances in formula that have
occurred in the past two decades.
Mothers Breast Milk for the SGA Infant: Outcomes
of Trials
Neurodevelopment. Most studies show that SGA infants
have poorer neurodevelopment than AGA infants, espe-
cially SGA infants who do not exhibit catch-up growth.
One study showed that infants who were breastfed exclu-
sively for >12 weeks scored 5.0 points (range, 0.7-9.30)
greater on the Wechsler Preschool and Primary Scales
than those breastfed for <12 weeks.
41
Another study com-
pared outcomes in term SGA infants at 18 months of age
whose mothers chose to breastfeed (n = 137) with those
whose mothers chose to formula feed (n = 235).
42
Mean
scores on the Bayley Mental Development Index and Psy-
chomotor Development Index were 8.2 points greater
(95% CI 5.0-11.4) and 5.8 points greater (95% CI 2.8-
8.7), respectively, for the breastfed group. In an RCT of
term SGA infants who received a 76 kcal/100 mL enriched
formula had a signicantly lower Psychomotor Develop-
ment Index (99.5 vs 102.0) scores at 9 months than infants
fed the standard term formula. From this, the authors con-
cluded that an enriched formula should not be promoted
for term SGA infants.
43
The group fed enriched formula
had better length and head circumference growth than the
group fed term formula, with the larger benet in females.
Breastfed infants showed no advantage over term formula
when confounding factors were considered.
44
Another
study assessed 1-year olds who were born SGA and found
that breastfed infants had higher motor development scores
than formula-fed infants; no other differences between the
groups were detected.
45
Growth. Most studies show that term SGA infants remain
smaller than their AGA peers at 7-8 years of age. One study
showed that although only 6%-7% of term SGA infants
were below the 5th percentile for height at 18 years, they ac-
counted for 14%-21% of short 18 year-olds.
35
However, the
authors of a cohort study from the United Kingdom of term
SGA infants (n = 474) reported no signicant differences in
mean weight, length, and head circumference in breastfed
compared with formula-fed infants at 18 months of chrono-
logical age.
44
Summary of Studies on Breastfeeding SGA Infants
There are limited data on most outcomes in SGA infants. The
available data suggest that the benets of feeding mothers
milk to SGA infants, such as feed tolerance, infection, NEC,
and neurodevelopment, are similar to those for preterm in-
fants. There seems to be no adverse effect of this modality
of feeding on growth. Breast milk feeding is preferred over
formula feeding because of benets related to reduced infec-
tion and improved neurodevelopment. Although most pub-
lished studies are from developed countries, the few available
studies from developing countries show similar results.
Breastfeeding and feeding mothers expressed breast milk
are likely to have an even greater impact in reducing infec-
tions in developing countries due to the higher incidence
of infections in these settings.
Donor Breast Milk for SGA Infants
No studies describing the use of donor breast milk (DBM)
for SGA infants were found. Although almost all studies on
DBM have been conducted in developed countries, the re-
sults are unlikely to be different in developing country set-
tings. Because of the proven benets of mothers breast
milk in preventing infection in SGA infants and for DBM
in studies with preterm infants in developed countries, it
is tempting to suggest that increased efforts to establish
and maintain donor milk banks in developing countries
might be as or even more benecial than in developed
countries.
Consensus Position on Feeding SGA Infants
Assessment and Patterns of Growth in the Hospital
The ideal postnatal growth rate for SGA infants is not
known. The current goal of current nutritional management
is to achieve a postnatal growth rate similar to normal intra-
uterine growth. Compared with this standard, postnatal
growth failure and associated poor neurodevelopmental out-
comes occur commonly in SGA infants. A fetus grows in
utero at a rate of at least 15-20 g/kg/day. To attain this
rate, the SGA infant would need approximately 110-135
kcal/kg/day with additional energy for catch-up growth.
The slower the rate of intrauterine growth, the less likely
the infant will exhibit catch-up growth. Less-affected and
healthier SGA infants are more likely to respond to nutri-
tional intervention and exhibit catch-up growth during the
rst 6 months. Gestational age also inuences growth recov-
ery; the lower the gestational age, the longer it takes to
achieve nal catch-up growth and the worse the long-term
prognosis.
When possible it is recommended that catch-up growth
be gradual: not too much and not too fast. If an infant is
SGA at birth and subsequently has a discharge weight
AGA, this represents early postnatal catch-up growth and
may be a risk factor for metabolic syndrome in adult life.
Healthy catch-up growth is paralleled by an increase in lin-
ear growth and lean body mass, and unhealthy catch-up
growth is associated with an increase in fat mass, central ad-
iposity, and insulin resistance.
46
Population studies show
that the majority of SGA infants achieve catch-up growth
during the rst 2 years of life, and a failure to show early
compensatory growth in that time period predicts perma-
nently decreased growth.
47,48
SGA infants are prone to per-
sistent decits in muscle mass but normal or excessive gains
in fat.
Feeding SGA Infants
Model of Care. Standard practice in neonatal units is to
promote mothers own milk as the feed of choice for all
LBW infants. Breastfeeding should be promoted and ac-
tively supported for SGA infants. In the absence of any peri-
natal compromise, it is recommended to encourage
kangaroo mother-baby skin-to-skin contact, attempt breast-
feeding as early as feasible,
49
and initiate feeds within 30
minutes of birth
50
with breastfeeding or expressed breast
milk (mother or donor). If the SGA infant is reluctant to
feed or does not feed well, the mother may need encourage-
ment to express her breasts up to 8 to 10 times per day.
Many of these initiatives are interrelated, and it is unlikely
that specic clinical interventions will be effective if used
alone.
10
For SGA infants who require admission to the nurs-
ery, allowing parents to spend at least 24 hours with their
infant in a parent room before discharge provides a smooth
transition to home. Complementary infant formula feeds
should be given only if medically indicated with consent
from the mother.
If the mother plans to formula feed, feeds should com-
mence at 60 mL/kg on day 1 (80 mL/kg if <2000 g) in in-
fants with moderate-to-severe IUGR. The infant should be
encouraged to demand feed, but not less than every 3
hours or more than 4 feeds hourly. The passage of an en-
teral tube should be considered for gavage feeding of ex-
pressed breast milk and/or infant formula in the event of
continued poor feeding or for extra volume to keep blood
glucose levels >2.6 mmol/L.
Role of Parenteral Fluids for Nutrition. Intravenous
(IV) uids are commenced with 10% dextrose at 60 mL/
kg/d if enteral feeding is not possible or problematic hypogly-
cemia occurs with difculty maintaining normal blood glu-
cose levels with enteral feeds. IV uids may be required to
support a more gradual increase in enteral volume intake
and may be reduced as feed volume increases. This is often
the preferred option for the mother who wants her baby to
be fed exclusively with breast milk when donor milk is not
available. In term or near-term infants with severe IUGR
(<2000 g), especially when absent or reversed umbilical ar-
tery end diastolic ow has been demonstrated on antenatal
Doppler studies, a more conservative approach to enteral
feeding should be adopted with a low threshold for IV uids
while waiting for the mothers colostrum and immature milk
to become available. The infant should be carefully moni-
tored for signs of feed intolerance (vomiting, increasing/large
residual gastric aspirate if tube feeding).
SGA is a risk factor for NEC in term babies, but the risk is
very low in the absence of other problems, and the limited in-
formation available suggests that feeding volume is not a fac-
tor.
51-53
However, an Australian study from 2007-2009
reported infants >33 weeks gestation contributed 24.5% to
mortality from NEC.
54
All literature reports of absent or re-
versed umbilical artery end diastolic owand NECare in pre-
term infants.
53
From a nutritional point of view, the liberal
approach to parenteral nutrition adopted during the last
two decades has markedly improved nutritional intakes of in-
fants with severe IUGR.
Special Care Nursery Versus Rooming In with the
Mother on the Postnatal Ward. Most SGA infants
should room in with their mothers on the postnatal ward
to enhance the success of breastfeeding, promote mother-
infant attachment, and initiate skin-to-skin contact to assist
with thermoregulation.
44
Whether the infant should room
in with mother or be admitted to the neonatal nursery
must be a decision based on neonatal and maternal factors
and on hospital policy. Hospital policy will be inuenced
by physical environment (eg, proximity of the postnatal
ward to the nursery), staff ratios and competence, and feed-
ing guidelines. Key principles underpinning feeding guide-
lines include developmentally supportive care, support of
breastfeeding, and the individual feeding plan developed by
parents and a multidisciplinary team. The requirement for
admission to a neonatal unit will depend on evaluating the
perinatal history (eg, asphyxia, congenital anomaly, severity
of growth restriction [<2000 g], and the ongoing need for
specialized care [eg, IV uids]). Moderate-to-severe growth
restriction and abnormal Doppler umbilical blood ow mea-
surements antenatally might dictate a more conservative ap-
proach to enteral feeding, with need for IV uids while
awaiting breast milk to become available.
53
With the assis-
tance of supportive and skilled nursing, term babies of birth
S86 Tudehope et al
weight >2000 g cope well with rooming in and breastfeeding
on the postnatal ward. Provision of specialized, individual-
ized care for the motherbaby dyad can mitigate the need
for transfer to the nursery on occasion. Additional supports
include performance of blood glucose estimations, occa-
sional gavage feeds, nursing baby on a heated water bed,
and permitting additional hospital admission days when nec-
essary.
Discharge Criteria. Each motherbaby dyad should be
evaluated individually to determine the optimal time for dis-
charge. Early discharge can be practiced safely and may pro-
mote attachment. Weight by itself should not be a criterion
for decision-making about suitability for discharge. Discharge
may be considered providing the following criteria are satis-
ed: physiological stability (maintains temperature in open
incubator), no clinical illness, feeding is progressing well,
not losing weight, and steady weight gain. Most importantly,
the mother and family need to be assessed for their readiness,
competence, and willingness to accept social support and ac-
cess the health care system and resources if necessary.
55
Postdischarge Nutrition and Growth for SGA Infants:
Possible Adult Disorders Resulting from IUGR.
There is a strong association between LBW and insulin re-
sistance. The thrifty phenotype hypothesis, which postu-
lates that fetal programming for adaptation to an adverse
intrauterine environment results in lower insulin sensitiv-
ity in utero, is one of the hypotheses to explain this asso-
ciation. Later in life, metabolic syndrome may develop,
featuring hypertension, dyslipidemia, central obesity, and
type 2 diabetes associated with excessive weight gain. Re-
cent epidemiologic evidence indicates that obesity, insulin
resistance, diabetes, and cardiovascular disease are more
common among adults who were smaller than normal at
birth and very likely were SGA, and particularly among
those with a high placental:fetal weight.
56
These examples
suggest that certain adult pathologies may be unavoidable
complications of environmentally imposed conditions such
as severe and prolonged fetal malnutrition leading to fetal
growth restriction to ensure fetal survival. Such conditions
may represent examples of programming in which an in-
sult applied at a critical or sensitive stage in development
may result in a lifelong effect on the structure and devel-
opment of the individual.
57
An RCT from Honduras ran-
domized SGA infants who were breastfeeding at 4 months
to continue exclusive breastfeeding until 6 months or to
introduction of complementary feeds at 4 months; this
study found no difference in developmental outcome at
12 months.
58
Monitoring of Nutritional Practices and
Status
Growth Charts
The WHO Multicenter Growth Reference Group growth
curves are based on healthy, breastfed children of socio-
economically afuent, healthy women from diverse ethnic
and cultural settings.
59
After reaching postmenstrual term
age, growth of preterm and SGA infants should be mon-
itored with the use of these new prescriptive postnatal
standards for term infants, which have been adopted by
more than 100 countries. The WHO growth charts pro-
vide globally applicable standards of growth for children
under optimal conditions of breastfeeding in 6 countries
from birth until 2 years of age. These sex-specic growth
curves should be used to plot longitudinal growth for
preterm and SGA infants after the expected date of deliv-
ery. More controversial is the choice of growth chart to
use for monitoring growth trajectory for SGA babies
who are born preterm. The INTERGROWTH-21st study
currently is monitoring longitudinal growth in a cohort
of infants 23-36 weeks gestation to provide new growth
standard curves.
60
Recommendations for SGA Infants >34
Weeks Gestation
Breastfeed within the rst 30 minutes and prevent hypother-
mia. Breastfeeding is preferred; alternative feeding method if
necessary. Feed according to gestational age; consider supple-
ments for iron and other micronutrients. Do not promote
rapid weight gain because it increases risk for metabolic syn-
drome. Maternal nutritional interventions (including iron
and micronutrients) must be focused during preconception
or pregnancy to prevent SGA birth.
Case Study
A 31-year-old primigravid woman developed pregnancy-
induced hypertension and poor fetal growth from 35 weeks
gestation. She was treated with antihypertensive agents and
fetal monitoring with growth assessments, and tests for fetal
well-being were performed by maternal-fetal medicine spe-
cialists. At 37 weeks, with absent end-diastolic ow on
Doppler studies and progressive growth failure, a cesarean
delivery was performed. Baby boy D measured 1950 g in
weight (<3rd percentile); 45.8 cm in length (10th percen-
tile); and 33.4 cm in head circumference (35th percentile)
and was vigorous at birth with Apgar scores of 7 at 1 minute
and 9 at 5 minutes. There were no dysmorphic features, but
there was evidence of muscle wasting and decreased subcu-
taneous fat tissue.
