Infant Formulas - ACCP

PSAP-VII • Gastroenterology and Nutrition 127 Infant Formulas

Learning Objectives 1. Assess the appropriate role of altered macronutri-

ent sources in infant nutrition.2. Judge the appropriateness of the addition of various

nutrition supplements to infant formulas.3. Distinguish specialty infant formulas on the basis

of their macronutrient composition.4. Choose an appropriate formula for an infant with

a disease or condition requiring a specialty infant formula.

5. Apply knowledge of the role of altered protein sources in the prevention of disease, such as atopic dermatitis and diabetes mellitus.

Introduction The substantial health benefits of human milk for the infant are well described, and breastfeeding should be actively promoted and supported whenever possible. On the basis of data from 2006 used in developing the Healthy People 2020 objectives, 74% of infants in the United States are breastfed at some time. In 2006, the breastfeeding rates at 6 months and 12 months were 43.5% and 22.7%, respectively. Exclusive breastfeeding rates through 3 months and 6 months were 33.5% and 14.1%, respectively. The Healthy People 2020 targets for exclusive breastfeeding at 3 months and 6 months are 60.6% and 34.1%, respectively.

With the current breastfeeding rates, most infants receive a commercially available infant formula at some time in their lives. A recent cost analysis revealed that if 90% of U.S. families would exclusively breastfeed their infants for 6 months, $13 billion per year would be saved and about 911 infant deaths averted. At 80% adherence, these numbers would be $10.5 billion and 741 deaths. More information regarding these cost and risk reduc-tions can be found in the annotated bibliography (refer-ence No. 2). Formula manufacturers continually alter the com-position of their infant formulas to more closely mimic the composition of human milk. However, the Interna-tional Expert Group representing both the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Federation of International Soci-eties for Pediatric Gastroenterology, Hepatology, and Nutrition has stated that “the mere presence of a sub-stance in human milk by itself doesn’t justify its addi-tion to formula, but a benefit of the addition should be shown.” Available infant formulas differ primarily in their macronutrient composition, and this variation is most often the basis for selecting a product for a given infant. In addition, non-nutrient ingredients (e.g., prebiotics, probiotics) are added to some products. Content infor-mation for formula products is summarized in Table 3-1. The most up-to-date formula content information

Infant Formulas

By Katherine Hammond Chessman, Pharm.D., FCCP, BCPS, BCNSP

Reviewed by Catherine M. Crill, Pharm.D., FCCP, BCPS, BCNSP; and Lisa C. Hutchison, Pharm.D., MPH, FCCP, BCPS

Baseline Review Resources The goal of PSAP is to provide only the most recent (past 3–5 years) information or topics. Chapters do not pro-vide an overall review. Suggested resources for background information on this topic include:• Chessman KH. Infant nutrition and special nutritional needs of children. In: Berardi RR, Ferreri SP, Hume

AL, Kroon LA, Newton GD, Popovich NG, et al, eds. Handbook of Nonprescription Drugs, 16th ed. Washington, DC: American Pharmacists Association, 2009:467–96.

• American Academy of Pediatrics. Pediatric Nutrition Handbook, 6th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2009.

PSAP-VII • Gastroenterology and Nutrition128Infant Formulas

can be found on each formula manufacturer’s Web site. This chapter will review the use of specialty infant for-mulas in a variety of circumstances and the potential role of infant nutrition in the prevention of diseases in later life.

Macronutrients in Infant Formulas The macronutrient composition of human milk is about 40% to 45% carbohydrates, 48% to 50% fat, and 9% protein. However, human milk has a dynamic com-position, constantly changing, even from feeding to feeding. The components of infant formulas also vary, but most use cow’s milk as the base. Lactose is the pri-mary carbohydrate in human milk, but it also contains oligosaccharides (carbohydrate polymers) whose struc-tures mimic specific bacterial antigen receptors and prevent bacterial attachment. These oligosaccharides are also prebiotics, which will be discussed later in this chapter. Casein protein predominates in cow’s milk; whey is the predominant protein in human milk. The protein quality of human milk differs from cow’s milk. Lipids in human milk are complex, and their structure facilitates fat digestion and absorption.

Carbohydrates There are several classes of dietary carbohydrates, including starch and disaccharides (e.g., sucrose, lac-tose), but only monosaccharides can be absorbed. Diges-tion of monosaccharides depends on the brush border enzymes in the intestinal mucosa: sucrase, isomaltase, glucoamylase, and lactase. Brush border enzymes are produced in response to a meal and then degraded, so they must be resynthesized by the enterocytes before the next meal. All but lactase are synthesized in excess of need, making lactase the most vulnerable enzyme to disease-related reduction. Once digestion to monosaccharides occurs, the water-soluble sugars (i.e., glucose, fructose, and galactose) must be transported across the enterocyte membrane.

Glucose and galactose uptake is sodium-dependent; fructose is absorbed by facilitated diffusion. The various proteins involved in the transport of these molecules (e.g., sodium-glucose linked transporter protein-1, glu-cose transporter-2) can be modified by genetic muta-tions, resulting in problems with carbohydrate malab-sorption and necessitating alteration of dietary carbo-hydrates. Galactosemia is a rare inborn error of metab-olism in which a genetic defect results in the inability to metabolize galactose, leading to galactose accumu-lation when either galactose or lactose is consumed. Symptoms of galactosemia are nonspecific and include vomiting, irritability, diarrhea, poor feeding, failure to thrive, lethargy, and jaundice. Long-term, galactose-mia can result in intellectual impairment as well as liver, kidney, and eye complications. In the United States, all infants are routinely screened at birth for this disorder. Infants with galactosemia will require dietary altera-tions to completely avoid galactose and lactose because lactose is converted to glucose and galactose by lactase. Primary, hereditary lactase deficiency is an uncom-mon problem in infancy. In most children, lactase con-centrations begin to decline only after 2–3 years of age. By adulthood, 15% of whites, 40% of Asians, 50% to 80% of Hispanics, and 85% of African Americans will develop lactase deficiency. A more common problem is secondary lactose intolerance, which can occur after a severe bout of gastroenteritis, especially enterocoli-tis. The degree of mucosal damage will determine the extent and severity of symptoms. In addition, some evi-dence suggests that lactose intolerance is more common in infants with Hirschsprung’s disease. In infants wit h decreased lactase activity, colonic bacteria ferment the unabsorbed sugar producing carbon dioxide and short-chain fatty acids, resulting in abdominal distention. The stool is also more acidic, causing painful, watery, and explosive stools. Carbohydrate sources in infant formulas vary. Cow’s milk–based formulas contain lactose or corn syrup sol-ids (glucose) if the lactose has been removed. Formulas intended for use in infants with carbohydrate maldiges-tion or malabsorption contain corn syrup solids (glu-cose) or modified corn starch. Sucrose is added to some products to improve the taste.

Proteins Proteins must be digested into small peptides or amino acids to be absorbed. Protein digestion begins in the acidic environment of the stomach with pepsin, and then pancreatic endo- and exopeptidases work in the duodenum and jejunum to further break down the pro-tein to absorbable components. Individual amino acids must be bound to a transporter to be absorbed. There are many amino acid transporters in the enterocytes. Mutations can occur that alter transporter function. However, there is a lot of redundancy in the transporter

Abbreviations in This ChapterAAP American Academy of PediatricsARA Arachidonic acidCMA Cow’s milk-protein allergyDHA Docosahexanoic acidFOS Fructo-oligosaccharidesGER Gastroesophageal refluxGOS Galacto-oligosaccharidesIgE Immunoglobulin EMCT Medium-chain triglycerideNEC Necrotizing enterocolitisT1DM Type 1 diabetes mellitus


Tabl

e 3-

1. In

fant

For

mul

a Mac

ronu

trie

nt C

ompo

sitio

na

Form

ula

(Man

ufac

ture

r)C

arbo

hydr

ate

Sour

cePr

otei

n So

urce

Fat S

ourc

eO

ther

Stan

dard

Cow

’s M

ilk–B

ased

Ter

m F

orm

ulas

Enfa

mil

PREM

IUM

N

ewbo

rn (M

J)La

ctos

eW

hey p

rote

in co

ncen

trate

; non

fat

cow

’s m

ilk (w

hey:

case

in, 8

0:20

)Pa

lm o

lein

, coc

onut

, soy

, and

hig

h ol

eic

sunfl

ower

oils

; DH

A, A

RAFo

r ful

l-ter

m n

ewbo

rns t

hrou

gh 3

mon

ths,

incr

ease

d vi

tam

in D

, con

tain

s Nat

ural

Def

ense

Dua

l Pre

biot

icb

Enfam

il PRE

MIU

M In

fant/

En

fam

il LI

PIL

(MJ)

Lact

ose

Redu

ced

min

eral

s whe

y; n

onfa

t co

w’s

milk

(whe

y:ca

sein

, 60:

40)

Palm

ole

in, c

ocon

ut, s

oy, a

nd h

igh

olei

c sa

fflow

er o

ils; D

HA

, ARA

Con

tain

s Nat

ural

Def

ense

Dua

l Pre

biot

icb

Enfa

mil

A.R

. (M

J)La

ctos

e, ric

e sta

rch,

m

alto

dext

rinN

onfa

t cow

’s m

ilk (w

hey:

case

in,

18:8

2)Pa

lm o

lein

; coc

onut

, soy

, and

hig

h ol

eic

saffl

ower

oils

; DH

A, A

RAVi

scos

ity in

bott

le is

10

times

hig

her t

han

stand

ard

form

ula

Enfa

mil

Gen

tleas

e (M

J)C

orn

syru

p so

lids,

lacto

se

Part

ially

hyd

roly

zed

nonf

at co

w’s

milk

, whe

y pro

tein

conc

entra

te

(soy

), ta

urin

e, l-

carn

itine

Palm

ole

in, s

oy, c

ocon

ut, a

nd h

igh

olei

c su

nflow

er o

il; D

HA

, ARA

20%

of l

acto

se in

stan

dard

form

ulas

Ger

ber G

ood

Star

t G

entle

(G/N

)La

ctos

e, co

rn m

alto

dext

rin10

0% p

artia

lly h

ydro

lyze

d w

hey

prot

ein

from

cow

’s m

ilkPa

lm o

lein

, soy

, coc

onut

, and

hig

h ol

eic

saffl

ower

or s

unflo

wer

oils

; DH

A, A

RAC

onta

ins N

UT

RIPR

OT

ECT,

c GO

S

Ger

ber G

ood

Star

t Pr

otec

t (G

/N)

Lact

ose,

corn

mal

tode

xtrin

100%

par

tially

hyd

roly

zed

whe

y pr

otei

n fro

m co

w’s

milk

Palm

ole

in, s

oy, c

ocon

ut, a

nd h

igh

olei

c sa

fflow

er o

r sun

flow

er o

ils; D

HA

, ARA

Con

tain

s IM

MU

NIP

ROT

ECTd

Ger

ber G

ood

Star

t So

othe

(G/N

)La

ctos

e, co

rn m

alto

dext

rin10

0% p

artia

lly h

ydro

lyze

d w

hey

prot

ein

from

cow

’s m

ilkPa

lm o

lein

, soy

, coc

onut

, and

hig

h ol

eic

saffl

ower

or s

unflo

wer

oils

; DH

A, A

RA30

% o

f the

lact

ose i

n sta

ndar

d fo

rmul

as; c

onta

ins

prob

iotic

(Lac

toba

cillu

s reu

teri)

Sim

ilac A

dvan

ce (A

)La

ctos

eN

onfa

t cow

’s m

ilk, w

hey p

rote

in

conc

entra

teH

igh

olei

c saffl

ower

, coc

onut

, and

soy o

ils;

DH

A, A

RAC

onta

ins E

arly

Shie

lde w

ith G

OS

Sim

ilac O

rgan

ic (A

)O

rgan

ic m

alto

dext

rin,

orga

nic s

ucro

seO

rgan

ic n

onfa

t cow

’s m

ilkO

rgan

ic h

igh

olei

c soy

, sun

flow

er, a

nd

coco

nut o

ils; D

HA

, ARA

Con

tain

s Ear

lySh

ield

e with

GO

S; ce

rtifi

ed U

SDA

Org

anic

Sim

ilac P

M 6

0/40

(A)

Lact

ose

Whe

y pro

tein

conc

entra

te, s

odiu

m

case

inat

e fro

m co

w’s

milk

Hig

h ol

eic s

afflow

er, s

oy, a

nd co

conu

t oils

Low

er m

iner

al co

nten

t; lo

w ir

on; f

or in

fant

s with

hy

perp

hosp

hate

mia

and

kid

ney a

nd h

eart

dise

ase

Sim

ilac S

ensit

ive (

A)Su

cros

e, co

rn m

alto

dext

rinC

ow’s

milk

pro

tein

isol

ate

Hig

h ol

eic s

afflow

er, s

oy, a

nd co

conu

t oils

; D

HA

, ARA

Con

tain

s Ear

lySh

ield

e with

GO

S, la

ctos

e fre

e

Sim

ilac S

ensit

ive f

or

Spit-

Up

(A)

Cor

n sy

rup,

rice

star

ch,

sucr

ose

Cow

’s m

ilk p

rote

in is

olat

eH

igh

olei

c saffl

ower

, soy

, and

coco

nut o

ils;

DH

A, A

RALa

ctos

e fre

e; vi

scos

ity in

bott

le is

10

times

hig

her t

han

stand

ard

form

ula

Soy

Prot

ein

Form

ulas

Enfa

mil

ProS

obee

( M

J)C

orn

syru

p so

lids

Soy p

rote

in is

olat

ePa

lm o

lein

, coc

onut

, soy

, and

hig

h ol

eic

sunfl

ower

oils

; DH

A, A

RALa

ctos

e fre

e, su

cros

e fre

e, an

d co

w’s

milk

free

Ger

ber G

ood

Star

t So

y (G

/N)

