sucedaneos de la leche revisión

DOI: 10.1542/pir.32-5-179 2011;32;179-189 Pediatr. Rev.

J. Andres Martinez and Martha P. Ballew Infant Formulas

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The online version of this article, along with updated information and services, is

Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned, Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

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Infant FormulasJ. Andres Martinez, MD,*

Martha P. Ballew, MEd,

RD, CNSC, LDN†

Author Disclosure

Dr Martinez and Ms

Ballew have disclosed

no financial

relationships relevant

to this article. This

commentary does not

contain a discussion

of an unapproved/

investigative use of a

commercial product/

device.

Objectives After completing this article, readers should be able to:

1. Describe the macronutrient content of formulas used as substitutes for human milk forterm and preterm infants.

2. Identify appropriate clinical applications of infant formulas that have altered nutrientcontents based on the physiologic significance of specific changes in formulacomposition.

3. Discuss the physiologic role and potential health benefits associated with four compo-nents added to infant formulas in the past decade.

4. Delineate current regulatory guidelines that define standards for composition andperformance and safety criteria for commercial infant formulas.

Historical BackgroundDevelopment of infant formulas can be traced to the late 19th century. In 1867, Liebigdeveloped and marketed a product for infant feeding that contained cow milk, wheat flour,malt flour, and potassium bicarbonate. In 1915, Gerstenberger reported a 3-year experi-ence using “synthetic milk, adapted” that contained nonfat cow milk, lactose, oleo oils,and vegetable oils. This product represented early understanding that cow milk requiredalteration to improve its acceptability for human consumption and is considered theprecursor to modern infant formulas. (1)

Government regulation of infant formula composition in the United States began in1941 and underwent significant expansion with passage of the Infant Formula Act of1980, a direct and prompt response to an epidemic of a Bartterlike syndrome (hypochlo-remic, hypokalemic metabolic alkalosis). Most cases were later attributed to consumptionof a chloride-deficient soy infant formula. The Infant Formula Act of 1980 and itsamendments in 1986 defined minimum concentrations of 29 nutrients and establishedquality control standards for commercial production of infant formulas. Current standardsare summarized in the Electronic Code of Federal Regulations: Title 21:107—Infant

Formula. (2) Organic infant formulas must also meet allstandards required for United States Department ofAgriculture Organic certification.

The addition of nucleotides to infant formulas in 1999 andlong-chain polyunsaturated fatty acids (LCPUFAs) in 2002marked a new era in infant formula development. In 2004,anticipating continued competition among infant formulamanufacturers to develop products that mimic the com-plexities and performance of human milk, a special commit-tee of the Food and Nutrition Board of the Institute ofMedicine proposed enhanced regulatory and research proce-dures to assess the safety of potential new ingredients ininfant formulas. (1)

Challenges continue in ensuring the quality and safety ofcommercial infant formulas. Within the past 5 years, pow-dered infant formulas have been recognized as potentialcarriers of food-borne illness after the death of an infant due

*Assistant Professor, Director Pediatric Nutrition Support Program, Department of Pediatrics, Division of Gastroenterology,Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN.†Pediatric Nutrition Support Dietitian, Department of Nutrition Services, Monroe Carell Jr Children’s Hospital at Vanderbilt,Nashville, TN.

Abbreviations

AAP: American Academy of PediatricsARA: arachidonic acidCMPA: cow milk protein allergyDHA: docosahexaenoic acidEHF: extensively hydrolyzed formulaGERD: gastroesophageal reflux diseaseIg: immunoglobulinLCPUFA: long-chain polyunsaturated fatty acidMCT: medium-chain triglycerideNEC: necrotizing enterocolitisPHF: partially hydrolyzed formulaVLBW: very low birthweight

Article nutrition

Pediatrics in Review Vol.32 No.5 May 2011 179. Provided by Health Internetwork on May 3, 2011 http://pedsinreview.aappublications.orgDownloaded from


to Enterobacter sakazakii meningitis in the United Statesand a case of infantile botulism in the United Kingdom.These incidents led to stricter safety guidelines for homeand institutional preparation and handling of commercialinfant formulas. (3) The Table offers a comparison ofcurrently available formulas.

Cow Milk-based Formulas for Term InfantsOften referred to as “standard” infant formulas, these prod-ucts are the most commonly used substitutes for humanmilk. They are available as ready-to-use liquids (20 kcal/ozor 67 kcal/100 mL) and as powder or liquid concentratesthat may be mixed with specific quantities of water to yieldcaloric densities between 20 and 30 kcal/oz.