The clinical team decided to provide care on the postna-
tal ward with mother and infant rooming in. The infant was
nursed initially in an open cot with a heated water mattress
to prevent hypothermia, and breastfeeding was attempted
at 2 hours. Blood glucose estimation was 2.4 mm/L at 4
hours of age just before the second feed. The infant received
2 complementary feeds of 25 mL of a partially hydrolyzed
formula on day 1 when blood glucose estimations were
again <2.8 mmol/L. With support from a lactation con-
sultant, skin-to-skin contact (kangaroo cuddling), and
feeding every 2-3 hours, the mother rapidly established
a transitional milk supply. By day 3, blood glucose estima-
tions were all >3.0 mmol/L; complementary feeds were
ceased, and the baby was completely breastfed. Weight
loss was minimal, the nadir was 1890 g on day 4; the infant
had regained his birth weight when weighed on day 6 and
was discharged home, with midwifery follow-up on day 7
with a weight of 1980 g.
Discussion
Was Rooming-In on a Postnatal Ward an
Acceptable Model of Care?
Considerable variation in practice exists depending on facil-
ities and rigor of glucose monitoring. In developing coun-
tries, this model is the norm and such infants do better
when kept with mother in a mother-baby unit. Kangaroo
care for mother and father should be practiced as early as pos-
sible.
Should the Baby Have Received IV Dextrose
Infusion and/or Gavage Feeding for 3 Blood
Glucose Levels 2.3-2.7 mmol/L on day 1?
Consensus opinion is that IV dextrose is not indicated
unless baby is symptomatic, has blood glucose estima-
tion< 2.4 mmol/L, or has little prospect of sucking
and swallowing properly in the short term. Continue
to place on breast frequently plus express and administer
colostrum.
Was Partially Hydrolyzed Formula the Most
Appropriate Complimentary Feed?
Pasteurized DBM is preferred if available; otherwise, there is
a diversity of practice among term, preterm, and partially hy-
drolyzed formulas.
Should the Baby Have Been Discharged Home on
Day 7 Weighing Only 1980 Grams?
Weight should not be the major consideration for dis-
charge but rather physical stability, feeding well, starting
to gain weight, maternal competency, and adequate com-
munity support. If weight were the arbiter it would be
about 1800 g.
What Feeding and Monitoring Regime Is
Recommended after Discharge?
As breastfeeding was well established, this should be contin-
ued and home visitation from a pediatric nurse is desirable.
Supplementation or hospital readmission is rarely required.
What Is the Optimal Growth Velocity and Who
Should Oversee Follow-Up?
Weight loss <10% within the rst week and a weight gain
of 15-20 g/day in the rst 4 weeks is expected. Health
care professionals who are familiar with follow-up of
LBW infants should plot growth on a WHO growth
chart. Catch-up growth should not be too rapid or too
slow. n
Author Disclosures
preparation. D. T. wrote the rst draft of this manuscript.
Research Institute, Level 3 Quarters Building, Annerley Rd, Wooloongabba
4102, Queensland, Australia. E-mail: david.tudehope@mater.org.au.
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Nutritional Recommendations for the Late-Preterm Infant and
the Preterm Infant after Hospital Discharge
1,2
, Deborah L. OConnor, PhD, RD
3
, Danhua Wang, MD
4
, and Jacques Rigo, MD, PhD
5
Early nutritional support of preterminfants is critical to life-long health and well being. Numerous studies have dem-
onstrated that preterm infants are at increased risk of mortality and morbidity, including disturbances in brain de-
velopment. To date, much attention has focused on enhancing the nutritional support of very lowand extremely low
birth weight infants to improve survival and quality of life. In most countries, preterm infants are sent home before
their expected date of term birth for economic or other reasons. It is debatable whether these newborns require
special nutritional regimens or discharge formulas. Furthermore, guidelines that specify how to feed very preterm
infants after hospital discharge are scarce and conicting. On the other hand, the late-preterm infant presents
a challenge to health care providers immediately after birth when decisions must be made about how and where
to care for these newborns. Considering these infants as well babies may place them at a disadvantage. Late-
preterm infants have unique and often-unrecognized medical vulnerabilities and nutritional needs that predispose
themto greater rates of morbidity and hospital readmissions. Poor or inadequate feeding during hospitalization may
be one of the main reasons why late-preterminfants have difculty gaining weight right after birth. Providing optimal
nutritional support to late premature infants may improve survival and quality of life as it does for very preterm in-
fants. In this work, we present a review of the literature and provide separate recommendations for the care and
feeding of late-preterm infants and very preterm infants after discharge. We identify gaps in current knowledge
as well as priorities for future research. (J Pediatr 2013;162:S90-100).
M
uch attention has focused on enhancing the nutritional support of very low birth weight (VLBW) and extremely low
birth weight (ELBW) infants to improve survival and quality of life. Signicant efforts have been made to provide
adequate nutrition to VLBW/ELBW(henceforth VLBW) infants before discharge and for term infants during the rst
months of life. Nutritional requirements of VLBW infants have been dened to prevent cumulative nutritional decits soon
after birth.
1,2
The goal of these efforts is to improve growth early so that preterm and VLBW infants reach normal weight
and length by the expected date of delivery or, at most, by the time they are discharged from the hospital.
In most countries, preterm infants are sent home before their expected date of term birth for economic or other reasons. It is
debatable whether these newborns require special nutritional regimens or discharge formulas. Guidelines that specify how to
feed VLBW infants after hospital discharge are scarce and conicting. Furthermore, the nutritional support provided during
hospitalization has improved and decreased the incidence of acquired nutritional decits. Thus, the systematic use of special
nutrient-enriched discharge formulas must be considered carefully.
Similarly, the nutritional requirements of term infants during the early months of life may need to be re-evaluated to prevent
excess protein and energy intakes and more strictly mimic intakes of breastfed term infants.
3
Feeding regimens designed specif-
ically to meet the nutritional requirements of late-pretermnewborninfants have not beenestablishedandought to be considered.
We present a review of the literature and provide recommendations for the care and feeding of late-preterm infants and
VLBW infants after discharge, separately. We identify gaps in current knowledge as well as priorities for future research.
Nutritional Requirements for the Late-Preterm Infant
A variety of terms have been used to describe preterm infants born at a number of different intervals between 32 and 36 weeks
gestation (ie, late preterm, near term, marginally preterm, moderately preterm, minimally preterm, and mildly
preterm). Only the terms moderately preterm and late preterm are dened
From the
1
Paris Descartes University, APHP Necker
Hospital, Paris France;
2
CNRC, Baylor College of
Medicine, Houston, TX;
3
Department of Nutritional
Sciences, University of Toronto and The Hospital for Sick
Children, Toronto, Ontario, Canada;
4
Department of
Pediatrics, Peking Union Medical College Hospital,
Beijing, China; and
5
Department of Neonatology,
University of Liege, CHR Citadelle, Liege, Belgium
article.
AAP American Academy of Pediatrics
EUGR Extrauterine growth retardation
GA Gestational age
HM Human milk
LCPUFA Long-chain polyunsaturated fatty acid
S90
well and should be used. The term late-preterm infants de-
scribes infants born between 34.0 and <37.0 weeks gestation,
and moderately preterm describes infants born between
32.0 and <37.0 weeks gestation.
4
Late-preterm births com-
prised 8.8% of all live births in the US in 2008 and close to
10% of all births in developing countries.
Late-preterm infants are at risk for mortality and perinatal
morbidity. Although severe illness may be uncommon, late-
preterm infants are 2 to 3 times more likely than term infants
to experience mild-to-moderate morbidities such as hypo-
thermia, hypoglycemia, respiratory distress and delayed
lung uid clearance, jaundice, infection, feeding intolerance,
nutritional compromise in the early neonatal period, and
greater rates of readmission after hospital discharge.
5
Pres-
ently, long-term neurologic and developmental outcomes
of late-preterm infants are a major concern. The brain of
the late-preterm infant is less mature than that of the term
infant. Given that late-preterm infants comprise 9%-10%
of all births, even minor increases in the incidence of neuro-
logic disability and/or school failure in this group can have
a huge impact on the effectiveness of educational systems
and health care needs.
Current Nutritional Practices
The late-preterm infant presents a challenge to health care
providers immediately after birth when decisions must be
made about how and where to care for these newborns. Tri-
age of late-preterm infants varies among hospitals. Some in-
stitutions admit these infants directly to a newborn nursery,
and others admit them to a neonatal intensive care unit
(NICU). In many institutions, the limited availability of
acute care beds in the NICU and established clinical practices
determine that these infants are admitted to the well-baby
nursery or to mothers rooms in accordance with rooming-
in practices.
However, considering these infants as well babies may
place them at a disadvantage. For example, mothers of pre-
term infants who are admitted to a NICU are more likely to
initiate and continue breastfeeding than mothers of infants
placed in the well-baby nursery.
6
Late-preterm infants have
signicantly greater medical risks and require specic sup-
port more often than term infants.
7
Late-preterm infants
can develop hypoglycemia and have difculty feeding, situa-
tions that may require intravenous treatment, which is a rela-
tively labor-intensive treatment for a well-baby nursery.
8
Striking variations in the clinical care of late-preterm infants
in 10 NICUs located in California and Massachusetts were re-
ported.
9
Five percent to 66% of infants received hyperali-
mentation, and 4%-72% of infants were sent home with
recommendations to be fed a postdischarge formula.
Weight gain by moderately premature infants (30-35
weeks gestational age [GA]) during hospitalization falls
well below intrauterine norms.
10
In a study of 15 NICUs,
98% of moderately premature infants (30-35 weeks GA)
failed to gain at least 15 g/kg/d, the recommended intrauter-
ine growth rate.
10
The z-score for weight decreased from
birth to discharge by 0.45 to 0.93 (average, 0.67) across
all NICUs. The NICUs that reported optimal growth worked
to minimize postnatal weight loss so that birth weight was re-
gained more quickly, and better mid-term growth was
achieved.
10
The provision of protein and energy supplements
increased the growth velocity of moderately preterm in-
fants.
10,11
In one study, shorter duration of gavage feeding
correlated with growth velocity, suggesting that terminating
gavage feeding may reect variation in the recognition, rather
that true attainment, of mature feeding ability. In fact, gavage
often may be discontinued too early to allow for proper
growth.
10
The advantages of breastfeeding for late-preterm infants
appear to be even greater than those for term infants. How-
ever, establishing breastfeeding in this group frequently is
more problematic than in term infants. Late-preterm infants
may be sleepier, have less muscle strength, and, thus, have
more difculty with latch, suck, and swallow. Furthermore,
they are more likely to be separated from their mothers,
who may have medical conditions that interfere with breast-
feeding.
12
Any one or a combination of these conditions pla-
ces the mothers and infants at risk for breastfeeding failure.
Breastfeeding initiation in the US is 59%-70% in the late-
preterm population, and the likelihood of breastfeeding be-
yond 4 weeks or the recommended 6 months is signicantly
less than for term infants, and, possibly, less than for infants
born before 34-35 weeks gestation.
13
Consequences of Poor Feeding in the Late-Preterm
Population
Growth. Poor or inadequate feeding during hospitalization
may be one of the main reasons why late-preterm infants
have difculty gaining weight right after birth.
10
When phys-
ical growth was measured in a population-based cohort of
late-preterm and term infants,
14
late-preterm infants were
found to be at increased risk of being underweight and
stunted at 12 and 24 months of age (aOR: 2.57 and 2.35,
and 3.36 and 2.30, respectively). Wasting was signicantly
different between the groups in the rst year of life, but
only a small number of infants were reported to have wasting
at 12 and 24 months. Whether or not poor growth of late-
preterm infants during the rst years of life is linked to inad-
equate early nutrition remains to be determined.
General Health and Readmission. Late-preterm infants
are 2 to 3 times more likely to be readmitted than term in-
fants.
5,13
The main presenting diagnoses are jaundice, sus-
pected sepsis, and feeding difculties. Feeding may be
successful during the birth hospitalization but can become
problematic after discharge. Feeding difculties secondary
to poor oral-motor tone, function, and neural maturation
predispose the infants to dehydration and hyperbilirubine-
mia. Late-preterm infants also may be discharged home after
successful transition to the extrauterine environment, but be-
fore lactation is established and problems with latch and milk
transfer are identied and addressed adequately. Parental ed-
ucation and timely outpatient follow-up by a provider
Nutritional Recommendations for the Late-Preterm Infant and the Preterm Infant after Hospital Discharge S91
knowledgeable in breastfeeding should be included in the
proper management of these motherinfant dyads.
15
Development. The risk of adversely affecting brain devel-
opment during the last trimester is well known. Although
most attention has focused on VLBW infants, moderately
preterm infants are also at risk of impaired development.
The preterm infant brain weighs approximately two-thirds
that of the term infant at 34 weeks GA, and the relative per-
centages of gray matter and myelinated white matter to total
brain volume increase exponentially between 34 and 40
weeks gestation.
16
Late-preterm infants can have various
neonatal complications, such as poor feeding, that increase
the risk of brain injury and abnormal neurodevelopmental
outcome.
Long-chain polyunsaturated fatty acids (LCPUFAs) play
an important role in early infant development and visual
acuity in preterm infants (see article on lipid needs by Lapil-
lonne et al in this Supplement).
17
They may be important in
late-preterm infants as well. Supplementation of formula
with docosahexaenoic acid (DHA) and arachidonic acid im-
proves visual acuity and cognitive development in moder-
ately preterm infants (ie, 30-37 weeks GA).
18
Late-preterm
infants may require preformed DHA in early life for optimal
neurologic development.
Late-preterm infants are at more risk of adverse develop-
mental outcomes and academic difculties for up to 7 years
of age than terminfants.
19
Late-preterminfants have a greater
risk of cerebral palsy, speech disorders, neurodevelopment
handicaps, behavioral abnormalities, and competence issues
(behavioral, scholastic, social, and global). Given the known
relationship among poor early growth, inadequate nutrition
during hospitalization, and long-term development of
VLBW infants, it may be speculated that similar risks exist
for late-preterm infants. Large population-based studies
that evaluate long-term neurodevelopmental and behavioral
outcomes in relation to nutritional intake, feeding perfor-
mances, and early growth are needed to test this hypothesis.