Cor

n m

alto

dext

rin,

sucr

ose

Hyd

roly

zed

soy p

rote

in is

olat

e;

l-m

ethi

onin

ePa

lm o

lein

, soy

, coc

onut

, and

hig

h ol

eic

saffl

ower

or s

unflo

wer

oil

Cow

’s m

ilk fr

ee an

d lac

tose

free

; con

tain

s N

UT

RIPR

OT

ECTc

Sim

ilac E

xper

t Car

e for

D

iarr

hea (

A)C

orn

syru

p so

lids,

sucr

ose

Soy p

rote

in is

olat

e, l-

met

hion

ine

Soy a

nd co

conu

t oils

Cow

’s m

ilk fr

ee, la

ctos

e fre

e; co

ntai

ns so

y fibe

r 6

g/L;

RT

F on

lySi

mila

c Soy

Isom

il (A

)Su

cros

e, co

rn sy

rup

solid

sSo

y pro

tein

isol

ate,

l-m

ethi

onin

eH

igh

olei

c saffl

ower

, coc

onut

, and

soy o

ils;

DH

A, A

RAC

ow’s

milk

free

and

lacto

se fr

ee; c

onta

ins E

arly

Shie

lde

with

FO

S


Tabl

e 3-

1. In

fant

For

mul

a Mac

ronu

trie

nt C

ompo

sitio

na

Form

ula

(Man

ufac

ture

r)C

arbo

hydr

ate

Sour

cePr

otei

n So

urce

Fat S

ourc

eO

ther

Exte

nsiv

ely

Hyd

roly

zed

Prot

ein

Form

ulas

Nut

ram

igen

/Nut

ram

igen

w

ith E

nflor

a LG

Gf (M

J)C

orn

syru

p so

lids,

mod

ified

corn

star

chC

asei

n hy

drol

ysat

e fro

m

cow

’s m

ilkPa

lm o

lein

, soy

, coc

onut

, and

hig

h ol

eic

sunfl

ower

oils

; DH

A, A

RA

MC

T: 0

%

Lact

ose f

ree

Preg

estim

il (M

J)C

orn

syru

p so

lids,

mod

ified

corn

star

chC

asei

n hy

drol

ysat

e fro

m co

w’s

milk

Hig

h ol

eic s

afflow

er o

r sun

flow

er, c

orn,

soy,

and

MC

T o

ils; D

HA

, ARA

MC

T: 5

5%

Lact

ose f

ree

Sim

ilac E

xper

t Car

e Al

imen

tum

(A)

Cor

n m

alto

dext

rin,

sucr

ose

Cas

ein

hydr

olys

ate f

rom

cow

’s m

ilk, l

-cys

tine,

l-ty

rosin

e, l-

tryp

toph

an

Hig

h ol

eic s

afflow

er, M

CT,

and

soy o

ils;

DAT

EMg (D

HA

, ARA

)M

CT:

33%

Lact

ose f

ree a

nd co

rn fr

ee

Free

Am

ino

Aci

d Fo

rmul

asEl

eCar

e (A)

Cor

n sy

rup

solid

sFr

ee am

ino

acid

sH

igh

olei

c saffl

ower

, MC

T, an

d so

y oils

; D

HA

, ARA

MC

T: 3

3%

Lact

ose f

ree,

cow

’s m

ilk fr

ee, a

nd so

y fre

e

Neo

cate

Infa

nt D

HA

an

d ARA

(Nu)

Cor

n sy

rup

solid

sFr

ee am

ino

acid

sPa

lm ke

rnel

and/

or co

conu

t (M

CT

), hi

gh

olei

c sun

flow

er, a

nd so

y oils

; DH

A, A

RAM

CT:

33%

Lact

ose f

ree

Neo

cate

Nut

ra (N

u)C

orn

syru

p so

lids,

corn

starc

h, su

cros

eFr

ee am

ino

acid

sC

ocon

ut, h

igh

olei

c sun

flow

er, c

anol

a, an

d su

nflow

er o

ilsM

CT:

5%

Lact

ose f

ree;

for i

nfan

ts 6

mon

ths a

nd o

lder

Nut

ram

igen

AA

LI

PIL

(MJ)

Cor

n sy

rup

solid

s, m

odifi

ed ta

pioc

a sta

rch

Free

amin

o ac

ids

Palm

ole

in, h

igh

olei

c sun

flow

er, c

ocon

ut,

and

soy o

ils; D

HA

, ARA

MC

T: 0

%

Lact

ose f

ree

Hig

h M

CT-

Con

tain

ing

Form

ulas

Enfa

port

(MJ)

Cor

n sy

rup

solid

sC

alci

um an

d so

dium

case

inat

e fro

m co

w’s

milk

MC

T an

d so

y oils

; DH

A, A

RAM

CT:

84%

30 kc

al/o

z RT

F on

ly; 4

5% o

f cal

orie

s fro

m fa

t; su

cros

e fre

eM

onog

en (N

u)C

orn

syru

p so

lids

Whe

y pro

tein

conc

entra

te fr

om

cow

’s m

ilk, s

oy le

cith

inFr

actio

nate

d co

conu

t and

wal

nut o

ilsM

CT:

80%

For c

hild

ren

≥ 1

year

of a

ge; 2

4% o

f cal

orie

s fro

m fa

t

Porta

gen

(MJ)

Cor

n sy

rup

solid

s, su

cros

eSo

dium

case

inat

e fro

m

cow

’s m

ilk

MC

T an

d co

rn o

ilsM

CT:

87%

40%

calo

ries f

rom

fat;

pow

der o

nly;

not

reco

mm

ende

d as

an in

fant

form

ula

a The m

ost u

p-to

-dat

e inf

orm

atio

n ca

n be

obt

aine

d on

the m

anuf

actu

rers

’ Web

site

s: A

bbott

Nut

ritio

n, w

ww.

abbo

ttnut

ritio

n.co

m; M

ead

John

son

Nut

ritio

n, w

ww.

mea

djoh

nson

.com

(fol

low

the l

ink t

o th

e U.S

. Hea

lth

Prof

essio

nals

site)

; Ger

ber/

Nes

tlé, w

ww.

med

ical

.gerb

er.co

m; a

nd, N

utric

ia, w

ww.

nutr

icia

-na.

com

. All

info

rmat

ion

obta

ined

from

com

pany

Web

site

s; la

st ac

cess

ed M

ay 2

8, 2

012.

b Nat

ural

Def

ense

Dua

l Pre

biot

ic is

GO

S an

d po

lyde

xtro

se.

c NU

TR

IPRO

TEC

T is

a pr

oprie

tary

mix

ture

of v

itam

ins A

, C, a

nd E

and

zinc

.d IM

MU

NIP

ROT

ECT

is a

prop

rieta

ry m

ixtu

re o

f vita

min

s A, C

, and

E; z

inc,

and

BIFI

DU

S BL

, a p

ropr

ieta

ry cu

lture

of B

ifido

bacte

rium

lacti

s.e Ea

rlySh

ield

is a

prop

rieta

ry d

esig

natio

n fo

r the

addi

tion

of lu

tein

, DH

A, A

RA, c

alci

um, n

ucle

otid

es, p

rebi

otic

s, an

d ca

rote

noid

s and

the a

bsen

ce o

f pal

m o

lein

oil.

f Enflo

ra L

GG

is a

prop

rieta

ry d

esig

natio

n fo

r Lac

toba

cillu

s GG

.g D

ATEM

is a

prop

rieta

ry so

urce

of D

HA

and

ARA

.A

= A

bbott

Nut

ritio

n, C

hica

go, I

L; A

RA =

arac

hido

nic a

cid;

DH

A =

doco

sahe

xano

ic ac

id; F

OS

= fru

cto-

olig

osac

char

ides

; G =

Ger

ber;

GO

S =

gala

cto-

olig

osac

char

ides

; MC

T =

med

ium

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system so that a defect in one transporter usually does not result in the inability to absorb a particular amino acid. Peptides are absorbed either through diffusion or through a sodium-dependent process by peptide transporter I, which is also involved in the absorption of some drugs. Peptides are converted in the entero-cytes to amino acids, which are then transported into the portal system. Recent evidence suggests that, rela-tive to intact protein, hydrolyzed proteins are absorbed and metabolized in a way that promotes satiety, possibly because of the gut nutrient-sensing system and/or more rapid nutrient absorption. Protein sources in infant formulas include cow’s milk protein (casein and whey), soy protein, and hydrolyzed casein or whey in the form of peptides or amino acids. Whey protein is a collection of water-soluble globular proteins that remain soluble in gastric acid, which makes them easily digestible. Casein protein is more difficult to digest than whey protein because it is poorly soluble in water; thus, it is prone to curdling in the stomach. Human milk has a whey/casein ratio of 70:30, whereas the ratio in cow’s milk is 18:82. Human milk also has a different amino acid profile from cow’s milk. The pro-tein in human milk is more easily digestible than the protein in cow’s milk–based formulas. For this reason, some infant formulas are altered to contain primarily whey protein, or they are supplemented with whey pro-tein to improve digestion. Some specialty infant formu-las contain hydrolyzed proteins that vary in the degree to which the allergy-causing proteins have been mod-ified – partially hydrolyzed or extensively hydrolyzed. The most hypoallergenic infant formulas have only free amino acids as the protein source.

Fats Fat is an important source of calories in the infant. About 50% of the calories in human milk and most infant formulas are provided by fat. Nonfat cow milk is used in the manufacture of infant formulas. The pri-mary form of fat in formulas is long-chain fatty acids provided by the addition of corn, soy, sunflower, or saf-flower oil. Because evidence suggests that palm olein oil allows fat to bind with calcium, thereby decreasing calcium absorption, most manufacturers have removed palm olein oil from their infant formulas. Sufficient intake of the long-chain polyunsaturated fatty acids linoleic acid and linolenic acid is needed to ensure optimal formation of phospholipid membranes, which is especially important in central nervous sys-tem development. Arachidonic acid (ARA) and docosa-hexanoic acid (DHA) are long-chain fatty acids found in human milk and are important in the brain and ret-ina. Infants fed a formula not supplemented with these two fatty acids have lower serum concentrations than infants fed human milk. Supplementation of these two fatty acids is associated with improved cognitive

function, and they are now added to most infant for-mulas. The routine addition was based on short-term studies; long-term results from postmarketing assess-ments may provide additional information regarding the safety and efficacy of adding these fatty acids. The American Academy of Pediatrics (AAP) has published no official position on the supplementation of infant for-mulas with ARA and DHA. Digestion of fat begins in the stomach but primar-ily occurs in the intestine because of the action of pan-creatic lipase as well as phospholipase A and cholesterol esterase, which are similar to enzymes found in human milk. Bile salts are needed to solubilize the lipid particles to make them more hydrophilic and thus absorbable. As the fat particles are broken down, micelles are formed. Unlike carbohydrate and protein, which after entering the enterocyte go directly into the portal circulation, fats are re-esterified and then combined with proteins to form chylomicrons, which are taken up by the lymphatic capil-laries (lacteals) in the lining of the small intestine, bypass-ing the portal circulation. Chylomicrons eventually enter the superior vena cava through the thoracic duct. Once in the blood, free fatty acids are transported into the mito-chondria by carnitine-dependent transport, where they undergo ß-oxidation to provide energy. The toxic by-products of this metabolism are then transported out of the mitochondria by carnitine esters. Some fat can be absorbed without micelle formation. However, choles-terol and fat-soluble vitamins are almost totally insoluble in water and require micelles to be absorbed. Thus, if bile salts are decreased below a critical level, fat-soluble vita-min deficiencies can occur. Medium-chain triglycerides (MCTs) are absorbed by simple diffusion across the mucosal membrane directly into the blood. Thus, MCT absorption is independent of normal function of the pancreas (lipase), biliary tract (bile), and lymphatic system. In addition, transport of MCTs into the mitochondria is a carnitine-independent process. The amount of MCTs in infant formulas, which varies from 0% to 87%, is generally based on the intended use of the formula. Medium-chain triglycerides do not provide essential fatty acids; thus, the use of formulas with a high MCT content carries the risk of producing essential fatty acid and fat-soluble vitamin deficiencies.

Formula Types Term Infant Formulas Formula choice for the term infant depends on mac-ronutrient considerations and cost. The decision regard-ing which formula to initiate is made by the parents, the hospital, or The Special Supplemental Nutrition Pro-gram for Women, Infants, and Children – better known as the WIC program – for families that qualify. Changes in an infant’s formula are frequently made by parents or other caregivers without consulting the primary care


provider, often in response to concerns regarding vari-ous gastrointestinal symptoms (e.g., straining, gas, con-stipation, vomiting) or infant behavior (e.g., colic).

Standard Cow’s Milk–Based Formulas Many formulas are available for healthy term infants (Table 3-1). These formulas generally are cow’s milk based, containing primarily lactose and casein as well as vegetable oils (no MCTs), vitamins, and minerals. When mixed to the standard concentration, they pro-vide 20 kcal for each ounce consumed. Many products, proprietary and generic, are available in this category. Requirements for infant formula composition are man-dated by the Federal Food, Drug, and Cosmetic Act. Parents can be confident that a marketed product sup-plies nutrients that meet the minimum standards set by the U.S. Food and Drug Administration (FDA). These standards can be found at www.fda.gov/Food. The FDA monitors infant formula manufacturers closely to ensure that products provide appropriate nutrition for the infants receiving them. The most recent sub-stantial change in term infant formula composition occurred around 2000, when the polyunsaturated fatty acids DHA and ARA were first added to infant formu-las. Now, most infant formulas are supplemented with these fatty acids. Recently, both probiotics and prebiot-ics were added to some term infant formulas in the con-tinued quest to make them more like human milk.

Lactose-Free or Lactose-Reduced Formulas Lactose confers health benefits, including prebiotic effects, stool softening, and enhanced water, sodium, and calcium absorption. However, there is no nutri-tional need for lactose. All extensively hydrolyzed pro-tein- and soy-based formulas are lactose free. Cow’s milk–based products can be made lactose free by enzy-matic hydrolysis of the lactose. Formulas in this cate-gory include Similac Sensitive and Similac Sensitive for Spit-up (Abbott Nutrition, Chicago, IL). Other formu-las are considered lactose reduced as they have substan-tially less lactose than other standard term infant for-mulas. Gerber Good Start Soothe (30% lactose; Société des Produits Nestlé, Vevey, Switzerland) and Enfa-mil Gentlease (20% lactose; Mead Johnson Nutrition, Evansville, IN) are formulas in this category. These for-mulas are intended for use in infants who have intoler-ance to cow’s milk–based formulas thought to be related to the lactose content because of their symptoms. Only formulas that are 100% lactose free can be safely used in infants with galactosemia. The cost of these products is comparable to other standard term infant formulas.

