Annales Nestlé Hot Topics in Nutrition

An

nales N

estlé

Annales Nestlé

Karg

er

76 | 1 | 18

Vo

l. 76, No. 1, 2018

Hot Topics in Nutrition – 75 Years Later

Hot Top

ics in Nutrition – 75 Years Later

5 Foreword Saavedra, J.M. (Vevey)

6 Editorial Haschke, F. (Salzburg)

8 Timeline of Annales Nestlé

Hot Topics in Nutrition

12 Focus/Summary

13 Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect Szajewska, H. (Warsaw)

24 Focus/Summary

25 Nutrition for Preterm Infants: 75 Years of History van Goudoever, J.B. (Amsterdam)

32 Focus/Summary

33 Food Allergy Prevention and Treatment by Targeted Nutrition Heine, R.G. (Vevey)

46 Focus/Summary

47 The Double Burden of Malnutrition in Countries Passing through the Economic Transition Prentice, A.M. (London/Banjul)

55 Focus/Summary

56 Nutrition for the Next Generation: Older Children and Adolescents Das, J.K. (Karachi); Lassi, Z.S. (Adelaide, SA); Hoodbhoy, Z. (Karachi); Salam, R.A. (Karachi/Adelaide, SA)

76 | 1 | 18

Hot Topics in Nutrition –75 Years Later

Editor: F. Haschke

Annales NestléAnnales NestléAnnales Nestlé

Hot Topics in Nutrition –

75 Years Later

Editor

Ferdinand Haschke, Salzburg

Editorial Board

Jatinder Bhatia, Augusta, GACarlos Lifschitz, Buenos AiresWeili Lin, Chapel Hill, NCAndrew Prentice, Banjul/LondonFrank M. Ruemmele, ParisHania Szajewska, WarsawFred Were, Nairobi

S. KargerMedical and Scientific PublishersBasel . Freiburg . Paris . London . New York . Chennai . New Delhi . Bangkok . Beijing . Shanghai Tokyo . Kuala Lumpur . Singapore . Sydney

Supported by

E-Mail [email protected]

S. KargerMedical and Scientific PublishersBasel • Freiburg • Paris • London • New York • Chennai • New Delhi • Bangkok • Beijing • Shanghai • Tokyo • Kuala Lumpur • Singapore • Sydney

DisclaimerS. Karger AG cannot be held responsible for errors or omis-sions, or for any consequences arising from the use of the in-formation contained herein.

Drug DosageThe authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the rec-ommended agent is a new and/or infrequently employed drug.

All rights reserved.No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retriev-al system, without permission in writing from the publisher.

© Copyright 2018 by Nestlé Nutrition Institute, Switzerland/S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)

Reprint of Annals of Nutrition and Metabolism Vol. 72, Suppl. 3, 2018

Sponsor Note

This publication was supported by an unrestricted educational grant by the Nestlé Nutrition Institute. The institute is a not-for-pro-fit association which was created to provide latest medical and sci-entific information to health professionals in the field of pediatric and adult nutrition and nutrition-related disorders (available at www.nestlenutrition-institute.org).Any liability of the sponsors for the content of the papers is hereby expressly excluded.

Disclosure Statement Guest Editor

F. Haschke is an executive board member of the Nestlé Nutrition Institute.

Vol. 76, No. 1, 2018

Contents

5 Foreword

Saavedra, J.M. (Vevey)

6 Editorial

Haschke, F. (Salzburg)



12 Focus/Summary 13 Evidence-Based Medicine and Clinical Research: Both Are Needed,

Neither Is Perfect

Szajewska, H. (Warsaw)

24 Focus/Summary 25 Nutrition for Preterm Infants: 75 Years of History

van Goudoever, J.B. (Amsterdam)

32 Focus/Summary 33 Food Allergy Prevention and Treatment by Targeted Nutrition

Heine, R.G. (Vevey)

46 Focus/Summary 47 The Double Burden of Malnutrition in Countries Passing through the

Economic Transition

Prentice, A.M. (London/Banjul)

55 Focus/Summary 56 Nutrition for the Next Generation: Older Children and Adolescents

Das, J.K. (Karachi); Lassi, Z.S. (Adelaide, SA); Hoodbhoy, Z. (Karachi); Salam, R.A. (Karachi/Adelaide, SA)

The above articles were originally published as a supplementary issue ofAnnals of Nutrition and Metabolism and are reprinted here with permission.


© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel

Policy Statement

Annales Nestlé appears three times a year. Each article is supported by a Focus Page, and each issue by an Infographic illustrating the core topic. Published on www.nestlenutrition-institute.org as well as in print, Annales Nestlé is one of the most widely read pediatric journals in the world.

Annales Nestlé is edited by an independent editorial board of opinion leaders in pediatric research, thus guaranteeing the medical and scientific impartiality of the journal, and hence the high regard it enjoys in medical and scientific circles. The editorial board sets the editorial policy, identifies topics to be addressed, selects authors, and oversees the review process for each issue.

Every issue of Annales Nestlé initially appears as a supplement to Annals of Nutrition and Metabolism – a journal from Karger Publishers, Basel, Switzerland – and is listed in all major bibliographic services, such as Medline, PubMed, and Web of Science. This has been our practice since 2011.

We are pleased to offer you our innovative product, which results from a creative and effective cooperation with Karger Publishers, Switzerland.

Natalia Wagemans, MDGlobal HeadNestlé Nutrition InstituteVevey (Switzerland)



Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):5 DOI: 10.1159/000488514

Foreword



We are proud to present to you the 75th anniversary issue of Annales Nestlé .

The origins of Nestlé, exemplified by Henri Nestlé’s first commercial prod-uct, are rooted in infant and childhood nutrition guided by the scientific knowledge of the time. And since its very beginnings, the dissemination of knowledge in pediatric health and nutrition guided the progress and develop-ment of the enterprise.

Annales Nestlé , a continuously running publication dedicated to the prop-agation of this knowledge, began when Nestlé was marking 75 years of its 150-year history. The contents of each issue of Annales reflect the topics of interest and the state of the art and knowledge of the time, providing historical insights into the evolution of infant health and nutrition, as explained in the Editorial of this issue by Prof. Ferdinand Haschke.

As such, Annales Nestlé epitomizes this longstanding commitment to edu-cation in nutrition. Annales today constitutes the longest standing pillar of the Nestlé Nutrition Institute, which was created to consolidate and further ex-pand this commitment. The Nestlé Nutrition Institute is dedicated to provid-ing the most up-to-date information in nutrition science as well as clinical and public health nutrition, using all channels, including print and digital tech-nologies, to enhance its reach, and serve all those devoted to supporting the healthy growth and development of infants and children worldwide.

Prof. Jose M. Saavedra, MD Chairman of the Board Nestlé Nutrition Institute

Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):6–7 DOI: 10.1159/000487424

Editorial



This edition of Annales Nestlé is a significant milestone in the history of pediatric medical communications. It is the 75th year in the international series that was origi-nally launched in 1942, following on from an exclusively French-language version that first appeared in 1935.

Although eminent exceptions do exist, few publica-tions manage to survive in continuous form for as long as three-quarters of a century. That Annales Nestlé has reached this anniversary is a tribute to the editors-in-chief, editorial board members, and contributors who have given the publication purpose, direction, and au-thority over the seven and a half decades since its first inception. It is also a tribute to the many healthcare pro-fessionals who have read Annales Nestlé over the years, using its content to keep abreast of new directions in the rapidly evolving field of pediatric medicine in general and, more recently, pediatric nutrition in particular. Last but not least, it is a tribute to the vision and commitment of Nestlé, which has consistently supported the review through its various incarnations, and which continues to do so today via the Nestlé Nutrition Institute.

The editorial decision to focus exclusively on nutri-tion, which dates from 1995, was taken in response to the speed of developments taking place in pediatric medicine as a whole. This focus has been maintained ever since. The subject of pediatric nutrition was always an impor-tant concern of Annales Nestlé , however, with articles on breast milk (1950), rickets (1951), vitamins (1951), pre-term nutrition (1953), and nutrition and eczema (1953) appearing alongside papers on topics as diverse as whoop-ing cough, rheumatism, and premature pneumonia dur-ing the review’s early years. The social and emotional context of pediatric medicine has also featured on occa-

sions, with contributions on, for example, social influ-ences on the physiopathology of children (1951), the beaten child (1968), and accidents in children (1968).

Writing in the Foreword to the milestone 40th edition, which appeared in October 1982, the Editorial Commit-tee observed: “The review enjoys a wide readership, with a print run of 60,000 being distributed in many countries, and this in five languages (English, German, Spanish, French and Portuguese). This considerable success oblig-es us to continually strive for further improvements.” In their preface to the 60th anniversary edition (volume 60, number 3, 2002), the Editorial Committee provided an update: “More than 120,000 copies of this review are dis-tributed three times per year in five languages (English, French, German, Spanish and, more recently, Chinese).” They went on to observe: “Its objective is to keep updated the pediatric community and others interested in infancy by relating research progress in the fields of epidemiolo-gy, diagnostic, prevention and treatment of the principal illnesses that strike children in different parts of the in-dustrialized and developing world. Thus, it addresses a varied public whose preoccupations are not necessarily the latest developments in molecular biology or imaging devices, but the means to fight malnutrition, infections and their consequences for the development of the child.”

Today, the content of Annales Nestlé is initially pub-lished in Annals of Nutrition and Metabolism , a leading international peer-reviewed journal (current impact fac-tor 2.42). It then appears as Annales Nestlé , being mainly distributed in online form via the Nestlé Nutrition In-stitute (www.nestlenutrition-institute.org). The journal therefore addresses a global readership, bringing state-of-the-art thinking on pediatric nutrition to the scientific

Editorial 7 Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):6–7 DOI: 10.1159/000487424

community as well as to many pediatricians who work in remote parts of the world. The Editorial Board of Anna -les Nestlé would like to thank Prof. Bert Koletzko, the Ed-itor of Annals of Nutrition and Metabolism , for his excel-lent support and cooperation during the past years.

The evidence-based, holistic, and global view of pedi-atric nutrition that characterizes Annales Nestlé is well represented in this 75th issue, with contributions from authors based in The Gambia, Pakistan, Poland, the Netherlands, Switzerland, and Australia. Topics which were burning decades ago and are still sensitive were se-lected for this issue.

In his paper “The Double Burden of Malnutrition in Countries Passing through the Economic Transition,” An-drew Prentice outlines how, although many low- and middle-income countries (LMICs) are undergoing eco-nomic advancement, the accompanying “nutrition transi-tion” occurring within their populations is triggering a new health challenge. Increasingly sedentary lifestyles and energy-dense diets have led to a rapid increase in the prev-alence of overweight and obesity. Improvements in nutri-tion in many LMICs have succeeded in reducing rates of stunting, but in Africa, rapid population growth has led the absolute number of children suffering from stunting to rise. The populations of many parts of Africa, as of many other LMICs, are faced with the “double burden” of mal-nutrition, whereby under- and overnutrition are simulta-neously present in the same population, and sometimes even in the same individual. Prentice hopes that these countries will at least have the benefit of learning from the experience of other countries that have previously under-gone the “nutrition transition” and all it entails.

Focusing on the nutritional requirements of older chil-dren, adolescents, and young women of childbearing age, Jai K. Das and fellow contributors note that supplementa-tion of the diet with iron and multiple micronutrients has been shown to reduce levels of anemia, but that evidence for effective strategies to prevent and control malnutri-tion and obesity is lacking, especially in developing coun-tries. The diet and nutritional status before and during pregnancy can have a long-term effect on the nutritional status, growth, and health of offspring. Stressing the in-tergenerational link between adequate nutrition before and during pregnancy and the health of future genera-tions, the authors argue that guidelines are needed to sup-port nutrition interventions targeting these sections of the population.

Hans B. van Goudoever’s contribution focuses on a much younger demographic – preterm infants – and dis-cusses the crucial role played by human milk in delivering

adequate nutrition to support growth and health during this vulnerable life stage. Placing his observations within the context of the history of modern preterm care, van Goudoever references the first article that Annales Nestlé published on the subject of the nutrition of neonates, which appeared in 1983. van Goudoever discusses the de-velopment of human milk fortifiers, essential for meeting the high nutritional requirements of infants born prema-ture, and also outlines improved methods for pasteuriz-ing human donor milk.

Given the steadily rising prevalence of food allergies, food allergy prevention has become a global health prior-ity. Breastfeeding is a key pillar of primary allergy preven-tion, and in recent years, research has encouraged the proactive introduction of hypoallergenic formulas in non-breastfed infants and of food allergens from the age of 4 months. Ralf G. Heine discusses this in his contribu-tion, “Food Allergy Prevention and Treatment by Tar-geted Nutrition,” and also assesses the transformations that have recently taken place in the treatment of food allergies, with immunotherapy via the oral or epicutane-ous route offering the promise of effective future treat-ment strategies.

None of the above articles – or indeed any of the articles that have appeared in Annales Nestlé during the past 75 years – would have been possible without the contribution of evidence-based medicine (EBM) and clinical research. Hania Szajewska argues that although EBM had a positive influence on medical practice in the last quarter of the 20th century, it still needs further refinement, and that considerably more rigor is required in the design, execu-tion, analysis, and reporting of clinical research. Szajews-ka’s belief is that the collation, combination, distribution, and analysis of data from new sources – “big data” and “real-world data” – have the potential to bring about sig-nificant improvements in both EBM and clinical research, which are both likely to be transformed in the process.

From the perspective of this 75th anniversary issue of Annales Nestlé , it is intriguing to ponder which issue of this review might carry a discussion of how the changes envisaged by Szajewska have come about, and what im-provements they have made to pediatric practice. The 100th, perhaps?

Thanks to Jonathan Steffen, who helped with the re-search, and thanks to all who have made this milestone issue of Annales Nestlé possible, along with all the many issues that preceded it.

Prof. Ferdinand Haschke , MD Guest Editor of the 75th issue of Annales Nestlé April 2018

1861

1866

1871

1876

1881

1886

1891

1896

1901

1906

1911

1916

1921

1926

1931

1936

1941

1946

1942

1934

1931

Burnet and Macnamara discover there is more than one type of poliovirus.

AN

NA

LES

NES

TLÉ

Ever since its inception, Annales Nestlé has disseminated best practice in the

treatment of critical pediatric conditions. The following timeline is a

selection from among the many topics covered by the journal over the years.

Considerations of space preclude the presentation of all the papers

published, but our thanks go out to all the contributors and editors who have

created this ground-breaking body of work in the field of pediatric medicine.

Launch of Pelargon, a full-milk powder for babies enriched with lactic acid bacteria to improve its digestibility.

Henri Nestlé invents the first Farine Lactée (’flour with milk’), for infants who cannot be breastfed.

Anglo-Swiss and Nestlé merge to form the Nestlé and Anglo-Swiss Company.

Annales Nestlé is relaunched as an international journal covering all fields of pediatrics.

DEV

ELO

PMEN

TS A

T N

ESTL

ÉD

EVEL

OPM

ENTS

IN P

EDIA

TRIC

MED

ICIN

E 1906

1908

1865

1890

Medin is the first to recognize the epidemic character of poliomyelitis.

1961: Image courtesy of Nigel Cox

Von Liebig creates the first infant formula milk. It will be launchedin Europe in 1867 and in the USA in 1869.

1928

Fleming discovers penicillin while studying influenza.

Jules Bordet and Octave Gengou discover whooping cough.

Landsteiner and Popper identify poliovirus.

1910

Schick invents the Schick test for susceptibility to diphtheria.

1861

Jacobi establishes the first pediatrics department at a general hospital (Mount Sinai, NYC, USA).

1896

The Japan Pediatric Society is established in Tokyo.

1948

1930

1944

Blalock and Taussig perform the first ‘blue baby’ operation (John Hopkins University, Baltimore, MA, USA).

Asperger publishes his definition of autistic psychopathy in childhood.

1936Theiler develops the first yellow

fever vaccine.

1926

The American Pediatric Society and American Academy of Pediatrics are founded.

Archives of Disease in Childhood in launched.

The World Health Organization (WHO) is founded.

1867

The Anglo-Swiss Condensed Milk Company opens the first European condensed milk factory.

1866

1905

Nestlé & Anglo-Swiss acquires Norwegian dairy company Egron, which has patented a spray-drying process for producing milk powder.

1916

Nestlé adds vitamins A and D to infant cereals. 19

29

Nestlé launches the vitamin supplement Nestrovit. 19

3619

35

Nestlé introduces infant cereal in the form of a powdered product. 19

48

The Pediatric Journal Annales Nestlé appears in its original from, in French only.

1949

1950

1951

1952

1953

1954

1955

1956

1957

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

CON

TIN

UED

OV

ERLE

AF

Weller isolates the varicella virus, leading to a greater understandingof chickenpox.

Enders and colleagues create the world’s first measles vaccine.

The WHO launches the Intensified Smallpox Eradication Programme.

Great Ormond Street Hospital leads the first UK clinical trials of the rubella vaccine.

1953

1967

1963

The first heart and lung bypass machine for children is used at Great Ormond Street.

1962

The first live poliovirus vaccine, developed by Sabin, is licensed. 19

60

The first leukemia research unit in Britain is established, at Great Ormond Street Hospital (London).

1961

Del Mundo establishes thefirst pediatrics department inthe Philippines.

1957

The Indian Academy of Pediatrics is established in Mumbai.

1963

Nestlé infant cereal is rebranded as Cerelac.

1973 »» 2018

Rai

sing

pre

mat

ure

and

unde

rdev

elop

ed c

hild

ren

Pre

vent

ion

of r

icke

ts

Pro

blem

s in

chi

ldre

n's

soci

al m

edic

ine

Men

ingi

tis tu

berc

ulos

is

Nut

ritio

n in

pre

mat

ure

babi

es

Test

of p

olio

mye

litis

vac

cine

Ped

iatr

ic c

ardi

olog

y

Rhe

umat

ic d

isor

ders

in c

hild

ren

Ref

lexe

s in

pre

-ter

m a

nd te

rm in

infa

nts

Oto

lary

ngol

ogy

in in

fant

s

Gas

troe

nter

olog

y in

infa

nts

Epid

emic

dis

ease

s in

chi

ldre

n

Infa

nt n

utri

tion

Ped

iatr

ic h

emat

olog

y

Acci

dent

al in

toxi

catio

n in

chi

ldre

n

The

role

of i

nfec

tion

in m

orta

lity

ofpr

emat

ure

babi

es

Der

mat

olog

ical

pro

blem

s in

chi

ldre

n

Non

-tra

umat

ic o

steo

path

olog

y in

chi

ldre

n

Pas

t and

rec

ent p

robl

ems

in in

fant

nut

ritio

n

Non

-sur

gica

l acu

te a

bdom

en in

chi

ldre

n

Hem

iple

gic

synd

rom

e in

chi

ldre

n

The

use

of b

iops

y in

ped

iatr

ics

Ant

ivir

al v

acci

natio

ns in

chi

ldre

n

Mic

robi

al v

acci

natio

n

1961

1954 Nestlé launches the first infant

formula with demineralized whey.