Changes in Nutritional Needs in Late Gestation
Nutritional requirements for late-preterm infants can be
evaluated in the same manner applied to VLBW infants
and with a similar goal.
20
Specic data about late-preterm in-
fants are scarce. However, extrapolation from data for VLBW
and term infants can be made with a reasonable degree of
condence. In general, nutritional recommendations for pre-
term infants need to: (1) consider fetal growth as appropriate
for a particular GA; (2) focus on lean body mass deposition;
(3) consider age-appropriate accretion rates of protein, min-
erals, and various essential constituents; (4) incorporate an
understanding of gastrointestinal tract development; (5)
consider the cumulative nutrient decit that may accrue dur-
ing the early days or weeks of life; and (6) adapt recommen-
dations relative to postconceptional age.
Growth velocity decreases dramatically from 18-20 g/kg/
d at 28 weeks GA to 10 g/kg/d at term.
21,22
Protein accretion
and, therefore, requirements related to body weight decrease
in proportion during this time. Resting energy expenditure is
45 kcal/kg/d in VLBW infants and 50 kcal/kg/d in larger pre-
term infants. The additional energy requirements needed for
heat generation and physical activity (eg, movement, crying)
are slightly less in VLBW infants (15 kcal/kg/d) than in larger
preterm infants (20 kcal/kg/d). Fat accumulation increases as
a proportion of the weight gain from 12% at 28 weeks GA to
20% at term and 40% in breast-fed term infants.
22
Fetal en-
ergy deposition per gram of weight gain also increases from
1.8 kcal/g at 28 weeks GA to 2.3 kcal/g at term and 3.8
kcal/g in breast-fed term infants. Therefore, energy require-
ments vary across all preterm groups.
Mineral requirements are controversial. On one hand,
mineral requirements for bone development can be estimated
exclusively from placental transport. Accordingly, the Amer-
ican Academy of Pediatrics (AAP) and other groups
23
recom-
mend that preterm infants receive relatively large amounts of
mineral supplements. On the other hand, smaller amounts of
highly bioavailable calcium and phosphorous are recommen-
ded if adaptation to extrauterine life is taken into account.
2
After birth, bone turnover is stimulated, and calcium and
phosphorous are released to the mineral pool. Thus, activa-
tion of bone turnover reduces the need for exogenous
calcium and phosphorus and, therefore, on that basis the Eu-
ropean Society of Pediatric Gastroenterology, Hepatology,
and Nutrition Committee on Nutrition recommended re-
cently smaller amounts of highly bioavailable calcium and
phosphorus. Mineral requirements are relatively high in
late-preterm infants because bone mineralization lags bone
growth in all preterm infants, and their bones contain smaller
mineral stores than those of similar GA newborn infants.
Nutritional stores of essential nutrients in newborn infants
(ie, LCPUFAs, iron, trace elements) are derived from trans-
placental transfer and related to GA. To date, no data justify
providing late-preterm infants with different amounts of
these nutrients than those recommended for other preterm
infants. Therefore, similar intakes are recommended.
The nutritional requirements of late-preterm and early-
term infants are shown to be greater than those of full-term
infants. The values do not take into account the nutrient sup-
ply needed to compensate for any nutritional decit and,
therefore, may not apply to the very preterm infant at time
of or after hospital discharge.
Recommendations, Gaps in the Literature, and
Research Priorities
The nutritional needs of late-preterm infants differ from
those of term infants, especially with regard to energy, pro-
tein, calcium, and phosphorous requirements. Late-preterm
infants have unique and often-unrecognized medical vulner-
abilities and nutritional needs that predispose themto greater
rates of morbidity and hospital readmissions.
Breastfeeding is the preferred way to feed late-preterm in-
fants. However, donor or mothers milk often does not meet
the theoretical nutritional needs of the late-preterm infant.
When late-preterm infants have a signicant comorbidity
and/or when the gap between actual and recommended
nutrient intakes is signicant, fortiers and supplements may
be necessary to meet a particular infants needs.
Presently, clinical judgment is applied to balance the ben-
ets (improved nutrition) with the risks (interruption of
breastfeeding and transient undernutrition) associated with
providing nutrient-enriched supplements or formula to
late-preterm infants. Studies designed to determine the best
way to provide optimal nutrition to late-preterm infants,
the largest subgroup of preterm infants, are needed.
Late-preterm infants appear to have poorer rates of breast-
feeding initiation and duration than term and, possibly, ear-
lier preterm infants. Health care providers should monitor
breast milk supply, nutrient transfer, and problems related
to poor intake. Individualized feeding plans should be pro-
moted and include special considerations to compensate
for immature feeding skills and inadequate breast milk pro-
duction, including the need to stimulate lactation. Mothers
of late-preterm infants should receive qualied, extended lac-
tation support, frequent follow-up, and due consideration of
delayed hospital discharge.
Current nutritional practices are likely to induce transient
undernutrition in late-preterm infants, the magnitude and
consequences of which are unknown. The possible link be-
tween early nutrition and long-term neurologic and develop-
mental outcomes in late-preterm, moderately preterm, and
early-term infants needs to be dened.
Nutritional Requirements for the Preterm
Infant after Discharge
Nutritional Status at Discharge from the Hospital
Growth and Quality of Growth. Extrauterine growth re-
tardation (EUGR) describes postnatal growth of preterm in-
fants that is less than the expected growth of a fetus at the
same postconceptional age. It is a major problem that occurs
in 60%-100% of preterm births globally.
24-28
EUGR has been
dened at discharge as growth values <10th percentile or
<2 SD from the mean of intrauterine growth expectation.
It has also been dened as a change in z-score of >1 SD
or >2 SD from birth to discharge.
29
The latter denition
was a better predictor of neurodevelopmental outcomes
than the former denition.
30
Body composition and bone mineral content at discharge
can be measured reliably in research settings.
31-35
There is no
standard for these measures in preterm infants because neo-
natal disease and undernutrition occur commonly and inu-
ence body composition strongly. Indeed, most studies show
that body composition is abnormal at discharge and marked
by a reduction in fat-free mass
32
and increased total
31-33
and
intra-abdominal adiposity.
32,35
This predominant fat mass
deposition among preterm infants is believed to be due to
imbalances in protein/energy nutrition during hospitaliza-
tion and recovery from early malnutrition, especially in the
ELBW groups.
20
It is important to assess lean-to-fat mass or lean-to-total
body mass routinely. Monitoring only weight-for-age may
result in an inappropriate classication of nutritional ade-
quacy (Figure 1).
36
Therefore, the assessment of growth
status of preterm infants in the NICU and at the time of
discharge should include weekly measurements of length
and recordings of weight-for-length or other measures of
body proportion. It remains to be determined how type of
growth and body proportion are associated with optimal out-
comes.
Finally, poor growth of head circumference postnatally is
associated with poor brain development, cerebral palsy,
Mental Development Index score <70, and Psychomotor In-
dex <70 at 18 months corrected age,
37
motor and cognitive
impairment at 3 and 7 years,
38,39
and a detriment of 4.1 IQ
points in adults.
40
Accordingly, assessments of growth should
include measurements of head circumference.
Effects of the Nutrition Strategies during
Hospitalization. The goal of providing nutrition to the
preterm infant is to ensure that the rate of growth and
body composition equal those of a fetus at the same GA.
This goal also can apply to the growing preterm infant after
discharge through the rst year of life. EUGR is attributed
to an early nutritional decit and poor growth during the sta-
ble growing period. Aggressive enteral and parenteral nu-
trition for very preterm infants reduces cumulative energy
and protein decits, promotes postnatal growth, optimizes
body composition,
21,41-45
and may, improve neurodevelop-
mental outcomes.
37,42,45-49
When infants are fed human
milk (HM), they should also receive fortiers.
50
There is con-
siderable interest in individualizing the nutrient fortication
of HM to address each preterm infants unique nutritional
Figure 1. Weight growth status categorization (ie, weight-for-
age vs weight-for-length) at discharge from hospital of
preterm infants born at 26 to 29 weeks GA (n = 1214). The
discordance at discharge between the weight-for-age and
weight-for-length methods of weight growth status assess-
ment is primarily caused by the small-for-age infants being
mostly appropriate-for-length (adapted from Olsen et al
36
).
requirements and differences in milk composition.
51,52
The
variability in the protein and/or fat content of HM may be re-
sponsible for slow growth in some HM-fed infants when for-
tiers are provided in a consistent manner, regardless of
differences in milk composition.
51-54
When infants are fed
formula, it is necessary to stress that the use of hydrolyzed
protein and/or bottled or canned sterilized preterm formula
has a reduced nutrient bioavailability that needs to be com-
pensated.
A prospective study of preterm infants with birth weights
<1250 g demonstrated that initiating aggressive nutritional
support early (ie, energy and protein intakes of 50 kcal/kg/
d and 2.5 g/kg/d at day 1; increased to 120 kcal/kg/d and 4
g/kg/d at day 6; and to 120-130 kcal/kg/d and 4-4.5 g/kg/
d during the stable growing period) signicantly reduced
growth restriction at the time of discharge. The incidence
of infants with a weight <2 SD did not change between birth
and discharge, and postnatal growth restriction was observed
in only 9% of infants.
55
Effect of Postdischarge Nutrition on Development
and Growth
Fewpublished studies have tested the hypothesis that a proac-
tive approach to feeding VLBW infants after hospital dis-
charge (eg, feeding VLBW infants differently than term
infants) improves growth and development better than
a reactive approach (eg, intervening when growth failure
has occurred). This gap in our knowledge is particularly
pronounced for VLBW infants fed HM predominantly after
hospital discharge and for VLBW infants with persistent
morbidities.
It is difcult to establish universal postdischarge feeding
guidelines because growth and nutritional status of preterm
infants vary considerably. Furthermore, the volume of feeds
consumed at discharge varies greatly and may reach 200
mL/kg/day or more if the infants are fed ad libitum. It is im-
portant to consider caloric density because infants on less
calorie-dense formulas ingest 22%-23% more formula than
those on more calorie-dense formulas.
56
Therefore, the calo-
ric density of feeds will determine the intake not only of en-
ergy but also of micronutrients and proteins, which are
important for physical growth.
Current Practices for Feeding after Hospital
Discharge. Postdischarge practices regarding breastfeeding
and nutrient enrichment of feedings vary widely by country,
NICU, and caregiver. Infants are sent home on HM alone,
partially or fully nutrient-fortied HM, nutrient-enriched
formula, or conventional term formula. Although there is
a lack of evidence to suggest a prescriptive approach to feed-
ing all VLBW infants after discharge, there is general consen-
sus that HM should be fed in preference to infant formula
and that certain subgroups of infants will be at risk for
poor nutritional status after discharge.
Many organizations recommend that mothers own milk
be the exclusive source of nutrition for the rst 6 months
of life.
57-59
These endorsements are based on abundant data
that demonstrate many advantages of HM.
60-62
Despite
awareness of these advantages, rates of HM feeding among
preterm infants fall signicantly below those of term infants
for a variety of reasons such as maternal illness, stress, lack of
adequate staff support, and other factors related to preterm
birth.
63
Premature infants are at greater risk for morbidity,
malnutrition, and likelihood that not all nutrient decits
will be resolved before discharge. Therefore, VLBW preterm
infants, and particularly those born ELBW, have the greatest
nutrient needs, especially if they: (1) are discharged well be-
fore their expected delivery date; fed predominantly HM; (2)
have fallen below the 3rd or 5th percentile in growth indices;
or (3) have persistent morbidities that elevate nutritional re-
quirements or limit the volume of feeds consumed.
The goals for VLBW preterm infants should be to promote
HM feeding, minimize nutrient decits, promptly address
decits when identied, and avoid overnourishing or pro-
moting postnatal growth acceleration beyond normal for
postconceptional age. Because the nutritional status of pre-
term infants varies widely, creating individualized feeding
plans is the best approach. Ideally, the pre- and postdischarge
nutritional concerns should be closely coupled, although it
generally is not achieved. VLBW infants are discharged at
younger ages and lower body weights than ever before.
Once home, they are cared for by health care providers
who had not been involved with their inpatient care. Close
nutritional monitoring of infants after hospital discharge fre-
quently is not accomplished because high-risk neonatal
follow-up clinics are concerned more with neurodevelop-
mental than nutritional status. Therefore, it is important
to establish postdischarge feeding guidelines to care for these
infants.
Evidence in Support of the Need for Nutrient-
Enriched Formula after Hospital Discharge. Infants
who weigh less than expected for their postconceptional
ages are at increased risk of long-term growth failure and re-
quire particular attention.
64
Breastfeeding and providing for-
tied HM should be promoted. If an infant is formula-fed,
a preterm formula or a special postdischarge formula that
contains more protein, minerals, trace elements, and LCPU-
FAs than standard term formula should be provided until the
preterm infant reaches 40 weeks postconceptional age and,
possibly, until the infant reaches 52 weeks postconceptional
age.
64,65
Henderson et al
66
identied 7 good-quality controlled tri-
als (N = 631 infants) in which the authors compared the ef-
fects of feeding preterm infants either a nutrient-enriched
formula or standard term formula after hospital discharge.
The authors found little evidence that nutrient-enriched for-
mula affected the growth or development of preterm infants
up to 18 months corrected age. However, this analysis was
limited because preterm infants at most nutritional risk
were either excluded or underrepresented. For example, in
all but 1 of the 6 trials (n = 20 infants), a signicant propor-
tion of infants weighed >1500 g. In one trial, preterm infants
(n = 103) were included only if they were growing well at
discharge (25 g/kg/d). In another, infants with an abnormal
suck and swallow were not included (n = 89). In yet another,
infants with chronic lung disease were not included
(n = 125). Thus, future research efforts should study sub-
groups of preterm infants who are not able to feed ad libitum
after hospital discharge or who have extra metabolic de-
mands secondary to growth restriction or chronic lung dis-
ease.