ProteinDifferences in the serum amino acid profiles of breastfedand formula-fed infants are due to variations in the specificprotein content of human and bovine milk. Human milkhas a higher whey-to-casein ratio (70:30) than bovine milk(18:82). Unlike casein, which forms large curds on expo-sure to gastric acid, whey protein is resistant to precipitationand undergoes more rapid gastric emptying. These charac-teristics are the primary reason for continued modificationof the whey:casein ratio of cow milk-based formulas. It isimportant to note that the whey proteins in human andbovine milk are vastly different from both compositionaland functional standpoints. In an effort to match the pro-tein quality of human milk, cow milk-based formulas cur-rently contain almost 50% higher total protein content (2.1to 2.2 g/100 kcal) than human milk. Most infant formulasalso contain supplemental taurine. The physiologic signifi-cance of differences in serum amino acid profiles of infantsfed cow milk-based formulas versus human milk remainsunclear. More importantly, casein-predominant (20:80),whey-predominant (60:40), and 100% whey formulas haveall been shown to support normal growth patterns in bothterm and preterm infants.

CarbohydrateLactose is the predominant carbohydrate in most cowmilk-based formulas and human milk. The lactase en-zyme in the brush border of the small intestine reachesmaximum concentrations late in fetal development, butsome unsplit lactose usually reaches the distal bowel,where its fermentation permits proliferation of acido-philic bacteria, namely, Lactobacillus. Lactose has alsobeen shown to enhance absorption of calcium in terminfants between 8 and 12 weeks of age. The significanceof this benefit in term infants is unclear because adequatecalcium absorption has been demonstrated in infantsconsuming lactose-free formulas.

FatApproximately 50% of the caloric content of human milkis contained in its lipid component, which is rich inpalmitic, oleic, linoleic, and linolenic fatty acids. Currentformulas contain specific blends of vegetable oils de-signed to mimic the ratios of saturated, monounsatu-rated, and polyunsaturated fatty acids in human milk;increase the essential fatty acid content; and reduce gas-trointestinal symptoms previously associated with infantfeeding of whole cow milk.

Docohexaenoic acid (DHA) and arachidonic acid(ARA) are LCPUFAs present in human milk (meancontent of DHA 0.32% and ARA 0.47% of total fattyacids) and have been found to accumulate rapidly in thefetal retina and brain during the last trimester of preg-nancy, continuing until 2 years of age. DHA and ARAcan be synthesized from precursor essential fatty acidsand before 2002 were not added to infant formulas.Studies have shown that breastfed infants have a highercontent of DHA in the brain cortex compared withinfants consuming nonsupplemented formulas. Fur-thermore, numerous studies have observed improvedvisual and neurodevelopmental outcomes in childrenwho had been supplemented with DHA or DHA plusARA as infants. In 2008, two Cochrane meta-analyses ofrandomized, controlled trials found that milks supple-mented with these LCPUFAs did not improve growth,visual acuity, or neurodevelopment in either preterm orterm infants, which called their standard supplementa-tion into question. (4)(5) However, recent studies thathave focused on higher doses of DHA (between 0.3%and 0.5% of total fatty acids) and at least equal amountsof ARA have consistently reported significant benefits.Preterm infants may have a higher requirement, based oncalculated accretion rates in the last trimester of preg-nancy. No negative effects have been observed withDHA and ARA supplementation, and both are presentlyadded to all formulas in a dose range of 0.15% to 0.32%DHA and 0.4% to 0.64% ARA (% total fatty acids).More studies are needed to define better the benefits andthe correct dose needed for supplementation. (6)

Vitamins and MineralsIron fortification was implemented in 1959 in responseto recognition of a high prevalence of iron deficiencyanemia among formula-fed infants. Iron from humanmilk is absorbed at a higher rate (20% to 50%) comparedwith cow milk (4% to 7%). To compensate for lowerbioavailability, all fortified formulas contain 1.8 mg/100 kcal of iron as compared with 0.45 to 0.9 mg/100 kcal in human milk. It is strongly recommended that

nutrition infant formulas

180 Pediatrics in Review Vol.32 No.5 May 2011. Provided by Health Internetwork on May 3, 2011 http://pedsinreview.aappublications.orgDownloaded from


Tab

le.In

fant

Form

ula

Com

paris

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Prim

ary

Prot

ein

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teFa

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Ratio

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Prot

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yzed

Case

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ced

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ber

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(%to

tal

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ucle

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tics

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cont

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free

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all formula-fed infants receive iron-fortified formulas toprevent anemia. Infant formula content of other micro-nutrients is based on a combination of data sets, includ-ing age-specific dietary reference intakes, human milkcomposition, inherent differences in the bioavailability ofspecific nutrients in human milk and formula, and regu-latory guidelines.