Partially Hydrolyzed Whey Formulas Several cow’s milk–based infant formulas contain 100% partially hydrolyzed whey protein (i.e., Gerber Good Start Protect and Gerber Good Start Gentle [Société des

Produits Nestlé, Vevey, Switzerland]). Although their pro-tein content is more similar to human milk, the predomi-nant whey protein in cow’s milk is ß-lactoglobulin, and the predominant whey protein in human milk is α-lactalbumin, which results in a different amino acid profile. The whey predominance of these formulas may improve digestion and absorption. These formulas may be the initial infant formula used or an alternative for infants who are intol-erant of standard cow’s milk–based formulas. The partial hydrolysis of the proteins in these formulas also makes them less antigenic than standard cow’s milk–based for-mulas; however, these formulas are not recommended for infants with cow’s milk-protein allergy (CMA).

Follow-up Formulas As the older infant grows more slowly, nutrient requirements per kilogram of body weight decrease. In addition, the older infant’s metabolic processes are bet-ter developed, and formula is no longer the sole source of nutrition because complementary feeding generally begins between 4 months and 6 months. For these rea-sons, most standard cow’s milk- and soy-based term infant formulas also come in formulations modified for use in older infants and toddlers, generally aged 9–24 months. When mixed to the standard concentration, these products also provide 20 kcal per ounce con-sumed. Compared with standard term infant formulas, the calcium and phosphorus intake provided by these products is higher, 190% to 300%, respectively. In addi-tion, iron is provided at an 11% to 33% higher concen-tration than standard term infant products. No avail-able data suggest that these products provide better out-comes than simply continuing a standard term infant formula through 12 months of age; thus, their use is pri-marily driven by caregiver preference and cost. Exam-ples of these products are Gerber Good Start 2 Gentle and Gerber Good Start 2 Soy (Nestlé); Enfagrow PRE-MIUM Toddler Natural Milk, Enfagrow PREMIUM Toddler, Enfagrow PREMIUM Older Toddler Vanilla, Enfagrow Soy Toddler, and Enfagrow Gentlease (Mead Johnson); and Similac Go & Grow Milk-Based Formula and Similac Go & Grow Soy-Based Formula (Abbott).

Preterm Infant Formulas The primary goal for nutrition of the premature infant is to supply sufficient nutrients so that the rate of growth and changes in body composition closely mimic those of the normal fetus of the same gestational age. Failure to achieve intrauterine growth rates, however, is common in neonatal intensive care units, especially for extremely low-birth-weight babies (birth weight 1000 g or less). Data from the National Institutes of Health Neonatal Research Network document that, at the time of discharge, the average weight of infants born between 24 weeks and 29 weeks gestational age is below the 10th percentile for expected weight at their


gestational age. Therefore, early nutritional manage-ment may have important implications for outcome in premature infants. Similar to the preferred source of nutrition for term infants, human milk is the preferred source of nutrition for premature infants. However, human milk does not meet the nutritional needs of pre-mature infants, particularly in protein delivery, so forti-fication of human milk with various products is needed. In addition, when human milk is unavailable, an alter-native is required, and because term infant formulas do not provide suitable nutrition for these infants, formulas intended for premature infants are marketed.

Human Milk Fortifiers Because human milk does not meet the nutri-tional needs of a premature infant, supplementation is required, especially during the early weeks of life. A human milk fortifier can be added to an aliquot of expressed human milk. For the two commonly used powder products, Enfamil Human Milk Fortifier (Mead Johnson) and Similac Human Milk Fortifier (Abbott), one packet of powder added to 25 mL of human milk yields a final caloric concentration of 24 kcal/oz and increases the protein, calcium, phosphorus, and other nutrient levels to better meet the needs of a premature infant. These products are expensive, usually about $1 per packet, and may be difficult for some to obtain in the outpatient setting. Some neonatal practitioners may also add protein and/or carbohydrate powders. Newer liquid human milk fortifiers, Similac Human Milk For-tifier Concentrated Liquid (Abbott), Prolact+ H2MF (Prolacta Bioscience, Monrovia, CA), and Enfamil Human Milk Fortifier Acidified Liquid (Mead John-son), may also be added. A new liquid protein supple-ment will soon be marketed by Abbott. The nutritional value of human milk can be increased by adding post-discharge formula (see Table 3-2) powder. One tea-spoon of powder added to 90 mL of human milk yields a 24-kcal/oz preparation and increases nutrient delivery by 20%. The role of postdischarge formulas and supplements for the breastfeeding neonatal intensive care unit grad-uate is still unclear. In a recent study, neither fortified maternal milk nor preterm formula, compared with unfortified maternal milk, improved growth outcomes at 1 year. Another study showed increased weight gain but no difference in bone mineral density or head cir-cumference in infants fed fortified milk compared with controls. Too-rapid growth during infancy has been associated with an increased risk of cardiovascu-lar disease, hypertension, obesity, and type 2 diabetes mellitus in adult life. Thus, too-rapid catch-up growth should be avoided. More information is needed to determine the role of human milk fortification in breastfeeding infants discharged from the neonatal intensive care unit.

Standard In-hospital Preterm Formulas Formulas intended for use in newborn premature infants (see Table 3-2) are generally available in ready-to-use bottles for in-hospital use only. Infants are not generally discharged home on these formulas, except in special circumstances. The use of these preterm infant formulas is appropriate for most preterm infants until they reach a body weight between 1800 g and 2000 g; however, infants with bronchopulmonary dysplasia, will benefit from the use of these products until a weight of 3000 g is reached. In general, preterm infant formu-las are higher in protein, calcium, phosphorus, vita-mins A and D, folic acid, and zinc than standard term infant formulas, and some of the fat is added as MCTs to improve fat absorption. Although the standard caloric density of these products is 24 kcal/oz, they are also available in 20-kcal/oz ready-to-feed products. Simi-lac Special Care 30 (Abbott) and Enfamil Premature 30 (Mead Johnson) are relatively new products that can be fed directly to an infant or mixed with other lower-concentration formulas to increase the caloric density and nutrient delivery, avoiding the use of powdered sup-plements. Growth in premature infants receiving these formulas is better than in infants fed unfortified human milk or term infant formulas.

Postdischarge Formulas With the continued need for catch-up growth, the nutritional requirements of premature infants after dis-charge are higher compared with those of their term infant peers. Although many studies have evaluated nutri-tion in hospitalized premature infants, few studies have investigated the nutritional requirements of premature infants once they are discharged from the hospital. At dis-charge, the weight of around 90% of extremely low-birth-weight infants falls below the 10th percentile compared with the reference fetus. At 30 months, about 32%, 24%, and 21% of these infants remain below the 10th percen-tile on the Centers for Disease Control and Prevention growth charts for weight, length, and head circumfer-ence, respectively. Therefore, nutrition after discharge is critical to ensure adequate catch-up growth. As previously noted, the preterm infant formulas used in the hospital are not generally prescribed for use after discharge. Three products are marketed as postdis-charge formulas for preterm infants (i.e., Similac Expert Care NeoSure [Abbott], Enfamil EnfaCare [Mead Johnson], and Gerber Good Start Nourish (Nestlé)]. These formulas provide lower nutrient concentrations than in-hospital premature formulas but higher nutri-ent densities than term infant formulas, particularly calories (i.e., 22 kcal/oz is the standard concentration), protein, calcium, phosphorus, and vitamins. Infants are generally transitioned to a postdischarge formula when they reach a weight of 1800–2000 g or at 34 weeks postconceptional age and they are continued on them


Table 3-2. Formulas for Premature Infantsa

Formulabkcal/dL

(kcal/oze)Proteinc (g/dL)

Fatd (g/dL)

Vitamin D (IU/dL)

Calcium (mg/dL)

Phosphorus (mg/dL)

Iron (mg/dL) Comments

Preterm, In-hospital FormulasSimilac Special Care 20 with iron (A)

68 (20)

2 3.7(MCT 50%)

101 122 68 1.2 Low-iron version available with 0.25 mg iron per dL

Similac Special Care 24 (A)

81 (24)

2.4 4.4(MCT 50%)

122 146 81 1.5 Low-iron version available with 0.3 mg iron per dL

Similac Special Care 24 High Protein (A)

81 (24)

2.7 4.4(MCT 50%)

122 146 81 1.5

Similac Special Care 30 (A)

101 (30)

3 6.7(MCT 50%)

152 183 101 1.8

Enfamil Premature 20 (MJ)

68(20)

2 3.4(MCT 40%)

162 111 56 1.2 Low-iron version available with 0.3 mg of iron per dL


80 (24)

2.4 4.1(MCT 40%)

193 133 67 1.4 Low-iron version available with 0.3 mg of iron per dL

Enfamil Premature 24 High Protein (MJ)

80 (24)

2.8 4.1(MCT 40%)

193 133 67 1.4


101(30)

3.1 5.2(MCT 40%)

246 169 85 1.8

Gerber Good Start Premature 24 (G/N)

80(24)

2.4 4.2(MCT 40%)

144 131 68 1.4

Gerber Good Start Premature 24 High Protein (G/N)

80 (24)

2.9 4.2(MCT 40%)

144 131 68 1.4

Postdischarge FormulasSimilac Expert Care NeoSure (A)

74 (22)

2.1 4.1(MCT 25%)

52 78 46 1.3

Enfamil EnfaCare (MJ)

74(22)

2.1 4(MCT 20%)

53 90 50 1.3

Gerber Good Start Nourish (G/N)

74(22)

2 3.8(MCT 20%)

58 88 47 1.3

aAll information obtained from company Web sites; last accessed May 28, 2012.bCarbohydrate sources for Enfamil Premature and Similac Special Care products are corn syrup solids and lactose; and for Gerber Good Start products, maltodextrin and lactose.cProtein sources for Enfamil Premature and Similac Special Care products are nonfat cow’s milk and whey protein concentrate (casein:whey = 40:60); and for Gerber Good Start products, 100% partially hydrolyzed whey protein.dFat sources for Enfamil Premature products are MCT, soy, high oleic safflower or sunflower oil; for Similac Special Care products, MCT, soy, and coconut oil; and for Gerber Good Start products, MCT, soy, high oleic safflower oils. All products contain DHA and ARA.eFluid ounce = 29.6 mLA = Abbott Nutrition, Chicago, IL; ARA = arachidonic acid; DHA = docosahexanoic acid; G = Gerber; MCT = medium-chain triglycerides; MJ = Mead Johnson Nutrition, Evansville, IN; N = Société des Produits Nestlé, Vevey, Switzerland.


until 40–52 weeks postconceptional age depending on their growth. Of interest, studies comparing the use of postdischarge formulas with standard term infant for-mulas in preterm infants after hospital discharge have found no significant differences in growth outcomes. However, if a term infant formula is used for a preterm infant, additional vitamin and iron supplementation is recommended.

Specialty Infant Formulas Soy Protein–Based Formulas Soy protein–based formulas (Table 3-1) have been available in the United States for almost 100 years, and they have about 20% of the infant formula market share. Despite their long-term availability and widespread use, the 2008 AAP statement on the use of soy formu-las advised few indications for these products. The state-ment also noted, however, that the contraindications are few if caregivers choose to use them. In soy protein–based formulas, soy replaces the cow’s milk, corn syrup solids, and sucrose used in standard cow’s milk–based products, so they are also lactose free. Soy protein–based formulas may be used for infants with lactose intolerance and galactosemia, as well as when the parents prefer a vegan or vegetarian diet. They are contraindicated in premature infants (birth weight less than 1800 g) in whom slower weight and length gains and decreased bone mineralization occur with soy formula use. In addition, infants with cystic fibro-sis should not receive soy formulas, even with pancre-atic enzyme supplementation, because of the poor nutri-tional outcomes noted with soy formula use in this pop-ulation. Their use in infants with CMA or those at high risk of atopic disease is controversial. Sensitivity to soy protein is present in 30% to 50% of infants with enter-opathy or enterocolitis associated with CMA; thus, soy formulas are not recommended for infants with CMA. Routine use of soy formulas in infants at high risk of atopic disease does not reduce risk. Prevention of atopic disease with infant formula modifications will be dis-cussed later in this chapter. Soy formulas contain soy isoflavones and phytoes-trogens. Concerns regarding the use of soy formulas in infancy and subsequent developmental and reproductive health issues in later life have been raised. Despite com-mon misconceptions, these concerns are unfounded. One study of more than 800 young adults (20–34 years of age) showed no differences in weight, height, age of puberty, fertility, or number of offspring between those who received soy-based formulas and those who received cow’s milk–based formulas during infancy.

Hydrolyzed Protein Formulas Extensively Hydrolyzed Protein Formulas In hydrolysate-based formulas, the protein has under-gone heat-treated, enzymatic hydrolysis into peptide

chains and free amino acids (see Table 3-1). Hydrolysis results in a continuum of protein particles ranging from intact to amino acids. These products are also referred to as extensively hydrolyzed protein formulas to distin-guish them from cow’s milk–based whey-predominant partially hydrolyzed protein formulas. The component that distinguishes one extensively hydrolyzed protein formula from another is not the protein but the mix-ture of long-chain fatty acids and MCTs in the product. The presence of MCT, helps improve fat absorption in patients with conditions predisposing to fat malabsorp-tion; thus, the MCT content may determine the most appropriate formula for a given infant. Common diag-noses for which these products are indicated include cystic fibrosis, biliary atresia, short bowel syndrome, generalized malabsorption, and non–immunoglobu-lin E (IgE)-mediated CMA. These formulas are signif-icantly more expensive (about twice the cost) and less palatable than standard infant formulas. Although these products are often recommended in infants with severe colic, data do not support their use for this indication. However, for an infant with severe colic unresponsive to other interventions, a 1- to 2-week trial of an extensively hydrolyzed formula is considered appropriate, and if no appreciable improvement in symptoms occurs, the for-mula should be changed to a less-expensive product.

