Infant Formula

1064

Doinfants

needl.

extraDHA,AA?u.s.products

soon maycontain

long-chainPUFA

period when dietary intake greatlyinfluences the stores of DHA and AA ininfants. Bur a solid foundation of DHAand AA is first built up during feraldevelopment (Sec "Pregnancy, infants,and toddlers").

In the brain, DHA is most abundanTin membranes associated wirh synapticfuncnon. In infants, DHA helps buildnerve cell membranes and also plays a

mothers' milk to breast-feeding infants,but they are not found in infant formulacurrently available in the United States.The topic may be controversial for sev-eral reasons, bUT one Thing is certain:LCPUFA-enriched infant formula isgoing TOreach U.S. STOreshelves soon.

By Tom Krawczyk. inform senior editor/writer

Infant formulas containing the long-chain polyunsaturated fatty acids (LCP-UFA) docosahexaenoic acid (DHA,22:6n-3) and arachidonic acid (AA,20:4n-6) may hit the Ll.S. market asearly as 2002. Considered basic build-ing blocks of the central nervous sys-tem, DHA and AA are provided Ilia

WHY DHA?The first 18 months of life is a crucial

Volume 12 • Noyember 200 I • Inform

role in phororeccpror-rnembrane func-tion in the retina. AA must be added roinfant formula supplemented with DHAto avoid a reduction in AA levels.Infants with lower levels of AAgrow more slowly (Sec"Infant AA still a mys-tery").

Based on earlierfindings that showedbreast-fed infantstend to have greatervisual acuity andhigher intelligencequotients thaninfants fed formula,researchers added LCP-UFA to infant formula rotest infants for proper devel-oprnenr of retinal and nervoussystem cells. The results have been farfrom definitive.

In fact, one of the largest studies ofits kind (involving 400 full-term infants)was published in the August 200! issueof Pediatrics, the journal of theAmerican Academy of Pediatrics. Thatstudy failed to find beneficial results inthe 245 term infants fcd infant formulassupplemented with DHA and AA (83 ofthese were fed brcnsr milk and supple-mented fomuln] Another 72 infants inthe study received a control formula; 82others were fed breast milk and controlformula. The study specifically lookedfor measurable differences in infants fedbreast milk, standard formula, formulaenriched with LCPUFA from fish(DHA) and fungal (AA) sources, andformula enriched with LCPUFA (DHAand AA) from an egg source. ln measur-ing several cognitive and visual OUT-

comes, the researchers could nor findsignificant differences among the fourgroups of infants.

How can this be, if DHA and AA arcso important in the development of

brain and retina cell membranes? Whywouldn't the addition of these fattyacids show a measurable effect?

Infant formula currently provides theprecursor fatty acids a-

linolenic acid (ALA) andlinoleic acid (LA). These

are called essentialfatty acids becausethe body cannotmanufacture themfrom orher precur-sors. ALA is theparent fatty acid

! from which members

D:Jof the n-j group,including DHA, are

derived. LA is the parentfrom which members of the

0·6 group, including AA, arederived.

Some researchers believe infants can-not synthesize enough DHA and AAfrom these essential fatty acids to meettheir needs. Other researchers say thatinfants can synthesize all the DHA andAA they need if ALA and LA are sup-plied in a proper ratio.

The study published in Pediatricswas conducted by associate research fel-low Nancy Auestad and colleagues andsponsored by U.S. formula manufac-turer Ross Products, a division ofAbbott Laboratories. Ross used its cur-rently marketed infant formula as thecontrol formula and as the base for thesupplemented formulas. According toAuestad, The Ross formula suppliedenough essential fatty acids (22.2% oftcral fat as LA and 2.6% as ALA) toenable term infants to synthesizeenough DHA and AA to meet theirneeds.