199619851949

1972

1959 2009

2017

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1978

1977Renamed Nestlé S.A.

the company continues its diversification strategy outside the nutrition sector.

The Nestlé NutritionCouncil is founded.

1981

1980

The First International Conference on Nutrition produces a World Declaration on Nutrition.

1979

1992

The 27th World Health Assembly establishes the Expanded Programme on Immunization.

The UN hosts the first World Food Conference.

1974

The first Fogarty Center International Conference on Obesity is held in Maryland, USA.

1973

The last case of indigenouspolio in the Western Hemisphere occurs (in Peru).

1991

In the USA, a major advance in the prevention of HIV infection is achieved by treating infected mothers with zidovudine during pregnancy.

1994

1987

WHO confirms that HIV can be passed from mother to child during breastfeeding.

DEV

ELO

PMEN

TS A

T N

ESTL

ÉA

NN

ALE

S N

ESTL

ÉD

EVEL

OPM

ENTS

IN P

EDIA

TRIC

MED

ICIN

E

1861 «« 1972

Acci

dent

s in

chi

ldre

n

Myc

osis

in c

hild

ren

Pre

pube

scen

t gyn

ecol

ogy

Ped

iatr

ic u

rolo

gy

Lipi

ds in

the

diet

of p

rem

atur

e ba

bies

Men

tal d

isab

ility

in c

hild

ren

Ped

iatr

ic c

hem

othe

rapy

Nut

ritio

n an

d ce

rebr

al d

evel

opm

ent

Obe

sity

in in

fant

s

Ped

iatr

ic c

ardi

olog

y

Imm

unop

atho

logy

and

food

alle

rgie

sin

infa

nts

and

child

ren

Hyp

erte

nsio

n in

new

born

s

Pro

tein

and

ene

rgy

mal

nutr

ition

in c

hild

ren

Spor

ts m

edic

ine

in c

hild

ren

Live

r di

seas

es in

chi

ldre

n

Opt

halm

olog

y in

ped

iatr

ics

Chr

onic

ren

al in

suff

icie

ncy

Ped

iatr

ic o

ncol

ogy

Suga

r di

abet

es

Sudd

en d

eath

of i

nfan

ts

AID

S in

chi

ldre

n

Hyp

erch

oles

tero

lem

ia in

infa

nts

Iron

def

icie

ncy

in in

fanc

y an

d ch

ildho

od

Nestlé introduces the first infant formula with probiotics.

Nestlé develops the first partially hydrolyzed infant formula.

Nestlé is one of the first companies to develop policies based on the WHO code on breast milk substitutes and to apply them across its business.

Maternal Nutrition in pregnancy: eating for two?, based on the workshop held in the previous year, is published.

1995

1987

The first Nestlé NutritionWorkshop is held in Vaucluse, France.

Annales Nestlé is edited in 5 languages (English, French, German, Spanish, Portuguese).

The World Health Assembly formally adopts the international code of marketing of infant formula and other products used as breast-milk substitutes, following initial endorsement in 1980.

1981

Levinsky performs the UK’s first bone marrow transplanton a child.

DEV

ELO

PMEN

TS A

T N

ESTL

É

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

Nestlé acquires Wyeth Nutrition, the infant formula division of Pfizer.

Nestlé Health Science and the Nestlé Institute of Health Sciences are established.

Annales Nestlé is indexed in PubMed.

Inaugural Creating Shared Value Forum, which becomesan annual event.

The Nestlé Nutrition Institute becomes a not-for-profit association based in Switzerland.

A new alternative to open heart surgery for children is invented at Great Ormond Street. 20

01

2017

The American Academy of Pediatrics finds that breastfeeding can help protect against sudden infant death syndrome (SIDS).

The Lancet releasesa milestone series of papers on Maternal and Child Nutrition.

2008

2010

Pediatric Emergency Medicine Switzerland (PEM) is founded in Fribourg, Switzerland.

New Lancet series on Maternal and Child Nutrition. 20

13

The WHO establishes a high-level Commission on Ending Childhood Obesity.

2014

2012

The Scaling Up Nutrition (SUN) movement releases ‘Scaling Up Nutrition – what will it cost?’

2009

The first National Immunization Days against polio begin in Sudan.

1998

Bio

activ

e fa

ctor

s in

milk

Die

tary

fats

in in

fanc

y an

d ch

ildho

od

Neo

nata

l scr

eeni

ng

Pai

n in

infa

ncy

and

child

hood

Acut

e re

spir

ator

y in

fect

ions

in c

hild

hood

Lear

ning

in c

hild

hood

Ast

hma

in c

hild

hood

Epile

psy

in c

hild

hood

Chi

ld a

buse

and

neg

lect

Type

2 d

iabe

tes

Cys

tic fi

bros

is

HIV

and

nut

ritio

n

Cho

lest

atic

dis

ease

in c

hild

hood

Emer

ging

infe

ctio

us d

isea

ses

in c

hild

ren

Mot

her

and

child

nut

ritio

n

Earl

y pr

ogra

mm

ing

effe

cts

of n

utri

tion

Nut

rige

netic

s

Wha

t chi

ldre

n ea

t

Obe

sity

from

mot

her

to c

hild

Feed

ing

diso

rder

s in

infa

nts

and

child

ren

The

role

of d

ocos

ahex

aeno

ic a

cid

in th

e Fi

rst 1

,000

Day

s

Swee

tnes

s: D

evel

opm

enta

l and

func

tiona

l eff

ects

Hot

Top

ics

in N

utri

tion

– 75

Yea

rs L

ater

2010

201220

09

2011Nestlé develops a unique process to

improve the protein quality and reduce the protein content in infant formula.

Launch of the first Infant Feedingand Toddlers Study.

2002

Creation of Nestlé Skin Health.

2014

2017Nestlé develops

formula with Human Milk Oligosaccharides.20

07 Nestlé acquires the Novartis Medical Nutrition business.

Nestlé acquires American baby food manufacturer Gerber.

Nestlé acquires weight management business Jenny Craig.

2006

2004Nestlé adds special fatty

acids to infant formula.

1997 Nestlé

becomes the leader in ‘Nutrition, Health and Wellness’.

1996 The Nest first

appears, in English.

UN Secretary-General Ban Ki-moon launches the ‘Zero Hunger Challenge’.

Image courtesy of Edward Thompson


To avoid wasting time and resources, research needs to be not only well performed,

but also adequately reported

Key insights

Evidence-based medicine (EBM) embodies clinical expertise and the judicious application of the latest best evidence to-wards the care of individual patients. If available, the evidence base relies on data obtained from randomized controlled trials and meta-analyses. However, if not available, moving to a low-er level of evidence from observational studies to basic research is needed. Each type of study that contributes to the larger body of knowledge has its own specific flaws. Problems with sample size, over-reliance on p values, lack of methodological rigor, and the tendency to emphasize only “positive” findings are some of the common limitations. The information explosion also poses a serious challenge, as clinicians face the problem of how to deal with the sheer volume of data.

Current knowledge

The application of EBM towards patient treatment involves 4 basic steps. Beginning with identifying the question or prob-lem, this is followed by gathering the best evidence to help answer the question. Then, the available evidence needs to be critically appraised before it can be applied to help in clinical decision-making. The overarching goal should be to improve health outcomes for the patient.

Practical implications

A number of actions can be taken to overcome the limitations of healthcare research. Overall, the solutions can be broadly clas-sified into 3 domains. First, initial efforts should focus on proper design and conduct of studies, in order to maximize the key learn-ings that can be derived from the data. Next, the results need to be reported in an accurate and timely manner, to facilitate the dis-

Reprinted with permission from: Ann Nutr Metab 2018;72(suppl 3):13–23

Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect by Hania Szajewska

wasting time

F O C U S


semination and uptake of the latest findings. Finally, the old “pub-lish or perish” mentality needs to be overhauled to emphasize the quality of publications rather than mere quantity.

Recommended reading

Heneghan C, Mahtani KR, Goldacre B, Godlee F, Macdonald H, Jarvies D: Evidence based medicine manifesto for better health-care. BMJ 2017;359:j2973.

Expertiseof the individual

physician

Valuesand expectations

of the patient

Improved patientoutcome

EvidenceBest available

Evidence-based medicine

Clinical decision

Over the past decades, the concept of evidence-based medicine has revolutionized clinical practice and the conduct of clinical research.



Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect

Hania Szajewska

Department of Pediatrics, The Medical University of Warsaw, Warsaw , Poland

Hania Szajewska Department of Pediatrics, The Medical University of Warsaw Zwirki i Wigury 63A PL–02-093 Warsaw (Poland) E-Mail hania @ ipgate.pl



Key Messages

• Over the past 25 years, evidence-based medicine

(EBM), defined as individual clinical expertise,

best research evidence, and patient values and

circumstances, has reshaped medical practice. EBM,

however, is not perfect, and the concept is evolving

in response to its critics.

• Much of clinical research is poorly designed,

conducted, analyzed, and/or reported. Strategies for

the development of high-quality research have been

developed. If strictly adhered to by all stakeholders,

this should lead to more valid and trustworthy

findings.

• In the future, considering that new ways of obtaining

health data will continue to emerge, the world of EBM

and clinical research is likely to change. The ultimate

goal, however, will remain the same: improving

health outcomes for patients.

Keywords

Science · Research · Methodology · Evaluation · Critical appraisal

Abstract

Currently, it is impossible to think of modern healthcare that ignores evidence-based medicine (EBM), a concept which relies on 3 pillars: individual clinical expertise, the values and

desires of the patient, and the best available research. How-ever, EBM is not perfect. Clinical research is also far from be-ing perfect. This article provides an overview of the basic principles, opportunities, and controversies offered by EBM. It also summarizes current discussions on clinical research. Potential solutions to the problems of EBM and clinical re-search are discussed as well. If there were specific issues re-lated to pediatric nutrition, an attempt was made to discuss the basic principles and limitations in this context. However, the conclusions are applicable to EBM and clinical research in general. In the future, considering that new ways of ob-taining health data will continue to emerge, the world of EBM and clinical research is likely to change. The ultimate goal, however, will remain the same: improving health out-comes for patients.


Introduction

Currently, it is impossible to think of modern health-care that ignores evidence-based medicine (EBM), a con-cept which relies on 3 pillars: individual clinical expertise, the values and desires of the patient, and the current best evidence ( Fig. 1 ). However, EBM is not perfect. A widely cited expert, John Ioannidis, professor of epidemiology at Stanford University, claims that EBM is “becoming an industry advertisement tool.” Clinical research, one of the EBM pillars, is also far from perfect. Among the prominent figures in medicine who questioned research is

Szajewska Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):13–23 DOI: 10.1159/000487375

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Richard Horton, editor of The Lancet , who stated: “The case against science is straightforward: much of the scien-tific literature, perhaps half, may simply be untrue. Af-flicted by studies with small sample sizes, tiny effects, in-valid exploratory analyses, and flagrant conflicts of inter-est, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness” [1] . Marcia Angell, who served as the editor of The New England Journal of Medicine for over 2 decades, wrote: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines” [2] . Ioannidis, based on a theoretical model, concluded that “most published research findings are probably false” [3] . Earlier, he also argued that as much as 30% of the most influential original medical research papers later turn out to be mistaken or overstated [4] .

The situation in pediatric research is particularly dif-ficult. Interventions tested in adults but used in infants/children may be ineffective, inappropriate, or harmful. A 2008 review, found in 6 leading journals, such as The New England Journal of Medicine , The Journal of the American Medical Association , Pediatrics , Archives of Pediatrics and Adolescent Medicine , Annals of Internal Medicine , and Archives of Internal Medicine , that compared studies in children with those in adults found that studies in chil-dren were significantly less likely to be randomized con-trolled trials (RCTs), systematic reviews, or studies of therapies. If such studies viewed as sources of the highest evidence are lacking, this has major implications for medical practice and the quality of care for children [5] .

Even if the choice of journals and the time period assessed (3 months only) are unlikely to reflect all of the published literature, it points out a problem of many pediatric stud-ies.

This article provides an overview of the basic princi-ples, opportunities, and controversies offered by EBM. It also summarizes current discussions on clinical research, and how to overcome problems with EBM and clinical research. If there were specific issues related to pediatric nutrition, an attempt was made to discuss the basic prin-ciples and limitations in this context. However, all con-clusions are applicable to EBM and clinical research in general.

History of EBM

More than a quarter of a century ago, in 1991, Gordon Guyatt, at that time a young resident at McMaster Uni-versity, first coined the term “scientific medicine” (which euphemistically speaking was not well accepted by his senior colleagues), and then, the term “evidence-based medicine” [6] . Soon after, in 1996, his mentors, David Sackett and colleagues, all considered the fathers of EBM, defined it as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” [7] ( Fig. 1 ). The concept which revolutionized clinical practice worldwide was born. It has changed and, in many ways, continues to change the medical world, providing healthcare profes-sionals a tool to determine which treatments work and which do not. Thus, it is not surprising that, in 2007, when The BMJ chose the top 15 milestones in medicine over the last 160 years, EBM was one of them, next to achievements as anesthesia, antibiotics, the discovery of DNA structure, sanitation, vaccines, and oral rehydration solution [8] .

Steps for Practicing EBM

The following 4 steps are needed for practicing EBM ( Table 1 ): (1) formulation of an answerable question (the problem); (2) finding the best evidence; (3) critical ap-praisal of the evidence; and (4) applying the evidence to the treatment of patients.

Hierarchy of Evidence

Although only a general guideline, a hierarchy (levels) of evidence provides useful guidance about which types of evidence, if well done, are more likely to provide trust-

Individualclinical

expertise

Patientvalues and

expectations

Bestresearchevidence

Evidence-based medicine

Fig. 1. Elements of the evidence-based medicine triad (expertise, values, and evidence) play a similar role in health decision-making.

Evidence-Based Medicine and Clinical Research

15 Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):13–23 DOI: 10.1159/000487375

worthy answers to clinical questions. Which hierarchy is appropriate depends upon the type of clinical question asked ( Table 2 ). An extended hierarchy (levels) of evi-dence that includes diagnostic, prognostic, and screening studies in addition to therapeutic studies has been pub-lished by the Oxford Center for Evidence-Based Medi-cine [9] . Of note, irrespective of the type of question, sys-tematic reviews are considered to offer the strongest evi-dence.

For intervention questions, systematic reviews and meta-analyses are followed by (in descending order of ev-idence strength) RCTs, cohort studies, case-control stud-ies, case series studies, and lastly, expert opinions or theo-ries, basic research, and animal studies ( Fig. 2 ). Thus, if available, RCTs and meta-analyses should be used in sup-port of clinical decision-making. If the best level of evi-dence is not available, moving to a lower level of evidence is needed. However, the lower a methodology ranks, the less robust the results and the less likely the findings of the study represent the objective findings; thus, there is less confidence that the intervention will result in the same health outcomes if used in clinical practice. At the base of the hierarchy is animal and basic research (cell/labora-tory studies). Discussing methodological problems of an-imal and cell research is beyond the scope of this article. However, a number of studies have revealed that animal

experiments often fail to predict outcomes in humans. Tests on isolated cells can also produce different results to those performed in the body. On the other hand, many of the remarkable discoveries would not have been pos-sible without vital experiments on animals (e.g., organ transplantation). Moreover, since 1901, nearly every Nobel Laureate in physiology or medicine, if not all, has relied on basic/animal data for their research!

Criticism of EBM

From the first publications related to EBM, accusa-tions that EBM is “cookbook medicine” [10] , “denigrates clinical expertise” [11] , or “ignores patient’s values” [12] have been commonly used by critics. In a 2000 commen-tary, all of these criticisms (many of which were consid-ered misperceptions of EBM) were addressed by Straus and McAlister [13] . However, the passage of time did not ease the criticism. Even more, nowadays, are concerns about the current direction of EBM being raised by many “EBM insiders.” Recently, Ioannidis challengingly stated that “evidence-based medicine has been hijacked” [14] . He says: “As EBM became more influential, it was also hijacked to serve agendas different from what it original-ly aimed for.” He also claims that clinical evidence is “be-coming an industry advertisement tool.” In brief, one of

Table 1. Steps for practicing EBM [48]

Step Comment

1 Formulation of an answerable question (PICO)

The four elements of a well-formulated question are:– participants (P),– interventions (I),– comparisons (C),– outcomes (O) of interest

2 Finding the best evidence (hierarchy of evidence)

A hierarchy (levels) of evidence provides guidance about the types of evidence more likely to provide trustworthy answers to clinical questionsFor details, see Figure 2 and text

3 Critical appraisal of the evidence

Checklists for critical appraisal of the evidence are freely available [48]– Are the results of the study valid?– What are the results?– Will the results help me locally?

4 Applying the evidence to the treatment of patients

The ultimate aim of practicing EBM is to integrate current best evidence from research with clinical expertise and the patient’s features and values– Are my patients similar to those in the study?– Is the intervention realistic in my setting?– Have all important outcomes been considered?


16

the concerns is the impact of industry on the way in which research is performed and reported, and consequently, the way in which medicine is practiced, and even the def-inition of what constitutes health or disease. Overuse and misuse of the term EBM is another concern. As Ioannidis pointed out, there are “eminence-based experts and con-flicted stakeholders who want to support their views and their products, without caring much about the integrity, transparency, and unbiasedness of science.”

In 2014, Greenhalgh et al. [15] , on behalf of the Evi-dence-Based Medicine Renaissance Group, provocatively asked in The BMJ : “Evidence based medicine: a move-ment in crisis?” The group provided a number of argu-ments to support this view. First, it includes misappro-priation of EBM by vested interests. Indeed, under certain circumstances, industry involvement/funding (i.e., com-mercial interests) can introduce this bias. Second, the un-manageable volume of evidence, especially clinical guide-lines, being produced represents a challenge. Third, sta-tistically significant but clinically irrelevant benefits are being exaggerated. Fourth, contrary to the original con-cept, EBM is currently not patient-centered. Finally, the failure of EBM guidelines to properly address patients with multiple conditions (multi-morbidity) is a problem. The coexistence of 2 or more long-term conditions in 1 patient presents unique challenges. A “one size fits all” approach with evidence targeted to a single condition and treatment option is clearly inappropriate. In the pediatric setting, many diseases that were once deadly are now cured by modern medicine; however, these patients may face multiple, lifelong health problems.