NucleotidesThese nitrogenous substances have been added to severalcow milk-based formulas since the late 1990s due toexpanding knowledge of their physiologic role and rec-ognition of their presence in relatively high concentra-tions in human milk. Nucleotides, which consist of oneRNA nucleoside (adenine, guanine, cytosine, or uri-dine), one 5-carbon sugar moiety, and one or morephosphate groups, have been proposed as conditionallyessential during periods of rapid growth because theypossess immunomodulating capabilities. In clinical stud-ies, nucleotide supplementation has been shown to en-hance growth in small-for-gestational age infants, en-hance immunoglobulin A (IgA) and IgM concentrationsin preterm infants, decrease the incidence of diarrhealdisease, and enhance antibody response to certain vac-cines. However, additional research is needed to definethe mechanism of action, confirm the clinical response,and monitor long-term effects of nucleotide supplemen-tation of infant formulas.

Prebiotics, Probiotics, and SynbioticsThe intestinal flora of breastfed infants differs from thatof formula-fed infants. Breastfed infant flora is predomi-nantly composed of Bifidobacterium and Lactobacillus,whereas the flora of formula-fed infants is more complex,including also Bacteroides, Enterobacteriaceae, Clostrid-ium, and Streptococcus. This difference is due, in part, tothe high concentrations of oligosaccharides present inhuman milk that selectively stimulate bifidobacteria andlactobacilli. These bacteria are believed to be importantfor nutrient absorption, protection against pathogencolonization, development of the intestinal and systemicimmune systems, and acquisition of mucosal tolerance.In an attempt to reproduce the intestinal flora of hu-man milk-fed infants, prebiotics, probiotics, and synbiot-ics have been added to formulas with promising results.

Prebiotics are nondigestible short-chain carbohydrates,commonly galacto-oligosaccharides, fructo-oligosaccharides,or lactulose, that stimulate growth and function of specificspecies of bacteria. When added to formulas, prebioticshave been shown to increase the concentration of bifido-bacteria and lactobacilli in the stools of preterm and term

infants. The fermentation of prebiotics in the colon can leadto acidic, more frequent, and looser stools, but they are safeat the currently prescribed doses. Probiotics are live micro-organisms that survive digestion and colonize the colon,leading to a more beneficial colonic microbiota. Synbioticsare a combination of prebiotics and probiotics. Both pre-biotics and probiotics allow for normal growth in infancy.

Prebiotics and probiotics have been used for the pre-vention and treatment of allergy. The intestinal flora ofatopic infants differs from that of nonatopic infants in thefirst few weeks after birth. These differences were notedbefore the development of atopy, suggesting a possiblecausative relationship. A lower number of bifidobacteriaand higher numbers of clostridia may lead to an unbal-anced, Th2-predominant immune response with in-creased IgE secretion, which is theorized to be a factorin the development of atopy. Both prebiotics and pro-biotics have been used in an attempt to achieve a morefavorable intestinal flora, thereby preventing the devel-opment of atopic diseases. Evidence for the use of pre-biotics in the prevention of atopy is inconclusive. Thisuncertainty could be due to a significant heterogeneityamong the studies, including types and doses of pre-biotics, types of milk used, and patient selection.

A Cochrane review showed that probiotic supplementa-tion to high-risk infants decreased the incidence of clinicaleczema but not of other atopic diseases. However, cautionwas raised about the heterogeneity of studies, the lowfollow-up numbers, and the fact that this effect did not holdfor eczema with proven sensitization. (7) Probiotics havebeen studied for the treatment of allergies. One studyshowed that infants suspected of having cow milk proteinallergy (CMPA) had faster recoveries when LactobacillusGG was added to an extensively hydrolyzed formula, withfaster resolution of blood per rectum and increased reduc-tion of fecal calprotectin concentrations. (8)

Perhaps the most promising effect of probiotics is inthe prevention of necrotizing enterocolitis (NEC). NECis believed to have a multifactorial cause, with contribu-tory factors including prematurity, aggressive initiationof feedings, pathogenic bacteria, and ischemia, all ofwhich ultimately lead to immunologic injury to the gut.The intestinal flora of preterm infants contains less ben-eficial bacteria, which may be due to delayed feedings,broad-spectrum antibiotic courses, and acquisition ofpathogenic environmental bacteria. Probiotics are be-lieved to reduce the intestinal inflammatory response andmay prevent NEC. In a recently updated meta-analysis,probiotics led to a reduction in cases of NEC (at least a30% reduced incidence) and all-cause mortality in verylow-birthweight (VLBW) infants (1,000 to 1,500 g).