"Evidence has been published sug-gesting that formulas containing a min-imum of 1.75% fatty acids as ALA anda ratio of linoleic to ALA of 5: I to IS: I

1065

8 5 COOH

~~11 14

Arachidonic acid

./.'.~HO-C~

"oDocosahexaenoic acid

Volume 11 • November 100 I • Inform

Infant Formula

in formula, even though the effects interm infants have not been conclu-

sively proven (inform12:836-837).

Ross Products andMead Johnson, a Bristol-Myers Squibb company,together hold approxi-mately 85% of the U.S.market for infant for-mula, but neither has

indicated it will soonmarket an LCPUFA-supple-

menred formula in the UnitedStates. Ross does not currently

manufacture LCPUFA-enrichcd for-

"66

may adequately support visual and cog-nitive development, despite lowercirculating levels of AA andDHA," Auestad said.

U.S. BATTLEGROUND

In the United States, theU.S. Food and DrugAdministration (FDA)docs nor require theaddition of DHA andAA to infant formula forfull-term infants. The FDAannounced in May 2001 thatit would allow a blend of theserwo LCPUFA as an optional ingredient

Pregnancy, infants, and toddlersThe controversy over DHA and AA in infant nutritionextends over a wide spectrum of maternal and child health.The current battle is over infant formula for full-term infants,or those born beyond 37 week's gestation.

OHA and AA are even more important for babies bornprematurely. Preterm babies miss our on some of the "braingrowth spurr" that occurs during the last trimester of preg-nancy, when DHA is transferred directly to the infant'sbloodstream via the placenta. Prererm infants have a DHAdeficit, and much research has gone into measuring how well"preemies" respond to higher levels of DHA in their diet.

Although the consensus appears to be that prcrerminfants benefit from receiving supplemental DHA and AA informula, the irony is that these fatty acids arc not currentlyapproved in the United Stares for use in prererm formula.

This may by changed after FDA receives a report it com-missioned 011 preterm infant formula. FDA asked the LifeSciences Research Office (LSRO) to review the research onprererm formula and give FDA recommendations on its com-position. The LSRO report on preterm infant formula isnearing completion and is expected to be sent to FDA by theend of 2001 or early 2002, according to William Heird, pro-fessor of pediatrics at Baylor University College of Medicine,researcher at the Children's Nutrition Research Center oper-ated in conjunction with the USDA's Agricultural ResearchService (ARS), and a member of the LSRO panel.

Volume 12 • November 200 I • Inform

FDA may decide, based on what LSRO recommends, thatit is time to propose federal rules for the manufacture ofpreterm infant formula.Meanwhile. prererm formulaproducts have beenapproved by the agencyon a case-by-case basis.

Regardless, the mar-ket for preterm infantformula is not large-approximately 5-10% ofbirths are premature-andthe product is typically dis-pensed in a hospital setting, not purchased by parents. Amongthe factors involved in possible addition of DHA and AA topreterm infant formulas in the United States is that FDA has notaccepted any source of LCPUFA for addition to preterm formu-las. Prcterm infants are a more fragile population, so demon-strating the safety of new ingredients is more complex than itwould be for full-term infants.

With the recent FDA approval to allow addition of DHAand AA to full-term infant formula, however, LCPUFA maybe proposed for other food products within the genre. Forexample, DHA supplements are already being marketed topregnant women SOthey can provide a higher level of DHAto the infant in utero.

mula, bur Mead Johnson makes suchproducts for sale in other countries. TheWashi1lgt01I Post, in an article onMarrek published Nov. 3, 2000, saidMead Johnson and Abbott Labs, parentof Ross Products, have licensedMarrek's oils.

The No.4 U.S. infant formula man-ufacturer, Wyeth NutritionalsInternational, produces infant formulafor distribution and sale by stores orother third-parry firms (private-labelbrands) in the U.S. market. Outsidethe United Stares, however, Wyeth isthe largest manufacturer of LCPUFA-supplemented infant formula world-

wide. Wyeth sells its products in numer-ous countries that allow infant formulasto contain additional DHA and AA (theWorld Health Organization advises sup-plementing infant formula with DHA).Canada and the United States areamong the few nations where LCPUFAis nor available in formula.