Criticism of RCTs

Among the most heavily criticized aspects of EBM is the use of RCTs and meta-analyses. A randomized con-trolled trial is defined as an experiment in which 2 or more interventions are compared by being randomly al-located to participants. Large, well-designed, and well-implemented RCTs are considered the gold standard for

Table 2. Different types of clinical questions require different types of research

Type of clinicalquestion

Best type of study to answer thequestion

Therapy RCT; systematic review/meta-analysis of RCTs

Diagnosis Controlled trial; systematic review/meta-analysis of controlled trials

Harm Cohort studies Prognosis Cohort studies; case-control

studies; case studiesEtiology Cohort studiesPrevention RCT; cohort studiesQuality improvement RCTQuality of life Qualitative studyCost-effectiveness Economic evaluationClinical examination Prospective, blind comparison to gold

standard

RCT, randomized controlled trial.

RCTs

Cohort studies

Case-control studies

Case series studies

Expert opinions, theories based on physiology orplausibility, benchtop research, and animal studies Weak

StrongSystematic reviews/meta-analyses

Fig. 2. The hierarchy (levels) of evidence (in descending order of evidence strength). RCTs, randomized controlled trials.



evaluating the efficacy of healthcare interventions (ther-apy or prevention). RCTs are the best way to identify causal relationships and can determine efficacy (establish definitively which treatment methods are superior). The fact that they are less likely to be biased by known and unknown confounders is an added strength relative to all other study designs. However, there are some concerns with regard to RCTs. In addition to internal validity, which is the extent to which the design and conduct of a study is likely to have prevented bias or systematic error, the external validity, defined as the extent to which results may be generalized to other circumstances and beyond study populations [16] , is one of the major concerns and is considered to be the Achilles’ heel of RCTs. One such example is studies carried out in term infants with results that may not be extrapolated to very-low-birth-weight in-fants.

RCTs in Pediatric Nutrition

With the increasing number of RCTs, investigators have recognized limitations of RCTs in the field of pedi-atric nutrition. First, critically relevant outcomes that re-late to nutritional practices in infants/children may take years to become apparent. Therefore, it is difficult to de-sign and implement RCTs that last for a sufficient time to cover more than just a small fraction of the process lead-

ing to the final outcome. Second, diet/nutritional and re-lated exposures are complex and interrelated, and in most cases, short-term effects do not persist in the medium to long term. Most studies assess responses to single macro- or micronutrient changes, which may not reflect real-life conditions in which multiple exposures (deficiencies or potential excesses) coexist and interact to define specific outcomes. Third, the outcome of a trial is to show (or to fail to demonstrate) efficacy in achieving a desired out-come. Results of such trials can be simply and robustly interpreted in light of the specific intervention and the given study population. However, extrapolation to other populations or to interventions not exactly the same as those tested in the trial may be inappropriate. Table 3 summarizes main barriers to the conduct of randomized clinical trials.

Still, the results of RCTs may change medical practice. In pediatric nutrition research, one example of a clinical question that has been addressed by an RCT is: Does the fortification of human milk with either human milk-based human milk fortifier or bovine milk-based human milk fortifier ( intervention ) have an effect on the risk of necrotizing enterocolitis (NEC) ( outcome ) in extremely premature infants ( population )? This RCT, involving 207 infants (birth weight: 500–1,250 g), showed that the groups receiving exclusively human milk had a signifi-cantly reduced risk of NEC and NEC needing surgical

Table 3. Main barriers to the conduct of randomized clinical trials

Barriers affecting all clinical trials1

– Inadequate knowledge of clinical research and trial methodology– Lack of funding– Excessive monitoring– Restrictive privacy law and lack of transparency– Complex regulatory requirements– Inadequate infrastructures

Barriers to research in the field of nutrition1

– Testing a nutrient– Testing a food intervention– Assessing dietary intake– Selection of outcomes

Additional barriers to research in children – Unethical to randomize breastfed infants into an infant formula-feeding group– The threshold for gaining consent is often higher and more complex because parents have to make

decisions about trial participation on behalf of their child– Ethical issues (infants/small children cannot give consent)

1 Identified by the European Clinical Research Infrastructure Network (ECRIN) panel in the context of the ECRIN-IA project.


18

intervention. Lack of blinding was one of the limitations of the study. Still, the findings strongly support the use of human milk for reducing the risk of NEC in preterm in-fants [17] .

Criticism of Meta-Analyses

A meta-analysis begins with a systematic review, i.e., a review of a clearly formulated question that uses system-atic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyze data from studies that are included in the review. However, in contrast to a systematic review alone, statistical tech-niques are then utilized to pool the results of all of the RCTs, so that they can be analyzed together. The primary reasons for performing a meta-analysis are to increase statistical power, thus, in-creasing the chance to reliably detect a clinically important difference, if such a difference exists, and to improve preci-sion in estimating effects, en-abling the confidence interval around the effects to be narrowed. When determining whether results of individual trials should be pooled or kept separate, it is important to consider if the studies are sufficiently homogeneous in terms of both the question and the methods. The “PICO” acronym should ideally be the same (or very similar) across studies to be pooled: population, intervention, comparison, and outcome. Thus, it is always appropriate to perform a systematic re-view, and every meta-analysis should be preceded by a systematic review. However, not every systematic review should be finalized with a meta-analysis; in fact, it is sometimes erroneous and even misleading to perform a meta-analysis.

Since the beginning, meta-analyses have received crit-icism, being labeled as “mega-silliness” [18] , “shmeta-analysis” [19] , “statistical alchemy” [20] , or “mixing ap-ples and oranges” [21] . Despite these criticisms, the num-ber of meta-analyses (including those in the field of pediatric nutrition) is increasing rapidly, and they are un-likely to disappear. However, hand in hand with the in-creasing number of meta-analyses is an increase in criti-cism. For example, concerns have been raised about the exponential increase in the number of meta-analyses. For some topics, there are more systematic reviews than indi-vidual trials included in these reviews. Ioannides recently stated “The production of systematic reviews has reached epidemic proportions. Possibly, most systematic reviews

are unnecessary, misleading and/or conflicting” [22] . Possible flaws in a meta-analysis include failure to iden-tify all relevant studies (that is why searching one data-base is never enough); risk of bias in the included trials (any meta-analysis is only as good as the constituent stud-ies); exclusion of unpublished data (inclusion of unpub-lished data reduces the risk of publication bias); opposite conclusions (differences in the review question, search strategy, etc. may be responsible for this); and inconclu-siveness (frustrating statements such as “no clear evi-dence” or “further research is needed”) [23] .

Meta-Analyses in Pediatric Nutrition

Is this accusation of overproduction of systematic re-views/meta-analyses true for pediatric nutrition? In just

2 years (2016–2017), at least 14 published meta-analyses aimed to evaluate the effect of probiotics in reducing the risk of NEC, adding to a sub-stantial number of previously published meta-analyses on

the same topic [24] . Still, as most existing meta-analyses fail to adequately account for strain-specific effects, it re-mains unclear which probiotic strain(s) to use. This ex-ample shows that overproduction of systematic reviews/meta-analyses may be a problem in pediatric nutrition as well. Considering that there are too many meta-analyses, perhaps it is time to go back to conducting large, multi-center, well-planned, and well-executed trials with well-defined outcomes. Something to be seriously considered by the co-authors of many published meta-analyses (such as myself!).

Problems with Clinical Research

In the era of EBM, the quality of clinical research, one of the pillars of EBM, is of paramount importance. How-ever, as stated earlier, there are concerns that much of clinical research is poorly designed, conducted, analyzed, and/or reported. Consequently, the conclusions drawn from clinical research are probably false. Among the first to address this issue was Altman [25] . In a 1994 BMJ Ed-itorial, he stated that “less research, better research, and research done for the right reasons” is needed. More re-cently, Ioannidis (alone or with colleagues) has published a large number of papers on this subject, including a high-ly cited publication “Why Most Published Research Find-ings Are False” [3] . Based on a mathematical model,

Perhaps it is time to go back to conducting large, multicenter,

well-planned, and well-executed trials with well-defined outcomes



Ioannidis concluded that more than 50% of published biomedical research findings with a p value of less than 0.05 are likely to be false positive. However, not everyone agrees. For example, Jager and Leek [26] in another paper (again, based on a statistical model) argued that only 14% of p values are likely to be false positive. While the discus-sions in regard to the extent of bias may continue, it nev-ertheless indicates that problems exist.

Why does the quality of clinical research remain sub-optimal? Important factors to consider include the fol-lowing [3] (see also Table 4 ).

Sample Size and Underpowered Studies The smaller the studies, the less likely the research

findings are to be true. Low statistical power weakens the purpose of scientific research and reduces the chance of detecting a true effect. It also lowers the likelihood that a statistically significant result reflects a true effect.

Effect Size When effect sizes are smaller (often the case in under-

powered studies), the research findings are less likely to be true.

Unjustified Reliance on the p Value of 0.05. Sole reliance on p values may be problematic. Both

false-positive and false-negative results are possible. Of note, in March 2016, the American Statistical Association (ASA) warned against the misuse of p values. In its state-ment, the ASA advises researchers to avoid drawing sci-entific conclusions or making policy decisions based on p values alone [27] .

Lack of Confirmation (Replication) The reproducibility of research is a critical component

of the scientific process. There are various factors that discourage simple repetition of studies, such as a lack of

scientific novelty and/or a lack of interest in interventions that have been proven effective in a single study. Still, as a rule, repeat studies are needed, as a single study is, right-ly, never sufficient to change clinical practice. If research findings cannot be replicated, it means they are less likely to be true. Discordance of findings does not indicate which results are correct. Both may be incorrect; howev-er, it indicates that difficulties exist in replicating the orig-inal findings. Publishing of both positive and negative re-sults is important.

Pre-Selection The greater the number of hypotheses tested, the more

likely it is to find false-positive results. Similarly, the less-er the selection of tested relationships, the less likely the research findings are to be true.

Flexibility in Analysis The more flexibility in study designs and in defini-

tions, outcomes, and analyses, the less likely the research findings are true. Methodological rigor is likely to reduce the risk of biased findings.

“Hot” Areas of Science The hotter the research field, the more scientific teams

are likely to be involved in a particular field; this greater competition to find impressive results increases the likeli-hood of false findings.

Financial Interest The greater the financial (and other) interests and

prejudices in a scientific field, the less likely the research findings are to be true. In addition to financial and non-financial conflicts of interest (discussed below), this also includes manipulation of research data and fraud and/or selective outcome reporting.

Sample size When the studies conducted are smallerEffect size When effect sizes are smallerAnalysis When there is a greater number and less

pre-selection of tested relationshipsFlexibility in research design When there is greater flexibility in designs,

definitions, outcomes, and analytical modesConflict of interest When there are greater financial and other

interests and prejudice“Hotness” of the research field The “hotter” (more competitive) the research field

Table 4. Interpretation of the research findings (when they are less likely to be true) (based on [3])


20

In Bed with Industry

Ideally, the authors of any type of research should have no conflicts of interest. In the real world, however, this is not always the case. In many settings, research collabora-tion between academic investigators and industry is even encouraged by universities, public funding bodies, and governmental organizations. For example, Horizon 2020, the biggest EU Research and Innovation program, pro-motes collaboration with the ultimate goal of making it easier to deliver innovations.

In medicine, conflict of interest generally implies fi-nancial ties of the authors with industry. However, con-flict of interest is a much broader matter. Examples of nonfinancial conflicts of interest include strongly held personal beliefs related to the research topic, personal re-lationships, institutional relationships, or a desire for ca-reer development [28] . Other players might also not be free of conflict of interest, either financial or nonfinancial. For example, lobbyists, patients’ associations, research-ers, lawyers, medical writers, advertising and social net-working specialists, physicians, administrators, and poli-cy makers may also be industry supported [29] . Taken together, while eliminating any conflict of interest of all parts involved might be an unrealistic goal, moving to-ward greater transparency and disclosure of potential or factual conflicts of interest should be a priority. Com-pared with non-industry-sponsored studies, industry-sponsored studies tended to have more favorable effec-tiveness and harm findings and more favorable conclu-sions [30] .

In pediatric nutrition, funding of research by manu-facturers of infant formulae may be considered even more controversial because of the need for protection and pro-motion of breastfeeding. However, in the case of studies involving infant formulae, industry involvement is un-avoidable, as investigators lack the means to manufacture quality infant products. Still, independently funded re-

search to obtain reliable evidence on the effects, safety, and benefits of drugs and other commercial products and services is a desirable goal.

What Can Be Done to Solve Problems with EBM?

As a response to “systematic bias, wastage, error and fraud relevant to patient care,” a group of prominent in-dividuals published the “EBM Manifesto for Better Health” ( Table 5 ) [31] . Thus, the problems were not only identified, but an agenda for fixing EBM was proposed. The list of proposed solutions may not be complete. Thus, as part of the “EBM Manifesto,” anyone can contribute with suggestions through an online form.

Overall, the solutions proposed by the authors of the “EBM Manifesto” are similar to those proposed by others [16] . EBM should have the care of an individual patient as the top priority. In line with the original understanding of EBM as the integration of the best research evidence with clinical expertise and patient values, individualized application of evidence to patients, with less reliance on following guidelines, is emphasized. Research should be clinically relevant, better reported, and applied. Critical appraisal skills training, while important, should not be done in isolation; shared decision-making skills are need-ed. The language, format, and presentation of evidence summaries and clinical guidelines should serve those who use the evidence-based information in real practice. Pub-lishers and journal editors have the responsibility for en-suring that published materials can be used by healthcare professionals.

What Can Be Done to Improve Clinical Research?

Standards for Conducting Research In 2014, The Lancet published a series of 5 articles

called “Research: Increasing Value, Reducing Waste,” in

– Expand the role of patients, health professionals, and policy makers in research– Increase the systematic use of existing evidence– Make research evidence relevant, replicable, and accessible to end users– Reduce questionable research practices, bias, and conflicts of interests– Ensure drug and device regulation is robust, transparent, and independent– Produce better usable clinical guidelines– Support innovation, quality improvement, and safety through the better use of

real-world data– Educate professionals, policy makers, and the public in evidence-based healthcare to

make an informed choice– Encourage the next generation of leaders in EBM

Table 5. EBM Manifesto for better health [31]



which they discussed: (1) setting research priorities so that funding is based on issues relevant to users of re-search [32] ; (2) research design, conduct, and analysis (key problems include poor protocols and designs, poor utility of information, statistical power and outcome mis-conception, and insufficient consideration of other evi-dence) [33] ; (3) biomedical research regulation and man-agement [34] ; (4) the role of fully accessible research in-formation [35] ; and (5) incomplete or unusable research [36] .

Standards for Conducting Pediatric Research Independently, significant developments have taken

place in recent years to strengthen pediatric clinical re-search. In 2009, the Standards for Research (StaR) in Child Health initiative was founded [37] . This initiative addressed the current paucity of and scarcities in pediat-ric clinical trials. The aim of the StaR is to improve the quality of the design, conduct, and reporting of pediatric clinical research by promoting the use of modern re-search standards, so that the evidence is methodological-ly robust and important.

Standards for Reporting Clinical Research To avoid wasting time and resources, research needs

to be not only well performed, but also adequately report-ed. There is evidence that incomplete and/or poor and/or inaccurate reporting of clinical research is a problem, thus, reducing its role in clinical decision-making. Fre-quent shortcomings in reporting include non-reporting or delayed reporting of whole studies; selective reporting of only some outcomes in relation to study findings; the omission of crucial information in the description of re-search methods and interventions; omissions or misin-terpretation of results in the main article and abstract; inadequate or distorted reporting of harms; and confus-ing or misleading presentations of results, data, and graphs [38] . Being aware of the reporting problems, jour-nal editors, together with other stakeholders such as methodologists, researchers, clinicians, and members of professional organizations, have developed a number of standards for reporting clinical research to ensure that all details of design, conduct, and analysis are included in the manuscript. Among others, these standards (all available at the EQUATOR Network website: www.equator-net-work.org) include the following: CONSORT (Consoli-dated Standards of Reporting Trials) [39] ; PRISMA (Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses) [40] ; STARD (Standards for the Reporting of Diagnostic Accuracy Studies) [41] ; and MOOSE (Meta-

Analysis of Observational Studies in Epidemiology) [42] . Endorsement of these reporting guidelines by journals is highly variable. However, increasingly, the editors now require that authors follow these standards when submit-ting a manuscript for publication.

Initiatives to Change How Scientists Are Evaluated The current science evaluation system relies heavily on

bibliometrics; thus, it promotes quantity over quality of research. However, there are a number of initiatives fo-cusing on how to improve research quality by changing how scientists are evaluated and rewarded. One example is “The Leiden Manifesto” published in 2015 by a group of experts on altmetrics who identified 10 principles to guide better research evaluation [43] ( Table 6 ). If fol-lowed, these criteria are likely to improve the integrity of research. At least some scientific institutions are already developing policies to encourage quality over quantity [44] .

The Changing Face of Clinical Trials

Clinical research is evolving. In 2016, The New En-gland Journal of Medicine published a collection of arti-cles called “The Changing Face of Clinical Trials” that examine the current challenges in the design, perfor-mance, and interpretation of clinical trials written by tri-alists for trialists. Among others, this series covers new trial designs. Recognition of the limitations of current re-search methods leads towards newer research designs. Examples include pragmatic trials (the major strength is that participants are broadly representative of people who

Table 6. The Leiden Manifesto for research metrics: 10 principles to guide research evaluation [43]

1. Quantitative evaluation should support qualitative, expert assessment

2. Measure performance against the research missions of the institution, group, or researcher

3. Protect excellence in locally relevant research4. Keep data collection and analytical processes open,

transparent, and simple5. Allow those evaluated to verify data and analysis6. Account for variation by field in publication and citation

practices7. Base assessment of individual researchers on a qualitative

judgment of their portfolio8. Avoid misplaced concreteness and false precision9. Recognize the systemic effects of assessment and indicators

10. Scrutinize indicators regularly and update them


22

will receive a treatment or diagnostic strategy, and there is potential for high generalizability) or adaptive trial de-signs (used by the investigators to alter basic features of an ongoing trial).

“Big Data” and “Real-World Data”

In the future, decision-making may be influenced by “big data” and “real-world data.” “Big data” (often char-acterized by 3 Vs: volume, velocity, and variety) is a term that describes the collection of extremely large sets of in-formation, which require specialized computational tools to enable their analysis and exploitation [45] . A subset of “big data” is “real-world evidence” (also known as “real-world data”), defined as data derived from sources such as electronic health records, registries, hospital records,

Real-worlddata

Databases (cross-sectionaland longitudinal)

Patient chart reviews

Patient and populationsurveys

Observational cohortstudies

Pragmatic clinical trials

Registries

Fig. 3. Sources of “real-world data” (evidence).

and health insurance data [46] ( Fig. 3 ). “Real-world” data allow one to see whether a treatment works in “real” pa-tients outside of clinical study settings [47] . However, as attractive as “big data” and “real-world data” may be, their real value and whether the evidence is unbiased re-main unclear. As with a meta-analytical approach, these data will be only as good as they are accurate.