Probiotics did not reduce the risk of sepsis or mortalitydue to NEC. (9) There are rare reports of probiotic-associated sepsis in neonates, but this complication wasnot seen in the studies reviewed for the meta-analysis.Other potential concerns about the safety of probioticshave been raised, including risks for transmission of anti-biotic resistance and negative effect on neurodevelopment.In conclusion, probiotics appear to be effective in reduc-ing the risk of NEC, but more studies are needed todetermine the most beneficial type, dose, and durationof probiotic therapy. The safety and efficacy need to beestablished for each product. Currently, data in extremelylow-birthweight (�1,000 g) infants are insufficient toreach any conclusions. The evidence for use of prebioticsin the prevention of NEC is very limited.

Studies have shown that formulas supplemented withprebiotics led to prevention of respiratory and intestinalinfections. In one study, this beneficial effect persisted at2 years of age. (10)

Preterm Infant FormulasPreterm formulas were developed to meet the unique nu-tritional needs of rapidly growing preterm or low-birthweight infants. These products have a higher caloricdensity than standard formulas (24 kcal/oz or 80 kcal/100 mL). They contain supplemental taurine and 3 to3.3 g/100 kcal of whey-predominant protein, which hasbeen demonstrated to support growth and body composi-tion changes comparable to intrauterine standards. The fatand carbohydrate compositions of these formulas are de-signed to overcome nutrient losses from low concentrationsof lipase, bile salts, and intestinal lactase. In currently avail-able products, medium-chain triglyceride (MCT) oil pro-vides between 40% and 50% of total fat, with the remainderderived from a vegetable oil blend and supplemental DHAand ARA. MCT is absorbed directly into the portal vascularsystem and does not depend on the availability of bile acidsfor micellar solubilization.

Although lactase concentrations do not reach maxi-mal values until term, carbohydrate is provided as a60:40 or 50:50 mixture of glucose polymers and lactosedue to the beneficial effects of lactose for calcium absorp-tion and as a prebiotic. Preterm formulas contain higheramounts of numerous minerals and vitamins (particularlycalcium, phosphorus, and vitamins A and D). It is impor-tant to note that intakes of some nutrients may beexcessive if preterm formulas are consumed in quantitiesthat exceed 12 oz/day (360 mL), and this risk increasesas the infant’s weight approaches 2,000 g. Preterm for-mulas should always be discontinued before hospitaldischarge.

Preterm Transitional Formulas“Transitional” or “enriched” formulas that have inter-mediate nutrient concentrations have been available forseveral years and are marketed to bridge the gap betweenpreterm and term formulas. Preterm infants are usuallytransitioned from preterm formulas to enriched formulas(22 kcal/oz or 73 kcal/100 mL) at 1,800 to 2,000 g or34 weeks gestational age and continued on these for-mulas until 6 to 9 months of age. These formulas canachieve vitamin and mineral goal requirements withoutadditional supplementation. However, the data on growthand neurodevelopment have been disappointing. In fact,a 2007 Cochrane meta-analysis found no evidence thatfeeding enriched formulas (versus standard infant for-mulas) to preterm infants after hospital discharge leadsto improvements in growth or neurodevelopment by18 months of age. (11)

Human Milk FortifiersHuman milk alone is inadequate to meet the nutritionalneeds of preterm infants, particularly VLBW infants(�1,500 g). Thus, fortification of human milk (ie, theaddition of multinutrient supplements) is recommended.Currently available commercial human milk fortifiers con-tain protein, carbohydrate, fat, and up to 23 vitamins andminerals. When mixed according to manufacturer’s direc-tions, fortified human milk matches growth and metaboliceffects of preterm infant formulas. As with preterm formu-las, ongoing use of commercial human milk fortifiers even-tually may lead to excessive intake of certain nutrients thathave known potential for toxicity. Therefore, it has becomecommon clinical practice to use specific quantities of stan-dard infant formula powder or liquid concentrate to fortifyhuman milk in preterm infants who have progressed be-yond specific age, weight, and intake volumes.