What makes the U.S. market differ-ent from markets in other countries isthe existence of a federally funded foodassistance program called the SpecialSupplemental Nutrition Program forWomen, Infants, and Children, com-monly referred to as WIC. The pro-gram's goal is to decrease health-care

costs through proper counseling andnutrition for pregnant women andinfants considered "at risk." Officialfederal policy, and thus WIC policy, is(0 promote breast-feeding as the pre-ferred way to lower maternal and childhealth care expenditures. (See ..Morethan JUStDHA and AA. ")

WIC also supplies infant formulato mothers who do not breast-feed.Approximately half of all U.S.infants are enrolled in WIC, and theprogram purchases nearly 60% of allthe formula consumed by infants in theUnited States. The sheer size of the pro-gram's purchases, combined with a fed-

"While this might make sense, studies of DHA supple-mentation for pregnant women have unfortunately lookedexclusively at the effect of DHA on length of gestation, with-out seeing much of an effect-one or two days at most," saidRobert Gibson, director of the Child Nutrition ResearchCenter at Flinders Medical Center located in South Australia."New studies will need to be conducted on pregnant womenin order to assess how the infant develops after receivinghigher levels of DI-IA in the womb."

Supplements also are available to boost DHA concentra-tions in breast milk. Infants already receive DHA throughbreast milk, but women in the United States have perhaps thelowest average concentration of DHA in breast milk foundworldwide. The U.S. average is approximately 0.10-0.15%of total fany acids; the global average is about 0.35%, withsome countries closer to 1.0% (the national average inJapan), and as high as 3.0% (China).

Many factors influence the fatty acid content of breastmilk, but diet is key. It is certainly one of the easiest factors tomanipulate, and more supplement manufacturers will likelyenter the maternal DHA market once LCPUFA-supplementedinfant formula hits the store shelves.

"A woman could change her milk from American toJapanese with JUSt a couple of fish oil capsules each day, It

Gibson said. That said, there is little research to back upthe theory that increasing maternal consumption of DHA

1067

erally mandated competitive biddingprocess, enables WIC to buy infant for-mula at a fraction of the normal retailprice. Many experts are waiting to seehow well LCPUFA-supplemented for-mula fares in this low-bid high-volumesystem.

"WIC is not going to be very inter-ested in having the price of infant for-mula increase," said William Heird,professor of pediatrics at BaylorUniversity College of Medicine inHouston, Texas, and researcher at theChildren's Nutrition Research Centeroperated in conjunction with theUSDA's Agricultural Research Service

will benefit the breast-fed baby.Baby food manufacturers may also reason that if DHA

and AA are good for infants, then surely they must also begood for toddlers. After all, what's a mother to do if she stopsbreast-feeding or bottle-feeding her baby at 12 months? Ifinfants are still building up stores of DHA and AA until 18months of age, then a window of opportunity exists for man-ufacturers of postformula baby foods.

"This is a wake-up call for the food industry. We need toprovide DHA in baby foods besides infant formula," saidNorman Salem Jr. of the National Institutes of Health inBethesda, Maryland. "The posrformula infant diet isextremely low in DHA. Baby food manufacturers use veg-etable oils as sources of fats, so generally they will ncr con-tain any LCPUFA. The levels of the DHA precursor, ALA, areso low that they may ncr be adequate to support the optimallevels of DHA in the nervous system and therefore optimalbrain and retina function."

DHA-enriched foods may be marketed to toddlers as afollow-on to infant formula, but it is doubtful that proof ofbenefit could ever be detected in a trial, Gibson said.

"JUSt as you can see an effect of DHA supplementation inpremature infants but not so readily in term infants, I expectit would be even harder to measure such outcomes in tod-dlers based on DHA supplementation of baby foods,"Gibson said.