Concluding Remarks

All health decisions should be based on high-quality scientific data. Thus, both EBM and clinical research are needed. However, neither EBM nor clinical research is perfect. Clinical research varies significantly in quality and, therefore, in the trustworthiness of the yielded evi-dence. A better understanding of the strengths and limi-tations of EBM and clinical research is vital. Solutions to fix EBM have been proposed. Similarly, strategies for the development of high-quality research have been devel-oped. If strictly adhered to by researchers, academia, funding bodies, industry, journals, and publishers, this should lead to more valid and trustworthy findings. In the future, considering that new ways of obtaining health data will continue to emerge, the world of EBM and clin-ical research is likely to change. The ultimate goal, how-ever, will remain the same: improving health outcomes for patients.

Disclosure Statement

H.S. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Arla, Bioga-ia, Biocodex, Danone, Dicofarm, Hipp, Nestlé, Nestlé Nutrition Institute (NNI), Nutricia, Mead Johnson, Merck, and Sequoia. The writing of this article was supported by NNI.

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Since the early days of caring for preterm infants, it has been widely held that human milk was

the food of choice for these infants

Key insights

Early nutrition has a tremendous impact on the health and de-velopmental outcomes of preterm infants. Unlike term infants, those who are born preterm have specific nutritional require-ments. For example, preterm and low-birth-weight infants are at high risk of iron deficiency, due to their lower internal iron stores at birth and higher iron demands during catch-up growth. The survival rates of preterm infants have greatly im-proved over the last few decades, largely due to advances in neonatal care and feeding research.

Current knowledge

An understanding of the key role played by folate in neural tube development was a landmark in maternal and infant nu-trition. This led to the implementation of maternal folic acid supplementation policies across many countries. The develop-ment of enteral formulas and the establishment of donor milk banks were also significant advances in preterm infant nutri-tion. However, the ideal composition of formulas remains to be determined, and new techniques are needed to optimize the storage of human donor milk. Another key question that re-mains is to define the protein requirements for preterm infants.


The best practices for feeding preterm infants have evolved over the past decades. Recent studies have shown that breast milk feeding reduces the incidence of necrotizing enterocolitis and


Nutrition for Preterm Infants: 75 Years of History by Johannes B. van Goudoever

rly days of c

F O C U S


nosocomial infections in preterm infants. However, there is great variability in the composition of human milk. Current evidence supports the use of a fortifier alongside human milk to support the growth and development of these infants. Iron supplementa-tion is also recommended at a dose of 1–3 mg/kg/day to prevent iron deficiency.

Recommended reading

Buckle A, Taylor C: Cost and cost-effectiveness of donor human milk to prevent necrotizing enterocolitis: systematic review. Breastfeed Med 2017;12:528–536.

Hypothermia Infections

Preterminfant

Nutrition

Growth and development

Pierre Budin, one of the founders of modern preterm infant care, high-lighted 3 basic challenges faced by preterm infants.



Nutrition for Preterm Infants: 75 Years of History

Johannes B. van Goudoever

Emma Children’s Hospital – AMC & VU University Medical Center, Amsterdam , The Netherlands

Johannes (Hans) B. van Goudoever Emma Children’s Hospital – AMC & VU University Medical Center AMC, Room H7-276, PO Box 22700 Meiberg dreef 9, NL–1100 DE Amsterdam (The Netherlands) E-Mail h.vangoudoever @ amc.nl



Key Messages

• Early nutrition has a huge impact on the short- and

long-term health of preterm infants.

• Human milk has been and is again the preferred

enteral supply, although fortification is required to

meet the requirements.

Keywords

Iron · Folate · Human milk · Donor milk · Fortifier · Probiotics

Abstract

As technology has advanced, survival rates of preterm in-fants have improved dramatically. Human milk was the pri-mary source of enteral nutrition during the early days of neo-natology, but the HIV/AIDS epidemic resulted in an increased use of preterm formula. More recently, the benefits of hu-man milk were rediscovered, resulting in increased use of donor human milk as well. The awareness that human milk does not contain the amounts of nutrients to meet the high requirements of infants born premature resulted in the de-

velopment of human milk fortifiers. The development of these fortifiers is still ongoing, as are alternative methods of pasteurization of donor milk. Those initiatives will increase the use of human milk with consequently short- and long-term benefits for preterm infants.


Introduction

Modern preterm infant care has its origins at the Hôpi-tal de la Charité in Paris. Pierre Budin, influenced by the former head midwife of the Maternité, Madame Henry, installed the first specialized care unit for “weaklings,” as underweight infants were then referred to, in 1893 ( Fig. 1 ). Budin was then called as head of Obstectrics at Hôpital de la Maternité in 1898. Under his direction, both hospitals became the world’s first centers of specialized study on caring for preterm infants. In his lectures to students, published in 1890, Baudin highlighted 3 main basic prob-lems for preterm infants: • Risk of hypothermia through cooling • Vulnerability to infections • Feeding

van Goudoever Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):25–31 DOI: 10.1159/000487378

26

Although the first neonatal unit was already opened in 1893, it took a long time before anything was published on preterm nutrition in the scientific literature and espe-cially in this journal.

The First Article on Preterm Nutrition in Annales Nestlé (Annals of Nutrition and Metabolism) The first article that appeared in the Annals of Nutri-

tion and Metabolism which was somehow related to nu-trition and neonates was published by Zittoun et al. [1] from France in 1983. They investigated the effect of iron supplementation during pregnancy, and this placebo-controlled (!) trial demonstrated that iron supplements to iron-deprived mothers had no effect on the ferritin status of the newborn, on the folate status of the moth-ers or infants, or on the frequency of obstetrical com-plications. A significant relationship was found be-tween maternal folate levels and length of gestation. The authors concluded that folate supplementation during pregnancy might reduce the incidence of pre-mature delivery.

Folate and Iron: Present Knowledge and Advice That folate was important became more obvious in the

following years, but not so much with regard to anemia, but as an actor in prevention of neural tube defects. Un-ambiguous evidence of the effectiveness of periconcep-tional folic acid in preventing neural tube defects has been available since 1991 [2] and is still undisputed [3] . The first governments to formulate a periconceptional folic acid supplementation policy were the United Kingdom (1992), Ireland (1993), and the Netherlands (1993); six more (Switzerland 1996, Denmark 1997, Norway 1998, Portugal 1998, France 2000, and Spain 2001) followed. Despite firm evidence, adherence is low.

Many studies have appeared regarding maternal iron supplementation since 1983, and at present it is clear that iron supplementation reduces maternal anemia inci-dence in pregnancy but the effects on infant outcomes are less clear [4] . Compared with controls, women taking iron supplements less frequently had low-birth-weight newborns (8.4 vs. 10.3%, average RR 0.84, 95% CI 0.69–1.03, 11 trials, 17,613 women; low-quality evidence) and preterm babies (RR 0.93, 95% CI 0.84–1.03, 13 trials, 19,286 women; moderate-quality evidence).

Fig. 1. “Maternité de Paris” from The Illustrated London News , March 8th, 1884.

Nutrition for Preterm Infants 27 Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):25–31 DOI: 10.1159/000487378

Preterm and low-birth-weight infants are at high risk of iron deficiency due to low iron stores at birth and high-er iron requirements due to rapid growth. Already in 1971, Lundstrom et al. [5] demonstrated that 2 mg/kg was adequate to prevent anemia in infants with a birth weight of 1,000–2,000 g at 3 months of age. The randomization procedure was that infants with odd birth dates received 2 mg iron as ferrous sulfate/kg/day starting at 0.5 months; those with even birth dates received no additional iron unless they developed anemia. Interestingly, almost 50 years later, with many additional randomized controlled trials performed, the most recent recommendation (pub-lished in the Annals of Nutrition an Metabolism De-cember 2017 issue) is almost identical: 1–3 mg/kg/day (1–2 mg for marginally low birth weight and 2–3 mg for very low birth weight) is needed to effectively prevent iron deficiency [6] . There is some recent evidence that these levels of iron intake will prevent some of the nega-tive health consequences associated with low birth weight, especially behavioral problems and other neurodevelop-mental outcomes and possibly even hypertension.

Milestones in Enteral Preterm Nutrition

Preterm Formula Since the early days of caring for preterm infants, it has

been widely held that human milk was the food of choice for these infants. This belief, however, has not prevented some pediatricians from suggesting that human milk might not in fact be the ideal food on the grounds that its low protein content is insufficient for growth require-ments. Especially the lack of adequate protein content to meet the requirements has driven the development of for-mulas especially designed for preterm infants. One of the earlier publications on protein content of preterm formula originated from Professor Peter Davies in 1975 [7] . He acknowledged that adequate protein intake in the early weeks of life is necessary if growth is to proceed normally. The question of optimum protein requirements for preterm infants is therefore an important one. He investigated 106 preterm infants who were fed 1 of 3 isocaloric milks for a period of 2 months. Milk A was high-protein milk (21% calories as protein), milk B was medium-protein milk (15% calories as pro-tein), and milk C was human breast milk (7% calories as protein). Changes in weight, length, head circumference, and triceps skinfold thickness were evaluated. The results

suggested that though human milk was adequate for the growth needs of the more mature preterm infants (33–36 weeks’ gestation), less mature infants (28–32 weeks’ ges-tation) fed human milk failed to achieve adequate growth rates compared with infants on higher protein intakes. At the same time, a landmark paper by Goldman et al. [8] appeared in the Journal of Pediatrics , warning about very high protein intake because of deleterious effects on IQ development. This study was a follow-up of an earlier double-blinded study, performed in 1963 [9] , where less edema was observed in infants fed 6 g/kg/day of cow’s milk protein, but more fever, lethargy, and poor feeding behavior as well as higher levels of plasma protein than the infants fed 3 g/kg/day of cow’s milk protein in the di-rect postnatal phase. Specifically infants with a birth weight < 1,300 g were at risk of developing strabismus and low IQ scores.

As product development enhanced, casein whey frac-tions were modified to increase tolerability, many studies addressed the optimal intake and relationship between energy and protein intakes.

Cow’s milk contains approximately 20% whey protein and 80% casein proteins, whereas formulas were gradu-ally modified to a ratio of whey proteins to caseins of 60: 40. These modifications resulted in a plasma amino acid pattern more resembling that of a fully breastfed in-fant [10] . Pivotal in that development were the studies by Kashyap and Heird [11, 12] who studied the effects of varying protein and energy intakes. These studies fol-lowed the observation that premature infants have high rates of energy expenditure, using different techniques [13, 14] . Acknowledging that sufficient energy must be provided for maintaining high rates of protein synthesis, many studies were undertaken to determine the optimal

protein energy ratio in vari-ous groups [15] . This resulted in recommendations that en-terally fed infants should re-ceive 110–135 kcal/kg/day and at least 3.6 g/kg/day of proteins [16] .

While the breast milk of mothers who deliver preterm contains higher amounts of proteins, this effect dimin-ishes after approximately 1 month. The quality of the milk may also be different, especially with regard to the im-mune proteins [17, 18] . These observations led to a gen-eral believe that human milk did not meet the require-ments of rapidly developing preterm infants with subse-quent effects on growth and development. This led to the development of formulas specifically designed for pre-

While the breast milk of mothers who deliver preterm contains higher amounts of proteins, this effect

diminishes after approximately 1 month


28

term infants. An important paper published in The Lancet in 1990 [19] suggested that infants fed a higher nutrient density formula for a period as short as 1 month had long lasting effects on neurodevelopment and regional brain volumes [19–21] . Preterm formula became standard feed-ing in many neonatal units, and rates of infants fed own mother’s milk declined significantly. Editorials with sug-gestive titles such as “Breast Not Necessarily Best” ap-peared in 1998, in an era in which AIDS and its effects became very apparent [22] . However, already 5 years later, arguments were made to use own mother’s milk because of evidence that human milk reduced rates of infections and necrotizing enterocolitis (NEC) and enhanced the de-velopmental outcome of preterm infants [23] .

Donor Milk Approximately 75 years ago, human donor milk be-

came increasingly popular throughout Europe. Especially

after the Second World War, many countries started a human milk bank. Figure 2 shows the workflow in these days. Milk was collected at home, brought to a central place (blood bank or hospital) and vacuum dried. Pow-ered human milk was available for preterm born infants and neonates with gastrointestinal problems.

With the discovery of HIV and knowing that breast milk could serve as transmitter, many milk banks closed throughout Europe. Concomitantly, preterm formula was developed. Although preterm formula administra-tion results in higher in-hospital growth rates than own mother’s milk, the use of cow’s milk-based preterm for-mula when own mother’s milk was not available has not been without controversy. Already in 1990, Lucas and Cole [24] reported that in exclusively formula-fed babies, NEC was 6–10 times more common than in those fed breast milk alone and 3 times more common than in those who received formula plus breast milk. Numerous

Fig. 2. Human Milk Center in Amsterdam 70 years ago.


papers report also an association with a lower incidence of nosocomial infections when own mother’s milk is fed instead of preterm formula [e.g., 25 ]. Following these ob-servations and implementing methods to prevent the transmission of contagious microbes in human milk, the use of donor milk as substitute for own mother’s milk be-came increasingly popular again. At present, more than 500 donor milk banks are operating around the world, most of them in Europe and South America. Processing techniques have been optimized and guidelines on the preferential use have been issued [26] . Preservation tech-niques have been optimized ( Fig. 3 ), increasing the length of storage and therewith the price [27] .

The exact mechanism as to how human milk exerts a beneficial effect on the prevalence of NEC is at present unknown. Many factors might contribute to the particu-larly increased risk of preterm infants to develop NEC ( Table 1 ). The altered microbiome in addition to an al-tered immune response may be the two most important mechanisms.

The colonization of the gut of the preterm infant is progressing slower than that of a term infant, while the numbers of microbiota are reduced and less diverse. That may be influenced by the high prevalence of antibiotic use in the first period of life [28] , the environment (a NICU with many selected pathogens [29] ), the altered mucin production rates and quality [30] , the motility [31] , and the immune system.

The fetal immune system is generally characterized as tolerogenic to prevent graft-versus-host responses during pregnancy. T cells in the fetal intestinal mucosa allow for early compartmentalization of TH1 responses, predomi-nated by TNF-α and IL-2-producing T cells early in human development [32, 33] . These fetal mucosal TH1 cells can contribute to mucosal development by producing TNF-α, which promotes the outgrowth of fetal intestinal epithelial stem cells. However, when this process is disturbed by pre-term birth, preferential induction of TH1 cells may insti-gate an inflammatory cascade providing the underlying conditions for NEC, which might explain why premature infants are more susceptible to NEC than term infants are.

Cow’s milk protein might cause an immunomodula-tory effect, for instance an increased production of TNF-α, which subsequently may result in a disturbed outgrowth of these intestinal epithelial stem cells with consequently an inflammatory bowel condition. Some evidence was provided by small studies suggesting that an exclusive hu-man milk diet would results in lower NEC rates [34] . A recent randomized controlled trial, however, did not sug-gest that cow’s milk protein exposure resulted in a higher rate of NEC, when compared to pasteurized donor milk provided in the first 10 days of life [35] .

Thus, most likely, several factors present, especially in unpasteurized milk, exert a beneficial effect, although re-sults from the available high-quality studies are not over-whelming. Schanler et al. [36] did not find an effect on NEC in their blinded randomized controlled trial, but the most recent blinded randomized controlled trial did find a significant association between donor milk and the in-cidence of NEC [37] . These developments, the cost-effec-tiveness of human donor milk [38] , and the potential ben-efits in the long term will probably lead to a policy where the use of preterm formula will only be limited to those infants of whom the parents do not want to use donor milk [39–41] . New techniques of pasteurization will in-crease the effectiveness of donor milk [42] .

Fortification of Human Milk With the knowledge that human milk reduces NEC

and nosocomial infections and the fact that nutrient re-

Fig. 3. Present human milk bank in Amsterdam, The Netherlands.


30

quirements are not met with human milk alone, the usage of fortifiers became increasingly popular at the end of the 20th century. Variability in the composition of human milk and the high nutrient demands of preterm infants was acknowledged and commercial fortifiers became in vogue.

The first study on the use of human milk fortification was published in 1986 by Modanlou et al. [43] . They com-pared small groups of infants fed either preterm human milk ( n = 10), fortified preterm human milk ( n = 8), or premature formula ( n = 12) and concluded that weight gain rates were similar in the infants fed preterm formula and fortified human milk, but infants fed preterm moth-er’s milk had lower rates of weight gain. Fourteen high-quality studies followed and current practice is that pre-term infants receive fortified human milk. The observa-tion is that fortification leads to higher in-hospital growth, but there are no effects on growth or neurodevelopment observed beyond infancy [44] . As time will proceed, not only cow’s milk proteins, vitamins, and minerals are sup-plied, but also fat and one might think of specific bioac-tive products. Lactoferrin is such a promising substance that might be added to the fortifiers in the future [45] .

Probiotics The knowledge that human milk contains bacteria

originates from the 1950s [e.g., 46 ]. The first study that showed an effect of adding specific strains to preterm for-mula originated in the previous century [47] . Prior to that study, some reported the effect of adding probiotics on

the microbiome [48–50] . Despite many trials that fol-lowed, and an overall clear effect of probiotic supplemen-tation on reducing NEC incidence, probiotics were not used at all units. The heterogeneity of organisms and dos-ing regimens studied have prevented a species-specific treatment recommendation from being made so far [51–54] . Furthermore, quality control of the available prod-ucts remains an issue [55] .

In conclusion, tremendous developments, both tech-nological and nutritional, have been made, enabling higher survival rates but also higher quality of life. The revival of the use of human milk in the NICU will affect both these outcomes, certainly when the appropriate ad-ditives will be used.


J.B. van Goudoever is a member of the National Health Coun-cil and director of the National Donor Milk Bank. The writing of this article was supported by Nestlé Nutrition Institute.

Table 1. Contributing factors to the increased risk of preterm in-fants developing NEC

– Delayed and altered microbial colonization– Altered mucin barrier– Decreased gut motility– Increased gut permeability– Altered immune system

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In view of the dramatic rise in the prevalence of food allergy globally, effective prevention strategies have

become a public health priority

Key insights

Nutritional interventions play a key role in promoting healthy immune development, particularly in infants. A range of strate-gies have been explored in the prevention of food allergies. In addition to the promotion of breastfeeding, these have includ-ed the use of partially hydrolyzed whey-based formula in non-breastfed infants. Formula supplementation with probiotics or prebiotics has been shown to reduce the risk of atopic derma-titis in several studies. Maternal allergen elimination diets play a role in the treatment of breastfed infants with established food allergies but have no role in allergy prevention. Extensively hydrolyzed and amino acid-based formulas remain the main treatment options for infants with cow’s milk allergy who are not breastfed.