Soy FormulasCurrently available soy formulas contain a higher con-centration of protein (2.45 to 2.8 g/100 kcal) andsupplemental amino acids (L-methionine, taurine, andL-carnitine) to improve their biologic value. Glucosepolymers from corn syrup solids or maltodextrin are theprimary source of carbohydrate in soy formulas. Someproducts also contain sucrose, and all soy formulas arelactose-free. Fiber oligosaccharides, naturally occurringsoy carbohydrates, are also present in soy formulas. Thesecompounds and soy phytates have a high affinity forcalcium, phosphorus, zinc, and iron and have beenshown to interfere with their absorption. Therefore, soyformulas contain 20% higher concentrations of calciumand phosphorus and additional zinc and iron to compen-




sate for their diminished bioavailability. The fat contentof soy formulas is similar to cow milk-based formulas,containing a blend of vegetable oils and supplementalARA and DHA in all currently marketed products.

According to the 2000 United States Census, 18% ofinfants were fed soy formula in their first postnatal year.However, evidence-based indications for their use arelimited. Soy protein-based formulas have been shown tobe safe in term infants, with evidence for adequategrowth rates and bone mineralization compared withinfants fed cow milk-based formulas. However, for pre-term infants, soy formulas cannot meet the increasedrequirements for calcium and phosphorus to match intra-uterine accretion values, and this inadequacy can lead toosteopenia. Soy formulas contain increased concen-trations of aluminum, which may compete with calciumfor absorption, further affecting bone mineralization.For these reasons, soy formulas are not recommendedfor preterm infants. Concerns have been raised about thehigh concentrations of phytoestrogens/isoflavones insoy. These compounds bind to estrogen receptors andhave been reported to have various negative effects onestrogen-related functions in animal studies, althoughresults are conflicting and may be species-specific. In fact,a recent retrospective follow-up study showed no repro-ductive or estrogen-related adverse effects in adults whohad been fed soy formula exclusively as infants. (12)

Soy formulas have not been shown to be of benefitin the management of infantile colic or cow milk intol-erance, and there is no indication for their use in theprevention of atopic diseases. Infants who have nonIgEallergic enteropathy or enterocolitis due to CMPA havea 30% to 64% rate of cross-reaction to soy protein.Therefore, soy formulas are not indicated in the manage-ment of nonIgE allergies to cow milk protein. However,only 8% to 14% of infants who have IgE-mediated aller-gic reactions to cow milk proteins are sensitized to soy.

A statement by the European Society for PediatricGastroenterology, Hepatology, and Nutrition recom-mends that use of soy formulas be limited to infants olderthan 6 months of age who have signs consistent withIgE-mediated allergy after successful clinical challenge.(13) Soy formulas are free of all lactose and are indicatedwhen strict lactose avoidance is required, as in the rarecase of congenital lactase deficiency or in the manage-ment of galactosemia. It is important to note that cowmilk protein formulas said to be free of lactose, in whichother sugars are the predominant source of carbohy-drates, still can contain small amounts of lactose and arenot appropriate for infants who have galactosemia. Anyformula said to be lactose-free may be used for transient

lactase deficiency, such as a postviral enteropathy, al-though such affected infants generally tolerate continu-ation of a standard lactose-containing formula. Becausesoy formulas in this setting were only shown to decreasethe duration of the diarrhea from 6 to 4 days without asignificant change in weight at 14 days, their use for thispurpose is discouraged. (14) Finally, strict vegetarianfamilies may prefer soy formula for their infants.

Hydrolyzed and Amino Acid-based FormulasMore than 50 years ago, infant formulas containingextensively hydrolyzed protein were developed for feed-ing infants who were unable to digest or tolerate formu-las containing intact cow milk protein. Casein, which isheat-treated and enzymatically hydrolyzed, is the proteinsource for all currently marketed formulas of this typein the United States. Hydrolysis results in a combina-tion of short-chain peptides and free amino acids. Spe-cific free amino acids are supplemented to improve thebiologic value of the resulting nitrogenous content. Ithas been shown that peptides containing as few as threeamino acids can induce T-cell activity in vitro. Thus, tobe labeled as hypoallergenic, the American Academy ofPediatrics (AAP) guidelines state that “formulas mustdemonstrate that they do not provoke reactions in 90% ofinfants or children with confirmed cow milk allergy with95% confidence when given in prospective randomized,double-blind, placebo-controlled trials.” Currently, onlyextensively hydrolyzed and free amino acid-based formu-las are considered to be hypoallergenic by these criteria.

Glucose polymers from various combinations of in-gredients are the primary carbohydrate source in exten-sively hydrolyzed formulas (EHFs). One currently avail-able formula (Similac Expert Care Alimentum®, AbbottNutrition, Columbus, OH) contains a combination ofglucose polymers and sucrose. All formulas are lactose-free.