Volume 12 • November 200 I • Inform

Infant Formula

1068

Infant AA still a mysteryDHA is the fatty acid most often mentioned when LCPUFA supple-mentation is discussed, but AA is typically added along with DHA inorder to avoid reduced AA levels in infants, which can slow theirgrowth rate.

The proof of that correlation, however, is far from conclusive. IntWO out of II studies, the lowering of AA was associated withreduced growth in preterm infants, according to Robert Gibson,director of the Child Nutrition Research Center at Flinders MedicalCenter located in South Australia. In term infants, however, supple-menting with DHA alone did not slow the growth rate, even thoughAA levels dropped.

"There is little evidence from randomized controlled trials that AAmust be added along with DHA in term infant formula," Gibson said.~Adding AA with DHA seems to be based mostly on our overridingconcern to 'First, do no harm.' Breast milk contains AA, so it seemsreasonable to add it."

AA is found in breast milk around the world. In looking at 50women in nine countries, AA levels generally were within0.30-0.55% of total fatty acids, according to Eric Lien, vice presidentof nutrition research and development at Wyeth-Ayerst Laboratories,part of Wyeth Nutritionals International. In his review, Lipids inHuman Milk, published in the December 1999 issue of Lipids, R.G.Jensen noted AA levels as low as 0.05% were reported in Canada andas high as 1.22% reported in China.

The levels of OHA in breast milk vary from extremes of 0.15% insome Western countries to 3.0% in some Eastern countries, Liennoted.

"Even though it might seem reasonable, there just isn't a scientificbasis for adding it, even if AA levels arc decreased by the addition ofDHA to infant formula," Gibson said. "'A more important questionmight be, 'Why does AA decrease with the addition of DHA to infantformula?' That is one of the more challenging questions you can askus right now. The point is, we just don't know."

Future research will also explore the role of AA in infant develop-ment. What does it do, and how does it do it?

AA is a precursor for series-2 prostaglandins, which along withtheir metabolites can be linked to heart arracks. Taking fish oil sup-plements high in DHA will decrease AA and series-2 prostaglandinsin adults, which is one of the ways fish oil can be shown to decreasethe risk of heart attacks, Gibson said. In the infant, however, the goalis to avoid decreasing AA levels, because the same mechanisms are notin place, or perhaps net yet fully developed.

~I don't think you can find one person who can tell you the role ofAA in the human infant," Gibson said.

Volume 12 • Noveml>er 200 I • Inform

lARS). "The COStof producing formulagoes up when you add ingredients likeDHA and AA. If there is a 10% priceincrease, somebody is going to have to

eat that cost."LCPUFA·enriched formula is typical-

ly sold as a higher-cost niche-markerproduct in other countries, fetching apremium of up to 15% over standardinfant formula. Formula companiescould arrernpr the same strategy in rhcUnited States, marketing higher-costLCPUFA formula to the 40% "non-WIC" market share that can afford thecost. There may be concerns, however,about giving half of U.S. infants alower-cost infant formula that is notsupplemented with DHA and AA whilesimultaneously marketing an enrichedformula to parents who can pay topdollar.

"The formula companies probablywill be forced to add it to all their for-mulas, not JUSt the top of the line, H

Heird said.

THE FUTURE OF FORMULA

Either way, the FDA will require post-market surveillance from companiesthat sell LCPUFA·supplemented fOT1llU-las in the United States. This will pro-vide an additional source of data to

back up the safety of LCPUFA supple-mentation. In addition, the volume ofresearch on DHA and AA in infants willonly grow, something that is hard tobelieve for those who have been in thefield for years.

"DHA has been studied for over 15years in randomized trials around theworld. It's been studied more than anyother single ingredient ever added toinfant formula," said Susan Carlson,professor of pediatrics and also ofdietetics and nutrition at the Universityof Kansas Medical Center in KanasCiry, Kansas, who added that the '101-

"69

ume of reseach on DHA and AA isgoing to grow.