Free Amino Acid–Based Formulas The distinguishing feature of amino acid–based for-mulas is that 100% of the protein is provided as free amino acids (see Table 3-1), making them the most hypoallergenic infant formulas. They are indicated in children with severe cow’s milk or soy protein hyper-sensitivity and many food protein intolerances, includ-ing those with eosinophilic esophagitis. These prod-ucts also vary in MCT content, and many of them can be used in infants with malabsorption syndromes. Free amino acid–based formulas are very expensive (at least twice the cost of standard infant formulas) and less pal-atable than other products; thus, they should be used only in infants who need them.

High MCT-Containing Formulas Several infant formulas contain MCTs, which are important in patients with impaired digestion and absorption of long-chain fats because of pancreatic or biliary disease or short bowel syndrome (Table 3-1). Infants who develop parenteral nutrition–associated cholestasis and are not already receiving a formula high in MCTs may benefit from changing to one to improve fat absorption. These patients are often also receiving ursodiol. Ursodiol does not form mixed micelles and thus has no effect on fat absorption. Infants with cys-tic fibrosis may also benefit from the use of these prod-ucts. However, 5% to 10% of infants with cystic fibrosis receiving these products still have fat losses higher than


25% and protein losses of 18%, so the use of pancreatic enzyme supplementation is recommended even when one of these predigested formulas is used. Several products have a very high MCT concentra-tion (80% to 87% of the fat) and thus minimal long-chain triglycerides. These products are indicated in patients with inborn errors of fatty acid metabolism, such as long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and hyperlipoproteinemia type 1, and patients with chylo-thorax, chylous ascites, or lymphatic dysplasia. For many years, the only available product in this category was Por-tagen (Mead Johnson; 87% MCT), which is available only as a powder. In 2001, an outbreak of Enterobacter sakazakii in one neonatal intensive care unit raised con-cerns about the use of nonsterile infant formula powders in neonates and other immunocompromised patients. A newer liquid product, Enfaport (Mead Johnson; 84% MCT), is available as a 30-kcal/oz formulation. This caloric density necessitates dilution of the product to a more appropriate concentration for infants, adding a risk of mixing errors. Monogen (Nutricia, Gaithersburg, MD; 80% MCT) is a milk protein–based powdered for-mula also in this category. Because MCTs do not provide essential fatty acids, use of these products with 80% or more of the fat pro-vided as MCTs increases the risk of developing essen-tial fatty acid deficiency, especially in very young infants with minimal fat stores. Signs and symptoms of essen-tial fatty acid deficiency in infants include dry, scaly skin and scalp; dry, brittle hair; and failure-to-thrive. Serum fatty acid concentrations also can be used to monitor for deficiency. A high amount of MCTs in the diet has been associated with a greater incidence of diarrhea.

Iron Fortification of Infant Formulas Iron-deficiency anemia is associated with long-term cognitive, psychomotor, behavioral, and developmen-tal effects. Iron-fortified infant formulas, together with iron-fortified cereals beginning at age 4–6 months, decrease the risk of iron deficiency. The WIC program requirement that all formulas distributed through the program be iron-fortified has been credited with a sub-stantial reduction in the incidence of iron-deficiency anemia in the United States. Since 1999, the AAP has stated that no medical condition is a contraindication to the use of an iron-fortified formula and has recom-mended that all formulas be fortified with iron. For this reason, almost all formulas sold in the United States are iron-fortified. The preterm infant formulas, however, are available in low-iron formulations. Parents often blame certain gastrointestinal symp-toms (e.g., colic, constipation, diarrhea, vomiting, straining upon defecation) on the iron in the formula.

Well-controlled studies have consistently failed to show any increase in the prevalence of fussiness, cramping, colic, constipation, gastroesophageal reflux (GER), or flatulence with iron-fortified formulas.

Nutritional Supplements in Infant Formulas Gut microflora play an important role in infant health. Before birth, the gastrointestinal tract of a fetus is sterile. Early colonization plays a crucial role in the development of innate and adaptive immune systems. The composition of the gut microflora differs depend-ing on the infant’s diet. Colonizing bacteria (primarily bifidobacteria in the normal human milk–fed infant) stimulate enterocytes and lymphoid elements, promot-ing a T-helper type 1 cell response and restoring balance toward tolerance. In the first 2 days after birth, Esche-richia coli and enterococci predominate in the gastro-intestinal tract of the breastfed infant, but by the end of the first week, bifidobacteria are the predominant organisms, with a ratio of bifidobacteria to enterobacte-ria greater than 1000:1. The introduction of infant for-mula results in a change in the gut microbiota, resulting in a change in stool color, consistency, and odor. At any time, diet, environmental stresses, infection, and anti-biotic use can alter the gut microflora. The gut flora can also be altered by the addition of probiotics or prebiotics to the diet. One strategy employed by formula manufacturers has been to add either prebiotics or probiotics to their infant formulas, making them more like human milk, with the goal of producing gut microflora similar to that seen in human milk–fed infants.

Probiotics Probiotics are live microorganisms that confer ben-eficial effects on the host. These organisms provide pro-tective effects by enhancing the defenses of the gastro-intestinal tract mucosal immune system, probably by preventing colonization and translocation of patho-genic bacteria. These organisms also compete for recep-tor sites and nutrients to produce antibiotic substances and to increase immunoglobulin A production. Certain probiotic organisms, Bifidobacterium infantis, Lactoba-cillus spp., and Saccharomyces boulardii, are found in rel-atively high concentrations in human milk. Probiotics can be added to infant formulas by their manufactur-ers without substantial testing because they are cate-gorized as Generally Regarded as Safe (GRAS) by the FDA. Probiotics, usually added extemporaneously to an infant’s formula, have been evaluated in controlled clinical trials and found effective for many indications, including the prevention of antibiotic-associated diar-rhea, prevention of necrotizing enterocolitis (NEC)


in very low-birth-weight neonates, and prevention of atopic disease. Data in atopic disease have been conflict-ing. Probiotic use appears to be safe in healthy infants, but there have been case reports of systemic infec-tion with bacteria given as probiotics in critically ill or immunocompromised patients. However, in 11 con-trolled trials where probiotic administration was evalu-ated in neonates to reduce the risk of developing NEC, no systemic infections with the probiotics administered were reported. Lactobacillus reuteri is now added to Ger-ber Good Start Soothe (Nestlé), Lactobacillus rham-nosus GG is added to Nutramigen with enflora LGG (Mead Johnson), and BIFIDUS BL is added to Gerber Good Start Protect (Nestlé). BIFIDUS BL is a propri-etary product with Bifidobacterium lactis cultures.

Prebiotics Human milk stimulates the growth of Bifidobacterium spp. because of its high oligosaccharide content (10–12 g/L). Prebiotics are dietary oligosaccharides, primarily fructo- or galacto-oligosaccharides (FOS, GOS), that are indigestible and not absorbed, but they stimulate the growth and activity of beneficial colonic bacteria, such as Lactobacillus spp. and Bifidobacterium spp. Many dif-ferent forms of oligosaccharides are found in human milk, comprising 0.7% of the content. Oligosaccharides likely contribute to the anti-infective and allergy-pre-ventive properties associated with human milk. Several infant formulas have been supplemented with GOS, including Enfamil PREMIUM Newborn and Enfamil PREMIUM Infant (Mead Johnson), Similac Advance Early Shield and Similac Sensitive (Abbott), and Gerber Good Start Gentle (Nestlé). In one study that assessed the use of an infant for-mula supplemented with GOS compared with the use of a standard hypoallergenic formula, weight gain and linear growth were similar; however, infants in the sup-plemented group had more diarrhea, eczema, and irri-tability. Flatulence, borborygmi, abdominal cramping, bloating, and increased stool volume have also been reported in infants receiving formulas supplemented with GOS.

Formula Selection for Specific Conditions Gastroesophageal Reflux Gastroesophageal reflux affects 20% to 40% of all infants. One long-established practice in the manage-ment of GER is to thicken feedings with rice cereal to keep the liquid nutrition in the stomach and prevent reflux. Although adding rice cereal does not decrease the time that the pH is less than 4, it does decrease the frequency of overt regurgitation, time spent crying, and time spent awake. However, several problems exist with

adding rice cereal to formula. It is inconvenient for the parents to add rice cereal to each bottle. Thicker formula is harder to get through the nipple, so either the hole has to be made bigger or the infant must exert a lot of energy to suck the thickened formula from the bottle. Thick-ened feedings with rice cereal have been associated with increased coughing during feedings, difficulty sucking, and delayed gastric emptying. A significant potential disadvantage of using rice cereal to thicken feeds is the excessive energy intake that often results and that this excess caloric intake comes primarily from increased carbohydrate intake. For example, 1 teaspoon of infant rice cereal or oatmeal (60 kcal/tbsp) added to 1 oz of 20-kcal/oz formula (typical mixture for nectar consis-tency) increases the energy density to around 40 kcal/oz. Some practitioners report adding 1 tablespoonful of cereal to each 1 oz of formula, which would result in a caloric density of about 80 kcal/oz. Despite the con-cern with overfeeding, one study evaluating rice cereal as a thickening agent found no difference in weight gain between the thickened formula and control formula groups. Another disadvantage of rice cereal–thickened feedings is increased difficulty with defecation or consti-pation, which has been reported in up to 36% of infants receiving smaller-volume, rice cereal–thickened feeds. Changing the thickening agent to oatmeal has been associated with fewer negative effects on defecation. Because of the issues noted with using rice cereal or oatmeal to thicken formula, several cow’s milk–based formulas with added rice starch are marketed: Enfamil A.R. (Mead Johnson) and Similac Sensitive for Spit-Up (Abbott). These prethickened formulas have a 10 times greater viscosity in the bottle than that of standard for-mula and 3 times less viscosity than rice cereal–thick-ened formula. However, in the acidic environment of the stomach, the rice starch swells, increasing the vis-cosity to 100 times the viscosity of standard infant for-mula. Using prethickened formulas has several advan-tages. The increase in viscosity compared with standard infant formula does not impede flow through the nip-ple, so the infant does not have to work harder to eat. The caloric density (20 kcal/oz) is maintained as well as the delivery of other nutrients, and there appears to be no effect on gastric emptying. Use of prethickened for-mula has not been shown to reduce GER episodes and reduces regurgitation episodes by about 0.6 episodes per day. Thickening and thus efficacy of these products also depend on gastric acidity. The viscosity of Enfamil A.R. increases significantly at a pH of 5.5 or less. The use of a histamine-2 receptor antagonist, which is common in infants with GER, blocks only 70% of gastric acid pro-duction, and the resulting gastric pH will likely be in the range to allow increased viscosity. A proton pump inhibitor, however, potentially blocks 100% of acid pro-duction. Proton pump inhibitors can increase gastric


pH to greater than 5.5, potentially decreasing efficacy of these prethickened products. In one study document-ing a significant decrease in regurgitation with one of these products, only 4% of the patients were receiving concomitant acid suppression therapy. For this reason, the use of these prethickened infant formulas should be tried before initiating drug therapy for GER. The 2009 clinical practice guidelines for pediatric GER published by the North American Society for Pediatric Gastroen-terology, Hepatology and Nutrition and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommend a trial of thickened feedings for infants with mild, uncomplicated GER.

Cow’s Milk-Protein Allergy Cow’s milk contains more than 30 proteins, the most antigenic being ß-lactoglobulin. Although many of the proteins in cow’s milk are similar to those in human milk, ß-lactoglobulin is not found in human milk. Enteropathy caused by CMA is the most common food sensitivity in infancy. The incidence is 0.3% to 0.7% in the general population but is higher in infants with a high risk of atopy because of a family history of atopy (i.e., food allergies, eczema, and asthma). In addition, secondary CMA has been reported after severe gastro-enteritis. Infants with CMA are often extremely irrita-ble, which may be initially diagnosed as colic. Gastroin-testinal symptoms of CMA include vomiting, diarrhea, abdominal pain, bleeding, colitis, protein-losing enter-opathy, and, in some cases, constipation. Respiratory symptoms include recurrent infections, rhinitis, wheez-ing, hemoptysis, and otitis media. Other symptoms include eczema, irritability, failure to thrive, sudden infant death syndrome, and anaphylaxis. Symptoms of CMA can be divided into two categories: IgE-mediated and non–IgE-mediated. Symptoms of IgE–mediated CMA include angioedema, urticaria, hives, wheezing, rhinitis, vomiting, eczema, and anaphylaxis. Non–IgE-mediated symptoms include pulmonary hemosiderosis, malabsorption with villous atrophy, eosinophilic proc-tocolitis and esophagitis, and enterocolitis. Treatment of infants with suspected CMA requires eliminating cow’s milk protein from the diet. About 8% to 14% of infants with IgE-associated symptoms will also react to soy protein, but anaphylaxis is extremely rare. In infants with non–IgE-mediated symptoms (e.g., proc-tocolitis, enterocolitis), the reaction rate to soy protein is much higher (25% to 60%). Mothers who are breast-feeding need to practice a strict allergen-free diet. It may be 5–7 days before the milk is free of all traces of the allergen. The AAP does not recommend the use of soy formulas in infants with suspected or confirmed CMA. Formulas with only partially hydrolyzed whey protein have provoked significant reactions in a high percent-age of infants with CMA and are not intended for this use. An extensively hydrolyzed formula is the preferred

primary intervention in infants with CMA. At least 90% of infants with CMA will tolerate one of these formu-las as well as a free amino acid–based formula. Thus, because of cost and palatability, free amino acid–based formulas should be reserved for infants with severe non–IgE-mediated symptoms (e.g., gastro-enterocoli-tis-proctitis syndromes, severe atopic eczema), infants with symptoms during exclusive breastfeeding, or infants who do not tolerate extensively hydrolyzed protein products. In infants with CMA whose diet is changed to an extensively hydrolyzed protein or free amino acid–based formula, symptom improvement can be seen quickly (within days), with complete resolution in 2–4 weeks. The specialty formula should be contin-ued at least until the infant reaches 1 year of age. At that time, the infant should be evaluated for the persistence of CMA before introducing cow’s milk to the diet.