66
Another limitation is that the growth could not be
evaluated until 6 months postterm because of lack of data.
It is important to evaluate growth before 6 months because
most preterm infants are at greatest nutritional risk soon af-
ter hospital discharge.
Recent studies indicate that nutrient-enriched discharge
formulas can provide advantages to preterm infants. Growth
at 4 and 12 months and mineralization at 4 months after dis-
charge are better in VLBW infants fed preterm formula dur-
ing the rst 2 months after discharge than in those fed term
formula.
67
Nutrient-enriched formula provided after term
does not change the quantity of growth but improves the
quality of growth in preterm infants. Infants fed nutrient-
enriched formula have lower fat mass, corrected for body
size at 6 months corrected age, than infants fed standard for-
mula or HM.
68
Preterm infants fed nutrient-enriched for-
mula after discharge exhibit an increase in fat-free and
peripheral fat mass but not central adiposity compared
with infants fed term formula.
69
These data indicate that
nutrient-enriched formulas do not promote central adiposity
in preterm infants, a feature that is associated with metabolic
syndrome later in life.
Evidence in Support of the Need for Nutrient-
Enriched HM after Hospital Discharge. Although
HM is purported to be superior to formula, HM-fed infants
often accrue the greatest nutritional decits before hospital
discharge.
64
To determine whether the provision of
nutrient supplements after discharge is benecial, VLBW
(750-1800 g) preterm infants fed predominantly HM were
randomly assigned at discharge (38 weeks postconceptional
age) to a control group (unfortied HM) or an intervention
group (half of HM feeds nutrient-enriched).
70,71
Both groups
received intensive lactation support. The infants fed nutrient-
enriched HM grew more rapidly during the 12-week study
period than infants fed HM alone. The observed differences
in absolute weight and length, and, among smaller babies,
head circumference were sustained for the rst year.
71
In
addition, the duration of HM feeding for both groups was
signicantly longer than had been reported previously for
preterm infants.
63
A larger, randomized controlled trial studied HM-fed
preterm infants (535-2255 g, n = 207) randomized to re-
ceive 20-50 mL of expressed breast milk containing a multi-
nutrient fortier (17.5 kcal and 1.4 g of protein) each day
from the time of discharge to 4 months corrected age or
HM alone.
72
In this study, the breast milk supplement
did not inuence breastfeeding, nor did it have a signicant
impact on growth. It is not clear why the results of the 2
studies differ, but it is possible that differences in the incre-
mental increase in the nutrition and the rate of breastfeed-
ing may play a role.
Nutritional Deciencies Other than Protein/Energy.
Considerable attention has focused on the macronutrient
content of feedings that contribute to caloric intake such as
protein, which has a direct effect on growth. Less attention
has focused on other nutrients, particularly minerals, iron,
LCPUFAs, and vitamin A.
Feeding postdischarge preterm infants formulas or
HM with greater concentrations of calcium and phospho-
rus than those contained in term formula improves
bone mineralization, particularly if the special formulas
used during hospitalization are continued after hospital
discharge.
65,73
Provision of large amounts of calcium and
phosphorous for long periods may not be necessary. Rela-
tive osteopenia of preterm infants resolves spontaneously
during the rst months after discharge in a manner similar
to that induced by the acceleration of growth at the rst
stage of adolescence. Bone mineral content improves spon-
taneously in most infants, and rapid catch-up mineraliza-
tion is observed after discharge in VLBW infants. At 3 to 6
months corrected age, spine and total bone mineral den-
sity, corrected for anthropometric values, are found to be
in the range of normal term newborn infants.
74,75
Nevertheless, potential long-term effects of supplementa-
tion after discharge on peak bone mass are not known.
Bone mass may be reduced at adulthood, but this is mainly
the result of a persistent growth restriction because it is ap-
propriate for the body size achieved. Furthermore, early
diet or HM feeding does not affect bone mass during child-
hood.
75,76
Therefore, on the basis of the limited data avail-
able, it is likely that mineral intake after discharge should
exceed that of term infants when catch-up growth occurs
and is supported by enriched feeds, but it is unlikely that ex-
tra mineral supplementation is necessary when a mineral-
rich postdischarge or preterm formula or enriched HM
is used. With regard to vitamin D intake, there is no
evidence that preterm infants after discharge should receive
greater doses that term infants to maintain a normal plasma
25-hydroxy vitamin D concentration.
Body iron stores are highly variable at discharge, so it is im-
portant to screen for iron deciency at discharge and during
the rst year of life. The AAP and European Society of Pedi-
atric Gastroenterology, Hepatology, and Nutrition recom-
mend that preterm infants receive iron supplements for up
to 1 year after discharge.
2,77
The AAP recommends at least
2 mg/kg/day, which is the amount of iron provided by
iron-fortied formulas. Preterm infants fed HM should re-
ceive an iron supplement of 2 mg/kg/day by 1 month of
age, and this should be continued at least until the infant is
weaned to iron-fortied formula or begins eating comple-
mentary foods that supply 2 mg/kg of iron per day. Infants
who receive iron loads from multiple transfusions of packed
red blood cells do not require supplements.
Lapillonne et al discuss providing LCPUFAs to preterm
infants (see article on lipid needs by Lapillonne et al in
this issue) and recommend that DHA and arachidonic
acid be provided until the expected due date in amounts
greater than had been previously recommended. After
the due date, preterm infants should receive the same
quantity of LCPUFAs as term infants until more data be-
come available.
Vitamin A status may be suboptimal in formula-fed
VLBW infants for many months after discharge.
78
It has
been shown that preterm infants who ingest 3000 IU of vita-
min A per day for 90 days fail to exhibit plasma vitamin A
concentrations at levels characteristic of repletion status.
79
This observation is in contrast to previous studies of term in-
fants, in which a similar supplementation protocol was suf-
cient to maintain plasma vitamin A concentrations.
80
The
failure to achieve optimal vitamin A concentrations may be
due to immaturity of fat digestion mechanisms in premature
infants. Additional studies are needed to determine the dose
and duration of vitamin A supplementation that allows in-
fants to reach full repletion values.
How to Monitor the Postdischarge Infant
Accurate serial measurements of weight, length, and head cir-
cumference plotted precisely on validated growth charts fa-
cilitate early identication of potential nutritional or health
problems after hospital discharge. To ensure accuracy,
measurements should be made by trained personnel who
use standardized techniques. Expensive equipment is not
necessary.
81
Selection of a Growth Chart
Two types of growth charts can be used to monitor the
growth of preterm infants after hospital discharge. One is
based on fetal growth until term and growth of preterm in-
fants thereafter; the other tracks growth of term infants.
Most growth charts describe how infants actually grow,
rather than how they should grow to promote optimal neu-
rodevelopment and achieve the best long-term health out-
comes. For a detailed discussion of growth charts, see the
article on growth curves by Bhatia, in this Supplement
82
;
for the effects of early growth on optimal neurodevelopment
and long-term health outcomes, see the article on metabolic
and cardiovascular outcomes by Lapillonne and Grifn, in
this Supplement.
83
A single chart cannot be used to monitor and plot the
growth of infants during their initial hospital course and
through the early discharge period when the risk of nutrient
decits is greatest. To address these issues, the Fenton
charts
84
were designed to commence monitoring infants at
22 weeks postconceptional age and continue for 10 weeks
postterm. However, intrauterine and postnatal growth in
term infants are sex-related. The use of sex-related intrauter-
ine growth charts such as those of Olsen et al
85
reduces the
false detection of intra-uterin growth retardation, especially
in girls. Therefore, we have created new sex-related fetal-in-
fant growth charts from 22 wks GA to 66 or 92 weeks post-
conceptional age to evaluate the growth adequacy during the
rst year of life in preterm infants according to sex
(Figure 2).
24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
Postconceptional Age (Weeks)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
11.0
12.0
13.0
14.0
B
o
d
y

W
e
i
g
h
t

(
K
g
)
BOYS
Mean
- 2 SD
+ 1 SD
+ 2 SD
+ 1 SD
24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
Postconceptional Age (Weeks)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
11.0
12.0
13.0
14.0
B
o
d
y

W
e
i
g
h
t

(
K
g
)
GIRLS
+ 2 SD
- 2 SD
- 1 SD
Mean
+ 1 SD
Figure 2. Examples of sex-related fetalinfant growth charts from 22 weeks GA to 92 weeks postconceptional age by com-
bining the Olsen et al
85
and the World Health Organization growth curves.
86
Body weight versus GA for A, boys and B, girls.
Monitoring During the First Weeks after Discharge.
As a general rule, infants should be transitioned to the feed
that they will go home consuming several days before dis-
charge to assess tolerance and growth. Close monitoring of
feeding and growth is recommended after hospital discharge,
especially for infants at risk for nutritional decit (ie, those
who have an uncoordinated suck swallow, have persistent co-
morbidities, or are predominantly breast fed). Parents should
be reminded that breastfeeding is the optimal way to feed
their infants. Breast-fed infants should be fed every 1.5-3
hours and allowed no more than one period of prolonged
sleep (5 hours) to maintain mothers milk supply. Ad libitum
feeding is encouraged to optimize infant growth. Infants
should be weighed within 48 hours of discharge to assess in-
take and provide reassurance to families. This is particularly
important for families that had been transitioned from naso-
gastric or enriched feedings to breastfeeding just before dis-
charge. A complete feeding assessment should be
conducted within the rst week of discharge. Parents should
be made aware how to contact a dietitian and/or lactation
consultant, ideally one who has experience working with
mothers of preterm infants.
Recommendations for Preterm Infants after
Hospital Discharge
Guidelines for all preterm newborn infants should be similar
because postconceptional nutritional needs are very similar.
Therefore, the recommendations below are appropriate
for all groups of preterm infants, except where indicated
otherwise.
Prevention
We strongly emphasize the importance of proactive nutri-
tional support during hospitalization to prevent nutritional
decits and reduce the incidence and the degree of growth
failure. Proactive support limits the need for specialized
feeding after discharge. Nutrient intake and growth should
be monitored in all groups of preterm infants (ELBW,
VLBW, moderately preterm) after birth to reduce the risk
of nutritional decits occurring during the early days or
weeks of life.
A paucity of data exists on the effects of a poor nutri-
tion supply at different stages of gestation, and we stress
the need for future research in this area. At the present
time, good clinical judgment is required to balance the
benets (improved nutrition) versus risks (interruption
of breastfeeding and transient undernutrition) and provide
appropriate, nutrient-enriched feeds to all preterm infants
including the moderately preterm infants.
Monitoring
Close monitoring of growth (weight-, length-, and head
circumference-for-age, indexes of body proportionality)
and feed intake should be performed at discharge, at expected
term, and every 2 to 4 weeks after discharge until indexes of
growth are >2 SD on an appropriate growth curve (ie,
World Health Organization growth standard).
Predominantly breast-fed infants, infants with persistent
morbidities, and infants who were recently transitioned to
a different type/mode of feeding should be monitored closely
immediately after discharge and during the rst week after
discharge.
Selective biological indexes (ie, blood urea nitrogen, ferri-
tin, retinol binding protein, alkaline phosphatase, 25[OH] vi-
tamin D) may be useful in assessing selective nutrient
deciencies but should be determined on an individual risk
basis.
Nutritional Counseling
Because of the heterogeneity in nutritional status, postnatal
age, and corrected age of preterm infants at the time of hos-
pital discharge, an individualized approach is highly recom-
mended over the use of general guidelines. Individualized
nutritional plans should be based on growth, quality of
growth, and selective nutrient deciencies. As a rule of
thumb, however, infants who weigh <1000 g at birth and
those who weigh <2000 g at discharge require detailed in-
structions at discharge, close monitoring and, potentially,
nutritional intervention.
Table. Nutritional needs by GA (weeks)
Variables (per kg/d)
GA, weeks
<28 28-31 32-33 34-36 37-38 39-41
Fetal growth
Weight gain, g 20 17.5 15 13 11 10
Lean body mass gain, g 17.8 14.4 12.1 10.5 7.2 6.6
Protein gain, g 2.1 2 1.9 1.6 1.3 1.2
Requirements
Energy, kcal 125 125 130 127 115 110
Proteins, g 4 3.9 3.5 3.1 2.5 2
Calcium, mg 120-140 120-140 120-140 120-140 70-120 70-120
Phosphorus, mg 60-90 60-90 60-90 60-90 35-75 35-75
Weight gain, lean body mass, and protein gain during the last trimester of pregnancy and theoretical energy and protein requirements for enteral nutrition are indicated by GA group. Before 39
weeks GA, requirements are based on fetal growth, fetal accretion rate, and intestinal absorption; after 40 weeks GA, requirements are based on the composition of HM (adapted from Rigo
20
and
Ziegler
21
). The values indicated in this table are theoretical values per GA groups. They show that both the late-preterm infant (ie, 34-36 weeks GA) and the early-term infant (ie, 37-38 weeks GA)
have nutritional requirements that are different than the full-term infant (ie, 39-41 weeks GA). The values indicated do not take into account the nutrient supply needed to compensate for any
nutritional decit and therefore are not applicable as such for the very preterm infant at time of, or after, hospital discharge.
To avoid creating nutritional decits after discharge, pre-
terminfants should at least receive the nutrient intake of their
respective corrected age (Table) until they reach full term
(ie, 39-41 weeks). This strategy does not take into
account the nutrient supply needed to compensate for any
nutritional decit.
We strongly endorse HM feeding as the preferred method
of nourishing preterm infants after discharge and recognize
that providing mothers with lactation support is an impor-
tant component of care for the preterm infant.
Nutrient decits should be identied, promptly corrected,
and afterwards, nutrition should be normalized as soon as
possible to avoid overnourishing or promoting growth accel-
eration. Close monitoring of growth as outlined here and se-
lect follow-up of biochemical deciencies should accomplish
these objectives.