One area of ongoing study will likelybe [he level of supplementation. Is therean optimal level? Is there a level abovewhich there are no benefits to infants?Is there a threshold below which thereare no cognitive or visual cffects?

One criticism of the recent RossProducts study, which showed the com-pany's standard infant formula to per-form as well as LCPUFA-supplementedformula and breast milk, is that theresearchers added DHA at :I level of0.14% of total fatty acids. Someresearchers believe that is too low toproduce a measurable effect.

"If you provide formula with excep-tionally low levels of DHA, say under0.2% of total fatty acids, you shouldnor expect to see an effect," said EricLien, vice president of nutritionresearch and development at Wycth-Ayerst Laboratories in Philadelphia,Pennsylvania, part of WyethNurririonals International.

Lien notes that the most recent rec-ommendations of the Child HealthFoundation in Munich, Germany, spec-ify that term infant formula should con-tain at least 0.2% DHA and 0.35% AA,with most of the individual scientistsconducting research in this area signingthose recommendations.

Yet breast-feeding can show a benefi-cial effect on visual acuity and cognitioneven if the level of DHA in breast milkis below 0.2%. In fact, the 0.14% DHAsupplementation in the Ross study wasthe average the researchers measured inthe breast milk of women enrolled inthe study. Future research will deter-mille if there is truly a threshold effectin supplementing infant formula. Arecent study by Jorgensen et al. pub-lished in the [ournal of PediatricGastroenterology and Nutrition

More than just DHA and AADHA and AA can be added to infant formula in order to bet-ter approximate breast milk, but breast milk is more thanjust a carrier for LCPUFA. In addition to DHA and AA,breast milk also contains at least 160 farry acids not foundin manufactured infant formula, as well as unique aminoacids, micronurrienrs, immunologically active proteins,enzymes, oligosacchnrides, lymphocytes, macrophages, neu-rrophiles, Iysozymes, mucins, lactoferrin, and hormones.

In fact, the supposed brain-boosting power of DHA is notthe sole benefit to breast-feeding.

From epidemiologists' perspective, the main benefit ofbreast-feeding is clear: reduced risk of disease. Breast milkcontains antibodies and other components that give a boostto an infant's immune system and help prcrecr against infec-tions, allergies, and asthma.

Over $3.6 billion in health care costs would be avoided ifthe U.S. incidence of breast-feeding were increased from cur-rent levels (64% at birth, 29% at 6 months) to those recom-mended by the U.S. Surgeon General (75 and 50%, respec-tively), according to the Economic Research Service (ERS) ofthe U.S. Department of Agriculture.

"This figure is likely an underestimation of the total sav-ings because it represents cosr savings from the treatment ofonly three childhood illnesses: otitis media, gastroenteritis,and necrotizing enterocolitis," said Jon Weimer, author ofthe ERS report on the economic benefits of breast-feeding.

The report does not rake into account three costly dis-eases common to formula-fed infants. According to theTexas Department of Health's Bureau of Nutrition Services,formula-fed infants in the United States are three times morelikely than their breast-fed counterparts to suffer from diar-rheal diseases, four times more likely to suffer from menin-gitis, and have an 80% greater risk of lower respiratoryinfections.

Similarly, a study published in the April 1999 issue of the[ournai of the Amblllatory Pediatric Society tracked earinfections, respiratory infections, and bouts of diarrhea 111

1,000 infants. Formula-fed babies incurred an additional$400 in first-year health care expenses compared to breast-fed babies.

Of course, the COStof formula tee, g must include theCOStof purchasing the formula itself. During the first year oflife, U.S. infants consume $ 1,500-52,000 worth of infantformula on average.