Current knowledge

Prevention strategies are based on 3 main hypotheses on the etiology of food allergies: the hygiene hypothesis, the dual al-lergen exposure hypothesis, and the vitamin D hypothesis. According to the hygiene hypothesis, aberrant T-helper 2 im-mune responses arise from a lack of environmental microbial stimulation and reduced diversity of the gut microbiome. The dual allergen exposure hypothesis (via skin and gut) suggests that infants may become sensitized via eczematous skin before tolerance has been achieved by introducing the food allergen into the infant’s diet. The vitamin D hypothesis is based on the observation that vitamin D deficiency is associated with food allergies. However, this finding requires further research.


The prolonged avoidance of food allergens beyond 12 months of age is no longer recommended. Instead, the early introduc-tion from 4–6 months is one of the most promising food allergy prevention strategies in infants deemed at high risk of allergies.


Food Allergy Prevention and Treatment by Targeted Nutrition by Ralf G. Heine

f the dramat

F O C U S


It remains unclear if this strategy can be applied at the popula-tion level. Strict allergen avoidance remains the key treatment principle in infants and children with established food allergies. Oral and epicutaneous immunotherapy may soon become addi-tional treatment options in children and adolescents with peanut allergy. These novel treatment modalities aim for a clinical state of desensitization (non-reactivity) to a food allergen through regular exposure (under strict specialist supervision). However, food immunotherapy does not induce lasting tolerance, and the allergic phenotype generally recurs after the treatment is stopped. Recommended reading

West CE, Jenmalm MC, Prescott SL: The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin Exp Allergy 2015;45:43–53.

PreventionGoal: Reduce the risk of allergic sensitization to foods

• Exclusive breastfeeding• Partially hydrolyzed whey formula (in high-risk infants, if not breastfed)• Introduction of weaning foods from 4–6 months• Introduction of food allergens between 4 and 11 months (in high-risk infants)• Probiotics and prebiotics

TreatmentGoal: Prevent allergic reactionsto food (until tolerance hasdeveloped)

• Strict food allergen avoidance (while maintaining a nutritionally adequate diet)• Maternal elimination diet (if breastfed infant reacts to food allergens in breastmilk)• Hypoallergenic infant formula (if not breastfed), e.g., extensively hydrolyzed or amino acid-based formula• Oral or epicutaneous immunotherapy likely to be available soon (for children and adolescents with peanut allergy)

Nutritional strategies for food allergy prevention and treatment.



Food Allergy Prevention and Treatment by Targeted Nutrition

Ralf G. Heine

Paediatric Care, Nestlé Health Science, Vevey , Switzerland

Ralf G. Heine, MD, FRACP Paediatric Care Nestlé Health Science 55 Avenue Nestlé, CH–1800 Vevey (Switzerland) E-Mail ralf.heine @ nestle.com



Key Messages

• In view of the dramatic rise in the prevalence of food

allergy globally, effective prevention strategies have

become a public health priority.

• The early introduction of complementary diet and

food allergens from 4 months of age is currently one

of the most promising approaches in the prevention

of food allergies.

• While the strict food allergen avoidance remains

the main treatment strategy for food allergies,

immunotherapy via the oral or epicutaneous route

have emerged as effective and feasible future

treatment strategies.

Keywords

Allergy · Atopy · Breastfeeding · Infant formula · Microbiome · Prevention

Abstract

In view of the dramatic rise in the prevalence of food allergy globally, effective prevention strategies have become a pub-lic health priority. Several models have emerged around the etiology of food allergy, including the hygiene hypothesis, dual allergen exposure hypothesis, and vitamin D hypothe-sis. These form the basis for current and potential prevention strategies. Breastfeeding remains a key pillar of primary al-lergy prevention. Other nutritional interventions, including

the use of whey-based, partially hydrolyzed formula in non-breastfed infants, also play an important role. In recent years, there has been a shift away from prolonged food allergen avoidance to the proactive allergen introduction from 4 months of age. This approach is supported by 2 pivotal ran-domized clinical trials showing that the early introduction of peanut and other food allergens significantly reduces the risk of food allergy. However, the implementation of this strategy at the population level still raises significant logistic problems, including patient selection and development of suitable food formats for young infants. Other prevention strategies, including vitamin D supplementation, are cur-rently under evaluation. Maternal elimination diets during pregnancy and lactation are not recommended for allergy prevention. The treatment of food allergies has also seen major transformations. While strict allergen avoidance is still the key treatment principle, there is a greater focus on de-sensitization and tolerance induction by oral and epicutane-ous immunotherapy. In addition, specialized hypoallergenic infant formulas for the treatment of infants with cow’s milk allergy have undergone reformulation, including the addi-tion of lactose and probiotics in order to modulate the gut microbiome and early immune responses. Further research is needed to inform the most effective food allergy preven-tion strategies at the population level. In addition, the wider application of food allergen immunotherapy may provide better health outcomes and improved quality of life for fam-ilies affected by food allergies.


Heine Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):33–45 DOI: 10.1159/000487380

34

Introduction

Over the past 2 decades, the prevalence of allergic dis-orders has increased dramatically [1–3] . The greatest in-crease has been observed in infants and children with food allergies or atopic eczema [4, 5] . In Europe and Northern America, food allergy is estimated to occur in 1–5% of the population [1] . In Australia, a population-based study found a prevalence of challenge-proven food allergy of over 10% which is the highest rate globally [6] . Overall, prevalence figures for food allergy and anaphy-laxis appear to be steadily rising [7] . Effective allergy pre-vention has therefore become a global public health pri-ority [8] .

Nutritional interventions play a central role in the pre-vention and treatment of food allergies ( Table 1 ). In re-cent years, clinical approaches have undergone signifi-cant changes [3] . In the food allergy prevention space, greater focus has been placed on the early introduction of the complementary diet in infancy [9] ( Fig. 1 ). This is in contrast to the previous approach of prolonged food al-lergen avoidance which, in hindsight, may have paradox-ically increased the rate of food allergies [10–12] . In the area of food allergy treatment, there have also been major advances, including a shift from mere food allergen avoid-ance to proactive food allergen immunotherapy [13] . In addition, there is renewed interest in the role of gut mi-crobiome-modifying therapies in an attempt to promote immunological tolerance development via the gut-asso-ciated immune system [14–16] . This review summarizes the previous and current approaches to dietary food al-lergy prevention and treatment and highlights areas of uncertainty or controversy, as well as priorities for future research.

Breastfeeding Breastfeeding is one of the main pillars in both food

allergy prevention and treatment [17–21] . Breast milk provides the most appropriate source of nutrition for the young infant as it contains a specific nutrient mixture, growth factors, and protective maternal antibodies. The World Health Organization (WHO) guidelines on com-plementary feeding of 2001 recommend exclusive breast-feeding for at least 6 months. However, this recommen-dation has been challenged in countries with a high prev-alence of food allergies, as the early dietary introduction of allergens appears to protect from food allergies [22, 23] . Recent guidelines on the prevention of food allergies from Europe, the USA, and Australia have recommended the introduction of solids from 4–6 months of age [24–28] .

Breastfeeding is associated with the establishment of fecal microbiota high in Bifidobacteria [29] . Human milk oligosaccharides (HMO) promote the colonization of the gut with Bifidobacteria which is thought to promote mu-cosal tolerance via interaction with regulatory T-lympho-cytes and Toll-like receptors [30] . Breastfeeding itself does not appear to confer a strong protective effect against food allergies [21] . However, the duration of exclusive breastfeeding appears to influence the risk of allergic dis-ease [31, 32] . The protective effect of breastfeeding on eczema in the first 2 years of life appears to be modified by maternal allergy status [33] . Exclusively breastfed in-fants can express clinical manifestations of food allergy, including food protein-induced proctocolitis and multi-ple food intolerance of infancy [34–37] . These often re-spond to treatment with hypoallergenic maternal elimi-nation diets which eliminate cow’s milk or other food al-lergens [38, 39] . In some infants who failed a trial of maternal dietary elimination, treatment with a hypoaller-genic formula may be required [40–42] . Maternal elimi-nation diets during pregnancy and lactation for the pur-pose of allergy prevention are not recommended [18, 43] .

Prevention

Primary food allergy prevention aims to reduce the in-fant’s risk of sensitization to food allergens [44] . By con-trast, secondary prevention aims to prevent the clinical expression of allergic disease in individuals who are either

Table 1. Nutritional strategies for the prevention of food allergy

General– Exclusive breastfeeding for 4–6 months– Use of whey-based, partially hydrolyzed formula (if exclusive

breastfeeding is not possible)

Introduction of complementary diet from 4 months– Early introduction of food allergens (peanut, egg, and others)

in infants at high risk of developing food allergies

Microbiome-modifying interventions– Probiotics (e.g., Lactobacillus rhamnosus GG) – Prebiotics (e.g., fructo-oligosaccharides,

galacto-oligosaccharides)– Human milk oligosaccharides (e.g. 2′-fucosyllactose and

lacto-N-neotetraose)

Immune-modulating nutrients– Maternal omega-3 polyunsaturated fatty acid supplementation

(docosahexaenoic acid, eicosapentaenoic acid) – Vitamin D (under investigation)

Food Allergy Prevention and Treatment 35 Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):33–45 DOI: 10.1159/000487380

allergen sensitized or who already manifest other allergic disorders, such as atopic dermatitis or asthma. The pre-vention of food allergies and atopic dermatitis by nutri-tional interventions has been explored for the past 2 de-cades with a broad range of approaches. In addition to the promotion of breastfeeding, these have included the use of partially hydrolyzed formula (PHF) and a range of ma-ternal elimination diets [43, 45] . Supplementation with probiotics, prebiotics, and specific nutrients has also been explored [46, 47] . Some of these interventions have been trialed in high-risk populations, either in families with a history of allergies, or in infants who are showing evi-dence of food sensitization or eczema. Other studies have assessed the preventive effect of interventions at the pop-ulation level without selecting for allergic history. This distinction is important when the findings of prevention trials are translated into population-based health policies [22, 48] .

Prevention strategies have been developed around 3 main hypotheses on the etiology of food allergies: the hy-giene hypothesis, the dual allergen exposure hypothesis, and the vitamin D hypothesis [11, 49, 50] . The following sections will summarize current preventive strategies in the context of these hypotheses.

Hygiene Hypothesis Gut microbiota and environmental microbial burden

play a central role in early immune development and are likely to influence immunological events that lead to al-lergy [49, 51, 52] . The hygiene hypothesis assumes that there is an immune deviation to T-helper 2 reactions due to reduced early microbial exposure and a lack of fecal

microbial diversity [53, 54] . For example, growing up in a rural farm environment has been shown to significant-ly reduce the risk of asthma and allergic disease in chil-dren [49, 55] . There are significant differences in the gut microbiota profiles between allergic and nonallergic in-fants and children [56, 57] . Infants with IgE-associated eczema have significantly reduced fecal microbial diver-sity in the first month of life, compared to nonatopic in-fants [54, 58] . Modification of early gut colonization and fecal microbial diversity in infancy may thus provide an avenue for preventive or therapeutic strategies [59] . Pro-biotic or prebiotic supplementation has been shown to modify the risk of allergies, particularly for atopic derma-titis in infancy [60–62] . The World Allergy Organization Guidelines recommend the use of probiotics and prebiot-ics for the prevention of eczema and allergies, but caution that the available evidence is of very low certainty [63, 64] .

Probiotics Infants with allergies have been shown to have signifi-

cantly lower numbers of fecal Bifidobacteria, compared to healthy infants [65] . Allergy prevention via supple-mentation with probiotic bacteria therefore appears to be a promising approach. The effects of probiotics are main-ly mediated via the innate immune system (Toll-like re-ceptors), resulting in the promotion of T-helper 1 differ-entiation, production of regulatory cytokines (IL-10 and TGF-beta) and enhanced intestinal IgA responses [66] . Several studies have demonstrated that perinatal admin-istration of probiotics to mothers in the last weeks of pregnancy and to infants in the first few months of life was associated with a significant reduction in atopic ec-

LactationPregnancy Birth Complementary diet

LCPUFA

Complementary diet

Breast feeding/Partially hydrolyzed whey-based formula

Probiotics/Prebiotics/Synbiotics

If eczema present maintain intact skin barrierRegular moisturising/use of topical steroids (if required)

Introduction of food allergens

Fig. 1. Integrated model of nutritional in-terventions and skin care for food allergy prevention.


36

zema [67–69] . Nevertheless, results have been varied, de-pending on the probiotic strain, dose, timing and food matrix used. A study using Lactobacillus acidophilus (LAVRI A1) even showed a paradoxical increase in aller-gic sensitization [70] . These studies highlight that clinical outcomes depend on the specific probiotic strains used. The role of probiotics in allergy prevention requires fur-ther study [46] .

Prebiotics HMO are complex, nondigestible oligosaccharides

with prebiotic properties in breast milk which provide a specialized substrate for Bifidobacteria. In the past, infant formulas were devoid of prebiotic oligosaccharides [71] . Over the past decade, several manufactured prebiotics have been added to infant formula, including plant-based long-chain fructo-oligosaccharides (FOS) and short-chain galacto-oligosaccharides (GOS). GOS and FOS have been shown to increase counts of fecal Bifidobacte-ria in formula-fed infants [72, 73] . A randomized study examined the effects of a FOS/GOS-supplemented hy-drolyzed formula on atopic eczema in formula-fed in-fants during the first 6 months of life [74] . In that study, the FOS/GOS group had sig-nificantly lower rates of ecze-ma compared to the placebo group, although eczema se-verity was similar for both treatment arms. A more re-cent European multi-center randomized controlled trial assessed the effect of prebiot-ics in healthy, low-risk infants from 8 weeks to 12 months [75] . Prebiotics reduced the incidence of atopic dermati-tis by 44% at 12 months. Again, disease severity was not affected. Further studies are needed to assess the role of GOS and FOS in allergy prevention [62] .

HMO in breast milk provide the substrate for specific microbes and significantly influence early microbial gut colonization [76, 77] . Recently, 2 manufactured HMO (2 ′ -fucosyllactose and lacto-N-neotetraose) have been added to standard cow’s milk-based formula [78] . In pre-clinical studies, HMO have been shown to attenuate al-lergic responses in cow’s milk-sensitized mice [79] . The role of HMO in the prevention and treatment of food al-lergies is at this stage not clearly defined but represents a promising area for future research [80, 81] .

Dual Allergen Exposure Hypothesis The dual allergen exposure hypothesis (via skin and

gut) is based on the observation that infants with eczema

have a high risk of developing IgE-mediated food allergies [11] . While allergen contact via eczematous skin may cause allergic sensitization, the exposure via the gastroin-testinal tract is more likely to induce immunological tol-erance [11, 82, 83] . Prolonged avoidance of a food aller-gen in infants with eczema may paradoxically increase the risk of food allergies [12, 84] . Previously, the delayed in-troduction of common food allergens (cow’s milk after 12 months, egg after 2 years, and peanut after 3 years) was recommended in an attempt to prevent food allergy [10] . Findings from several small studies provided support for the concept of a “window period” for tolerance induction, whereby tolerance is more likely to be achieved if weaning solids are introduced between 4 and 6 months of age. This reflects feeding practices in many European countries, but is not supported by the WHO guidelines on comple-mentary feeding.

The Australian HealthNuts Study showed that the risk of developing egg allergy increased significantly if egg was introduced after 12 months of age [85] . This finding prompted to question the recommendation of delaying the introduction of egg beyond 12 months of age. The LEAP (Learning Early about Peanut) study was the piv-

otal study demonstrating that the early introduction of pea-nut into the infants diet from 4 months conferred a protec-tive effect against peanut al-lergy in high-risk infants [86] . This study was based on the

observation that infants in Israel who were exposed to peanut in a teething snack had a low risk of peanut al-lergy, while Jewish infants in the United Kingdom who introduced peanut generally after 12 months of age had a high risk. The subsequent clinical study enrolled infants with pre-existing egg allergy or eczema and randomized them to introduce peanut from 4 months, or to continue strict peanut avoidance. The study showed overwhelming evidence of a protective effect against peanut allergy (70–86% relative incidence reduction) in those who intro-duced peanut early between 4 and 11 months of age. A supplementary analysis found that the skin prick test wheal diameter at the time of peanut introduction pre-dicted the tolerance development in those who avoided peanut, with the greatest benefit seen between 6 and 11 months [87] . This analysis provided additional insights on the best timing of the dietary introduction of food al-lergens in high-risk infants.

A second study, the Enquiring about Tolerance (EAT) study, prospectively examined if the early introduction of

Prolonged avoidance of a food allergen in infants with eczema may

paradoxically increase the risk of food allergies


6 food allergens (from 4 months of age) while breastfeed-ing could reduce the risk of food allergy in a nonallergic population [88] . On per-protocol analysis, there was a significant protective effect against food allergy. Howev-er, the study overall failed on intention-to-treat analysis due to a large proportion of participants who were unable to adhere to the study regimen. This raised questions around the logistics of introducing foods early in infancy, including finding suitable food formats that would allow the delivery of food proteins in adequate doses to breast-fed infants [22, 27] .

Partially Hydrolyzed Formula The role of hydrolyzed formula in allergy prevention

has been studied for more than 2 decades. Several studies have explored the tolerogenic potential of cow’s milk pep-tides in hydrolyzed formula. The German Infant Nutri-tional Intervention (GINI) study is to date the largest, quasi-randomized trial examining the role of hydrolyzed formula in the prevention of allergies [89] . Infants with a family history of allergies were randomized to receive cow’s milk-based formula, whey-based PHF, whey-based extensively hydrolyzed formula (EHF), or casein-based EHF at the time of weaning. That study found a sustained protective effect against atop-ic eczema for whey-based PHF and casein-based EHF [89] . Follow-up studies of the GINI cohort have demon-strated a sustained preventive effect of hydrolyzed formu-las until 10 years of age, compared to cow’s milk-based formula [90] . A Cochrane review on hydrolyzed formulas in allergy prevention found a limited beneficial effect, compared to cow’s milk-based formula, in “high-risk” in-fants with a family history of atopy [91] . Two other meta-analyses also confirmed a preventive effect, mainly for atopic dermatitis [92, 93] . Others have questioned the role of PHF and cautioned against overstating its preven-tive effects [94, 95] . Boyle et al. [96] in their meta-analysis found no support for a preventive effect of PHF against allergic disease. However, pooling of data on hydrolyzed formulas in meta-analyses may be problematic due to sig-nificant heterogeneity of PHF products. A more recent meta-analysis addressed this issue and only included studies using 100%-whey PHF [97] . That study found a preventive effect for all allergies and eczema, but ac-knowledged limitations in the certainty of available data. The current Allergy Prevention Guidelines by the Euro-pean Academy of Allergy and Clinical Immunology

(EAACI) recommend the use of PHF with a documented preventive effect in infants at high-risk of allergy if breast-feeding is insufficient or not possible [98] .