The fat content of EHFs varies considerably. Allcontain a blend of vegetable oils similar to that in stan-dard formulas and a total fat content of 48%. In two ofthree currently marketed products (Pregestimil®, MeadJohnson Nutritionals, Evansville, IN, and Similac ExpertCare Alimentum®, Abbott Nutrition, Columbus, OH),a portion of this oil blend is replaced with MCT oil,which is helpful in certain malabsorptive conditions.Because essential fatty acids are long-chain triglycerides,no formula contains 100% MCT as a fat source.

Carbohydrate and fat composition are important cri-teria for specific EHF selection because clinical applica-tion of these formulas has expanded over time to in-clude various conditions characterized by malabsorptionof nutrients. Examples include short bowel syndrome,




hepatobiliary disease, pancreatic insufficiency, autoim-mune diseases, and immunodeficiency syndromes. Theseformulas may be poorly accepted unless introduced earlyin infancy, and their high cost necessitates judicious use.

In recent years, formulas containing partially hydro-lyzed whey protein have been marketed in the UnitedStates. They contain fat blends similar to those in stan-dard formulas as well as reduced lactose content (lactosepartially or fully replaced by glucose polymers).

Three amino acid-based formulas have been approvedby the United States Food and Drug Administration:Neocate® (Nutricia North America, Gaithersburg, MD),Elecare® (Abbott Nutrition, Columbus, OH), andNutramigen AA® (Mead Johnson Nutritionals, Evansville,IN). Unlike EHFs, the protein content of amino-acid basedproducts is composed of individual free amino acids.

Glucose polymers from various dietary sources are theprimary source of carbohydrate. With regard to fat content,one product (Nutramigen AA®) contains an oil blendsimilar to that in standard formulas. The other two products(Neocate® and Elecare®) contain a combination of oilsresulting in a long-chain triglyceride-to-MCT ratio (67:33)that can be beneficial for certain malabsorptive disorders.

The increasing incidence of atopic diseases in recentdecades has prompted interest in the use of hydrolyzedformulas for the prevention of atopy, particularly ec-zema, asthma, and food allergies. Hydrolyzed proteinformulas appear to be superior to standard cow milkformulas, but not to human milk, in the prevention ofallergy. The German Infant Nutritional InterventionProgram, a longitudinal prospective study, showed thatinfants who had a high risk for developing atopic diseases(first-degree relative who had allergy) had a 33% lowerincidence of atopic dermatitis when human milk wassupplemented with hydrolyzed protein formula com-pared with supplementation with regular cow milk for-mula in the first 4 postnatal months. (15) This beneficialeffect persisted at 6 years of age. Extensively hydrolyzedcasein was more effective than partially hydrolyzed whey;extensively hydrolyzed whey showed no benefit.

In 2008, updated AAP recommendations stated thatfor infants at high risk of developing atopic disease whoare not breastfed exclusively for 4 to 6 months or areformula-fed, there is evidence that atopic dermatitis maybe delayed or prevented by the use of EHF or partiallyhydrolyzed formula (PHF) compared with cow milk-based formula. (16)

A more recent meta-analysis of 18 studies of high-riskinfants who were fed a partially hydrolyzed whey formulafound a 45% reduced risk for atopic dermatitis at 1 year ofage and 36% reduction at 3 years of age. (17) Consider-

ing the high prevalence of allergic diseases in the popu-lation, one third of all infants would be candidates for ahydrolyzed formula, but their higher cost must be takeninto consideration. Amino acid-based formulas have notbeen studied in the prevention of allergy.

Today, CMPA or hypersensitivity is reported in 2%to 3% of all infants. PHFs are not indicated for themanagement of CMPA due to the high percentage ofreactions to these formulas. Therefore, infants who haveproven CMPA and are not breastfeeding should be fedEHFs. A subgroup of patients who have CMPA, thosewho have nonIgE-mediated enterocolitis and failure tothrive, severe eczema, or symptoms during exclusivebreastfeeding, may respond better to amino acid-basedformulas than hydrolyzed formulas. (18) However,amino acid-based formulas should be reserved for thosewho do not respond to EHFs.

A percentage of infants who experience colic do re-spond to hydrolyzed formulas. Thus, a 1- to 2-week trialof a hydrolyzed formula can be recommended.