Volume 12 • November 200 I • Inform

1070

'The cumulative effectsof n-3 LCPUFA on so

many disease statesqualify n-3 LCPUFAas nutrients that can

have an enormousimpact on the quality

of life in the long run.'-Smuts

Volume 12 • November 200 I • Inform

AOCS HEAlTH AND NUTRITION DIVISION.'.- - j' ..,'-'~ " _.... ~.~ . -., .... ~-. .

Infant Formula

(32:293-296, 2001) demonstrated thatthe level of DHA in human milk is acontributing factor to visual develop-ment in term infants-the higher theDHA level, the better the visual 3CU-

iry,Feeding trials also will

be repeated with moreparticipants to

achieve greater reso-lution of the effectsof lCPUFA supple-mentation.

"There are manypossible reasons forone study finding aneffect and another norfinding it, bur it couldbe that the effect isrestricted to a small sub-group," said Robert Gibson,director of the Child Nutrition ResearchCenter at Flinders Medical Centre locat-ed at Bedford Park in South Australia.His research in lCPUFA supplementa-tion in term infants has found slight butsignificant differences based on whetherinfants were born prior to or just after aconventional birth time. .. From thebaby's perspective, there is a big differ-ence berween being born at 38 weeksand at 42 weeks, even though both areconsidered full-term pregnancies."

In addition, male infants seem toshow a greater effect from LCPUFA

supplementation than female infantsdo, Gibson said. These and other sub-tleties must be teased out of datagleaned from new and larger studies if

the basis for sporadic results withterm infants is to be known.

"It may be possiblethat differences (advan-

tages or disadvantages)of AA and OHA sup-plementation do norappear until after thefirst year, that theymay be present in thedomains of develop-ment not measured

here, that they onlyappear in more differen-

tiated and subtle assess-merits, or thai they only

become apparent in direct responseto cognitive or social srressors,"Auestad said in the August 2001Pediatrics study.

LASTING EFFECTS?

Other researchers will be on the lookoutfor medium- and long-term conse-quences to lCPUFA supplementation.

"In the short term, the effects ondevelopment in preterm infants aremeasurable, but what effects are therein rhe long term?" asked Alexandrelapillonne, assistant professor of pedi-atrics at Baylor College of Medicine in

-....,. ,-tion.The ............... _fadl7 .. ~ ... carJ nfnbetween........"..ac.ademia, and JO'ft'nmenl proIetsionah to .tvarKe the fie?d dIruuIh orpnized ~ andtKfmical sessions Oil!he AOCS AnnlUll Meeti,,!" Expo; ~Iopment of intffnOltionOll conw·ences. ;and by contributing arlides and books 10 AOCS publications. To join, contact AOCS.Phont': 1-217·359·2344; fax: '-217-351--8091; e-mail: membershipft<locs.org.

Houston, Texas, and 3 researcher at theARS Children's Nutrition ResearchCenter there. "Whether or not LCPUFAsupplemeruarion in early life may havevery long-term effects is not yet knownand remains an open and challengingfield of research."

A report by C.L Jensen and col-leagues of the Children's NutritionResearch Center in Houston, Texas,during the Society for PediatricResearch meeting in May 2001, foundthat breast-fed infants whose mothersconsumed additional DHA had higherscores on a test of psychomotor devel-opment at 30 months of 3ge. Previoustests of visual acuity in the same chil-dren as infants had not indicated anybenefit of additional DHA in the mater-nal diet.

Other researchers are looking forevidence that the long-term effects ofLCPUFA supplementation will proveeven more beneficial than the disputedshorr-rcrrn effects.

"The short-term behavioral effectsmayor may nor be obvious," saidMarius Smuts, a scientist at the MedicalResearch Council of South Africa,Tygerberg, South Africa. "But if youthink more long term, the benefits arebecoming more clear."