HM fortiers and enriched formulas are effective nutrition
adjuvants that can be used to improve growth. These agents
should be discontinued as soon as possible after expected
term to avoid overfeeding.
The recommendations for DHA, and arachidonic acid,
supply for preterm infants should be continued until full
term. Thereafter, recommendations for term infants should
be applied. We recommend that iron status be measured.
Iron supplementation should be continued after discharge
from the hospital, at least until 6-12 months of age, depend-
ing on diet. n
Author Disclosures
All authors received an honorarium from Mead John-
son Nutrition for attendance, presentation, and manu-
script preparation. All authors have participated to
the review of the available data and to the writing of
the manuscript.
We thank Gretchen Duenas and the Association pour la Recherche et la
Formation en Neonatologie for their technical assistance.
Reprint requests: Alexandre Lapillonne, MD, PhD, Professor of Pediatrics,
Department of Neonatology, Necker-Enfants Malades Hospital, 149 rue de
Sevres, 75015 Paris, France. E-mail: alexandre.lapillonne@nck.aphp.fr.
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Feeding the Preterm Infant: Opportunities and Challenges of Bringing
Science to the Bedside
Josef Neu, MD
1
, Cristine L. Bradley, MSc, RD
2
, Zong-Yi Ding, MD
3
, Hugh N. Tucker, PhD, FACN, CNS
4
,
and Carol Lynn Berseth, MD
5
Designing an optimal feeding program for preterm infants is particularly challenging. These infants require individ-
ualized feeding plans and frequent medical interventions, and their health status and physical limitations necessi-
tate specialized products. This review highlights the challenges of translating new understandings into practical
application and, specically, the challenges of translating scientic knowledge into available nutritional products
that can be used to meet the special needs of preterm infants. All infant formula products are developed for use
in a heavily regulated environment, which is not integrated internationally. The regulatory framework for preterm
nutrition products can be particularly complex in the areas of composition and the degree of scientic and clinical
support required across countries. Registration and approval of products for preterminfants in most countries must
address the complexities for a population for which no well-recognized nonclinical safety or efcacy models exist.
Mandatory regulatory reviewfor science-based innovative product improvements may require two or more years. In
addition, throughout years of development, industry must justify the nancial support of programs that serve a small
specialty segment of the market. These industry-specic challenges may be neither visible nor appreciated by the
general public or health care professionals, and, yet, they are integral to the development process. Effective collab-
orations among academic scientists, regulatory authorities, and the industry are essential to bring science to the
bedside. Without such collaborations, preterm infants, and particularly very lowbirth weight infants, in the neonatal
intensive care unit will not be able to benet from innovative nutrition interventions designed to improve short- and
long-term clinical outcomes. (J Pediatr 2013;162:S101-6).
T
he preceding articles present a comprehensive view of the challenges clinicians face when making decisions about pro-
viding optimal nutritional support to the heterogeneous population of patients described as pretermor low-birth-weight
infants. These infants require individualized feeding plans and frequent medical intervention, and their health status and
physical limitations necessitate the creation of specialized products. Several phases are involved in developing new products
during which clinicians, academics, industry, and regulatory agencies play key roles. The process begins with the emergence
of product concepts that stem from clinicians who identify unmet needs in their patients and basic scientists who make novel
discoveries. Next, basic and translational scientists in academics and industry consider various concepts and test novel hypoth-
eses in the context of current knowledge to dene which of many possible concepts is the most reasonable to pursue. Consider-
able research is required to create the scientic rationale required to build broad consensus. Additional work is required to
meet regulatory requirements and provide evidence of product safety and efcacy. Regulatory agencies oversee the new
product development process to protect patient safety. Thus, bringing a product to the bedside requires years of close interplay
among academics, industry, and regulatory bodies, and many challenges arise during the process. Our goal is to improve un-
derstanding of the process involved in developing innovative products in an effort to speed the delivery of newdiscoveries to the
bedside.
Product Conception
The preceding articles make it abundantly clear that there is no lack of ideas for new products to serve the preterm infant pop-
ulation. For every current need that is met by available human milk fortiers or formulas, clinicians identify 3 or 4 unmet needs
that evolve continually from the diverse and burgeoning preterm infant population. The investigators who participated in the
Global Neonatal Consensus Symposium identied more than a dozen unmet
needs during 3 days of discussions.
Fromthe
1
Department of Pediatrics, University of Florida,
Gainesville, FL;
2
Regulatory Sciences, Mead Johnson
Nutrition, Evansville, IN;
3
The 1
st
August Childrens
Hospital, Afliated to The General Hospital of Beijing
Military Defense Area, PLA, Beijing, China;
4
Mead
Johnson Nutrition, Evansville, IN; and
5
Medical Affairs,
Mead Johnson Nutrition, Evansville, IN
article.
FDA Food and Drug Administration
NIH National Institutes of Health
S101
It is not possible to create a new product for every unmet
need. Ideas for new products arise organically from astute cli-
nicians, basic researchers, and industry scientists. Once a con-
cept emerges, it can take years before it is developed into
a product ready for market. For example, it has been known
since 1980 that the long-chain polyunsaturated fatty acids do-
cosahexaenoic acid (DHA) and arachidonic acid (ARA) accu-
mulate in the fetal brain during the third trimester.
1
It has
been appreciated for almost 40 years that DHA is the primary
fatty acid in membranes of the rods of the retina and that n-3
polyunsaturated fatty acids are essential for normal visual de-
velopment in rodents,
2
but it was not until 1987 that the rela-
tionship between DHA and visual development of premature
infants was rst investigated
3
and 2002 that a formula con-
taining DHA and ARA was made available in the US.
Product Denition
A product becomes dened and rened through the coordi-
nated efforts of basic and clinical academic research and
applied industry research. The key element of this phase is
the accumulation of a critical mass of knowledge that indi-
cates the potential for a unique and specic clinical applica-
tion. It is not uncommon for it to take 5 or more years before
broad concurrence develops among academic and clinical
scientists. This sound knowledge base is required before a pe-
riod of more rapid accumulation of evidence can occur.
Figure 1 illustrates the long development cycle required to
create nutritional products. For example, to gain consensus
that formulas or human milk did not meet the nutritional
needs for DHA and ARA of infants in some regions
required the collection of substantial long-term data regard-
ing the minimum daily dietary intake of these fatty acids.
Research support during the denition phase of product
development derives partially from public funding of basic
research but mostly from industry-sponsored research. Sup-
port for patient-oriented studies is needed to provide regula-
tory agencies the necessary substantiation that demonstrates
the safety and efcacy of new products.
Interactions between Academics and Industry
Overall, academics andindustry have a longstanding collabora-
tive relationship that has successfully brought innovative ideas
to patient care. However, the relationship between these two
sectors has beenuneasy at times. Concerns about potential con-
icts of interest have led to the creation of university and cor-
porate policies that dene their interactions. Awareness of
these concerns stems from certain sales activities and publica-
tion practices of some pharmaceutical companies. First, phar-
maceutical sale practices are geared toward inuencing
physician drug recognition so that their drug is the rst one
that comes to mind when prescriptions are written. Small gifts
and free lunches have been shown to inuence prescribing
practices. Second, some companies have supportedthe conduct
andpublicationof researchthat selectivelyfavors newproducts,
including those in which an author has a nancial stake.
Hence, conict of interest policies have been developed to
regulate product promotions, dene what industry can pro-
vide to academicians and clinicians, and protect patients
from promotional activities that could have detrimental
effects on the quality of their care. In the US, legislation has
been proposed that would establish government regulation
of the vendorhealth care provider relationship. The National
Institutes of Health (NIH)-supported Clinical Trials site
(clinicaltrials.gov) is a clearinghouse of information in which
journal editors andothers candetermine the source of support
and potential for conict of interest for clinical investigators.
Although the intent of these regulations is focused on mar-
keting activities, there is a risk that stringent regulations
could limit the industry from providing direct or indirect
w
e
b
4
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=
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P
O
Figure 1. Building consensus. The early accumulation of knowledge is not linear and accelerates only after the basic research
phase has evolved. The decision to move forward with required product development tasks must start several years before
general awareness and acceptance.
S102 Neu et al
support to academic institutions for research activities. Some
consideration should be given to the potential impact on the
ability of academia and industry to collaborate in a collegial
manner. Continued success is dependent, in part, upon the
development of a regulatory environment that does not hin-
der progress.
The growing drive to protect intellectual property poses
additional new challenges. Many interactions between uni-
versity and industry are now subject to formal, contractual
exchanges dened by codied rules and regulations. The
recent emergence of University Technology Transfer Ofces
and the increasing attempts of universities to capture intel-
lectual property formally have had a profound impact on
industryacademia collaborations, often thwarting the open
collaboration that is the basis of scientic endeavors and
strangling the very activities that they hope to prot from.
Some academic institutions now view patenting and the cre-
ation of new commercial focus as a source of nancial gain.
Universities that create too many barriers to collaboration
may cause the industry to avoid interacting with their faculty
and, thus, delay the application of new knowledge.
Academia and the industry often have different, but im-
portant, complementary goals. Academics often conduct ba-
sic research that may not have an immediate clinical
application, and the industry focuses on the practical applica-
tion of a commercial product. Academic research is based
primarily on the impact it will have on the global research
community, and academic advancement often is based on
success in procurement of NIH funding rather than industry
support. Academic research often is focused on identifying
and elucidating the mechanisms involved in a biological or
disease process, and the industry is focused on translating
that understanding into products that benet patients.
Thus, both parties provide valuable efforts to the translating
of science to the bedside. Bridging these apparently disparate
goals of academia and industry often presents a challenge that
requires a great deal of solid support. The NIH has supported
these types of interactions through their Small Business Inno-
vation Research grant mechanism. However, these grants are
limited to small companies. More efforts are necessary to cre-
ate a broader working relationship and improved mutual
understanding.
Product Testing
Once a product is dened, considerable research and testing
is required to satisfy regulatory requirements before a product
gains approval for market. Because of the unique preclinical,
clinical, and regulatory requirements of products designed
for premature infants, many years of research and large fund-
ing commitments are required to get a product ready for
market approval and commercial launch. Even as the need
for a scientic nutritional intervention begins to be acknowl-
edged by experts, industry may be expected to have new, al-
ternative interventions commercially available as soon as
possible. This product demand may emerge well before the
development of adequate scientic consensus, and subse-
quent industrial development of specic products that em-
body these innovations require many years to complete.
When products specically for preterm infants are consid-
ered, the challenge becomes even greater because only a small
segment of patients are available for the important and re-
quired clinical studies.
Regulations Governing the Infant Formula Industry
Government authorities establish regulations to ensure foods
are safe and nutritionally adequate. Regulations governing
infant formula, and preterm infant nutrition products in par-
ticular, are even more strict because of the specic medical
and nutritional needs of preterm infants. Because specialized
infant formula is the only source of nutrition for many pre-
term infants, rigorous safeguards have been established for
these products. Codex Alimentarius, the US Food and
Drug Administration (FDA), the European Commission,
Food Standards Australia New Zealand, and others have es-
tablished regulatory provisions to assess preterm infant for-
mulas. However, some countries still lack a regulatory
framework for foods and formulas for this patient popula-
tion, which may create a barrier to the healthy development
of infants born prematurely in those regions. Where inte-
grated regulatory frameworks for preterm nutrition products
exist, specic approaches to product composition and scien-
tic substantiation are provided.
Composition
The general approach of competent authorities is to recog-
nize that the design of products created to meet the particular
nutritional needs of preterm infants differs from the compo-
sitional provisions for infant formulas designed for healthy
term infants. Most regulatory authorities have distinguished
the unique requirements for preterm formulas by creating
a regulation for infants with special needs, referred to as for-
mula for special medical purposes or exempt infant for-
mula, a term unique to the US. These regulations require
that the nutrient composition of the formula be adapted to
meet specic nutritional needs of the target infant popula-
tion. As such, preterm infant nutrition products can be dif-
ferent from normal (term-born) infant formulas if there is
sufcient scientic evidence to support healthy development
of preterm infants. Except those for China, virtually all global
regulations are absent of an explicit required range (mini-
mum/maximum) for nutrients in preterm formula. Across
all major regulatory bodies, regulations have incorporated
the requirement for scientic substantiation to dene the ap-
propriate composition of preterm formula. The Table
provides a summary of the general regulatory approach for
preterm infant nutrition products, applicable to formula
and human milk fortiers.
Scientic Substantiation
Preterm infant nutrition products have evolved since their
rst commercial introduction in the early 1980s. The accu-
mulation of new knowledge drives continual revision of nu-
tritional guidelines. Hence, there are now several sets of
Feeding the Preterm Infant: Opportunities and Challenges of Bringing Science to the Bedside S103
widely recognized expert recommendations for preterm
infant nutrition on the basis of reviews of available scientic
reports or on expert consensus. The European Society for Pe-
diatric Gastroenterology Hepatology and Nutrition (2010),
the American Academy of Pediatrics (2009), Life Sciences Re-
search Ofce of the American Society for Nutritional Sci-
ences (2002), Tsang et al in 2005 and other expert groups,
including the current meeting of international experts, have
all proposed that nutrient requirements for preterm infants
differ from those of term infants.
4-6
These recommendations
provide the most recent knowledge on neonatal nutrition
and are used by regulatory authorities as a preferred source
of scientic substantiation for appropriate deviations from
the composition of normal (term born) infant formula.
Industry Challenges
Challenges arise between industry and its regulators, who
may be more accustomed to the product development
path typically followed by pharmaceutical companies,
which is neither optimal nor appropriate for nutritional in-
terventions aimed at preterm and very low birth weight
(VLBW) infants. The mandatory sequence of milestones
needed to meet regulatory requirements and long lead
times associated with bringing infant products to market
can lead to the perception that industry is not responsive.