Vitamin D Hypothesis Several studies have demonstrated an association be-

tween low vitamin D levels and food allergy [99, 100] . An Australian study showed that vitamin D insufficiency (se-rum level < 50 nmol/L) was associated with a significantly increased risk of egg and/or peanut allergy [101] . This finding concurred with the observation that the preva-lence of food allergy and eczema follows a north-south gradient, being more common in regions with less sun exposure and lower skin-derived vitamin D levels [102] . Adequate vitamin D levels in the first year of life may therefore provide protection against the development of food allergies. By contrast, vitamin D may also have un-desirable immune-modulating effects and, in high doses, increase the risk of allergic sensitization. Vitamin D has been shown to inhibit the maturation of dendritic cells and impede the development of T-helper 1 responses. In theory, vitamin D therefore could increase the risk of al-lergic disorders in infancy [103] . This is supported by a

recent German birth cohort study (LINA study) which found that high vitamin D levels during pregnancy and at birth were associated with an increased risk of food al-lergy [104] . The varying ef-

fects of vitamin D on allergy risk have been explained by a U-shaped dose response curve, i.e., normal vitamin D levels may confer a protective effect while abnormally high or low levels may increase the allergy risk [100] . The aforementioned studies suggest that both vitamin D in-sufficiency and oversupplementation are risk factors for allergies [99] . The VITALITY trial, a prospective ran-domized trial, is currently underway to assess the role of postnatal vitamin D supplementation as a preventive strategy against IgE-mediated food allergy, eczema, and lower respiratory tract infections [105] .

Omega-3 Long-Chain Polyunsaturated Fatty Acids Maternal diets high in omega-3 long-chain polyunsat-

urated fatty acids (LCPUFA) are thought to have a pro-tective effect against the development of allergies in the newborn [106] . Supplementation with docosahexaenoic acid and eicosapentaenoic acid during pregnancy has been shown to increase LCPUFA concentrations in breast milk [107] . A large randomized clinical trial of maternal

Normal vitamin D levels may confer a protective effect while abnormally high or low levels may increase the

allergy risk


38

fish oil supplementation during pregnancy demonstrated a significant decrease in cord blood concentrations of Th-2 cytokines (IL-4 and IL-13) as well as increased levels of oral tolerance-inducing TGF-beta [108] . Palmer et al. [109] assessed the effect of high-dose fish oil supplemen-tation in high-risk infants (with a positive family history of atopy). Pregnant mothers were randomized to receive either 800 mg docosahexaenoic acid plus 100 mg eicosa-pentaenoic acid or vegetable oil from 21 weeks’ gestation until delivery. Primary outcomes were infantile eczema and food sensitization at 12 months of age. Infants in the fish oil-supplemented group had significantly lower rates of atopic eczema and egg sensitization. In another study by the same group [110] , high-risk infants were random-ized to 280 mg docosahexaenoic acid plus 110 mg eicosa-pentaenoic acid daily or olive oil (control) from birth to 6 months of age. In that study, between-group compari-sons revealed no differences in allergic sensitization, ec-zema, asthma, or food allergy. In summary, fish oil sup-plementation during pregnancy reduced the risk of atop-ic eczema and food sensitization, whereas dietary supplementation after birth appeared to be ineffective.

Treatment

The treatment of food allergies relies on the strict elim-ination of the offending allergens. In exclusively breastfed infants who react to allergens via breast milk, maternal elimination diets have been shown to be effective [34, 38] . The complementary diet also needs to be free of the food allergen. In formula-fed infants with cow’s milk allergy (CMA), specialized hypoallergenic formulas are the treat-ment of choice. The main types of these treatment formu-las are EHF and amino acid-based formula (AAF) [40, 111, 112] . Hypoallergenic elimination diets need to be carefully supervised for nutritional adequacy [38] . De-spite attempts to strictly eliminate offending food aller-gens from the diet, accidental reactions are relatively common. The risk of inadvertent allergic reactions and anaphylaxis significantly impacts the quality of life of pa-tients and families [113, 114] . Precautionary allergen la-belling is in many instances still confusing or incomplete [115, 116] . Reassuringly, several countries have intro-duced legislation towards more consistent allergen label-ling [117] .

Maternal Elimination Diets Food allergens that are secreted into breast milk may

elicit allergic symptoms in the infant [118] . While mater-nal elimination diets have no role in primary food allergy prevention, they have become a widely used intervention in breastfed infants with food allergies [38] . Poorly super-vised or broad-based maternal elimination diets are not without nutritional risks for both mother and infant [119] . The nutritional adequacy of the maternal diet should be assessed and monitored by a pediatric dietitian [120] . Calcium supplementation is generally recom-mended if cow’s milk products are eliminated from the maternal diet.

Extensively Hydrolyzed Formula Whey- or casein-based EHF are considered the first-

line treatment of formula-fed infants with CMA [121] . These formulas contain small cow’s milk peptides that are produced via enzymatic breakdown and ultrafiltration of intact cow’s milk proteins. There are significant differenc-es in the molecular weights and profiles of peptides in EHF. This may explain differences in the risk of allergic reactions to various EHF [122, 123] . A task force of the European Academy of Allergy and Clinical Immunology (EAACI) has therefore called for stricter standards for the definition of EHF marketed in Europe, including preclinical testing, quality assurance, and labelling requirements [124] .

Some recently developed EHF contain highly purified lactose. Contrary to common perception, lactose is toler-ated well by most infants with CMA [125] . The only ex-ception are infants with cow’s milk protein-induced en-teropathy and secondary lactase deficiency due to villous damage ( Table 2 ). These infants may develop increased diarrhea after lactose ingestion. However, a lactose-con-taining EHF can generally be reintroduced once the diar-rhea has settled and the small intestinal mucosal integrity has been restored. As young infants do not absorb all in-gested lactose, it is considered a prebiotic compound with positive effects on the gut microbiome of infants [126] . Compared to lactose-free formula, lactose-containing formula is associated with increased counts of Bifidobac-teria and increased concentrations of short-chain fatty acids. This may confer a protective effect on colonic mu-cosal integrity and have a beneficial effect on early im-mune development [53] . There is to date no data showing a direct effect on tolerance development or allergic risk.

EHF contains trace amount of allergenic peptides and therefore has a small residual allergenicity with the risk of allergic reactions [127] . Conversely, the antigenic content in EHF may have the potential to actively promote toler-

The treatment of food allergies relies on the strict elimination of the

offending allergens


ance development [128] . This ability may be further en-hanced by the addition of probiotic bacteria or other in-gredients. Berni Canani et al. [129] conducted a random-ized clinical trial of EHF supplemented with Lactobacillus rhamnosus GG (LGG) in infants with CMA. In that trial, infants receiving the probiotic-supplemented formula had a greater chance of achieving tolerance to cow’s milk protein at 6 and 12 months of age. This effect appeared to be, at least in part, modulated by an expansion of buty-rate-producing gut microbiota [130] . At the 3-year fol-low-up of another cohort, there appeared to be a greater rate of resolution of IgE-mediated CMA as well as a low-er incidence of other allergic manifestations in response to LGG-supplemented EHF [15] . These studies highlight the potential for probiotic supplementation of EHF to hasten tolerance development as well as the importance of butyrate as a likely key mediator in tolerance acquisi-tion. However, further clinical trials are required to con-firm the tolerogenic effects of LGG and assess the poten-tial benefits of other probiotic strains with regard to early immune development.

Amino Acid-Based Formula AAF is a synthetic, nutritionally complete, cow’s milk

antigen-free formula containing free amino acids, which is used in the treatment of infants with severe CMA. AAF is therefore not a first-line treatment but recommended for infants who have failed treatment with EHF, as well as infants with cow’s milk anaphylaxis [112] , multiple food

intolerance of infancy [36, 131] , or eosinophilic esopha-gitis [132] . As tolerance development is thought to be an antigen-driven process [128] , AAF is unlikely to promote tolerance development [128] . The addition of prebiotics or probiotics to AAF may have beneficial effects on gut microbiome, but clinical outcome data are not currently available [133] .

Other Potential Formula Options Should EHF or AAF not be available, other formula

options may be considered. Soy formula is frequently used for economic reasons in countries with limited ac-cess to hypoallergenic formulas [134] . However, the role of soy formula in the treatment of infants with CMA remains controversial. Generally, soy formula is not rec-ommended as a first-line treatment in infants with CMA under 6 months of age [112] . Hydrolyzed rice-based formula has become available in recent years as a hypoal-lergenic formula in infants with CMA [135, 136] . The hy-drolysis is required due to the poor solubility and hydro-phobic properties of rice protein. These formulas are tol-erated well and may have a taste advantage over casein- or whey-based EHF. The exact role of hydrolyzed rice-based formulas needs to be clarified. Importantly, rice-based in-fant formulas must not be confused with rice “milk” bev-erages which are low-protein, low-energy cereal milks which are not suitable for infant feeding due to the risk of severe protein-energy malnutrition [137] . Mammalian milks, including goat’s or sheep’s milk formula, are often

Table 2. Treatment of cow’s milk allergy (CMA) in infants

Diagnosis Maternal elimination diet First-line formulatreatment

Second-lineformula treatment

Need for lactose restriction

IgE-mediated CMAWith anaphylaxis Only required if reacting to

cow’s milk protein in breast milkAAF EHF1 No

Without anaphylaxis EHF No

Cow’s milk protein-induced enteropathy

Only required if reacting to cow’s milk protein in breast milk

EHF AAF Yes, until diarrhea has resolved and normal small intestinal mucosa has been restored

Cow’s milk protein-induced proctocolitis

Only required if reacting to cow’s milk protein in breast milk

EHF AAF No

Cow’s milk protein-induced enterocolitis syndrome (FPIES)

Generally not required EHF No

EHF, extensively hydrolyzed formula; AAF, amino acid-based formula, FPIES, food protein-induced enterocolitis syndrome. 1 In infants with a history of anaphylaxis, EHF should be first trialed under medical supervision.


40

considered as alternatives to cow’s milk formula but are not suitable due to a high rate of protein homology and allergic cross-reactivity [138] . Cross-contamination with cow’s milk protein during production may also occur. Al-though often perceived as safe alternatives to cow’s milk formula, these mammalian milk formulas may cause sig-nificant allergic reactions, including anaphylaxis [139] .

Food Allergen Immunotherapy The concept of food allergen immunotherapy is not

new. The concept was first described by Schofield in 1908 in a 13-year-old boy with egg allergy who was success-fully desensitized by introducing egg in incremental dos-es [140] . Since then, 3 main clinical immunotherapy con-cepts to food allergens have emerged: oral, sublingual, and epicutaneous immunotherapy. The focus has so far mainly been on children with the most prevalent food al-lergies to peanut, egg, and cow’s milk.

Oral immunotherapy (OIT) involves the stepwise in-troduction of a food allergen via the oral route, starting with milligram doses [141] ( Fig. 2 ). The administration of initial doses and stepwise updosing occurs under med-ical supervision, generally with fortnightly intervals, until

a maintenance dose has been achieved after about 6 months [13] . For OIT to peanut, 79% of peanut-allergic patients were effectively desensitized to 443 mg of peanut protein [141] . The remaining patients were unable to tol-erate the treatment due to significant allergic side effects, ranging from persistent gastrointestinal symptoms to anaphylaxis. Combination therapy of OIT with anti-IgE (omalizumab) or other biologicals is being explored as an avenue to reduce the rate and severity of adverse events during updosing [142] . Importantly, patients generally do not achieve true, lasting immunological tolerance but a state of non-responsiveness, called “desensitization.” The duration of “sustained unresponsiveness” to an al-lergen after cessation of OIT maintenance treatment var-ies, but the allergic phenotype generally recurs gradually over weeks to months [13] .

Epicutaneous immunotherapy (EPIT) is based on the delivery of food allergens via intact skin [143] . The aller-gen is bound to a thin plastic membrane that is placed onto the skin under an occlusive patch, similar to the ap-proach for atopy patch testing [144, 145] . The allergen is taken up by Langerhans cells in the epidermis. These are immune-competent antigen-presenting cells that have

The allergen dose is increasedstepwise under medical supervision,as toleratedPatients may experienceallergic reactions or anaphylaxis

Once the maintenance dose hasbeen reached (after about 6months), patients will continuethis dose on an ongoing basis

The desensitization effect is assessedby oral food challengeA repeat challenge after a period ofallergen avoidance is used to assess theduration of “sustained unresponsivess” (generally 1–3 months)

Dos

e, m

g

Fortnightlydose escalation

Maintenancephase

Ora

l foo

d ch

alle

nge

Ora

l foo

d ch

alle

nge

0 6 12 months

Sustainedunresponsiveness

Tolerance?

Fig. 2. Dosing schedule of oral peanut immunotherapy.


the ability to initiate a regulatory T-cell response and communicate with regional lymph nodes. Daily applica-tion of EPIT patches containing 250 μg of peanut for 12 months in patients with peanut allergy has been shown to significantly raise the threshold dose for allergic reactions on food challenge [146, 147] . The desensitization effect is not as marked as that of OIT, but the rate of adverse ef-fects is minimal and mainly limited to local skin irritation where the EPIT patch has been applied [143] . Guidelines for the clinical use of OIT versus EPIT in clinical practice still have to be defined.

Conclusion

Based on recent research, food allergy prevention and treatment have undergone significant improvements. Further research is needed to inform the most effective food allergy prevention strategies at the population level ( Table 1 ). Effective prevention has the potential to reverse the rising prevalence trends for food allergies. In addi-tion, the wider application of food allergen immunother-apy may provide better health outcomes and improved quality of life for families affected by food allergies.


Dr. Ralf G. Heine is an employee of Nestlé Health Science, Switzerland. There are no other disclosures.

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The poor and emerging nations of the world are, by definition, the least able to bear the health costs of treating

serious nutrition-related conditions such as severe acute malnutrition and obesity-related diabetes

Key insights

The economic advancement of low- and middle-income coun-tries (LMICs) has been accompanied by a rise in obesity. These nations must now cope with the severely malnourished plus an increasing number of individuals with obesity-related chronic diseases, especially diabetes. The result is that many countries bear the double burden of under- and overnutrition. Alongside the unfinished agenda of high levels of infectious diseases, this double burden of malnutrition is crippling the healthcare sys-tems of many LMICs, requiring urgent attention.

Current knowledge

The main drivers for undernutrition are all associated with pov-erty. These, in turn, are linked to low levels of education, par-ticularly among girls and women who end up as the primary caregivers of children. Despite the bleak outlook, developing nations have the opportunity to learn from the mistakes made by other countries that have already experienced this transi-tion.


The metabolic processes that regulate energy balance in humans are greatly influenced by a wide variety of environmental and cultural factors. Therefore, any attempts to combat obesity must address all aspects of human lifestyles, from individual health to hygiene, education, housing, and public transport. An impor-tant element is the understanding that childhood undernutri-tion has prenatal origins and intergenerational consequences. For instance, stunted infants are usually born to small mothers. Furthermore, the malnourished fetus has the tendency to adopt


The Double Burden of Malnutrition in Countries Passing through the Economic Transition by Andrew M. Prentice

nd emerging

F O C U S


a thrifty phenotype that is specially adapted to accrue fat in later life. In the obesogenic modern world, many such individuals are at risk of weight gain. Recommended reading

Black RE, Victora CG, Walker SP, et al: Maternal and child under-nutrition and overweight in low-income and middle-income countries. Lancet 2013;382:427–451.

Energy-denseprocessed

foods

Lower foodprices

Obesity

Genetics

Sedentarylifestyles Urban

environment

Limited education

Economicstatus

Many complex factors contribute towards the obesity pandemic in low- and middle-income countries.



The Double Burden of Malnutrition in Countries Passing through the Economic Transition

Andrew M. Prentice

MRC Unit The Gambia at LSHTM, Banjul , The Gambia ; London School of Hygiene & Tropical Medicine, London , UK

Andrew M. Prentice, PhD, FMedSci MRC Unit The Gambia at LSHTM Atlantic Boulevard, Fajara Banjul (The Gambia) E-Mail aprentice @ mrc.gm



Key Messages

• Most low- and middle-income countries that manage

to avoid conflict are undergoing economic

advancement to a greater or lesser degree.

• The prevalence of undernutrition is strongly

correlated with a country’s wealth and hence stunting

and underweight tend to disappear as wealth

advances. This is the good news.

• The bad news, which should be of great concern to

the governments of emerging nations, is that

economic advancement seems inevitably associated

with a rapidly increasing prevalence of obesity.

Without urgent actions to combat these trends,

countries will be faced with ever-growing health costs

as they try to cope with the obesity-related chronic

diseases, especially diabetes.

Keywords

Malnutrition · Obesity · Double burden

Abstract

Undernutrition in both its acute and chronic forms (wasting and stunting) is strongly inversely correlated with the wealth of nations. Consequently, as many low- and middle-income countries (LMICs) achieve economic advancement and pass through the so-called “nutrition transition,” their rates of un-

dernutrition decline. Many countries successfully achieved the Millennium Development Goal of halving undernutrition and whole continents have been transformed in recent de-cades. The exception is Africa where the slower rates of de-cline in the prevalence of undernutrition has been overtaken by population growth so that the absolute number of stunt-ed children is rising. In many regions, economic transition is causing a rapid increase in the number of overweight and obese people. The rapidity of this rise is such that many na-tions bear the simultaneous burdens of under- and overnu-trition; termed the “double burden” of malnutrition. This double burden, accompanied as it is by the unfinished agen-da of high levels of infectious diseases, is crippling the health systems of many LMICs and thus requires urgent attention. Although the prognosis looks threatening for many poor countries, they have the advantage of being able to learn from the mistakes made by other nations that have passed through the transition before them. Concerted action across many arms of government would achieve huge future divi-dends in health and wealth for any nations that can grasp the challenge. © 2018 Nestlé Nutrition Institute, Switzerland/

S. Karger AG, Basel

Introduction

The 2017 UNICEF-led report on the State of Food Se-curity and Nutrition in the World contains both good news and bad news [1] . The good news is that the number of undernourished people in the world has declined since

Prentice Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):47–54 DOI: 10.1159/000487383

48

the early 2000s ( Fig. 1 ). Sadly, even this good news is tin-ged with bad; the decline was less than 20% and the very latest data suggests that the decline halted in 2015 and has now reversed. The other bad news is that rates of obesity have been climbing steadily over the past 40 years and that this rise affects all continents ( Fig. 2 ). In Asia, which started with the lowest prevalence of obesity and still has the best statistics, there is nonetheless some evidence that the rate of increase is accelerating.