Chylous Effusions A chylous pleural effusion or chylous ascites is another indication for a specialty infant formula. Leaks in the lymphatic system, because of either a surgical procedure or congenital malformation, result in chylous effusions. Treatment of these types of effusions involves minimizing flow through the lymphatic system. Because long-chain triglycerides are absorbed into the intestinal lacteals and travel by chylomicrons through the lym-phatic system, reducing the dietary intake of long-chain triglycerides is the initial therapy. With the elimination of long-chain fats from the diet, flow through the lym-phatic system is significantly reduced, decreasing the effusion size and allowing an injury to heal, if applicable. In general, when a significant chylous effusion develops in an infant, the initial therapy is total parenteral nutri-tion, which will essentially stop the flow through the lymphatic system. Depending on the response, after 4–6 weeks or longer of parenteral nutrition, a diet low in long-chain fats and high in MCTs is instituted with one of the high MCT-containing infant formulas. For smaller effusions, a low-fat, high-MCT diet may be tried initially. Once the lymphatic leak has ceased, either due to surgical correction or healing of the damaged lym-phatic vessel(s), the diet may be gradually transitioned back to a normal diet over several months. Only a few products have a very high concentration of MCTs (80% to 87%) and minimal long-chain triglycerides: Porta-gen, Enfaport, and Monogen. The long-term use of a high-MCT–containing formula as the sole source of nutrition increases the risk of developing essential fatty acid deficiency.

Kidney Disease There is no product marketed specifically for infants or children with kidney disease. Infants with kidney dysfunction may not tolerate a standard term infant for-mula because of the high phosphorus content. Potassium


restriction is generally not needed until the glomerular filtration rate is less than 10% of normal. The degree of kidney dysfunction rather than the cause determines the type of nutritional intervention required. Preven-tion of growth failure in infants with kidney dysfunc-tion is an important therapeutic goal. Often, young chil-dren may receive a product intended for adults; how-ever, these products will not adequately meet an infant’s nutritional needs. One product, Similac PM 60/40 (Abbott), is lower in phosphorus (19 mg/100 mL vs. 24–36 mg/100 mL in standard term infant formulas), making it a suitable alternative for infants with kidney disease and reduced phosphorus elimination. Soy pro-tein–based products should be avoided in infants with kidney disease because of their higher phosphorus con-tent and the increased renal solute load produced by these formulas.

Inborn Errors of Metabolism A number of congenital defects in nutrient metabo-lism can affect infants. These defects range from those associated with one amino acid (e.g., phenylketonuria, histidinemia) to defects associated with macronutrient metabolism (e.g., fatty acid oxidation disorders) or elim-ination of waste products (e.g., urea cycle disorders). Many products are available to meet the specific dietary needs associated with these defects. A full discussion of these products, their specifications, and their indica-tions is beyond the scope of this chapter, but more infor-mation can be obtained from the manufacturers’ Web sites and the New England Consortium of Metabolic Program’s Web site at http://newenglandconsortium.org/for-professionals/acute-illness-protocols/.

Formula Choice for Disease Prevention Atopic Disease One significant change in the field of food allergy and atopy is the implementation of preventive strategies in early infancy, rather than focusing solely on treat-ment. Allergic diseases result from a strong relationship between genetic and environmental factors. Although it is not documented that cow’s milk–based infant nutri-tion induces a higher risk of allergic disease than breast-feeding, it is well established that infants who are exclu-sively breastfed have a lower rate of atopic disease. Hypoallergenic formulas are promoted as a preventive strategy in infants at high risk of developing allergy symptoms, and some studies support this use. Methods to determine which infants are at high risk are not well defined. Markers used to classify risk of later atopic dis-ease include elevated cord blood and serum IgE and a family history of at least one first-degree relative (par-ent or sibling) with an atopic disease. A family history of

atopy alone may be the most sensitive predictor of later atopic disease. However, many children with atopic dis-ease during the first year of life have families with no history of allergic disease. Breastfeeding exclusively for at least 6 months reduces the risk of later allergic symptoms and eczema, especially in high-risk infants and if the mother avoids cow’s milk, eggs, fish, peanuts, and tree nuts in her diet. Breastfeed-ing to 12 months, the elimination diet noted above, and feeding the infant no solid foods until 6 months, dairy after 1 year, eggs after 2 years, and peanuts, nuts, and fish after 3 years significantly reduce atopic disease in high-risk infants. In addition, alternatives to cow’s milk decrease the future risk of allergic disease or delay the onset of allergic diseases. All the studies assessing the role of infant formula in atopy prevention have evalu-ated high-risk infants defined by various criteria. Exten-sively hydrolyzed protein formulas have a short-term, but not long-term, preventive effect, such as decreased incidence of CMA and, to some extent, atopic dermati-tis. For example, in one study, the use of an extensively hydrolyzed formula compared with a cow’s milk–based formula resulted in a decrease in allergic disorders at 1 year of age but not at 7 years. However, extensively hydrolyzed protein formulas do not appear to confer any long-term negative outcomes, such as increased risk of later allergy because of the possible lack of induc-tion of intolerance. At least six independent meta-anal-yses have concluded that in high-risk infants fed some-thing other than human milk, a partially hydrolyzed whey protein–based formula reduces the risk of allergy. Extensively hydrolyzed formulas, which also confer a protective effect, are recommended by many experts, but these formulas may not be accepted because of poor taste, and they are much more expensive. Soy formulas should not be used for this indication. Adding prebiotics to formula also decreases the inci-dence of atopic dermatitis. When a group of intermedi-ate-risk infants (i.e., one family member with an atopic disease) was fed an extensively hydrolyzed whey formula supplemented with an oligosaccharide (Immunofor-tis, N.V. Nutricia, Zoetermeer, Netherlands), there was a 50% reduction in atopic disease at 6 months compared with infants fed the same unsupplemented formula.

Type 1 Diabetes Mellitus Despite important advances in insulin therapy, type 1 diabetes mellitus (T1DM) remains a devastating diag-nosis for a child and his or her family. The treatment of T1DM is often time-consuming and expensive, and adherence is critical to reducing the short- and long-term complications. Thus, developing a cure or meth-ods to prevent T1DM has received significant focus. Although the cause of T1DM is the loss of insulin-pro-ducing beta-cells in the pancreatic islets, the pathogen-esis has been only partly explained. There is a definite


genetic component, and overt disease is preceded by an asymptomatic period of variable length of increased autoantibodies in the peripheral circulation. Five dis-ease-related autoantibodies predict progression to clini-cal T1DM: islet cell antibodies, insulin antibodies, glu-tamic acid decarboxylase, tyrosine phosphatase–related insulinoma-associated and 2 molecule, and zinc trans-porter 8 autoantibodies. Positivity for two or more of these antibodies predicts a risk of T1DM development within 5–10 years of 50% to 100%, respectively. Almost all genes linked to an increased risk of T1DM also have a known role in immunity, and 90% of patients with T1DM will carry at least one of a few disease-associ-ated human leukocyte antigen (HLA) genotypes. Envi-ronment is also critical in T1DM development, as evi-denced by concordance in identical twins of 50%. Envi-ronmental triggers receiving the most attention are diet; microorganisms, especially enteroviruses; and toxins. The mechanisms of the effects of diet on T1DM in humans are unknown; however, three mechanisms have been proposed: (1) reduced gut permeability, (2) induction of maturation of regulatory T cells in the gut-associated lymphatic tissues, and (3) changes in the gut microflora. One or a combination of these mechanisms is likely involved. In rodent models of T1DM, despite differing study designs, one consensus conclusion has been reached: in controlled research environments, protection from T1DM is afforded by weaning to exten-sively hydrolyzed casein diets, whereas partially hydro-lyzed proteins still rich in potentially antigenic pep-tides promote T1DM development. Preliminary data in human case control studies have shown an inverse relationship between the length of breastfeeding and the risk of developing T1DM. Early formula exposure has also been linked to an increased risk of develop-ing T1DM, but these studies have looked at the general population, not a high-risk population. A pilot study was conducted in Finland, which has one of the highest prevalence rates of T1DM, to deter-mine whether altering the diet to an extensively hydro-lyzed protein formula could decrease the produc-tion of antibodies usually associated with progression to T1DM. In this study, there was a reduction in cer-tain antibodies associated with progression to T1DM, but no reduction in the risk of overt T1DM in infants who received an extensively hydrolyzed protein for-mula (Nutramigen, Mead Johnson) compared with those who received a standard cow’s milk–based for-mula (Enfamil, Mead Johnson). The standard formula was supplemented with hydrolyzed casein powder (4:1 ratio) for blinding to make the taste and smell similar to the extensively hydrolyzed formula. The results of this pilot study led to the development of the Trial to Reduce IDDM [insulin-dependent diabetes mellitus] in the Genetically at Risk (TRIGR), a multicenter, multi-national trial of high-risk infants comparing the results

using the same formulas as the pilot study but powered to detect a difference in the primary outcome of T1DM incidence. More information regarding this trial can be found in the annotated bibliography (reference No. 16). Because the first signs of beta-cell autoimmunity may appear before 3 months of age, T1DM preventive strate-gies are aimed at altering dietary intake in the first months of life. At this time, there is insufficient evidence to sug-gest that use of an extensively hydrolyzed protein for-mula prevents T1DM in high-risk infants; however, these formulas can be used safely in this population if parents, caregivers, or health care professionals wish to use them in infants with a strong family history of T1DM.

Role of the Pharmacist Pharmacists should provide information to families to encourage breastfeeding. When breastfeeding is not pos-sible, proper formula selection for an infant with intoler-ance of standard formula or a specific disease state requir-ing a specialty infant formula is often a challenge for both parents and health care providers. Practitioner knowledge related to infant formulas in general pediatric practice is variable, and parents often make these decisions without consulting their primary care provider. The pharmacist can be an excellent resource for families because phar-macists are readily accessible to parents, and various for-mulas are readily available in pharmacies, grocery stores, and other retail outlets. Specialty infant formulas may require special ordering by the pharmacy. Understanding the alterations required in various conditions and disease states will assist the pharmacist in providing up-to-date, accurate, and cost-effective information to both parents and health care professionals.

Conclusion Breastfeeding remains the gold standard for infant nutrition. However, breastfeeding is not always possible, and many infant formulas are marketed today. Although manufacturers strive to make the products as similar to human milk as possible, substantial differences remain. The proper selection of an infant formula can have a pro-found effect on short- and long-term outcomes in infants. All health care professionals involved in the care of chil-dren should have a working knowledge of these formulas to ensure their safe and appropriate use.

Annotated Bibliography 1. Teitelbaum JE, Lagmay JP. Familiarity of pediatricians

with different commercially available neonatal and infant formulas. Clin Pediatr 2007;46:418–23.

Although parents may ultimately choose the formula their infant receives, they may have many questions for their primary care provider or other health care provider


regarding their choice. These authors conducted a mul-tiple-choice survey that was designed to determine the recipient’s knowledge regarding 14 specific infant for-mulas, ranging from standard full-term infant formulas to free amino acid formulas. The recipients were asked 54 questions about their familiarity with a product, including protein and carbohydrate sources and energy content. They were also asked whether the formula could be used to treat CMA or colic. All pediatricians in New Jersey (n=1612) were mailed a survey, of which only 120 (7.4%) were returned: 101 from general pedi-atricians and 19 from subspecialists (i.e., neonatology, infectious disease, critical care, pulmonary, dentistry, gastroenterology, emergency medicine, allergy, neurol-ogy, cardiology, and medical consulting). Residents-in-training were not included. The recipients were split fairly equally regarding years in practice: less than 5 years, 27%; 5–10 years, 27.5%; and longer than 10 years, 30%. The overall average score was 46% (range, 4% to 70%). Only 10% received a score greater than 65%. Time in practice did not predict score. The protein and carbohydrate sources of the formulas were identified correctly by 51% and 32%, respectively. Energy content was correctly identified by 54%. Although the return rate for the survey was very low, the results suggest that many pediatric practitioners do not have a complete working knowledge of infant formulas. This knowledge deficit provides an opportunity for pharmacists and dietitians to educate caregivers and health care provid-ers and directly affect patient care.

2. Bartick M, Reinhold A. The burden of suboptimal breastfeeding in the United States: a pediatric cost anal-ysis. Pediatrics 2010;125:e1048–56.

Most medical authorities recommend exclusive breastfeeding until at least 6 months of age. Current U.S. breastfeeding rates are suboptimal despite over-whelming evidence to support improved outcomes in infants who are breastfed. Data collected from 1999 to 2006 show that only 69% of women were breastfeed-ing at hospital discharge, and by 6 months, this num-ber decreased to 29%. Recent U.S. data (2005) show that rates of exclusive breastfeeding at 2 days and 6 months are 55.6% and 12.3%, respectively. The rate of any breastfeeding at 6 months was 42.9%, which falls short of the Healthy People 2010 goal of 50%. These newer numbers for breastfeeding rates, together with information published by the Agency for Healthcare Research and Quality regarding cost savings and mor-tality risk reductions with breastfeeding for 10 diseases (i.e., NEC, otitis media, gastroenteritis, hospitaliza-tion for lower respiratory tract infection during infancy, atopic dermatitis, sudden infant death syndrome, child-hood leukemia, childhood asthma, T1DM, and obe-sity), were used for this updated analysis. The authors describe the disease-specific methodology used to esti-mate cost savings for each disease, which provides a sig-nificant amount of information to the reader regarding the risk reductions seen with breastfeeding in each dis-ease state. Based on current breastfeeding rates and evi-dence for disease risk reduction, if 90% of U.S. families

breastfed their newborns exclusively for 6 months, a cost savings of $13 billion annually and 911 fewer deaths would be realized. Numbers for 80% adherence would be $10.5 billion and 741 deaths. These numbers vary substantially from the cost savings estimated (i.e., $3.6 billion) in 2001, which included only three dis-ease states (i.e., NEC, otitis media, and gastroenteri-tis) and industry-collected breastfeeding rates. Of note, neither the 2001 nor this updated evaluation included direct formula cost. The WIC program’s grants to states totaled $7.1 billion in 2011, which includes infant for-mula as well as nutritious foods for children until 5 years of age and pregnant women. This study is impor-tant support for encouraging all mothers to breastfeed their infants, not only for the infant’s health, but also for public health reasons.