During the crucial postnatal dcvel-opmenr period, dietary fatty acids areincorporated into cell membranes,

Papers from the AOCS symposium on PUFAin Maternal and Child Health have been published in theSeptember 2001 issue of Lipids. That issue is available for $40 per copy.To order, e-mail: ordersfJaocs.org; phone: 1-800-ll6-AOCS ~ndb(within North America) or 1-217-359-5401, ext. 148 (out-side North America), or send a {ax to: 1-217-361-8091. 0 a

1071

the effects of which might be seenmuch, much later in life, Smuts said.Of the LCPUFA, n-3 fany acids maymitigate degenerative diseases such ascardiovascular disease in a multifac-roriat way, and the beneficial effectsof n-3 fatty acids on the immune sys-rem are becoming more clear withtime.

"In addition, decreased levels of n-3LCPUFA are being implicated in neuro-logical disorders. The cumulative effectsof n-3 LCPUFA on SO many diseasestates qualify n-3 LCPUFA as nutrientsthat can have an enormous impact onthe qualiry of life in the long run,"Smuts said.

The connection between DHA and ahost of measurable outcomes would beeasier to test if the mechanism of actionwere known. How does DHA do whatit does? For some researchers, that is thenext frontier.

"So far, we've been looking at behav-ior outcomes we know are related toneural function," Carlson said. "Thenext Step is to expand studies to othertypes of physiological functions as wellas to determine the underlying mecha-nism for the effects that have beenobserved with more research includingbiophysical, biochemical, electrophysi-ology, gene expression, and proreomicsstudies. We don't have all the answersyet. ..

Volume 12 • November 200 I • Inform

DHAIn

infantformula

•

In May 200 I, the U.S. FDA gave "gen-erally recognized as safe" (GRAS) srarusto Martek's single-cell oil blend of DHAand AA (inform 12:836-837), Formulamakers can now usc this source to makeinfant formula enriched with DHA andAA, clrhough they must notify FDAbefore taking the product to market,and FDA has 90 days to object. FDAalso said it would expect formula com-panies to conduct post-market surveil-lance to ensure the safety of the prod-UCl,

Despite these additional require-ments, Marrck expects LCPUFA-enriched formula (Q be on the U.S. mar-ker by early 2002. A SePL 3, 1001, arti-cle in the Washington POSTnoted thatMartek's oils were being sold in marc(han 60 other nations. The article saidthat in Hong Kong, where enrichedinfant formulas were introduccd inSeptember 2000, they had become thedominant product in thc market, eventhough they sell for about 15% morethan conventional formulas. As ofSeptember], 200], no U.S. infant for-mula manufacturer had yet stepped for-ward to publicly claim it would beginmaking DHA-enriched formula.

Regardless, even if only oneinfant formula manufacturer makesa LCPUFA-supplcmcnted product forthe U.S. marker, Martek may reap awindfall as the only LCPUFA supplierthus far to receive GRAS status for usein infant formula. Although Mnrrek hadsales of nearly $10 million in 2000, itestimates the potential global marketfor its LCPUFA product at $300-400million. One market analyst quoted bythe Washington POSt agrees, estimating200] revenue at $18 million, 2002 rev-enue at $50 million, and reaching $300million annually in the years ahead.Even so, LCPUFA-enrichcd infant for-mulas still represent less than 5% of rhe

1073

annual world infant formula market(estimated at $6 billion to $8 billion), asituation Marrek hopes will changeafter supplemented formulas hit theU.S. market. ATan estimated $3 billion,the U.S. market represents the lion'sshare of the $7.5 billion global marketfor infant formula.

"Not only is it the largest market,but it is perceived as a world leader interms of food safety, nor to mentiontrend-setting, '" said Angela Tsersts,director of marketing for Marrek.

Even before Martek's productreceived GRAS status, the company hadsigned licensing agreements with thethree major U.S. formula manufacturers(Ross, Mead, and Wyeth). Wyeth usesMarrek's DHA and AA in its formulafor term infants, sold in 20 countries,and in its more widespread product forprcrerm infants. In total, Marrck's prod-UCt can be found in preterm formulassold in 60 countries.