It is this coexistence of malnutrition at each end of the spectrum that is termed the “double burden” of malnutri-tion. It represents a major challenge for emerging nations as their governments try to meet the health costs of caring

for both conditions simultaneously [2] . This paper will discuss some of the basic etiological drivers and then use some country and regional case studies to try to capture some of the key drivers of the double burden and learn lessons for the future.

Undernutrition: The Basic Drivers

Undernutrition is classically defined by a body mass index (BMI) of less than 18.5 kg/m 2 in adults, and by 3 metrics in children (weight-for-age, WfA; height-for-age, HfA; and weight-for-height, WfH). In children, values less than –2 Z -scores compared to the WHO Anthrops

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Fig. 1. The number of undernourished people in the world has been falling since 2000, but may be rising again. Reproduced with permission from [1] .

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The Double Burden of Malnutrition in LMICs


reference values are respectively defined as underweight, stunted, or wasted. Wasting is a measure of acute malnu-trition and stunting of longer-term chronic malnutrition.

It goes without saying that the primary drivers of un-dernutrition are all associated with poverty, which in turn tends to be associated with low levels of education, espe-cially among girls who become the primary caregivers of children. This simplistic analysis conceals many com-plexities both in causation and in necessary interventions that are summarized in Figure 3 from the seminal Lancet series on Maternal and Child Undernutrition and Over-weight in Developing Countries [3] .

Figure 4 illustrates the very strong association between a country’s level of wealth and stunting rates. Stunting is rare in wealthy nations and where it does occur it is like-ly driven by a specific pathology within the child or to be confined to recent or second-generation immigrants who have yet to escape from the long-term intergenerational consequences in their parents’ and possibly grandpar-ents’ undernourishment. It is notable that there is wide diversity between stunting levels among the poorer coun-

tries on the left-hand side of Figure 4 . This emphasizes how progress against malnutrition can be achieved even in the poorest nations.

Nutrition-Specific and Nutrition-Sensitive Causes of

Undernutrition

There is an increasing awareness that a child’s nutri-tional status in not determined by dietary and nutritional factors alone. These operate within a constellation of oth-er environmental influences that can impact their growth and health. For instance, a child’s energy and nutrient status is determined by the cumulative balance between its intake and its utilization or losses. In young children, whose immature immune systems have to learn to cope with the many infectious and antigenic threats that sur-round them in unhygienic environments, the role of in-fections is thought to be paramount. This explains why early postnatal growth falls so far below the WHO refer-ence curves in the first 2 years of life, as illustrated in Fig-ure 5 for children in rural Gambia. The pattern shown in

Optimum fetal and child nutrition and development

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Fig. 3. Malnutrition often has many immediate and underlying causes and requires investments in solutions across many domains. Reproduced with permission from [2] .


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Figure 5 is replicated in all low-income settings as shown by Victora et al. [4] in their renowned meta-analysis of data from 54 low- and middle-income countries (LMICs) that formed the basis of the “first 1,000 days” concept. It is notable, at least in our Gambian data, that the children’s nutritional status stops deteriorating at about 2 years of age and starts a partial recovery. The effects of the infec-tions are thought to arise from the excess nutrient and energy drain needed to mount an immune response (es-pecially the adaptive responses), from children’s loss of appetite when sick and from malabsorption secondary to the condition of so-called environmental enteric disease, which is a chronic damage and persistent inflammation of the gut.

This strong link with early childhood infections and environmental enteric disease suggests that improved water, sanitation, and hygiene (WASH) should have a big impact on such outcomes, and large investments have been made to test this hypothesis. The largest trials have been the WASH Benefits trials in Bangaldesh and Kenya [5] and the SHINE trial in Zimbabwe [6] . The SHINE re-sults are not yet fully published in peer-reviewed journals, but have been presented at meetings. The WASH Benefits results have been published recently [7, 8] . The trial arms that included improved infant and young child feeding (IYCF) advice showed evidence of improvements in growth, but the effect sizes were very small. Disappoint-ingly, the WASH arms achieved no benefit. A possible interpretation of this is not that the concept is faulty but rather that the interventions were not nearly intensive enough. They improved latrines and educated mothers about hygiene and provided washing stands and soap, but they did not truly re-engineer the environment to give families the wherewithal to make substantive differences to their children’s exposure to dirt and pathogens.

The Emergence of Overweight and Obesity

Worldwide

Prior to the 1970s, obesity was a relatively rare condi-tion even in the wealthiest of nations, and when it did ex-ist it tended to occur among the wealthy. Then, a conflu-ence of events started to change the human condition. The average BMI of populations in first-world countries started to increase and, consequently, there was a raid in-crease in the proportion of people overweight and obese. Serial state-by-state surveys in the USA from the 1980s onwards describe a remarkable transformation and asso-ciated surveys of diabetes show delayed but otherwise highly correlated trends. These data can be accessed and

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downloaded from the Centers for Disease Control (CDC) website (www.cdc.gov).

Figure 6 shows that, unsurprisingly, the relationship between obesity (in this case plotted as childhood over-weight and obesity) and country wealth is reciprocal to that for undernutrition shown in Figure 4 . As noted for

the undernutrition statistics, there is a notable spread of prevalence rates among countries with similar levels of wealth. This partly reflects the fact that some coun-tries have undergone very rapid economic improve-ments and their (predictably rising) obesity rates have not yet caught up, but it also captures true differences that may be related to national behaviors and health policies. For instance, a country such as the Nether-lands with, among other things very high rates of cy-cling which are encouraged by cycle-friendly policies, has consistently lower obesity rates than neighboring countries such as the UK.

The factors leading to the obesity pandemic were sev-eral and complex. Food prices declined as a proportion of peoples’ disposable income and the energy density of foods increased rapidly as foods were subjected to high-er rates of extraction and refinement. An analysis of these trends in the UK demonstrated that such changes did not seem to greatly increase average per capita food intake, and thus an alternative (or additional) explana-tion was required. The same analysis showed that sed-entary lifestyles and the associated reduction in energy expenditure probably played (and still plays) a major role [9] . Genetic effects cannot explain these rapid pop-ulation shifts in obesity, though they can help to explain which individuals within any given population will be more or less susceptible. Recent research has revealed that epigenetic effects may explain a much greater pro-portion of population variance than genetic effects [10, 11] and this has implications for prevention as discussed below.

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Fig. 6. Childhood overweight and obesity rates as a function of countries’ per capita gross domestic product (GDP). Overweight and obesity statistics use the latest data available for each country (limited to countries with post 2000 data) collated by the Inter-national Obesity Taskforce (http://www.iaso.org/iotf/obesity/?map = children). GDP adjusted for purchasing power parity (PPP) mostly refer to 2012 and were accessed from the International Monetary Fund’s (IMF) World Economic Outlook Database, Oc-tober 2013.

Fig. 7. Overweight and obese patients queue for a diabetic clinic. Photo credit: Felicia Webb.

Fig. 8. Obesity is now a common sight in urban areas of Africa, especially among middle-aged women. Photo credit: Felicia Webb.


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The Demographic Switch in Social Groups Most

Susceptible to Obesity

In poorer nations, it is generally only the rich who can, and do, become obese, but as nations pass through the demographic transition a switch occurs and the wealthier strata tend to be less likely to be obese and the poorer strata more likely. The photographs in Figures 7 and 8 show relatively wealthy women waiting for their appoint-ments at the diabetes clinic and yet poorer women simi-larly afflicted; this is from a country in which the switch is in the process of playing out.

Within many poor countries, especially in Africa, there are 2 notable features of obesity distribution as il-lustrated in Figure 9 for The Gambia [2, 12] . First, there tends to be a strong urban-rural gradient with much more obesity in townships and cities. Second, within those ur-ban areas, women are often much more likely to be obese than men (see the white and light-grey areas at the top right hand of Fig. 9 ). There are deep social reasons for such trends [13] and an understanding of them is impor-tant in designing interventions.

The pace of the demographic transition is such that in some regions of the world it is not uncommon to see

stunted children living in households where one or both of their parents (usually the mother) is clinically obese [e.g., 14 ].

National Challenges Posed by the “Double Burden”

of Malnutrition

The poor and emerging nations of the world are, by definition, the least able to bear the health costs of treat-ing serious nutrition-related conditions such as severe acute malnutrition and obesity-related diabetes. As a consequence, treatment facilities are often poorly equipped and staffed, and hence the case fatality rates for such conditions are much higher than in rich nations. The photographs in Figures 10 and 11 were taken on the same day in a tertiary level hospital in urban Africa. The bed-ridden woman was awaiting amputation of her dia-betic foot (reported by the surgeons as one of the most common operations they performed). The malnourished child was in a ward directly below the adult ward, graph-ically illustrating the juxtaposition of the two extremes of malnutrition and the terrible challenges that this poses. When considered in the context of the high additional

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burden of treating infectious diseases, it is no wonder that so many health systems are failing. A visit to such hospi-tals can be a traumatic experience for visitors used to top-quality first-world medical care.

Solutions

A decade ago, the UK government published the sem-inal Foresight Report [15] that attempted to collate all the available evidence about the drivers of the obesity epi-demic and to use this knowledge to construct recommen-dations for government action. The report acknowledged that the metabolic mechanisms regulating (or failing to regulate) energy balance in humans were central to all ef-forts, but that these were influenced by a wide variety of social and environmental determinants that were rapidly changing in our modern world. They drew up a complex “systems map” to describe these influences and used it to press the case that strategies against obesity must be de-veloped by almost every government department from health to transport, housing, education, and sport, and all must have the support of treasury. Though developed for the UK, these lessons are applicable everywhere.

The World Health Organization has convened expert groups on obesity and noncommunicable diseases and is constantly updating the evidence base used to plan recom-mended initiatives [e.g., 16 , 17 ]. These are backed by ancil-lary reports on mechanisms to achieve these ends such as fiscal measures against sugary drinks [18] and development of a global action plan to promote physical activity [19] . The

report on childhood obesity makes a large number of rec-ommendations [17] , indeed probably an overwhelming number for low-income countries that already have major challenges in strengthening their school systems.

A relatively new element of all of these efforts is the re-cent appreciation of how important it is to consider both ends of the malnutrition spectrum with a life-course lens. In other words, to understand that childhood undernutri-tion has prenatal and probably intergenerational origins [11, 17] . Most children who are stunted at the age of 2 years were already stunted at birth [19] and were born to small mothers. Likewise, a malnourished fetus may adopt a “thrifty phenotype” [20] that is better able to accrue fat in later life if exposed to an obesogenic environment and is therefore at special risk of inappropriate weight gain.

Prospectus for the Future

The economic advancement and associated demo-graphic transitions that are happening in most countries except those marred by conflict will ultimately bring a nat-ural decline in undernutrition. Progress in recent decades has been good in all continents except Africa as a whole; and even here there were many nations that achieved their Millennium Development Goal of halving malnutrition. However, unless the governments and peoples of these emerging nations are able to learn lessons from the coun-tries that have passed through the transition before them, they will incur a huge burden of overweight and obesity. The challenge therefore is first to recognize the impending

Fig. 10. An overweight patient awaits treatment for her diabetic foot. Photo credit: Felicia Webb.

Fig. 11. A malnourished child in a nearby ward exemplifies the health system’s challenges of the double burden of malnutrition. Photo credit: Felicia Webb.


54

threat and then to take cross-government actions to halt the epidemic and its associated health crisis. The greatest hope lies in the fact that most governments are at least aware of the threat; finding the bandwidth and resources to tackle it would bring long-term gains in health and wealth to any government that can achieve it.


The writing of this article was supported by Nestlé Nutrition Institute.

References

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The nutritional issues of undernutrition and overnutrition among children and adolescents in

developing countries are intricately woven together in an intergenerational cycle of malnutrition.

Key insights

Globally, the focus of malnutrition interventions has been on pregnant women and young children under 5 years of age. Older children (aged 6–9 years) and adolescents (aged 10–19 years) have not received as much attention. In addition to un-dernutrition and obesity, adolescent girls in particular face pregnancy-related risks such as anemia, premature birth, still-births, and death. There is thus a need to develop guidelines for nutritional interventions that target this group, particularly in low- and middle-income countries (LMICs).

Current knowledge

Older children and adolescents are at high risk of malnutrition because they experience critical growth spurts which demand essential macro- and micronutrients. Approximately half of adult ideal body weight and approximately 20% of adult height are gained during adolescence, with most of this ac-quired rapidly in 1–2 years preceding the early stages of sexual maturation. In LMICs, there is a high prevalence of under- and overnutrition in older children and adolescents, compromis-ing growth and cognitive potential while increasing the risk of obesity and cardiovascular diseases in later life.


School feeding programs as well as multiple micronutrient sup-plementation and fortification have had beneficial outcomes in school-aged children. The World Health Organization (WHO) rec-ommends 3 months of preventive iron supplementation in ado-lescents living in areas with a high anemia prevalence. Teenage girls should receive folic acid supplementation during the precon-


Nutrition for the Next Generation: Older Children and Adolescents by Jai K. Das et al.

tional issues

F O C U S


ception period to prevent neural tube defects in the developing fetus. Schools have been one of the successful platforms used for delivering nutritional interventions, but the use of electronic and social media can also be explored as tools to promote a healthy lifestyle.

Recommended reading

Salam RA, Hooda M, Das JK, Arshad A, Lassi ZS, Middleton P, Bhutta ZA: Interventions to improve adolescent nutrition: a systematic review and meta-analysis. J Adolesc Health 2016;59(4S):S29–S39.

Ongoing or previously tested:• School feeding programs • Supplementation (with single or multiple micronutrients • Food and beverage fortification Older children

and adolescentsDelivery channels:• Mass media campaigns • Electronic or social media • Mobile health (mHealth) technology

A summary of interventions that can be used to improve nutritional outcomes in older children and adolescents.



Nutrition for the Next Generation: Older Children and Adolescents

Jai K. Das a Zohra S. Lassi b Zahra Hoodbhoy a Rehana A. Salam a, c

a Division of Women and Child Health, Aga Khan University, Karachi , Pakistan ; b Robinson Research Institute, University of Adelaide, Adelaide , SA , Australia ; c South Australian Health and Medical Research Institute, University of Adelaide, Adelaide , SA , Australia

Jai K. Das Division of Women and Child Health Aga Khan University Karachi 74800 (Pakistan) E-Mail jai.das @ aku.edu



Key Messages

• It is critical to ensure adequate nutrition for children

and adolescents as this is intrinsically linked to the

health of future generations.

• There is a need to make specific guidelines for

nutrition requirements and interventions for older

children and adolescents across various contexts,

including low- and middle-income countries (LMICs).

• There is a need for more evidence around

determining the most effective strategies to tackle

the rising burden of overweight and obesity,

especially from LMICs.

Keywords

Adolescents · Older children · Nutrition · Undernutrition · Overweight · Obesity · Nutrition interventions

Abstract

This paper reviews information on why the nutrition of older children (5–9 years) and adolescents (10–19 years) is impor-tant and the consequences that it can have over genera-tions. Developing countries still face a high burden of under-nutrition and anemia, while the burden of overweight and

obesity is on the rise in both developing and developed countries. There are evidence-based interventions which can improve the nutritional status and these include inter-ventions for a balanced and diverse diet and micronutrient supplementation, especially iron and multiple micronutrient supplementation where there is sufficient evidence to re-duce anemia. There is mixed evidence for the effective strat-egies to prevent and control obesity and a dearth of evi-dence from developing countries. Adolescent pregnancy also poses greater challenges to the health of mother and child, and advocacy should be rampant to delay the age of marriage and pregnancy. Interventions targeted to improv-ing the nutritional status among “pregnant adolescents” have shown improvement in birth weight and a reduction in low birth weight and preterm delivery. Traditional platforms including school-based and community-based approaches offer a mixed picture of effectiveness, but emerging avenues of mHealth and social media could also be channelized to reach this population. The population of this age group is on the rise globally, and failure to invest in improving the nutri-tion of older children and adolescents will further increase the number of dependents in coming generations and neg-atively influence the health of future generations and prog-ress of nations. © 2018 Nestlé Nutrition Institute, Switzerland/

S. Karger AG, Basel

Nutrition for the Next Generation 57 Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):56–64 DOI: 10.1159/000487385

Background

Malnutrition encompassing both under- and overnu-trition is a major public health crisis for children and adults across the world [1] . Developing countries are now facing the “double burden” of undernutrition and over-weight and obesity [2] , as the prevalence of overweight and obesity in children and adolescents has increased from 8.1% (7.7–8.6) in 1980 to 12.9% (12.3–13.5) in 2013 for boys and from 8.4% (8.1–8.8) to 13.4% (13.0–13.9) in girls [3] . And during the same period, the prevalence of overweight and obesity has increased remarkably in de-veloped countries: from 16.9% (16.1–17.7) in boys and 16.2% (15.5–17.1) in girls in 1980 to 23.8% (22.9–24.7) in boys and 22.6% (21.7–23.6) in girls in 2013 [3] . There is also a high burden of undernutrition in developing coun-tries and protein-energy malnutrition is responsible for 225,906 deaths (uncertainty level: 168,497–280,129) in children and adolescents aged 0–19 years [4] . Iron defi-ciency anemia is the leading cause of years lived with dis-ability among children and adolescents, accounting for 619 million (uncertainty level: 618–621 million) preva-lent cases in 2013 [4] .

Pregnancy in adolescence poses additional risks to the mother and newborn, as adolescent girls are not physi-cally mature enough, and undernutrition further exacer-bates these risks. The common risks during adolescent pregnancy include anemia, stillbirth, prematurity, and mortality. It is estimated that around 10% of the global total births occur to adolescent girls between the age of 15

and 19 years [5] . And around three-quarters of these ado-lescent pregnancies occur in developing countries [5] . Stunted adolescents have further risks of obstetric com-plications, including obstructed labor and weakened physical capacity [6] .

The major global focus of health has been on children under the age of 5 years and pregnant women, while old-er children (aged 6–9 years) and adolescents (aged 10–19 years) have not received the due attention until lately. Al-leviating malnutrition in this age group requires a com-plex, multifactorial approach and thus addresses a major public health concern.

Consequences of Undernutrition across the Life

Course

The nutritional issues of undernutrition and overnu-trition among children and adolescents in developing countries are intricately woven together in an intergen-erational cycle of malnutrition.