3. Mennella JA, Ventura AD, Beauchamp GK. Differ-ential growth patterns among healthy infants fed pro-tein hydrolysate or cow-milk formulas. Pediatrics 2011;127:110–8.

Recent evidence from animal models and adult stud-ies suggests that, relative to intact protein, hydrolyzed proteins are absorbed and metabolized in a way that promotes satiation, possibly because of the gut nutri-ent-sensing system and/or more rapid nutrient absorp-tion. On the basis of this research, these authors eval-uated the outcomes with respect to growth and for-mula acceptance in infants fed a protein hydrolysate formula (Nutramigen, Mead Johnson) compared with a cow’s milk–based formula (Enfamil, Mead Johnson). Infants were initiated on the formula at age 0.5 month, only if the mother had chosen not to breastfeed and was already providing some type of infant formula. Infants were evaluated monthly for 7 months by measurement of anthropometrics and videotaped feeding sessions. Infants in the protein hydrolysate formula group had lower weight-for-length z-scores and a slower weight gain velocity than did infants receiving cow’s milk–based formula. Those in the cow’s milk formula group had accelerated weight gain. Infants receiving protein hydrolysate formula also ate less volume before satia-tion than those receiving a cow’s milk–based formula. There was no difference between the groups in mater-nal ratings of formula acceptance. However, the infants were only followed for 7 months, negating the ability to determine the long-term consequences of these differ-ences in growth. Further research is needed to deter-mine whether there are any long-term consequences of these differences (e.g., increased rates of T1DM, obesity).

4. Osborn DA, Sinn JK. Probiotics in infants for pre-vention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev 2007;4:CD0064.

Patients with atopic disease have microflora that are different from those who do not. These differences in the gut microflora may precede the development of eczema. Human milk contains pre- and probiotics, and infants fed human milk have a lower incidence of atopic disease. The objective of this Cochrane review was to


determine the effect of probiotics given to infants for the prevention of allergic disease or food hypersensitiv-ity. All randomized and quasi-randomized controlled clinical trials published from 1966 to February 2007 that compared the use of a probiotic with no probiotic, the use of a specific probiotic compared with a differ-ent probiotic, or the use of a probiotic with added pre-biotic compared with control and reported outcomes related to atopic disease were included. Studies evalu-ated included the primary outcomes of all allergic dis-eases (i.e., asthma, eczema, rhinitis, and food allergy) and/or food hypersensitivity. Potential harms related to growth or increased cost were also assessed.

Six studies met inclusion criteria, enrolling 2080 infants; however, outcomes were available for only 1549 infants. Dropout rates of 17% to 61% were reported. A meta-analysis of five of the studies that reported the outcomes of 1477 infants found a significant reduction in the incidence of infant eczema (typical relative risk [RR] = 0.82; 95% confidence interval [CI], 0.7–0.95]. In one study, this difference in eczema rates persisted until 4 years of age, after which time there was no difference between the groups. When the findings were limited to confirmed atopic eczema (i.e., positive skin prick test or specific IgE), the results were no longer significant (typical RR = 0.8; 95% CI, 0.62–1.02). No significant adverse effects were reported with the use of probiotics.

The authors concluded that there was insufficient evi-dence to recommend the addition of probiotics to an infant’s diet to prevent allergic disease or food hyper-sensitivity. The results of this meta-analysis should be interpreted with certain limitations considered. Many patients were lost to follow-up. Findings were inconsis-tent between studies, and findings did not always per-sist; in only one study did the benefits persist to 4 years. All the studies reporting significant benefits used L. rhamnosus; there was limited information with other probiotics. Finally, the results cannot be extrapolated to all infants because only infants at high risk of allergy on the basis of family history were enrolled.

5. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necro-tizing enterocolitis in preterm neonates. Pediatrics 2010;125:921–30.

These authors evaluated 38 reports, of which 11 (four new and the seven included in a 2007 meta-analysis) involving 2176 preterm very low-birth-weight infants with gestational age younger than 33 weeks were included. The primary outcome assessed was efficacy of probiotic supplementation in preventing stage 2 or higher NEC; safety, based on blood culture–positive sepsis, including that caused by the organism(s) in the probiotic supplement; and any other reported adverse effects. Secondary outcomes included the time to reach full feeds (i.e., 120–150 mL/kg/day) and duration of hospital stay. A variety of probiotic organisms were used, including the Bifidobacterium spp. breve, longum, bifidus, infantis, and lactis; Lactobacillus spp. GG, aci-dophilus, and casei; Streptococcus thermophilus; and

Saccharomyces boulardii. Four studies used a combina-tion of two or more microorganisms. More patients in the control groups (n=71, 6.56%) than in the probiotic groups (n=26, 2.37%) developed definite NEC. The rel-ative risk of NEC in the probiotics group was 0.35 (95% CI, 0.23–0.55; p<0.00001), with no heterogeneity among the trials. The number needed to treat (NNT) with a probiotic to prevent one case of NEC was 25 (95% CI, 17–34). Trial sequential analysis results supported a 30% reduction in the incidence of NEC (α = 0.05; power = 80%). In addition, a significant effect was noted in all-cause mortality (RR = 0.42; 95% CI, 0.29–0.62; p<0.00001) in the probiotic groups, with no significant heterogeneity in the data. The NNT with a probiotic to prevent one death was 20 (95% CI, 14–34). There was no evidence of serious adverse effects associated with probiotic supplementation. No significant difference in the sepsis rates occurred between groups (RR = 0.98; 95% CI, 0.81–1.18; p=0.80), but there was significant heterogeneity in the data. The authors state that with the additional hospital charges incurred with one infant with NEC who survives (as high as $216,666), substan-tial cost savings would be realized with probiotic ther-apy added to routine neonatal care. Although a placebo-controlled trial is planned, these authors suggest that patient recruitment will be difficult once caregivers are given complete information on current data regarding probiotic use in the neonatal intensive care unit. Neona-tologists in the United States have been slower to adopt probiotic therapy compared with their European coun-terparts. This meta-analysis may provide sufficient evi-dence to incorporate this potentially lifesaving therapy into routine practice; however, confirmation of results in an adequately powered, randomized controlled trial is needed.

6. Euler AR, Mitchell DK, Kline R, Pickering LK. Prebi-otic effect of fructo-oligosaccharide supplemented term infant formula at two concentrations compared with unsupplemented formula and human milk. J Pediatr Gastroenterol Nutr 2005;40:157–64.

The authors of this study sought to determine whether supplementing a whey-predominant cow’s milk–based formula with FOS (inulin) at two different concentra-tions, 1.5 g/L or 3 g/L, would have a beneficial prebiotic effect on fecal flora compared with human milk feed-ing or unsupplemented formula feeding. A quantitative change in fecal flora, establishing a flora similar to that seen in human milk–fed infants, was the primary out-come measured. Secondary outcomes were decreased colony counts of Enterococcus, Bacteroides, or Clostridia spp. or Clostridium difficile toxin-positive stools. Safety objectives were tolerability and acceptability of FOS-supplemented formula. Infants were excluded if they had a sibling with cow’s milk intolerance or a gastroin-testinal, cardiac, respiratory, hematologic, or other sys-temic disease.

The study was a prospective, randomized, crossover design, and all formulas were identical except for the FOS amount. Formula-fed infants were randomized into one of four study groups; all infants received control formula


during weeks 1, 3, and 5. Infants received one of the sup-plemented formulas (1.5 g FOS/L or 3 g FOS/L) dur-ing either week 2 or week 4, with control formula during either week 4 or week 2, respectively. Eighty-seven infants 2–6 weeks of age were enrolled; results for 72 were evalu-able per protocol (58 formula-fed, 14 human milk–fed). The Lactobacillus spp. fecal count was similar in all groups; however, the Bifidobacterium spp. count was higher in the 1.5-g FOS/L group. All formula-fed infants had 100-fold more enterococci than human milk–fed infants before FOS supplementation; however, after FOS supplemen-tation, counts were similar. Formula-fed infants had more C. difficile toxin-positive stools than human milk–fed infants, but this finding was not statistically signifi-cant. Infants in the two FOS-supplemented groups had a greater number of adverse events compared with human milk–fed infants: 1.5 g of FOS/L, 83%; 3.0 g of FOS/L, 97%; human milk, 59%. Adverse events with statistically significant differences were flatulence, spitting up, and loose stools. Softer or looser stools are actually more sim-ilar to human milk–fed infants. Satisfaction ratings and tolerability decreased at the visit after FOS supplementa-tion. The authors concluded that FOS supplementation is safe but has minimal effect on fecal flora. In this trial, infants were fed FOS-supplemented formula for only 7 days; longer-term supplementation may increase bacte-rial counts.

7. Holscher HD, Faust KL, Czerkies LA, Litov R, Ziegler EE, Lessin H, et al. Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial. J Parenter Enter Nutr 2012;36:95S–105S.

This randomized, controlled, multicenter, double-blind, prospective clinical trial evaluated the effects on fecal microbiota of GOS addition to infant formula compared with human milk. Infants were healthy, born between 37 weeks and 42 weeks estimated ges-tational age, and 2–8 weeks of age at enrollment. The study’s primary objective was to evaluate the propor-tion of fecal bifidobacteria in infants fed with prebiotic-supplemented formula or non–prebiotic-supplemented formula compared with infants fed human milk exclu-sively. Secondary objectives were the absolute and rel-ative counts of fecal lactobacilli, bacteroides, and C. difficile; fecal pH; short-chain fatty acid concentrations; gastrointestinal tolerance; and body weight. Infants received a control formula (Nestlé Good Start Supreme DHA/ARA, Florham Park, NJ); the test formula, which was the control formula with GOS (4 g/L; Vivinal GOS, Domo, Amersfoot, Netherlands) and short-chain FOS (Beneo P95, Orafti N.V., Tienen, Belgium) in a 9:1 ratio; or human milk. Infants received the assigned for-mula for 6 weeks. Stool analysis was completed for 33 patients in the human milk and control groups and 36 in the test formula group. Absolute and relative bacterial abundance of bifidobacteria was higher in the prebiotic group than in the control group (p=0.0083) but did not differ between the prebiotic and human milk groups. Human milk–fed infants had less C. difficile than either formula-fed group (p=0.0087). Fecal pH, an indirect marker of fermentation, was lower in the prebiotic and

breastfed groups than in the control group (p=0.0161). Breastfed infants had more frequent stools (p<0.0001) than either formula-fed group (3.0 vs. 1.4 per day). Formula-fed infants had green stools 70% of the time; breastfed infants had yellow stools 80% of the time. Pre-biotic supplementation did not change parents’ percep-tions of gastrointestinal tolerance, and no differences in weight gain were seen between the three groups.

The effects of prebiotic supplementation had only a modest effect on fecal microbiota, less than a 1-log colony-forming unit increase. The authors list many rea-sons why the increase was small, including the timing of enrollment, the prebiotic type used, the inherent bene-ficial effects of the control formula, and the use of pH to measure fermentation. However, this study shows that prebiotic supplementation is well tolerated in infants who receive it.

8. ESPGHAN Committee on Nutrition; Aggett PJ, Agos-toni C, Axelsson I, DeCurtis M, Goulet O, Hernell O, et al. Feeding preterm infants after hospital discharge. A commentary by the ESPGHAN Committee on Nutri-tion. J Pediatr Gastroenterol Nutr 2006;42:596–603.

Infants discharged at a weight below the normal weight for a fetus or term infant of the same gesta-tional age are at increased risk of long-term growth failure. This commentary from The European Society for Paediatric Gastroenterology, Hepatitis and Nutri-tion (ESPGHAN) Committee on Nutrition describes infant growth patterns seen in the hospital and after dis-charge. The authors review the potential consequences of poor pre- and postnatal nutrition, including poor neurodevelopmental outcomes, stressing the difficulty in assessing nutrition’s role in these outcomes given the many factors that may contribute. The authors present the results from studies evaluating the use of nutrient-enriched formulas in premature infants after discharge. Their conclusions are that infants discharged with an appropriate weight for postconceptional age should be breastfed, when possible. If the infant is formula fed, then he or she can receive a standard term infant for-mula. Infants discharged at a weight below the appro-priate weight should receive fortified human milk, when possible, but when formula is used, they should receive a nutrient-rich postdischarge formula intended for pre-mature infants to improve protein, mineral, and trace element delivery until at least 40 weeks postconcep-tional age and maybe until 52 weeks. The recommen-dations in this statement were based on seven random-ized controlled trials and expert opinion. The studies all had limitations, including issues related to inclusion cri-teria, selection of major end points, follow-up, and the effects of complementary feeding. Once a premature infant is discharged from the hospital, regardless of the feeding type, careful monitoring is required to ensure appropriate growth.

9. Bhatia J, Greer F; and the Committee on Nutrition, American Academy of Pediatrics. Use of soy pro-tein-based formulas in infant feeding. Pediatrics 2008;121:1062–8.


This AAP statement updates the 1998 AAP review of soy protein–based formulas. The composition of soy protein–based formulas, the components of most concern being the phytates and the phytoestrogens, is reviewed. Soy protein–based formulas contain 1.5% phytates, which can interfere with phosphorus absorp-tion. For this reason, these formulas contain 20% more calcium and phosphorus than cow’s milk–based for-mulas. Bone mineralization and serum calcium, phos-phorus, and alkaline phosphatase concentrations in infants receiving soy protein–based formulas are com-parable with those in term infants receiving cow’s milk–based formulas. However, premature infants should not receive a soy formula because, even with the additional calcium and phosphorus supplementation, bone min-eralization may be compromised in this group because of their higher requirements. The authors discuss the role of phytoestrogens, nonsteroidal estrogens includ-ing isoflavones, in sexual development and reproduc-tion, neurobehavioral development, and immune sys-tem and thyroid function. Contrary to common mis-conceptions, no evidence supports any adverse effects in these areas with the use of soy protein–based formu-las. Consumption of soy protein with a thyroid supple-ment can result in decreased absorption of the thyroid hormone caused by phytate binding within the gas-trointestinal lumen, increasing fecal loss. If an infant receives thyroid replacement, then either soy protein–based formulas should be avoided or the patient should be monitored closely to assess the efficacy of thyroid hormone replacement. The increased aluminum con-tent (i.e., 600–1300 ng/mL vs. 4–65 ng/mL in human milk) in soy protein–based formulas is also of concern. The authors note that term infants with normal kidney function do not seem to be at increased risk of alumi-num toxicity; however, preterm infants or term infants with diminished kidney function should not receive a soy protein–based formula.