The continual emergence of new concepts makes it risky
for industry to invest in development of new products be-
fore the emergence of genuine scientic consensus that
a particular product is most likely to improve clinically rel-
evant outcomes.
Industrys Challenge of Meeting Regulatory
Requirements
After a specic nutritional intervention has been dened, sev-
eral additional steps remain on the development timeline. For
example, a research and development program for a new ad-
ditiontothe infant formula product category requires toxicol-
ogy and safety studies, nonclinical modeling, clinical studies,
and regulatory submissions. The ability to change the order
of these steps or to shorten the time needed to accomplish
each step is quite limited. Once the decision to develop a spe-
cic product is made, there is an obligatory time requirement
of ve to seven years prior to commercial realization and clin-
ical availability. Evenproduct improvements that appear to be
simple modications of a current neonatal intensive care unit
(NICU) nutrition intervention may take several years to be-
come available in this heavily regulated environment
(Figure 2). Because the timeline required to conduct
additional research and fulll regulatory requirements is
long, industry must begin developing a new product several
years ahead of the learning curve to be perceived as
responsive to the needs of health care professionals and
consumers. If product development has not begun well
before an unmet need is identied, the clinical innovation
will lag far behind the time that demand for a product is at
its height. This disparity between the time required to
meet all of the requisite development milestones and the
desire to have immediate clinical improvements produces
a perception that the industry is unresponsive or slow to
meet clinical needs.
On the opposite end of the timeline spectrum, there is risk
for the industry to create a product before the development
of scientic consensus around the need for that product. If
the product becomes available before consensus has devel-
oped, industry may be viewed as promoting unnecessary
innovations solely for commercial gain. Because there is little
way to predict the speed of the knowledge accumulation pro-
cess or shorten the development timeline, industry and its ac-
ademic partners must become adept at anticipating unmet
clinical needs and understanding the realistic time require-
ments for general acceptance. Product decisions must be
made with less than an ideal amount of information, and in-
dustry must assume the risk that scientic consensus may
evolve differently as more data are generated. Fostering an at-
mosphere of early collaboration and trust among industry,
clinicians, and regulators will facilitate more rapid consensus
on possible directions for therapeutic improvement, relative
priority, and nutrition interventions that will ultimately be of
greatest benet.
Complexity of Establishing Nonclinical Safety and
Suitability
The resource-intensive toxicology and nonclinical modeling
studies needed to meet early development safety require-
ments are sometimes invisible to academic scientists and
clinical practitioners. A critical rst step in product develop-
ment is to demonstrate the safety of the new intervention.
There are few models, if any, that can be relied upon rou-
tinely to simulate the response of VLBW humans in the
NICU. This lack of nonhuman models relevant to the
VLBW infant creates a void that is not found in other clinical
populations.
Table. General approach to regulation of preterminfant
nutrition products
Principles
Globally, very few national regulations include specic compositional
provisions (regulated minimum/maximum nutrient ranges) for preterm
infant formulas and human milk fortiers.
Major regulatory authorities apply principles of Formulas for Special Medical
Purposes (FSMP) for infants, or exempt infant formula.
FSMP formulas for infants are intended for use only under medical
supervision and advertising to the general public is prohibited.
FSMP products designed for preterm infants may deviate from the normal
(term) infant formula compositional standard to meet the unique nutritional
needs of the preterm patient population.
Sound medical and nutritional principles are required to justify such
compositional deviations from normal infant formula and to support
nutritional safety and adequacy of the formula.
Expert recommendations for feeding preterm infants such as those
elaborated by the European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition; Life Sciences Research Organization; American
Academy of Pediatrics; and Tsang et al [6] are the strongest form of widely
accepted scientic substantiation.
Most regulatory bodies have no explicit regulatory requirements for the
clinical testing of formula for preterm infants; however, it is well recognized
that clinical studies are essential to ensure the safety of these products.
S104 Neu et al
The timeline for development for any new or novel nutri-
ent for the infant formula category must account for the
requirement of a formal notication of safety based on infor-
mation considered available to the general public. The noti-
cation to the US FDA that an ingredient is Generally
Regarded as Safe requires that all data in the submission
have been published in peer-reviewed journals that have
been available to the public for at least six months. This por-
tion of the development timeline is dependent on manuscript
acceptance and publication, data review by an assembled
third-party expert panel, and, nally, review by the US
FDA Ofce of Food Additive Safety. This publication and re-
view process can last 2 years or longer after data are available
to health care professionals.
Once the decision is made to go forward with nonclinical
evaluations of a nutrient or nutrition intervention, the devel-
opment path and resulting product are largely determined
and unchangeable. It is understandable that new scientic
discoveries can justify a change to a product in development.
The impact of such a change must be evaluated carefully rel-
ative to the work done and resources invested to date.
Although scientic debate and challenge are healthy to ad-
vance knowledge, there comes a time in the development
pathway that further unproductive debate is not in the best
interest of public health. Continuing debate and scientic
challenge become problematic for regulators who must
make risk-benet decisions regarding patient care.
Clinical Trial Conduct
Conducting clinical trials in the VLBW NICU patient popu-
lation presents substantial challenges. These patients have
high morbidity and mortality, which can complicate the in-
terpretation of suitability data and understanding of adverse
events in a clinical trial setting. Frequently, clinical practice
for these special patients is not consistent across units or
even within subsegments of infants in the NICU. This incon-
sistency in patient management makes it difcult to develop
clinical trial protocols intended to mimic standard of care
and increases the requirement for large numbers of study
subjects to account for variability. It is not uncommon for
a clinical trial to require two years to complete. Most regula-
tory bodies have no explicit regulatory requirements for
clinical testing of preterm infant formula; however, it is rec-
ognized that clinical studies are essential to ensure the safety
of these products.
Return on Investment
There may be a perception that for-prot companies reap
large nancial benets from the research, development, and
commercialization of nutrition products for the NICU.
This perception is unfounded, however, because of the very
small market segment and volume of product usage com-
pared with the large expense of development. Anticipated fu-
ture revenues from specialized nutritional products cannot
be expected to support the investment required to accom-
plish all of the required development tasks. Company busi-
ness managers must balance reporting requirements for
corporate expenses with duciary responsibilities to the com-
pany shareholders. Those companies that continue to invest
in nutrition research and development to benet patients in
the NICU environment do so primarily from a desire to pro-
vide philanthropic contributions to the eld of clinical nutri-
tion rather than to generate prots.
Recommendations
The Global Neonatal Consensus Symposium has dened nu-
trient requirements for VLBW premature infants as they
progress through their clinical course and has recommended
adjustments in nutrient intake to meet their changing
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Figure 2. Product denition and testing. The challenge for industry, health care professionals, and regulators is to satisfy the
risk-avoidance environment in an emotional and politically sensitive population. In addition, clinical investigations must be
completed well before the accumulation of knowledge curve has crossed the line to general awareness and agreement. GRAS,
Generally Regarded as Safe.
Feeding the Preterm Infant: Opportunities and Challenges of Bringing Science to the Bedside S105
nutritional needs. The preterm infant population comprises
a number of subgroups that require different amounts and
proportions of nutrients, and it is a challenge to meet their
unique and varied needs. Academicians, clinical specialists,
industry scientists, and regulators who create and deliver in-
novative products to this population have common goals and
much common ground. To better meet the needs of this di-
verse patient population, they must leverage opportunities to
develop a collaborative approach. The best possible innova-
tion must be identied quickly and accepted broadly; regula-
tions must not be so cumbersome that they interfere with
healthy scientic discovery and debate nor should they un-
necessarily prolong the approval process. To assist in this
process, it is incumbent upon academic and industry scien-
tists to continue to rene guidelines that address the needs
of the evolving and burgeoning preterm infant patient pop-
ulation. These activities must be conducted on a global scale
to effectively bring new innovations quickly and safely to the
bedside.
Since the time the Global Neonatal Consensus Symposium
took place, China published new regulations applicable to
preterm infant formula products (GB 25596-2010). The reg-
ulations specify a permitted range for nutrients essential in
the composition of preterm formulas. This unique regulatory
approach for formula for special medical purposes for in-
fants may offer challenges to the implementation of new sci-
entic ndings that may expand the nutrient targets for
preterm infant nutrition. n
Author Disclosures
Josef Neu, MD, has received a research grant and honoraria
for speaking from Mead Johnson Nutrition and is currently
on its Scientic Advisory Committee. Cristine L. Bradley,
MSc, RD, and Hugh N. Tucker, PhD, FACN, CNS, are
employees of Mead Johnson & Company. Carol Lynn
Berseth, MD, is the Medical Director for Global Innovation
at Mead Johnson Nutrition. She organized and facilitated
the Symposium on Nutrition of the Preterm Infant. All
authors received an honorarium from Mead Johnson Nutri-
tion for attendance, presentation, and manuscript prepara-
tion. All authors wrote portions of the rst draft and
reviewed the nal version of this manuscript.
Reprint requests: Dr. Carol Lynn Berseth, MD, Mead Johnson
Nurtitionals, GR&D, 2500 Lloyd Expressway, Evansville, IN 47721-001.
E-mail: carol.berseth@mjn.com.
References
1. Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW.
Intrauterine fatty acid accretion rates in human brain: implications for
fatty acid requirements. Early Human Development, 1980 acid require-
ments. Early Human Development 1980;4:121-9.
2. Belkonen RM, Anderson RE, Wheeler TG. Membrane fatty acids associ-
ated with the electrical response in visual excitation. Science 1973;182:
1253-4.
3. Uauy RD, Birch DG, Birch EE, Tyson JE, Hoffman DR. Effect of dietary
omega-3 fatty acids on retinal function of very-low-birth-weight neo-
nates. Pediatr Res 1990;28:485-92.
2010;50:85-91.
nutrition handbook. 6th ed. Elk Grove Village, IL: American Academy
6. Tsang RC, Uauy R, Koletzko B, Zlotkin S. Nutrition of the preterminfant.
Scientic basic and practical guidelines. Cincinnati, OH: Digital Educa-
tional Publishing Inc.; 2005.
S106 Neu et al
Nutritional Management of the Low Birth Weight/Preterm Infant in
Community Settings: A Perspective from the Developing World
Aamer Imdad, MBBS and Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD
Globally, about 20 million infants are born with low birth weight (LBW; <2500 g). Of all LBW infants, approximately
95% are born in developing countries. The greatest incidence of LBW occurs in South-Central Asia; the second
greatest is in Africa. The two main reasons for LBWare pretermbirth (<37 weeks) and intrauterine growth restriction
(IUGR), which are risk factors for increased morbidity and mortality in newborn infants. Maternal nutrition status is
one of the most important risk factors for LBW/IUGR. Providing balanced protein energy and multiple micronutrient
supplements to pregnant women will reduce incidence of IUGR. Calcium supplementation during pregnancy will
reduce the incidence of pre-eclampsia and preterm birth in developing countries. Exclusive breastfeeding is pro-
tective for a mother and her infant and has been shown to reduce morbidity and mortality in infancy. Kangaroo
mother care for preterm infants will reduce severe morbidity and mortality as well. Community-based intervention
packages are among the most effective methods of reducing morbidity and mortality in mothers and children. Fu-
ture research should focus on improving triage of pretermand IUGRinfants. Exclusive breastfeeding should be pro-
moted, and appropriate alternative food supplements should be provided when breastfeeding is not possible. (J
Pediatr 2013;162:S107-14).
D
uring the past decade, child mortality before the age of 5 years has decreased markedly. The child death rate was 10.6
million/year in 2000-2003; it decreased to 8.8 million in 2008.
1,2
A reduction in mortality among children 1 to 59
months of age accounts for most of this decline. This may be because child-survival programs have focused primarily
on important causes of death after the rst 4 weeks of life (ie, pneumonia, diarrhea, malaria, and vaccine-preventable disor-
ders).
3
At the same time, little progress has been made in reducing neonatal mortality.
4
Neonatal deaths now account for
41% of deaths compared with 37% from 2000 to 2003.
1,2
To achieve the Millennium Development Goal 4 to reduce child mor-
tality by two-thirds by 2015, it is important to reduce neonatal deaths.
3
Lowbirth weight (LBW) increases morbidity and mortality in neonates and is a common feature in most neonatal deaths.
3,5,6
LBW may result from preterm birth, intrauterine growth restriction (IUGR), or both.
7
Preterm infants are 7 to 13 times more
likely to die during the neonatal period than full-term infants.
8-10
Infants who are preterm with IUGR have an even greater risk
of death.
11
A term LBW infant is likely to have growth failure and an increased risk of morbidity and mortality in infancy.
12
It
has been estimated that the risk for neonatal death is 2.8 or 8 times greater for term infants who weigh 1500 to 1999 g at birth
than for infants who weigh 2000 to 2499 g or 2500 to 2999 g, respectively.
13
LBW infants who survive are likely to remain small
and more likely to experience developmental decits than normal-term infants.
14
Adults who had LBWs have a greater inci-
dence of chronic diseases such as type 2 diabetes, hypertension, and other cardiovascular disease.
14,15
According to the United Nations Childrens Fund (UNICEF), an estimated 15.5% (>20 million infants) of all births were
LBW (<2500 g) worldwide in the year 2000.
5
The prevalence of LBW infants in developing countries (16.5%) is more than
double than in developed countries (7%). The vast majority (95%) of LBW infants are born in developing countries, with
the greatest incidence in South-Central Asia (27%) followed by Africa, where incidence ranges from 13% to 15%, with little
variation across the region as a whole. Overall, 70% all LBW births occur in Asia.
5
The causes of LBW are different in developing and developed countries.
16
Preterm birth is major cause of LBW in developed
countries, whereas most LBW newborns are born at term but small for gestational age (SGA) in developing nations.