It is essential that women, particularly girls, are nour-ished well at all stages of growth and development be-cause the risk of malnutrition in women spans a life cycle and also across generations, termed as intergenerational effects of malnutrition [7] . Any nutritional deficiency ex-perienced during this critical period of life can have an effect on the future health of the individual and their off-spring ( Fig. 1 ).

Malnourished child

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Das/Lassi/Hoodbhoy/Salam Reprinted with permission from:Ann Nutr Metab 2018;72(suppl 3):56–64 DOI: 10.1159/000487385

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Addressing nutritional deficiencies in women and girls via life cycle approach can improve their nutritional status. Nutritional deficiencies experienced early on such as in utero, infancy, and childhood have consequences into the adult life. Stunting is often rooted from inade-quate fetal growth [8] and it also influences the childhood cognitive tests and educational achievement [9] . Changes in in utero nutritional environment are associated with hampered growth and development and increased risk of developing cardiovascular and metabolic disorders in adult life [10] . The same vicious cycle of malnutrition is repeated in children of mothers who were malnourished.

Women, in general, are more likely to suffer from nu-tritional deficiencies than men because of their reproduc-tive biology. However, children and adolescents in devel-oping countries suffer the most with additional underly-ing factors including poverty, illiteracy, poor social status, and disparity in society. Today, approximately 468 mil-lion nonpregnant women in low- and middle-income countries (LMICs) and half of all the pregnant women are anemic [11, 12] . Poor nutritional status increases the risks for morbidity and mortality. For women, anemia is an underlying cause in approximately 20% of maternal deaths [13] and being underweight increases the chances of being stunted and that increases the risk for obstetric complications such as obstructed childbirth [14, 15] . At a macro-level, malnourishment hinders work capacity and leads to further economic disadvantages.

Physiology and Metabolism

Malnutrition is the single most common reason for growth retardation. Inadequate nutrition in the early life of a child can delay sexual maturation and physical growth, which is necessary to reach the full development potential as an adult. For a girl, this is also important to prepare for her nutritional demands during pregnancy and lactation in adulthood. There are no standardized an-thropometric measures for adolescents [16] , and conse-quently various definitions are used by different studies to measure the burden of underweight and overweight in adolescents, thus hampering the determination of the ac-tual burden of adolescent malnutrition.

The nutritional status has a significant contributing ef-fect on the timing of adolescent sexual maturation, and it is well documented that undernutrition is associated with delayed age of menarche [17] . The growth spurt in ado-lescence requires rapid tissue expansion with special nu-trient requirements, thus it is necessary to ensure that en-ergy and nutrition requirements match the adolescent

needs. Approximately half of an adult’s ideal body weight is gained during adolescence, and approximately 20% of adult height is gained during the adolescent age period and most of this is gained rapidly 1–2 years preceding the early stages of sexual maturation [16] . Malnutrition pre-vents individuals from attaining normal bone structure, strength, and development, and the onset of puberty is delayed in adolescents who are undernourished. This can allow for a longer time to catch up on growth, although there are deliberations on whether young adolescents who are stunted can catch up to their optimal height.

Older children and adolescents are particularly at risk of malnutrition because they experience the growth spurt and need all essential macro- and micronutrients to sup-port the increased demand of the body for attaining pu-berty and development. Therefore, it is important that children and adolescents, particularly girls, are fed prop-erly and are given all required micronutrients. Young girls who become pregnant during this phase are at great-er risk of various complications since their body is sup-porting their own growth and that of the growing fetus; and the still-growing adolescent mother and her baby may compete for nutrients and increase the infant’s risk of low birth weight and early death [18] .

This age group also needs iron for their increased physiologic requirements for growth. Infectious diseases, such as malaria and hookworm, and menstruation in fe-males can also affect iron absorption, use, and loss in ad-olescents and frequently contributes to iron deficiency. Malaria-related inflammation also reduces iron absorp-tion and incorporation into red blood cells [19] .

There is an increase in appetite in this age group and individuals with a sedentary lifestyle have a greater chance to accumulate fat, which contributes greatly to over-weight and obesity, especially if they consume high-ener-gy food. The caloric requirement of adolescent males is higher than that of adolescent females, owing to greater increases in height, weight, and lean body mass. Table 1 shows the Dietary Reference Intakes (DRIs) and Ade-quate Intakes (AIs) for adolescents as recommended by the Institute of Medicine and includes recommendations on energy requirements and requirements for various macro- and micronutrients [20] .

Long-Term Health Impacts of Malnutrition

Malnutrition in women contributes to the growing burden of cardiovascular and other noncommunicable diseases. Undernutrition leads to numerous physiologi-cal and social alterations and is partly due to epigenetic


changes [21] . Undernutrition provokes stress in the body and stimulates the release of adrenaline and noradrena-line and the production of cortisol. The chronic physio-logical stress due to undernutrition over time weakens the body and leads to fatigue and unproductivity and also poses multiple-fold risks of getting an infection [22] . A study on malnourished children found a higher resting heart rate [23] and an association of nutritional stunting

with increased rates of arterial hypertension [24, 25] . Short maternal stature is associated with obesity and type 2 diabetes [26] , low birth weight, and stunting in children [27] . Undernutrition is also linked with hyperinsulinemia and reduced sensitivity to insulin, which is responsible for an increased BMI in adult life [28] . Animal studies have also proven that changes in in utero kidney develop-ment can occur due to maternal malnutrition and sug-

Table 1. Examples of population reference nutrient intakes (vitamins and minerals): Dietary Reference Intakes (DRIs) and Adequate Intakes (AIs) for adolescents in the USA [20]

Females Males

9–13 years 14–18 years 19–30 years 9–13 years 14–18 years 19–30 years

Energy, kcal/day 2,071 2,368 2,403a 2,279 3,152 3,067Carbohydrates, g/day 130 30 130 130 130 130Total fiber, g/day 26 28 25 31 38 38n-6 polyunsaturated fat, g/day 10 11 12 12 16 17n-3 polyunsaturated fat, g/day 1.0 1.1 1.1 1.2 1.6 1.6Protein, g/day 34 46 46 34 52 56

VitaminsVitamin A, μg/day 600 700 700 600 900 900Vitamin C, mg/day 45 65 75 45 75 90Vitamin D, μg/day 5 5 5 5 5 5Vitamin E, mg/day 11 15 15 11 15 15Vitamin K, μg/day 60 75 90 60 75 120Thiamin, mg/day 0.9 1.0 1.1 0.9 1.2 1.2Riboflavin, mg/day 0.9 1.0 1.1 0.9 1.3 1.3Niacin, mg/day 12 14 14 12 16 16Vitamin B6, μg/day 1.0 1.2 1.3 1.0 1.3 1.3Folate, μg/day 300 400 400 300 400 400Vitamin B12, μg/day 1.8 2.4 2.4 1.8 2.4 2.4Pantothenic acid, mg/day 4 5 5 4 5 5Biotin, μg/day 20 25 30 20 25 30Choline, mg/d ay 375 400 425 375 550 550

ElementsCalcium, mg/day 1,300 1,300 1,000 1,300 1,300 1,000Chromium, μg/day 21 24 25 25 35 35Copper, μg/day 700 890 900 700 890 900Fluoride, mg/day 2 3 3 2 3 4Iodine, μg/day 120 150 150 120 150 150Iron, mg/day 8 15 18 8 11 8Magnesium, mg/day 240 360 310 240 410 400Manganese, mg/day 1.6 1.6 1.8 1.9 2.2 2.3Molybdenum, μg/day 34 43 45 34 43 45Phosphorus, mg/day 1.250 1,250 700 1,250 1,250 700Selenium, μg/day 40 55 55 40 55 55Zinc, mg/day 8 9 8 8 11 11

Source: data from reports from the Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, copyright by the National Academy of Sciences, courtesy of the National Academies Press, Washington, DC, USA (http://www.nap.edu/).


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gested delays in intrauterine growth and a reduced num-ber of nephrons [29] . This phenomenon determines poor renal function and increased blood pressure. Studies have also shown the association of pancreatic function with undernutrition in early life [30] . Undernutrition and en-suing anemia can also effect cognitive development, the ability to learn, and hence compromise the standard of living throughout the life cycle [31] .

Evidence suggests that a poor maternal BMI before and during pregnancy has significant impacts on adverse pregnancy outcomes. A recent review reported that ma-ternal prepregnancy underweight is significantly associ-ated with preterm births, small-for-gestational-age babies and low birth weight [32] . On the other hand, maternal pre-pregnancy overweight is associated with increased risk of hypertensive disorders, pre-eclampsia, and gesta-tional diabetes. The risk of adverse pregnancy outcomes increases multifold if the mother is obese [32] .

Similarly, overweight and obesity among children and adolescents pose an increased risk for cardiovascular and other noncommunicable diseases. There is considerable evidence to show that childhood obesity is a risk factor for type 2 diabetes, hypertension, coronary heart disease, and stroke in adulthood (hazard ratios ranging from 1.1 to 5.4) [33, 34] . A systematic review of 23 studies reported that childhood obesity is significantly associated with adult systolic and diastolic blood pressure and triglycer-ides and inversely associated with high-density lipopro-tein [35] . And hypertension is the leading cause of other noncommunicable diseases, such as high serum choles-terol, diabetes, etc. These also lead to direct (medical) and indirect (nonmedical) costs related to obesity that impose a significant economic burden to individuals and health care infrastructure.

Nutrition Interventions for Older Children and

Adolescents

Intervening in infancy and early childhood is para-mount to improving the nutritional status and achieving long-lasting impacts as this is an age group which re-sponds well to the interventions not only to improve physical growth but also cognitive development and at-tainment of complete physical capacity. Various inter-ventions including optimal breastfeeding, complemen-tary feeding, and micronutrient supplementation have been recommended for infants and young infants. Apart from nutrition-specific interventions, water, sanitation, hygiene, and prevention of infection also play an impor-tant role [36] . Although older children and adolescents

often do not receive intervention and policy priority, in-tervening in this age is also vital for improving nutrition and achieving long-term health. A balanced, nutritious diet is the key to promote healthy growth and develop-ment of children and adolescents [37] , leading to a health-ier and productive generation. Below we discuss the evi-dence-based nutrition-specific interventions for older children ( Table 2 ) and adolescents. Younger adolescents (10–13 years) act as a special group, as they transition from older school-aged children to adolescents.

Older Children The interventions range from addressing under- to

overnutrition. A systematic review on school feeding pro-grams reported that balanced school meals provided in LMICs had a significant impact on weight but not on height [38] . Multiple micronutrient supplementation through fortified beverages has shown a significant im-pact on improving serum hemoglobin level and reducing the risk of anemia in school-aged children in low-re-source settings [39] . A systematic review on micronutri-ent powders suggested an impact on improving serum hemoglobin and reducing the prevalence of anemia in

Table 2. Evidence of impact of interventions in older children

Outcome Impact

School feeding programsWeight gain

Over 19 months MD: 0.39 kg (95% CI: 0.11 to 0.67)Over 11.3 months MD: 0.71 kg (95% CI:0.48 to 0.95)

Height gain MD: 0.38 cm (95% CI: –0.32 to 1.08)

Micronutrient powdersAnemia RR: 0.53 (95% CI: 0.25 to 1.12)Hemoglobin MD: 7.86 g/L (95% CI: –0.76 to 16.49)

Intermittent iron supplementationAnemia RR: 0.54 (95% CI: 0.33 to 0.90)Hemoglobin MD: 4.04 g/L (95% CI: 0.30 to 7.78)

Iron fortificationHemoglobin SMD: 0.46 (95% CI: 0.24 to0.67)Anemia RR: 0.60 (95% CI: 0.43 to 0.84)

MMN-fortified beveragesHemoglobin MD: 2.76 g/L (95% CI: 1.19 to 4.33)Anemia RR: 0.58 (95% CI: 0.29 to 0.88)Iron deficiency anemia RR: 0.17 (95% CI: 0.06 to 0.53)

MD, mean difference; MMN, multiple micronutrient; RR, risk ratio; SMD, standard mean difference.


children under the age of 5 years but not in older children [40] . A systematic review on intermittent iron supple-mentation in children aged 5–10 years showed a statisti-cally significant increase in serum hemoglobin but no effect on anemia, and this review also suggested no dif-ference when intermittent iron supplementation was compared to daily supplementation [41] . A review on iron fortification also suggested improvement in serum hemoglobin levels and reduction in anemia in preschool- and school-aged children [42] . There is some evidence suggesting that iodine supplementation in children aged 10–12 years leads to improvement in cognitive function-ing and fine motor skills [43] .

A review on interventions to prevent obesity in older children through altering dietary or physical activity-relat-ed factors, or both suggested a reduction in BMI with inter-ventions predominantly based on behavior change theories and implemented in education settings [44] . There is some ev-idence that school-based phys-ical activity interventions lead to an improvement in engage-ment in moderate to vigorous physical activity during school hours (odds ratio: 2.74, 95% confidence interval [CI]: 2.01 to 3.75) and children spend less time watching television [45] . A recent systematic re-view reported that school-based interventions moderately improved fruit intake (mean difference [MD]: 0.24 por-tions, 95% CI: 0.05 to 0.43) but had a minimal impact on vegetable intake (MD: 0.07 portions, 95% CI: –0.03 to 0.16) [46] . Targeted interventions that work on consumption of sweetened beverages in children reported a modest reduc-tion in the number of carbonated drinks consumed, which also led to a reduction in the prevalence of overweight and obese children [47] . The results for obesity prevention and management interventions in children are inconsistent and mostly from developed countries.

Adolescents The World Health Organization (WHO) recommends

that 3 months of preventative iron supplementation of 60 mg iron per day be given to adolescents living in areas where the population prevalence of anemia is greater than 40% [48] . Folic acid supplementation in the precon-ception period has been recommended to reduce the in-cidence of neural tube defects [49] . Calcium supplemen-tation in girls aged 10–18 years has been essential for achieving optimum bone mineral density and hence pre-venting osteoporosis [50] .

A recent systematic review of nutrition interventions in adolescents suggested that iron/iron folic acid supple-mentation alone or in combination with other micronu-trients leads to a reduction in anemia (risk ratio: 0.69, 95% CI: 0.62 to 0.76) and was associated with improved serum hemoglobin (MD: 1.94 g/dL; 95% CI: 1.48 to 2.41), ferri-tin (MD: 3.80 μg/L; 95% CI: 2.00 to 5.59), and iron (MD: 6.97 mmol/L; 95% CI: 0.19 to 13.76) [51] . Zinc supple-mentation led to improved serum zinc concentrations (MD: 0.96 μg/dL; 95% CI: 0.81 to 1.12), while calcium and vitamin D supplementation did not have a clear impact on vitamin D levels or parathyroid hormone [51] .

The nutritional effect of large-scale urbanization, of-ten coined the “nutrition transition,” is that as people as-sume a more sedentary lifestyle, have more ready access to snack or street foods, and reduce the consumption of more traditional foods, the prevalence of overweight and

obesity increases substantial-ly. As increased caloric input is one of the key mechanisms for weight gain, nutritional interventions are a key for preventing and managing obesity in adolescents. Inter-ventions targeted to adoles-

cents to improve fruit and vegetable consumption behav-iors suggest that these behaviors are dependent on home availability of fruits/vegetables and taste preferences [52] . A positive correlation between milk consumption and bone mineral density has also been reported in young girls [53] . Dietary interventions for obesity management in adolescents include caloric restriction [54] and/or traf-fic light diet (low added sugar and increased fiber intake) [55] , which have shown to have significant reductions in BMI and waist circumference [56] . The NEAT (Nutrition and Enjoyable Activities in Teen Girls) trial to prevent obesity in girls from a low socioeconomic background reported an insignificant effect on body composition but may still have potential clinical importance [57] .

Intervention Delivery Several platforms have been used to deliver nutrition

interventions to older children and adolescents. These in-clude schools, community groups, youth organizations, health centers, and mass media [58] . Schools have been the main medium that has been used and has been effec-tive to deliver nutrition interventions. Electronic and so-cial media platforms have gained much popularity over the years as a way to reach a vast number of youth. Mass media campaigns using television and radio have the po-

The combination of various settings can be proposed as one of the

solutions to effectively address nutritional interventions in older

children and adolescents


62

tential to improve dietary quality in youth [59] . mHealth technology has also been studied to promote a healthy diet and other lifestyle behaviors in children [60] . A re-cent systematic review reported that compliance to treat-ment and self-monitoring has been shown to improve with the use of this technology; however, the effect on outcomes such as BMI was limited [60] . A combination of various platforms such as schools, community, and media has been successful in implementing healthy di-etary patterns in elementary-school children [61] . The combination of various settings can be proposed as one of the solutions to effectively address nutritional inter-ventions in older children and adolescents.

Conclusion

Adolescent and older children health care is challeng-ing compared to that of children under the age of 5 years and adults, and this is due to various factors mostly re-lated to the ever-evolving physical and mental develop-ment. There is still a high burden of malnutrition in old-er children and adolescents globally, with developed countries facing a huge load of overweight and obesity,

while developing countries are engulfed with a tradition-ally high prevalence of undernutrition and the threats of recent hike in overweight and obesity. There is a greater need to focus exclusively on this population, as improv-ing the nutritional status of adolescents can help break the vicious cycle of intergenerational malnutrition. National governments together with development partners need to make specific guidelines and recommendations to tackle malnutrition in this age group, albeit this may require more evidence especially around determining strategies to combat obesity. This focus would not only improve the nutritional status of older children and adolescents but may also escalate the mental and cognitive growth and help individuals reach their true potential, which may have far-reaching repercussions by not only increasing the quality of life but influence the growth and productiv-ity of generations to come and countries at large.


All authors declare no conflict of interest and received no com-pensation. The writing of this article was supported by Nestlé Nu-trition Institute.

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Hot Topics in Nutrition – 75 Years Later

Hot Top

ics in Nutrition – 75 Years Later

5 Foreword Saavedra, J.M. (Vevey)

6 Editorial Haschke, F. (Salzburg)



12 Focus/Summary

13 Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect Szajewska, H. (Warsaw)

24 Focus/Summary

25 Nutrition for Preterm Infants: 75 Years of History van Goudoever, J.B. (Amsterdam)

32 Focus/Summary

33 Food Allergy Prevention and Treatment by Targeted Nutrition Heine, R.G. (Vevey)

46 Focus/Summary

47 The Double Burden of Malnutrition in Countries Passing through the Economic Transition Prentice, A.M. (London/Banjul)

55 Focus/Summary

56 Nutrition for the Next Generation: Older Children and Adolescents Das, J.K. (Karachi); Lassi, Z.S. (Adelaide, SA); Hoodbhoy, Z. (Karachi); Salam, R.A. (Karachi/Adelaide, SA)

76 | 1 | 18

Hot Topics in Nutrition –75 Years Later

Editor: F. Haschke

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