The role of soy protein–based formulas in infants with colic is discussed. The authors state: “The value of parental counseling as to the cause and duration of colic seems greater than the value of switching to soy for-mula.” The use of soy protein–based formulas in infants with severe gastrointestinal reactions is discussed. Sim-ilar to CMA, soy protein reactions can produce enter-opathy, enterocolitis, and proctitis. The cross-reactiv-ity between CMA and soy protein allergy is stressed. Finally, the authors discuss the role of soy protein–based formulas in preventing atopic disease. Given the available research, soy protein–based formulas cannot be recommended for this indication. This evidence-based AAP statement helps determine the appropriate role of soy protein–based formulas in infant nutrition.

10. Moukarzel AA, Abdelnour H, Akatcherian C. Effects of a prethickened formula on esophageal pH and gas-tric emptying of infants with GER. J Clin Gastroenterol 2007;41:823–9.

Adding rice cereal to infant formulas has been asso-ciated with a decrease in overt GER symptoms (i.e., emesis). The authors of this study investigated the effect

of a prethickened formula (Wyeth Nutritionals) com-pared with a standard formula (Wyeth Nutritionals) in healthy infants (n=74) younger than 6 months with GER. All infants underwent 24-hour esophageal pH monitoring while alternately receiving the study or the control formula and were then assigned to one formula group for 1 month. Parents were asked to record epi-sodes of regurgitation, vomiting, coughing, and crying and bowel movements during the month. The results of the pH monitoring showed a significant reduction in reflux index in the group receiving prethickened formula compared with the standard formula group (5.64% vs. 7.77%, p<0.01). While receiving the pre-thickened formula, 87% of infants showed an improve-ment in their reflux index. Parents also reported a signif-icant decrease in GER symptoms when infants received the prethickened formula. Daily episodes of regurgi-tation decreased by 68% (p=0.0009), and vomiting was reduced by 81% (p=0.0003) in the group receiv-ing prethickened formula. Regurgitation and vomiting decreased by 20% and 43%, respectively, in the regular formula group; these changes were not statistically sig-nificant. No adverse events were noted. In this study, prethickened formula was associated with improve-ment in both reflux index (objective measure) and clin-ical symptoms (subjective measure) of GER in other-wise healthy infants. One weakness of this study is the use of pH probe monitoring, which detects only acidic reflux. Formula buffers the acid in the stomach such that postprandial reflux is usually not acidic. The true effect on GER would be better determined using intra-luminal impedance monitoring.

11. Horvath A, Dziechciarz P, Szajewska H. The effect of thickened-feed interventions on gastroesophageal reflux in infants: systematic review and meta-analysis of ran-domized, controlled trials. Pediatrics 2008;122:e1268–77. Errata: doi10.1542/peds.2009-0135.

Thickening of formula with various agents or using a formula that has been prethickened by the manufac-turer is a common intervention in children with GER. These authors conducted a meta-analysis of 14 random-ized controlled trials, comparing thickened feeding with standard term infant formula in a parallel or cross-over design for at least a few days. Thickened feedings were associated with an increase in the percentage of infants with no regurgitation (RR = 2.9 [95% CI, 1.7–4.9]; NNT = 6 [95% CI, 4–10]), a slight decrease in the number of episodes of regurgitation per day (-0.6 epi-sode [95% CI, -1.7 to -1.11]), and an increase in weight gain (3.55 g/day [95% CI, 2.6–4.5] vs. 3.7 g/day [95% CI, 1.55–5.8]). Using pH probe analysis, no improve-ment was seen in the reflux index, the number of acid GER episodes per hour, or the number of GER epi-sodes lasting more than 5 minutes. However, there was a decrease in the duration of the longest GER episode of pH less than 4. In this analysis, five different thick-ening agents were used; some received prethickened formulas, some received a standard term infant for-mula with a thickener added. No serious adverse events were reported. Infants receiving carob thickener had


increased stools. Infants receiving rice cereal had an increased incidence of cough. Parents reported diffi-culty in sucking in some infants who had thickening agents added to their formula.

This meta-analysis confirms that the evidence to sup-port the use of thickened formulas for infants with GER has significant limitations. Only 14 studies were used in this analysis, some of which were small. Five different thickening agents were used: carob-bean gum, corn-starch, rice starch, cereal, and soy fiber, making it dif-ficult to extrapolate the findings to the more common approach in the United States, which is to add rice cereal or oatmeal. Many of the studies were sponsored by the manufacturers of prethickened formulas. The differ-ence in regurgitation episodes was modest, only 0.6 epi-sodes per day, but this amount might improve quality of life for the families of infants with GER. This study confirms that more evidence is needed to determine the role of thickening of feedings in infants with GER.

12. Hascoët JM, Hubert C, Rochat F, Legagneur H, Gaga S, Emady-Azar S, et al. Effect of formula composition on the development of infant gut microbiota. J Pediatr Gastroenterol Nutr 2011;52:756–62.

One strategy employed by formula manufacturers to make their infant formulas more like human milk has been to add either prebiotics or probiotics, both of which are naturally present in human milk. This study’s objective was to evaluate the effect of three different formulas: group 1, a whey-predominant infant formula with less protein and phosphorus, more like human milk (n=39); group 2, the same infant formula supple-mented with 2 x 107 colony-forming units of B. longum (BL999; n=40); and, group 3, a control formula (n=38), on the gut microflora, compared with the results in infants who received human milk (group 4; n=73). All infant formulas were manufactured and blinded by the sponsor (Nestlé, Konolfingen, Switzerland). The pri-mary objective was stool Bifidobacterium spp. count at 2 months of age. Secondary outcomes included non-Bifidobacterium spp. stool counts, weight, length, head circumference, digestive tolerance, stool immunoglob-ulin A, and adverse effects. At 2 months, Bifidobacte-rium spp. were detected in 83%, 79%, 67%, and 88.6% of patients in groups 1, 2, 3, and 4, respectively. Bifi-dobacterium spp. comprised 52.6%, 31.9%, 17.6%, and 49.7% of the bacterial stool count in groups 1, 2, 3, and 4, respectively, with only the difference between human milk and control being statistically significant. In addi-tion, Clostridium spp. comprised a not statistically dif-ferent percentage of the stool bacterial count (18.9% ± 20.4%) in group 3 (control) than in groups 1, 2, and 4 (9.5% ± 11.5%, 7.5% ± 11.2%, and 5.5 ± 13.9%, respec-tively). At 1 month, BL999 was isolated from the stools of infants who received the formula supplemented with it, but not at 2 months. Immunoglobulin A concentra-tions differed only between the control group and the human milk group (p=0.001). As expected, stool fre-quency was higher in the human milk group, but group 2 was more likely to have softer stools than groups 1 and 3. Fifty-three adverse events were noted, most of which

involved the gastrointestinal tract or upper respiratory system. None of the adverse events were severe; there was no difference between groups. Growth param-eters did not differ between the groups. There was a high dropout rate (26%); however, more than half (29 of 49) were in the human milk group. Reasons included adverse events (n=9), consent withdrawal (n=10), lost to follow-up (n=16), and other (n=16). The results of this small study are important for several reasons. First, it appears that formula modification (i.e., decreased pro-tein and phosphorus) to make it more like human milk can alter gut microflora, matching that seen in human milk–fed infants, without compromising growth. Sec-ond, adding probiotics improves gut microflora, but no more than just formula protein and phosphorus modifi-cation. Finally, either formula modification or probiotic supplementation appears to be a safe method for alter-ing the infant’s gut microflora. A larger study would help confirm these results; this study was underpow-ered to make definitive conclusions.

13. Lowe AJ, Hoskins CS, Bennett CM, Allen KJ, Axelrad C, Carlin JB, et al. Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 2011;128:360–5.

The objective of this trial was to determine whether feeding a partially hydrolyzed whey formula after wean-ing from exclusive breastfeeding could reduce the risk of atopic disease in at-risk infants. The primary out-come was the development of allergic manifestations (i.e., eczema and food reactions) measured 18 times in the first 2 years. Only infants with a family history of atopic disease (n=620) were enrolled. Infants were randomized to receive a partially hydrolyzed whey for-mula (NAN H.A.; Nestlé, Biessenhofen, Germany), a soy protein–based formula (ProSobee, Mead Johnson), or a cow’s milk–based formula (NAN, Nestlé, Tong-ala, Australia) at weaning. Skin prick tests for six com-mon allergens (i.e., milk, egg, peanut, dust mite, rye grass, and cat dander) were performed at 6, 12, and 24 months. The follow-up rate in this study was good: 93% at 2 years and 80% at 6 or 7 years. Infants assigned to the partially hydrolyzed whey or the soy protein–based for-mula groups had no evidence of reduced risk of atopic disease compared with cow’s milk–based formula (odds ratio [OR] = 1.21; 95% CI, 0.81–1.80 and 1.26; 95% CI, 0.84–1.88, respectively). The authors concluded that neither a partially hydrolyzed whey formula nor soy formula reduced the risk of atopic disease in high-risk infants. The formulas used in this study are comparable with formulas available in the United States. However, there were many randomization losses (38%) such that 238 infants received a “non-assigned” formula; there-fore, a large number were actually exposed to intact proteins. In addition, the first 97 patients were random-ized to only one of two formulas because the third was not yet available. Another important point is that 50% of subjects by 4 months and 39% by 6 months of age were still breastfeeding and did not receive their allo-cated formula. Although encouragement of exclusive


breastfeeding is the most ethical conduct, the extended time of breastfeeding would introduce considerable bias. These results could lead a practitioner to conclude that there is no role for the use of hydrolyzed whey for-mulas in infants at high risk of atopic disease. How-ever, because of its significant limitations, together with contradictory findings from other studies including two meta-analyses, the results of this study should not change the current recommended practice.

14. Alexander DD, Cabana MD. Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010;50:422–30.

Recent studies have shown a reduction in the inci-dence of atopic dermatitis with the use of a partially hydrolyzed whey formula. The authors of this study con-ducted a meta-analysis of clinical trials and interven-tion studies to validate this observation and estimate the magnitude and statistical significance of the poten-tial association. Included studies compared healthy infants who received a 100% partially hydrolyzed whey formula with infants who received a non-hydrolyzed cow’s milk–based formula. Included studies also had to report results for atopic disease or an outcome that included atopic disease expressed as a risk estimate (e.g., RR, OR) with an associated measure of variabil-ity (i.e., CI). After critical review, only 18 articles repre-senting 12 independent study populations and includ-ing about 1000 infants were included in the analysis. Six studies were identified as methodologically supe-rior. Meta-analysis models included all the studies that met inclusion criteria and models that included only the six superior studies. When all studies were included, there was a statistically significant reduction in risk of developing atopic dermatitis in infants fed the partially hydrolyzed whey formula (45%; [summary relative risk estimate, SRRE] 0.55; 95% CI, 0.40–0.76). When only the six methodologically superior studies were included in the analysis, there was also a statistically significant reduction in risk of atopic dermatitis (55%; SRRE 0.45; 95% CI, 0.30–0.70). The authors concur that breast-feeding is the most effective way to nourish infants and minimize the risk of developing atopic dermatitis. All infants included were identified as being at high risk of allergy (excluding one study). However, the criteria used to designate high-risk infants were not consistent across studies because there is no universal standard classification system. Therefore, extrapolating these findings to the entire infant population is inappropriate.

15. Knip M, Virtanen SM, Seppa K, Ilonen J, Salvilahi E, Vaarala O, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 2010;363:1900–8.

Preliminary data suggest that a short duration of breastfeeding and early exposure to complex dietary proteins (vs. highly hydrolyzed proteins) is associated with increased risk of advanced ß-cell autoimmunity. This study was a pilot study for the TRIGR trial. It was a randomized, double-blind trial conducted in Finland

in which 230 term infants (36 weeks or longer gesta-tion) with at least one first-degree relative with T1DM and an HLA genotype associated with increased T1DM risk were assigned to receive either an extensively hydrolyzed casein–based formula (Nutramigen [Mead Johnson]; intervention) or a cow’s milk–based formula (Enfamil [Mead Johnson]; control) for the first 6–8 months of life, whenever human milk was unavailable. To make the control formula similar in taste and smell, it was supplemented with hydrolyzed proteins, result-ing in a formula with 80% intact cow’s milk protein and 20% hydrolyzed protein. In addition, the Finnish National Health System efficiently tracks each resident, which made assessing the long-term clinical outcomes possible. The infants were primarily evaluated for the presence of islet cell antibodies and autoantibodies to insulin, glutamic acid decarboxylase, the insulinoma-associated 2 molecule, and zinc transporter 8. Samples were drawn every 3 months during the first year and then at 1.5, 2, 3, 5, 7, and 10 years. The subjects also were monitored for the development of overt T1DM until 10 years of age.