Modified Cow Milk- andSoy-based Formulas for Term InfantsIn the past several years, the infant formula market hasexpanded to include several formulas marketed as solu-tions to specific conditions such as acid reflux, diarrhea,and excessive gas or fussiness often associated with colic.These formulas vary considerably in their macronutrientprofile and typically contain one or more of the follow-ing modifications: partially hydrolyzed whey and soyproteins; reduced lactose or lactose-free carbohydrateblends; and other added ingredients such as thickeners,soy fiber, and prebiotics. With the exception of thickenedformula, evidence for and against these modifications hasbeen addressed in previous sections of this review.

Thickened infant formulas are commonly used to helpmanage gastroesophageal reflux disease (GERD). A recentmeta-analysis reviewed 14 randomized, controlled trialsthat used different thickeners, including carob-bean gum,cornstarch, rice starch, cereal, and soy fiber. (19) Thickenedmilk was associated with an increased percentage of infantswho had no regurgitation and reduced number of episodesof vomiting, regurgitation, and signs of GERD such asirritability and crying. However, the clinical significance ofthis reduction is unclear because vomiting was reduced byonly 0.9 episodes/day. pH probe indices were not signifi-cantly improved, with the exception of a shorter duration ofthe longest episode of pH lower than 4. Thickened feedingsmay reduce nonacidic episodes of reflux, which may explainthe disparity between clinical observations and standard pHprobe measurements. Prethickened formulas are not supe-




rior to formulas thickened later with corn starch or ricecereal. Concerns have been raised about the safety of thick-ened milks, including malabsorption of macro- and micro-nutrients. The only adverse effects reported in the meta-analysis were increased coughing and diarrhea. Largerstudies are needed to address these safety concerns better.

Follow-up FormulasFollow-up formulas were developed to meet the nutri-tional needs of infants and young toddlers whose solidfood intake is not fully adequate to meet age-specificnutritional requirements. As compared with standardformulas, follow-up formulas are slightly higher in thecontent of protein and selected minerals. They are avail-able as modifications of both cow and soy milk-basedproducts. According to the AAP, follow-up formulas areconsidered nutritionally adequate when used in combi-nation with solid foods but offer no clear advantage overinfant formulas designed to meet 100% of nutritionalneeds throughout the first postnatal year. These productsmay offer a small cost advantage over standard infantformulas.

References1. Committee on the Evaluation of the Addition of IngredientsNew to Infant Formula. Comparing infant formulas with humanmilk. In: Infant Formula: Evaluating the Safety of New Ingredients.Washington, DC: The National Academies Press; 2004:41–54

2. Electronic Code of Federal Regulations; Title 21:107, Infant For-mulas. Washington, DC: Government Printing Office; 20103. Robbins ST, Beker LT, Pediatric Nutrition Practice Group.Infant Feedings: Guidelines for Preparation of Formula and Breast-milk in Health Care Facilities. Chicago, IL: American DieteticAssociation; 20044. Simmer K, Patole S, Rao SC. Long-chain polyunsaturated fattyacid supplementation in infants born at term. Cochrane DatabaseSyst. Rev. 2008;1:CD0003765. Schulzke SM, Patole SK, Simmer K. Long-chain polyun-saturated fatty acid supplementation in preterm infants. CochraneDatabase of Syst. Rev. 2008;2:CD0003756. Hoffman DR, Boettcher JA, Diersen-Schade DA. Toward opti-mizing vision and cognition in term infants by dietary docosahexa-enoic and arachidonic acid supplementation: a review of random-ized controlled trials. Prostaglandins Leuko Essent Fatty Acids.2009;81:151–1587. Osborn DA, Sinn JK. Probiotics in infants for prevention ofallergic disease and food hypersensitivity. Cochrane Database SystRev. 2007;4:CD0064758. Baldassarre ME, Laforgia N, Fanelli M, Laneve A, Grosso R,Lifschitz C. Lactobacillus GG improves recovery in infants withblood in the stools and presumptive allergic colitis comparedwith extensively hydrolyzed formula alone. J Pediatr. 2010;156:397–4019. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis inpreterm neonates. Pediatrics. 2010;125:921–93010. Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S,Boehm G. Early dietary intervention with a mixture of prebioticoligosaccharides reduces the incidence of allergic manifestationsand infections during the first two years of life. J Nutr. 2008;138:1091–109511. Henderson G, Fahey T, McGuire W. Nutrient-enriched for-mula versus standard term formula for preterm infants followinghospital discharge. Cochrane Database Syst Rev. 2007;4:CD00469612. Strom BL, Schinnar R, Ziegler EE, et al. Exposure to soy-basedformula in infancy and endocrinological and reproductive out-comes in young adulthood. JAMA. 2001;286:807–81413. ESPGHAN Committee on Nutrition, Agostoni C, Axelsson I,Goulet O, et al. Soy protein infant formulae and follow-on formu-lae: a commentary by the ESPGHAN Committee on Nutrition.J Pediatr Gastroenterol Nutr. 2006;42:352–36114. Allen UD, McLeod K, Wang EE. Cow’s milk versus soy-basedformula in mild and moderate diarrhea: a randomized, controlledtrial. Acta Paediatr. 1994;83:183–18715. von Berg A, Filipiak-Pittroff B, Kramer U, et al. Preventiveeffect of hydrolyzed infant formulas persists until age 6 years:long-term results from the German Infant Nutritional InterventionStudy (GINI). J Allergy Clin Immunol. 2008;121:1442–144716. Greer FR, Sicherer SH, Burks AW. Effects of early nutritionalinterventions on the development of atopic disease in infants andchildren: the role of maternal dietary restriction, breastfeeding,timing of introduction of complementary foods, and hydrolyzedformulas. Pediatrics. 2008;121:183–19117. Alexander DD, Cabana MD. Partially hydrolyzed 100% wheyprotein infant formula and reduced risk of atopic dermatitis: ameta-analysis. J Pediatr Gastroenterol Nutr. 2010;50:422–43018. Hill DJ, Murch SH, Rafferty K, Wallis P, Green CJ. Theefficacy of amino acid-based formulas in relieving the symptoms of