"Of the infant formulas supplementedwith DHA and AA, the majority use ourproduct, '" Tsetsis said.

The only major company nor to signan agreement with Martck is Nestle,one of the global leaders in infant for-mula production. In the United Stares,however, Nestle has a small presenceestimated at approximately 2% of theU.S. market.

If Nestle or another company wantsto introduce a LCPUFA-enriched infantformula in the United States withoutusing Marrek's GRAS product, theywould need to submit a GRAS petitionto FDA or otherwise have their infantformula approved by FDA.

FROM FISH TO FUNGUS

Other sources of DHA for usc in infantformula include fish oils and egg yolkphospholipids. Fish oil is the main non-Martek source of DHA, especially in

Volume 11 • November 100 I • Inform

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Volume 12 • November 2001 • Inform

Infant Formula

time owned the Kelco biogums busi-ness. Kelco grew the algae in San Diego,California, with OmegaTech using theDHA for animal feed to produce DHA-rich eggs while Monsanto manufac-tured a DHA dietary supplement forhumans. In June 2000, Omega Techbought back its technology rights,although it still uses Kelco to grow thealgae.

AA is also manufacrured by fermen-tation, but there is only one commercialsupplier. Chemical company DSM fer-ments AA at its facility in Italy by usingthe fungus Mortiere/la alpina. All non-egg AA in supplemented infant formulacomes from this source, regardless ofthe source of OHA. The source of DHAmay not matter much to the body afterit is metabolized and used to build bet-rcr membranes in nerve and retinalcells.

"The different sources of DHA mayhave different kinetics of absorption,but in terms of compositional effects,they were all the same in our research,"said Norman Salem Jr. of the NationalInstitutes of Health. "Ultimately, what'simportanr is what's delivered to rhe ner-vous system."

Along those lines, the bioavailabilityof OHA from different sources wasinvestigated by Susan Carlson in theDepartment of Pediatrics and theDepartment of Dietetics and Nutritionat the University of Kansas MedicalCenter and her colleagues. They havefed many different sources of DHA(high-EPA and low-EPA fish oils, eggphospholipids, and single-cell oils) intheir studies without any obvious effecton circulating DHA.

"The biggest factor was not thesource, but getting a proper mixture,"Carlson said. "With an adequate disper-sion of far droplets in formula, allsources of DHA work the same."O

Asian countries where fish oil is a com-monly accepted food.

..Also, egg is not as likely to be usedas a source of DHA because of the riskof allergeniciry," said Georgina Cairns.executive director of the Asian roodInformation Center based in Singapore.

Ln addition, DHA derived from fishoil is, on average, less expensive thanDHA from single-cell fermentation.

"Fish oils are indeed cheaper thanfermentation sources, bur low-EPA fishoils are more expensive than standardfish oil blends," said Eric Lien, vicepresident of nutrition research anddevelopment at Wyeth-AyerstLaboratories. "The cost difference isthere, bur not enormous."

Large specialty chemical companiessuch as BASF, Merck, and Hoffmann-LaRoche are the major marketers ofDHA from fish oils. All three arc basedin Europe, which coincidentally is theirstrongest market.

"In Europe, most manufacturers ofpreterm infant formulas are using low-EPA fish oil and egg yolk phospho-lipids because these sources of LCPU-FA are commonly accepted foods forhumans," said Alexandre Lapillonne,assistant professor of pediatrics atBaylor University in Houston. Texas,and a member of the HumanNutrition Research Center in Lyon.France. "Only a few use single-cell oilsas the source of DHA, and these areconsidered as a 'novel food' in Europeand therefore fall under more strin-gent rcgulanon."

The chemical companies haveappeared to leave the single-cell fcnncn-ration business to smaller players suchas Martek and OmegaTech. Based inBoulder, Colorado, OmegaTech origi-nally sold its proprietary algal fermenta-tion DHA manufacturing process to

chemical gianr Monsanto, which at the