17
SGA
infants are dened as infants whose weight is below the 10th percentile or 2 SD below the mean in growth charts for their es-
timated gestational age.
18
Accurate assessment of gestational age is required to screen SGA infants. Because it is relatively dif-
cult to get accurate gestational age estimates, birth weight is the most commonly used variable used to compare different
populations.
16
Infants born with LBW at term have IUGR, whereas the subcategory very LBW comprises mainly preterm
From the Division of Women & Child Health, The Aga
Khan University, Karachi, Pakistan
article.
BMI Body mass index
MgSO
4
Magnesium sulfate
RR Relative risk
UNICEF United Nations Childrens Fund
S107
infants. Indeed, these 2 categories overlap because some pre-
term infants exhibit features of IUGR and other newborn in-
fants with evidence of IUGR may weigh more than 2500 g at
birth, and, thus, are not considered LBW.
16
In developing
countries, it is difcult to assess and evaluate LBW infants
and monitor rates of neonatal mortality because data are in-
complete. It is estimated that 58% of newborn infants are not
even weighed at birth in developing countries.
5
The incidence
is greatest in south Asia and sub-Saharan Africa, where 74%
and 65% of births are not weighed, respectively.
5
We reviewed the evidence base for strategies designed to
manage LBW/preterm infants in community settings in the
developing world to make specic recommendations for ac-
tion. We searched PubMed, Cochrane Library, World Health
Organization/UNICEF data bases and guidelines by using
a combination of terms for lowbirth weight, community,
nutrition, etc, and synthesized up-to-date evidence on nu-
tritional management of LBW infants in the community.
Etiology of LBW
The causes of fetal growthrestrictionandprematurity indevel-
oping countries are well known.
16,19
Some of the most impor-
tant maternal risk factors include: lowprepregnancy weight or
body mass index (BMI); inadequate energy intake and gesta-
tional weight gain; cigarette smoking; and specic complica-
tions of pregnancy, such as genital tract infections,
pregnancy-induced hypertension, and incompetent cer-
vix.
3,16,19
Fetuses with certain genetic or chromosomal
disorders are also at greater risk for IUGR.
20
The Table
summarizes the main known risk factors in the pathogenesis
of LBW/IUGR.
16,19
Figure 1 describes the interaction of
social, economic, and behavioral factors that can result in
LBW/IUGR.
16
The nutritional status of a woman before and during preg-
nancy is important for a healthy pregnancy outcome. Preg-
nancy is just one stage of a womans life, and women living
in a developing country become pregnant in a context of gen-
der inequality, inadequate educational opportunities, malnu-
trition, marriage and conception at a young age, short birth
intervals, and undesirably large families. Figure 2 helps us to
understand the cycle of malnutrition that runs among LBW,
childhood/adolescent stunting, and maternal undernutrition
and how repeated pregnancies with inadequate recovery
between pregnancies can lead to maternal depletion
syndrome.
21
Maternal undernutrition is widespread in low and middle-
income countries, especially in South-Central Asia where
more than 10% of women 15 to 49 years old are <145 cm
tall and show evidence of maternal wasting (BMI <18.5) in
most countries.
13
A serious problem of maternal undernutri-
tion (more than 20%of women with BMI <18.5) is evident in
most countries in sub-Saharan Africa, South-Central/South-
Eastern Asia. Yemen, India, Bangladesh, and Eritrea have
a critical problem because BMI is low in about 40% of all
women.
13
Low prepregnancy weight and BMI are important risk fac-
tors for LBW.
13,22
A recent meta-analysis of 78 studies that
included 1 025 794 women has shown that maternal under-
weight is associated with an overall increased risk of preterm
birth by 29% (relative risk [RR] 1.29; 95% CI 1.15-1.46) and
that of LBW by 64% (RR 1.64; 95% CI 1.38-1.94).
23
A sub-
group analysis showed that underweight women have an
increased risk of preterm birth in developing countries (RR
1.22; 95% CI 1.15-1.30) but not in developed countries
(RR 0.99; 95% CI 0.67-1.45). In both developed and develop-
ing countries, underweight women are at increased risk of
LBW births (RR 1.48; 95% CI 1.29-1.68 and RR 1.52; 95%
CI 1.25-1.85, respectively).
In addition to maternal nutrition status, increased physical
activity performed by women, such as farming or gathering
water, is reported to be associated with lower birth weights
and smaller head and mid-arm circumferences in infants.
24
Malaria during pregnancy is associated with LBW,
16
and
malaria chemoprophylaxis increases maternal hemoglobin
levels and infant birth weights.
25
In addition, women in
Table. Selected risk factors for LBW
Prepregnancy Pregnancy Social and environmental
Low weight for height
Short stature
Chronic medical illness
Poor nutrition
Low maternal weight at mothers birth
Previous infant of LBW
Uterine or cervical anomalies
Parity (none or more than 5)
Multiple gestation
Birth order
Anemia
Elevated hemoglobin
concentration
Fetal disease
Pre-eclampsia and hypertension
Infections
Placental problems
Premature rupture of membranes
Heavy physical work
Altitude
Renal disease
Assisted reproductive technology
Exposure to indoor air pollution
Maternal psycho-social stress
Mental health
Low socioeconomic status
Low educational status
Smoking
No care or inadequate prenatal care
Poor gestational weight gain
Alcohol abuse
Illicit and prescription drugs
Short interpregnancy intervals (<6 months)
Age (<16 or >35 years)
Unmarried
Stress (physical and psychological)
Data derived from Qadir and Bhutta
16
and Valero De Bernabe et al.
19
S108 Imdad and Bhutta
developing countries may suffer fromchronic and communi-
cable diseases, which further aggravate their already poor nu-
tritional status. Certain social factors like drug abuse, poor
nutritional habits, and cigarette smoking are interrelated
and covary with poor socioeconomic status.
16
Some of the
other key risk factors associated with LBW are indoor air pol-
lution, environmental tobacco smoke, and maternal mental
health.
16,25,26
Interventions to Prevent LBW
Prevention and management of LBW in the community
requires a continuum of care and coordination among repro-
ductive health services that provide family planning support,
such as antenatal care for pregnant women, skilled atten-
dance and emergency obstetric care during birth, and postna-
tal care services.
6,16
Figure 3 summarizes evidence-based
interventions that can help prevent and manage morbidity
and mortality in LBW infants. We focus on nutrition inter-
ventions that can help to prevent or manage the LBW and/
or preterm infant in the community.
Birth Spacing
The relationship of adequate birth spacing (>36 months)
and neonatal and infant outcomes is well known.
27-30
Short
birth intervals increase the risk of LBW, preterm birth, neo-
natal mortality, and stunting.
27,31-33
A meta-analysis by
Conde-Agudelo et al
32
has shown that inter-pregnancy
intervals shorter than 6 months are associated with an in-
creased risk of preterm birth compared with interpregnancy
intervals of 18-23 months (OR 1.40; 95% CI 1.24-1.58),
LBW (OR 1.61; 95% CI 1.39-1.86), and SGA (OR 1.26;
95% CI 1.18-1.33). A retrospective study of 45 000 women
has shown that the women who use family planning services
are less likely to deliver a LBW infant than those who
do not.
34
Maternal Nutrition Interventions
Low folate levels are associated with LBW, preterm birth, and
IUGR.
35-39
Folic acid supplementation around the time of
conception reduces the incidence of neural tube defects and
other congenital anomalies.
40,41
Folate supplementation re-
duces the incidence of preterm birth and LBW.
35,42,43
Most
of this evidence is based on observational and nonrandom-
ized studies; any recommendation for providing folate sup-
plements to preterm and/or LBW infants should be made
after the intervention has been tested in randomized trials.
Balanced protein energy supplementation is considered one
of the most promising macronutrient interventions for the
prevention of adverse perinatal outcomes, including
IUGR.
44,45
A recent meta-analysis of randomized studies indi-
cate that balanced protein energy supplementation in preg-
nancy is associated with a 31% reduction in the risk of giving
birth to an SGA infant (RR 0.69; 95% CI 0.56-0.85).
46
It also
increases mean birth weight (mean difference, +59 g; 95% CI
33-86). This effect is more pronounced in malnourished
women than adequately nourished women. The authors of
a Cochrane review of balanced protein energy supplementa-
tionhas alsoconcludedshowedthat risk of stillbirthwas signif-
icantly reduced for women given balanced energy and protein
Figure 1. Factors associated with LBW. Figure used with permission from Qadir A et al.
16
S109
supplementation (RR 0.62, 95% CI 0.40-0.98), mean birth
weight was signicantly increased (mean difference +40.96 g;
95% CI 4.66-77.26).
45
There also was a signicant reduction
in the risk of SGA (RR 0.79, 95% CI 0.69-0.90). No signicant
effect was detected for preterm birth or neonatal death.
45
Micronutrient deciency is common in most low- and
middle-income countries.
13,47,48
Iron deciency is one of
the leading micronutrient deciencies among pregnant
women in these countries.
49
For example, anemia affects
41.8% of all pregnancies globally,
50
and iron deciency ac-
counts for half of these cases.
51
Intermittent or daily iron
or iron-folic acid supplementation during pregnancy in-
creases hemoglobin levels and decreases the incidence of ane-
mia at term.
52
Because maternal micronutrient deciencies during preg-
nancy in developing countries are common, there is interest
in administering multiple micronutrients during pregnancy
as an alternative to traditional iron-folic acid combina-
tions.
53
UNICEF has developed such a formulation called
the United Nations Multiple Micronutrient Preparation in
close collaboration with the United Nations University and
the World Health Organization.
48
The authors of a Cochrane
review showed that multiple micronutrient supplementation
has comparable effects on maternal anemia in the third tri-
mester (RR 1.03; 95% CI 0.87-1.22) and reduces the risk of
SGA births by 9% (RR 0.91; 95% CI 0.86-0.96) compared
with iron-folate supplementation.
54
A meta-analysis of 12
randomized, controlled trials has shown that multiple micro-
nutrient supplementation is associated with an increase in
mean birth weight (mean difference, 22.4 g; 95% CI 8.3-
36.4 g); a reduction in the prevalence of LBW (OR 0.89;
95% CI 0.81-0.97) and SGA (OR 0.90; 95% CI 0.82-0.99);
and an increase in the prevalence of large-for-gestational-
age babies (OR 1.13; 95% CI 1.00-1.28).
53
Another recent
meta-analysis that included 17 trials has shown that multiple
micronutrient supplements reduces incidence of SGA by 9%
(RR 0.91; 95% CI 0.86-0.96 [xed model]).
55
Recently, there has been an increased interest in providing
combined macro/micronutrient supplements because de-
ciencies for both exist concurrently. A study from Burkina
Faso has shown that supplementation with balanced protein
energy and multiple micronutrients increases length at birth
more than supplementation with multiple micronutrients
alone.
56
Future research efforts should focus on validating
these results in other parts of the world.
Calcium and Magnesium Supplementation during
Pregnancy
Hypertensive disorders of pregnancy increase maternal mor-
bidity and mortality and are associated with preterm birth
and IUGR.
57,58
Women with pre-eclampsia are 2.7 times
more likely than normotensive women to have infants with
Figure 2. Nutrition across the life cycle. Figure created by United Nations Administrative Committee on Coordination, Sub-
Committee on Nutrition and reproduced per United Nations Administrative Committee on Coordination, Sub-Committee on
Nutrition policy.
21
IUGR.
57
Calcium supplementation during pregnancy re-
duces gestational hypertensive disorders and risk of preterm
birth. A Cochrane review by Hofmeyr et al
59
has shown that
calcium supplementation during pregnancy signicantly re-
duces the incidence of gestational hypertension (RR 0.65;
95 % CI 0.53-0.81), preeclampsia (RR 0.45; 95% CI
0.31-0.65), and preterm birth (RR 0.76; 95% CI 0.60-0.97).
Another recent review of studies from developing countries
shows similar results for reduction in risk of gestational
hypertension (RR 0.55; 95% CI 0.36-0.85), pre-eclampsia
(RR 0.41; 95% CI 0.24-0.69), and preterm birth (RR 0.88;
95% CI 0.78-0.99).
60
Magnesium sulfate (MgSO
4
) supple-
mentation effectively prevents eclampsia in women with
pre-eclampsia.
51
A Cochrane review that included 6 trials
for MgSO
4
analysis shows that MgSO
4
supplementation re-
duces the risk of pre-eclampsia (RR 0.41; 95% CI 0.29-
0.58) and placental abruption (RR 0.64; 95% CI 0.50-0.83).
61
Breastfeeding
Breast milk is the natural and ideal rst food for infants,
including those born with LBW; it provides many immuno-
logic, psychological, and social, economic, and environmen-
tal benets.
62-64
Breastfeeding should be initiated within 24-
48 hours after birth and continued as the sole source of nu-
trition for the rst 6 months of life.
65
Suboptimal breastfeed-
ing is a risk factor for increased morbidity and mortality in
infants.
66
Partially breastfed infants have 3 times the risk of
all-cause mortality, and those who do not breastfeed have
14 times the risk of death in the rst 6 months of life com-
pared with those who breastfeed exclusively.
13
A study
from Ghana has shown that the risk of neonatal death is 4-
fold greater in children given milk-based uids or solids in
addition to breast milk.
67
There is increasing risk of neonatal
mortality with increasing delay in initiation of breastfeeding
from 1 hour to day 7. Late initiation of breastfeeding (after
day 1) is associated with a 2.4-fold increase in risk of mortal-
ity. Another study from Bangladesh has shown that partial or
no breastfeeding is associated with a 2.23-fold greater risk of
infant deaths resulting from all causes and 2.40- and 3.94-
fold greater risk of deaths attributable to acute respiratory in-
fections and diarrhea, respectively, compared with exclusive
breastfeeding in the rst few months of life.