Data were reported for only 208 infants who had at least one serum sample drawn. At least one autoanti-body developed in 17% in the intervention group com-pared with 30% in the control group (p=0.02). Infants in the intervention group had a decreased risk of sero-conversion to positivity for one or more of the autoanti-bodies evaluated (unadjusted hazard ratio [HR] = 0.54; 95% CI, 0.29–0.95 and HR adjusted for an observed dif-ference in duration of exposure to study formula = 0.51; 95% CI, 0.28–0.91). Overt T1DM developed in 6% and 8% of the intervention and control groups, respectively, a nonsignificant difference. Adverse events were simi-lar in the two groups. A strength of this study is its ran-domized, double-blind design. A weakness is the statis-tically significant difference between the two groups in the duration of intervention exposure. The duration and relative amount of breastfeeding for the subjects were not controlled because of ethical issues, which resulted in the control group’s exposure to formula starting at 1.1 months, whereas the intervention group was not exposed until 2.6 months (p=0.03). In addition, the study was not powered to detect a statistical difference in progression to overt T1DM. A large multicenter, mul-tinational study, TRIGR, is currently being conducted to address progression to overt T1DM. Although the results are inconclusive regarding patient-oriented out-comes and further study is warranted, these results sup-port that preventive dietary intervention in high-risk infants is a feasible method of reducing the risk of devel-oping T1DM.

16. The TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes 2007;8:117–37.

This article summarizes the study design for a multi-center, multinational, randomized, prospective, dou-ble-blind, placebo-controlled trial intended to deter-mine whether using an extensively hydrolyzed infant for-mula upon weaning from exclusive breastfeeding could


decrease the incidence of T1DM in high-risk infants. It is the first large-scale primary preventive effort aimed at T1DM. Patient screening began on May 1, 2002, and the targeted enrollment was reached on September 1, 2006. For this trial, a high-risk infant was defined as one having at least one first-degree relative with T1DM and at least one HLA genotype associated with T1DM development. Secondary trial objectives were to determine the associa-tion of feeding type and measured cow’s milk exposure with the development of cow’s milk antibodies and dia-betes-associated antibodies. Data will be analyzed at 6 years and 10 years after enrollment. Mothers with T1DM were screened at 35 weeks gestational age so that HLA typing could be done on cord blood samples and study formula could be initiated as soon as weaning occurred. If an infant was enrolled after birth, a heel stick sample was taken for HLA typing within the first 7 days of life. To meet 80% power to detect a 40% difference in auto-antibody development and subsequent T1DM, 2032 participants will be needed. Seventy-eight centers in 15 countries, including the United States, are participating in this study. The first results (i.e., the 6-year data) will be available in 2012. This article not only provides a detailed summary of the TRIGR protocol, but also, the authors provide a thorough review of the rationale for the TRIGR study intervention, including a summary of all the rele-vant animal data that led to the conclusion that diet mod-ification can lead to a reduction in T1DM incidence. This study potentially will provide practitioners with the data needed to make an evidence-based decision regarding the use of extensively hydrolyzed infant formula for prevent-ing T1DM in high-risk infants.



41. In the clinic today, the parents of a 6-week-old infant girl report that she has had bloody stools for about 2 days. The infant appears otherwise healthy, is afebrile, and has no abdominal distention. She is currently receiving a standard term infant formula 2 oz every 3 hours. The primary care provider sus-pects cow’s milk-protein allergy (CMA). Which one of the following infant formulas would be the best recommendation for this infant?A. Enfamil Gentlease.B. Nutramigen AA LIPIL.C. Similac Expert Care Alimentum.D. Gerber Good Start Soy.

42. A 2-month-old infant is seen in the clinic for man-agement of gastroesophageal reflux (GER). He cur-rently receives Enfamil PREMIUM Newborn, is growing normally, and is otherwise healthy. He is currently receiving no medications. The parents ask whether they can do anything to reduce the fre-quency of his vomiting. Which one of the follow-ing is the best recommendation for this patient?A. Change his formula to Enfamil Gentlease.B. Change his formula to Similac Sensitive for

Spit-Up.C. Add 1 teaspoon of rice cereal to each ounce of

his current formula.D. Change his formula to Similac Expert Care

Alimentum.

43. An infant underwent surgery for repair of a con-genital heart defect. One week after restarting oral feedings with human milk, she developed a small pleural effusion. Thoracentesis revealed a chylous effusion. Which one of the following would be the best initial treatment for this patient?A. Continue oral feedings with human milk.B. Initiate oral feedings with Enfaport.C. Initiate tube feedings with Pregestimil.D. Initiate parenteral nutrition with intravenous

fat emulsion.

44. A pregnant woman comes to the clinic today for her routine prenatal visit with the pediatrician whom she plans to use for her newborn. This is her first pregnancy, and she has many questions. Both she and her husband have severe eczema and asthma. She plans to breastfeed, but she will have to go back to work in 6 weeks, so she is looking for a formula to supplement, if needed. She has read on the Inter-net that some infant formulas can reduce the risk of

her baby’s having atopic disease, and she would like advice regarding formula choice. Which one of the following would be the most cost-effective choice to reduce the short-term risk of atopic disease in her child?

A. Enfamil ProSobee.B. Similac Advance.C. Similac Expert Care Alimentum.D. Neocate Infant.

45. According to the American Academy of Pediat-rics 2008 statement, which one of the following infants has an evidence-based indication for a soy protein–based formula?

A. A 2-month-old with severe GER disease.B. A 1-month-old with colic.C. A 12-week-old with CMA-associated hives.D. A 7-day-old with galactosemia.

46. A 21-day-old infant, now 30 weeks gestational age, in the neonatal intensive care unit (ICU) develops necrotizing enterocolitis (NEC) requiring surgi-cal intervention. At laparotomy, all but 38 cm of the bowel is removed (80% resection), resulting in short bowel syndrome. The infant will be initiated on enteral feedings in 14 days, as long as there is evi-dence of bowel function at that time. Which one of the following infant formulas would be the best choice to initiate feeding in this infant?

A. Similac Special Care 24.B. Enfamil EnfaCare.C. Pregestimil.D. Nutramigen.

47. A young couple is being seen today by the pediatri-cian for their prenatal visit. The mother has type 1 diabetes mellitus (T1DM). She has read that her choice of nutrition for her infant could affect her child’s risk of developing T1DM. She has heard that she should avoid cow’s milk–based formulas entirely. Which one of the following is the best advice to give this couple regarding feeding their infant for the first 4–6 months?

A. Exclusive breastfeeding with no infant formula.B. Breastfeeding with Gerber Good Start Gentle

supplementation.C. Breastfeeding with Similac Sensitive for

Spit-Up supplementation.D. Exclusive use of EleCare Infant; no

breastfeeding.

Self-Assessment Questions


48. A 3-month-old infant with chronic kidney disease is admitted from the clinic today because of electro-lyte abnormalities. She is currently receiving Sim-ilac Sensitive, which was initiated about 3 weeks ago because of issues with GER. The mother can-not remember the name of the formula she was on before that. The infant’s laboratory values earlier today were as follows: sodium 134 mEq/L; potas-sium 4.2 mEq/L; chloride 110 mEq/L; bicarbon-ate 19 mEq/L; magnesium 2.5 mg/dL; calcium 8.3 mg/dL; and phosphorus 7.2 mg/dL. The nephrol-ogist requests a recommendation for nutrition that will aid in the correction of her electrolyte abnor-malities. Which one of the following infant for-mulas would be the best choice for this infant?A. Similac PM 60/40.B. Enfamil Gentlease.C. Similac Soy Isomil.D. Enfamil A.R.

49. A 2-month-old girl (weight, 2.5 kg) who was born at 28 weeks gestational age is seen today and found to have failure to thrive and symptoms suggestive of significant GER disease. She is receiving Enfa-mil A.R. Her drug list includes erythromycin four times/day, omeprazole two times/day, and acet-aminophen as needed for irritability. Her mother states that the infant has been taking omeprazole for about 4 weeks, but she just changed her for-mula last week because a friend told her that Enfa-mil A.R. was good for babies with reflux. However, the mother has noticed no change in the baby’s spit-ting up since the formula change. Which one of the following is the best advice to give this mother regarding the use of Enfamil A.R. in her child?A. It is designed specifically for babies with GER;

she should continue to use it.B. Its benefits are likely being lessened by

omeprazole use; she should discontinue omeprazole.

C. It is not intended for use in premature infants; she should change her baby’s formula to Similac Expert Care NeoSure.

D. It and similar formulas often do not help premature infants with GER; she should switch her baby to Neocate Infant because her vomiting may be caused by CMA.

50. A 4-week-old infant who was born at 28 weeks ges-tational age is receiving human milk supplemented with human milk fortifier to a final concentration of 24 kcal/oz. The infant, who weighs 1850 g, will be discharged from the hospital in about 1 week. The medical resident caring for her wrote a prescription for human milk fortifier, but her insurance provider

rejected the claim. Which one of the following would best facilitate this patient’s discharge?

A. Change the infant’s formula to Similac Special Care 24 kcal/oz at discharge.

B. Change the infant’s formula to Enfamil EnfaCare at discharge.

C. Discontinue human milk fortifier and give non-fortified human milk after discharge.

D. Add 1 teaspoon of Similac Expert Care NeoSure to each 3 oz of human milk after discharge.

51. A 6-month-old African American infant is brought to the clinic today with the chief concern of fuss-iness, excessive gas, a slightly distended abdomen, and diaper rash. The stools are somewhat loose and explosive, but the mother has not noted any blood in them. The infant’s growth plotted on the age- and sex-specific World Health Organization growth charts is appropriate. The infant is receiving no medications. She was recently hospitalized for 5 days for dehydration secondary to severe gastroen-teritis. She is receiving Similac Advance and takes about 2–3 oz every 3–4 hours. Her mother wonders whether her symptoms could be related to her for-mula. After confirming that the formula could be causing these symptoms, which one of the follow-ing formulas would be best to recommend for this patient?

A. Similac Expert Care Alimentum.B. Gerber Good Start Gentle.C. EleCare Infant.D. Enfamil Gentlease.

52. A 9-day-old infant is brought to her primary care provider’s office today because she appears to be sleepy all the time and is not eating as well as she did when she first went home from the hospital. She is currently receiving Enfamil LIPIL. Her newborn metabolic screen results are not in the chart. The provider calls the state laboratory and finds that the screen for galactosemia was positive. Which one of the following is the best action to take at this time?

A. Continue her current infant formula and repeat laboratory tests to confirm galactosemia.

B. Change her formula to Similac Soy Isomil.C. Change her formula to Neocate Infant.D. Change her formula to Enfamil Gentlease.

53. A pregnant woman comes in today to pick up her prescription for prenatal vitamins. She is not plan-ning to breastfeed her child. She is a vegetarian, and


she would like to use a formula that does not con-tain cow’s milk or that is not derived from cow’s milk. Which one of the following formulas would be best to recommend to this young woman?

A. Enfamil Gentlease.B. Similac Sensitive.C. Enfamil ProSobee.D. Similac Expert Care Alimentum.

54. A mother comes to the pharmacy with her 3-month-old infant. She tells you that the baby has short bowel syndrome and has been receiving Pre-gestimil infant formula since shortly after birth. They are visiting from out-of-state, and unfortu-nately, she left the baby’s formula at home. No Pre-gestimil is on the shelf. Which one of the following infant formulas would be the best short-term sub-stitute for Pregestimil for this infant?

A. Similac Expert Care Alimentum.B. Enfamil PREMIUM Infant.C. Similac Advance.D. Enfamil ProSobee.

55. A father brings his 3-week-old son to the pharmacy. He is quite fussy, and the father asks for a recom-mendation for acetaminophen dosing. On further questioning, you learn that the infant is receiving Gerber Good Start Gentle. At his 2-week physician visit, his weight gain was appropriate, and there were no problems with feedings. However, in the past 2 days, he is fussy with and between feedings. This morning, he developed hives on his chest. Which one of the following recommendations is most appropriate for this patient?

A. Inform the father that his son is likely allergic to the protein in his formula; his formula should be changed to Similac Soy Isomil.

B. Inform the father that his son likely has lactose intolerance; his formula should be changed to Similac Sensitive.

C. Inform the father that his son likely has gastroenteritis; no change in his formula is warranted.

D. Inform the father that his son may be allergic to his formula; he should contact his primary care physician immediately or take his son to the emergency department.

56. A 2-month-old girl is brought to the clinic today because she has constipation. Otherwise, she is a healthy baby and is growing appropriately. The mother stated that the constipation started after she stopped breastfeeding and started using Enfamil PREMIUM Infant. She would like a

recommendation for a low-iron formula because she read on the Internet that the iron in formulas causes constipation. Which one of the following is the most appropriate plan of care for this infant?

A. Change to Enfamil Premature 20 Cal Low Iron.

B. Change formula to Neocate Infant.C. Change formula to Enfamil ProSobee.D. Encourage the mother to make an

appointment with her infant’s primary care provider to evaluate for constipation.

57. The parents of a 5-day-old, male infant born at 28 weeks gestational age were invited to meet with the neonatal ICU team today. At the meeting, they ask if their son is receiving a probiotic supplement as they have read that probiotic supplementation decreases the risk of NEC. The neonatologist explains that probiotic supplementation is not routine care in the neonatal ICU at this time. Which one of the following is the most likely reason that the neo-natologists have not adopted the routine use of probiotic supplementation for this indication?

A. Increased cost.B. Lack of randomized controlled trials showing

efficacy.C. High rate of severe diarrhea with probiotic

supplementation.D. Risk of bacteremia with the administered

microorganism.

58. A 3-week-old infant is seen in the clinic today for his initial well-baby check. He has been receiving Enfa-mil PREMIUM Newborn since birth. Hi growth is appropriate. Which one of the following is most likely to occur with the use of this infant formula?

A. Essential fatty acid deficiency.B. Eczema.C. Loose stools.D. Vitamin D deficiency.

59. A 9-month-old infant is admitted to the hospital with severe feeding aversion and failure to thrive. His formula has been changed several times, most recently to Similac Expert Care Alimentum. An endoscopy reveals severe eosinophilic esophagitis. Which one of the following is the most appropri-ate recommendation for this infant’s formula?

A. Continue Similac Expert Care Alimentum.B. Change formula to Nutramigen.C. Change formula to Neocate Infant.D. Change formula to Enfaport.


60. A 10-month-old infant has been receiving parenteral nutrition for 3 months secondary to the develop-ment of chylous ascites. The team caring for the infant is ready to attempt enteral feedings. Which one of the following would be the most appropri-ate formula for initial feedings?A. Pregestimil.B. Similac Expert Care Alimentum.C. Nutramigen AA LIPIL.D. Enfaport.

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Infant Formulas - ACCP