Summary• Based on strong research evidence, formulas

supplemented with DHA (between 0.3% and 0.5%of total fatty acids) and at least equal amounts ofARA are beneficial for visual and neurologicaldevelopment.

• Based on strong research evidence, formulassupplemented with probiotics reduce the incidenceof clinical eczema in high-risk infants (parent orsibling who has atopy).

• Based on strong research evidence, formulassupplemented with probiotics reduce the incidenceof NEC and all-cause mortality in VLBW infants.

• Based on some research evidence, formulassupplemented with prebiotics or probiotics decreasethe risk of infections during infancy.

• Based on strong research evidence, partially orextensively hydrolyzed formulas are effective inpreventing or delaying development of atopicdermatitis in high-risk infants.

• Based on strong research evidence, thickenedformulas reduce the number of episodes of vomiting,regurgitation, and signs of GERD such as irritabilityand crying.




cow’s milk allergy: a systematic review. Clin Exp Allergy. 2007;37:808–82219. Horvath A, Dziechciarz P, Szajewska H. The effect of

thickened-feed interventions on gastroesophageal reflux in infants:systematic review and meta-analysis of randomized, controlledtrials. Pediatrics. 2008;122;e1268–e1277

PIR QuizQuiz also available online at: http://pedsinreview.aappublications.org.

1. Which of the following statements about infant nutrition is true?

A. Human milk contains more casein than infant formulas.B. Infants who receive increased whey protein have been shown to grow better than those who receive

primarily casein.C. Iron is absorbed better from cow milk formulas than from human milk.D. Lactose-free formulas result in decreased absorption of calcium.E. There are no apparent negative effects from the addition of DHA and ARA to formulas.

2. Which of the following statements regarding prebiotics and probiotics is true?

A. Both have been proven to decrease the incidence of atopy.B. Prebiotics are live microorganisms.C. Probiotics are carbohydrates that stimulate bacterial growth.D. The use of probiotics has been shown to reduce the incidence of necrotizing enterocolitis.E. They should be routinely prescribed to exclusively breastfed infants.

3. The characteristic that is more typical of casein than of whey is that it:

A. Forms large curds on exposure to gastric acid.B. Is only found in trace amounts in cow milk.C. Is resistant to precipitation.D. Is the predominant protein in human milk.E. Undergoes more rapid gastric emptying.

4. Which infant feeding is best for the prevention of atopic disease?

A. Cow milk-based formula.B. Extremely hydrolyzed formula.C. Human milk.D. Partially hydrolyzed formula.E. Soy formula.

5. Which of the following supplements has been added to formulas for the longest period of time?

A. Arachidonic acid.B. Docosahexaenoic acid.C. Iron.D. Nucleotides.E. Prebiotics.

6. A young mother has brought her newborn to your clinic for his first visit. She has heard that soy formulasare better than milk-based formulas. For which of the following conditions is soy formula indicated?

A. Allergic enteropathy.B. Colic.C. Galactosemia.D. Gastroesophageal reflux.E. Prematurity.




DOI: 10.1542/pir.32-5-179 2011;32;179-189 Pediatr. Rev.

J. Andres Martinez and Martha P. Ballew Infant Formulas

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