68
Exclusive breastfeeding is not common in most coun-
tries.
69,70
Exclusive breastfeeding rates vary from 20% in cen-
tral and eastern European countries to 44% in South Asia.
71
Exclusive breastfeeding for 6 months might be difcult, par-
ticularly where maternal malnutrition is common.
72
One of
the main contributing factors is the lack of assistance to
mothers who wish to breastfeed.
73
Education and support
is, therefore, the cornerstone for the promotion of breast-
feeding.
74
The Baby Friendly Hospital Initiative and peer
counselors are considered the two most effective strategies
to promote exclusive breastfeeding, especially when infants
are delivered at home.
65
Comprehensive and culturally appropriate breastfeeding
education provided by counselors (physicians, nurses, mid-
wives, lactation consultants, or peer counselors) in the hospi-
tal during the prenatal period and continued support in the
mothers home is critical for facilitating breastfeeding among
mothers, especially those who have low incomes.
75-77
Prena-
tal and postnatal education is important because the inci-
dence of breastfeeding is affected primarily by prenatal
education, whereas prenatal and postpartum management
affects the duration and exclusivity of breastfeeding.
78,79
The authors of a Cochrane review have evaluated support
for the breastfeeding mother and show that all forms of ex-
tra support increases the duration of any breastfeeding
(RR 0.91; 95% CI 0.86-0.96) and increases likelihood of
exclusive breastfeeding compared with any breastfeeding
(RR 0.81; 95 % CI 0.74-0.89).
80
A review published in the
Lancet Undernutrition series shows that individual counsel-
ing increases the odds of exclusive breastfeeding substan-
tially during the neonatal period (OR 3.45; 95% CI
2.20-5.42) and at 6 months after delivery (OR 1.93; 95%
CI, 1.18-3.15).
65
Group counseling is also effective during
the neonatal period (OR 3.88; 95% CI 2.09-7.22) and at 6
months after delivery (OR 5.19; 95% CI 1.90-14.15). Mass
media campaigns have been shown to increase rates of
exclusive breastfeeding.
Kangaroo Mother Care
Kangaroo mother care is a simple and cost-effective method
to promote the health and well-being of preterm infants.
81
It
Figure 3. Proposed nutrition related interventions for preven-
tion and management of LBW/preterm birth in community
settings. MMN, maternal multiple micronutrient.
S111
is an effective way to meet an infants needs for warmth,
breastfeeding, protection from infection, stimulation, safety,
and love. Its key features include early, continuous and pro-
longed skin-to-skin contact between the mother and the in-
fant, exclusive breastfeeding, and support provided during
the hospital stay and continued at home.
Kangaroo mother care has been shown to reduce morbidity
and mortality in preterminfants. Arecent reviewfor the Lives
Saved Tool by Lawn et al
82
has shown that kangaroo mother
care inthe rst week of life reduced neonatal mortality by 51%
(RR 0.49; 95% CI 0.29-0.82) compared with standard care. A
meta-analysis of 5 randomized controlled trials suggested sig-
nicant reductions in serious morbidity for infants <2000 g
(RR 0.34; 95% CI 0.17-0.65).
82
Kangaroo mother care can
be practiced in facility as well as community settings. These
benets may also be evident in facilities in developing coun-
tries. Mother-infant dyads that practice kangaroo mother
care have reduced rates of mortality and lengths of stay.
83
Skin Barrier Therapy for Preterm Infants
An important determinant of the high morbidity and mortal-
ity rates for preterm infants is the integrity of the skin bar-
rier.
84
The immature skin barrier allows high rates of
transepidermal water loss and concomitant loss of uid
and heat and increases the susceptibility to invasive infec-
tions.
85-87
Enhancement of the skin barrier through topical
emollient therapy reduces morbidity and mortality in pre-
term infants.
88-90
A randomized trial from Bangladesh has
shown that applying sunower oil to the skin of preterm in-
fants reduces sepsis by 41% and mortality by 26%.
88
On the other hand, a multicenter study of extremely LBW
preterminfants (birth weight <1000 g) indicates that applica-
tion of a commercially available emollient ointment has no
effect on neonatal mortality.
90
Although the evidence is not
conclusive, a Cochrane review has shown that emollient in-
terventions improves daily weight gain by 5.1 g (95% CI
3.5-6.7), reduces length of stay by 4.5 days (95% CI 2.4-
6.5) and has a slight, positive effect on postnatal complica-
tions and weight gain at 4-6 months.
91
Another noteworthy
intervention for preterm infants is swaddling; infants who
are swaddled have improved neuromuscular development,
less physiologic distress, better motor organization, and
more self-regulatory ability than those who are not.
92
Discussion
Despite a number of limitations and gaps in evidence, there is
sufcient knowledge to recommend strategies to prevent and
mitigate morbidity and mortality of the LBW and/or preterm
infant in the developing world. Addressing maternal under-
nutrition and risk factors for IUGR through evidence-based
interventions such as balanced energy protein supplements
and strategies to address food insecurity. In addition, ad-
dressing maternal micronutrient deciencies and reducing
the burden of morbidity and malaria are important. In the
long term, reducing family size and increasing interpreg-
nancy intervals may also reduce maternal depletion and im-
prove birth weight.
On the basis of current evidence and the context of nutri-
tional management and thermal care of these infants, early
and exclusive breastfeeding is of key importance. Strategies
to address maternal antenatal care and promotion of breast-
feeding include providing education and support through
community support groups and trained health workers. Out-
reach services provided by lay health workers and community
structures offer the best platform for promoting context-
specic packages of early newborn care and for reaching
those in greatest need.
There is overwhelming evidence to support breastfeeding
or breast milk feeding of LBW and preterm infants in devel-
oping countries. It is now recommended that mothers with
HIV should breastfeed their infants when the infant or
mother is on effective antiretroviral therapy.
It is also important to underscore the need for further
studies in these areas where there is limited evidence. The
criteria used to identify and triage preterm (early and late)
and SGA infants at birth should be made cost-effective
and available to communities with minimal resources (eg,
robust and economical weighing scales should be made
more widely available). When breastfeeding is not possible,
products that are nutritionally adequate for preterm infants
(<35 weeks gestation or <1500 g birth weight) should be
made available. The provision and promotion of these nu-
tritional alternatives should be done in a way that does
not impact current breastfeeding strategies and recommen-
dations. Supplements developed for breastfed preterm in-
fants should be designed with due consideration of the
protein/energy and micronutrient needs, safety studies,
and risk-benet analyses that are appropriate for the devel-
oping world. Improved reference standards for intrauterine
and postnatal growth for infants that dene optimal
growth should consider the global population of preterm
infants. n
Author Disclosures
preparation. Z. B. wrote the rst draft of this manuscript.
Reprint requests: Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD,
Noordin Noormahomed Sharief Endowed Professor & Founding Chair,
Division of Women & Child Health, The Aga Khan University, Karachi 74800,
Pakistan. E-mail: zulqar.bhutta@aku.edu.
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Symposium Summary: Looking Back and Looking Forward
C
urrent clinical practice is based on the application of
the best-available knowledge. Nutritional guidelines
for preterm infants were last updated in 2005. This
symposium served to establish a global consensus and a rm
scientic base for neonatal nutrition practices. We feel con-
dent to present updated recommendations in the Table.
In addition, small-for-gestational-age infants were identi-
ed to be a unique population. The following recommenda-
tions for this group are: (1) feed according to gestational age,
with special consideration of supplements for iron and mi-
cronutrients; and (2) do not promote rapid weight gain
and avoid excess fat gain because they increase the risk for
metabolic syndrome in later life.
As a group, we also agreed on the following statements: (1)
There is no conclusive evidence to recommend the routine
use of prebiotics, probiotics, and synbiotics in preterm in-
fants. Although data supporting the use of specic probiotics
in the case of necrotizing enterocolitis are encouraging, avail-
able trials to not permit a decision to be made on optimum
strain, dose, or protocol of use; and (2) There are insufcient
data to recommend the routine use of glutamine, arginine,
nucleotides, omega-3 polyunsaturated fatty acids, and lacto-
ferrin to improve host defenses in preterm infants.
Although we know more than we did a decade ago, there is
a great need for additional knowledge about what works best
in practice and to explore new areas of interest. The following
gaps in knowledge were identied.
Growth
Improved reference standards for intrauterine and postnatal
growth for each subpopulation of preterm infants that take
short- and long-term outcomes into account need to be
developed.
Protein and Energy
Currently, protein delivery to the preterminfant does not meet
the infants need for protein, given the extraordinarily rapid
growth required to match intrauterine rates. We know that
more protein is needed early in life and less is needed later in
life whengrowthrate decreases. Strategies needtobe developed
that enable health care providers to dene and deliver the
appropriate amount of protein to each infant according to
his/her individual need. The quality of protein required by
preterm infants for optimal growth and development at
various postnatal ages must be dened in more detail.
Micronutrients
The optimal amounts of iron and vitamin D relative to
somatic weight and gestational age need to be dened.
Biomarkers of zinc, copper, and vitamin A stores must be
dened.
Prebiotics, Probiotics, and Synbiotics
Tools used to assess the microbiome at birth and subsequent
changes need to be identied. The optimal microbiome needs
to be dened, and efforts should be made to preserve it or re-
store it, as indicated by research evidence.
Community Support
The quality and quantity of education provided to pediatri-
cians and parents who care for late preterm and post dis-
charge infants need to be improved.
Human Milk
It is widely appreciated that human milk provides the best
nutrition for normal healthy term infants, but human
milk may not meet the needs of all preterm infants. Human
milk fortiers for preterm infants at a variety of postnatal
ages should be made available to infants who will benet
from them, given their special needs.
Extremely-low-birth-weight infants cared for in set-
tings where exclusive human milk feeding is used may
not receive all the required nutrients. Strategies to
meet their needs must be developed while efforts to
support and promote exclusive breastfeeding for healthy
infants are preserved. Baby Friendly hospital environ-
ment practices should be compatible with the need to
best serve the nutritional requirements of these high
risk infants.
Small-for-Gestational-Age Infants
There is a need for improved algorithms to identify and triage
preterm (early and late) and small-for-gestational-age infants
at birth that require minimal resources and are adaptable to
less-privileged community settings (eg, inexpensive and ro-
bust weighing scales).
Bringing Science to the Bedside
Extraordinary efforts are expended each year to make new
scientic discoveries designed to improve nutrition for pre-
term infants. After validating new science as a basis for nu-
tritional products, there is an equally important need to
Please see the Author Disclosures at the end of this article.
S115
quickly deliver new and effective solutions to preterm in-
fants globally. Efforts must be made to improve: (1) part-
nerships between the industry and academia to better
support the needs of all infants and children; (2) regulatory
approval processes by which new knowledge leads to better
products to meet the specic needs of these infants; (3) mu-
tual understanding of all concerned parties (academicians,
industry, and regulators) involved in creating and imple-
menting new advances in specialty nutritional support, for
low-birth-weight and very-low-birth-weight infants in
a manner that does not compromise the use of human
milk as the preferred mode of feeding normal infants; (4)
the ability of the health care community to provide the con-
text, support, and dissemination of new scientic discover-
ies; and (5) the manner in which new improvements are
analyzed for safety, risks, and benets. These tests must be
conducted in settings that are representative of developing
and developed countries. Key stakeholders, academia,
health care professional associations, United Nations
agencies, and industry representatives must be involved in
these processes that consider the best interest of children
as the rst priority.
It is clear that understanding the science of neonatal nutri-
tion is not the nal outcome; rather, it represents the begin-
ning of a journey. If it is our expectation that our scientic
knowledge will improve the well being of preterm infants,
we must engage in activities that will facilitate translating it
to practical application. We must consider that the overarch-
ing goal of the global neonatal community is reaching the
great majority of low-birth-weight infants who presently
have a high risk of death and disability from inadequate nu-
trition and care in the rst weeks of life. Most of these infants
are born in developing countries and account for nearly 50%
of the 4 million deaths that occur annually in infants and
young children. Most of these deaths are preventable; it is
up to us to create the environment where we make neonatal
careespecially good nutritionan essential component of
health investments at the local, national, and international
levels. We have to start by declaring that the present situation
is unacceptable and that all concerned parties must join
forces in securing better opportunities for health, growth
and mental development of all infants, especially those
most vulnerable.
Author Disclosures
Carol Lynn Berseth, MD, is the Medical Director for Global
Innovation at Mead Johnson Nutrition. She organized and
facilitated the Symposium on Nutrition of the Preterm In-
fant. Ricardo Uauy, MD, PhD, chaired the Symposium on
Nutrition of the Preterm Infant. Mead Johnson Nutrition
paid his travel expenses. He also received an honorarium to
compensate his time for contributing to, organizing, and
chairing the meeting and for his contribution to the nal
editing of the Supplement. C. B. wrote the rst draft of this
manuscript. n
Evansville, IN
INTA U of Chile and Neonatology
Division Catholic University
Santiago, Chile
Reprint requests: Carol Lynn Berseth, MD, Department of Medical Affairs:
Mead Johnson Nutrition, 2500 W Lloyd Expressway, Evansville, IN 47721.
E-mail: carol.berseth@mjn.com
Table. Daily nutrient needs of groups of preterm infants
Micropreterm,
29 weeks
Preterm,
$29 and 34.0 weeks
Late preterm,
34-38 weeks Postdischarge
Term,
$38 weeks
Energy, kcal/kg 120-140 110-130 110-130 105-125 90-110
Protein, g/kg 3.5-4.5 3.5-4.2 3.0-3.6 2.8-3.2 1.5-2.3
Calcium, mg/kg 120-180 120-160 70-140 100-120 80-100
S116

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March 2013 Volume 162 Number 3 Supplement 1 Copyright 2013 by Mosby, Inc.

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