food allergy have been shown to result in remission of symptoms, a decrease in allergen- specific...

7/28/2019 food allergy have been shown to result in remission of symptoms, a decrease in allergen- specific IgE concentrati

1/6

1004

sists of highly restricted dietary regi-mens.6,9,10 During this vulnerable periodof rapid growth, nutrition has long-termeffects on later development andhealth.11,12As our understanding of in-fant nutrition is evolving, it appears like-ly that a delicate balance exists between

the benefits and the risks of eliminationdiets.

To assist in identifying risks, if any, ofelimination diets, we evaluated thegrowth and nutrition of 100 consecutiveatopic patients with challenge-provencows milk allergy during eliminationdiets. Specifically, we examined factors

that can affect growth and nutrition atearly age including the duration ofbreast-feeding, the onset of symptoms,

the extent of sensitization, the manage-ment of cows milk allergy, and dietary in-

take.

METHODSSubjects and Study Design

The study involved 100 consecutivechildren aged 1 to 17 months (mean 7months) who had been referred to theTampere University Hospital Pediatric

Department on the basis of suspectedcow milk allergy. They fulfilled the Han-ifin criteria13 of atopic dermatitis inchildren and the additional criteria of

positive open or double-blind, placebo-controlled cows milk challenge and nobreastfeeding at the time of the study.Cow milk elimination diet was started ininfants


2/6

THE JOURNAL OF PEDIATRICS ISOLAURI ET AL.

VOLUME 132,NUMBER 6

older patients with calcium supplemen-tation (n = 11). Of those originally re-ceiving soy formula, 25 (56%) of 45 re-acted clinically to the formula and were

transferred to an extensively hydrolyzedformula. Of those assigned or trans-ferred to one of the extensively hy-

drolyzed formulas, 10 (14%) of 69 re-quired a change to an amino acid formulabecause of clinical reactions. On thebasis of clinical history, skin tests, ra-dioallergosorbent assay, and clinicalchallenges, additional dietary restrictionsincluded egg in all and cereals (wheat,barley, rye, oats), citrus fruits, and veg-etables in 70% of the patients. The re-strictions of cereals, fruits, and vegeta-bles were replaced by foods of the samegroup. After 1 month of the challenge,

when the patients were receiving theirassigned elimination diet, the symptomshad remitted.

The patients were then monitored fromthe diagnostic cows milk challenge to thefirst rechallenge (mean follow-up 13months), which was scheduled according

to usual clinical practice to evaluate theneed for continued elimination. Regular

visits were scheduled at the outpatientdepartment at 2- to 6-month intervals ac-cording to the patientss age for clinicalexamination and evaluation of growth.

The clinical examination was made by thepediatrician or dermatologist in charge,not by the investigators. The diet of the

patients was expanded with age-appro-priate foods, and at each control visit alist of foods was given to the parents for

this purpose. At the time of the rechal-lenge the growth and the nutritional bal-ance of the patients were estimated.

Because an unselected patient popula-tion was enrolled in the study, we stud-ied the growth and nutrition separatelyin a homogenous subgroup of 38 patients

in whom cows milk elimination diet wascommenced at 6 months of age. Dietaryintake was evaluated in these patientsduring the elimination diet at the age of12 months in connection with a visit to aclinical nutritionist.

The control group comprised 60healthy age-matched children chosenfrom one well-baby clinic in the city ofTampere; every fifth healthy child from

the relevant age group was enrolled.

Informed consent was obtained fromthe childrens parents. The study was ap-proved by the Committee on EthicalPractice of Tampere University Hospitaland the Health Care Centre of the Cityof Tampere.

Skin TestsSkin prick testing was done during the

elimination period on the volar aspect ofthe forearm with a long list of dietary

antigens of ALK (Allergologisk Labora-torium A/S, Horsholm, Denmark).4A 1mm, one-peak lancet with shoulder to

prevent deeper penetration was used.Histamine dihydrochloride 10 mg/ml(ALK) was the positive and pricking by

the vehicle (physiologic saline) the nega-tive control. Reactions were read at 15minutes, and a wheal size of at least 3mm was recorded as positive, when neg-ative control was 0.

Cows Milk Challenge ProtocolsFor 2 to 4 weeks before the challenge

the patients received no cows milk butinstead a tolerated formula or calciumsupplementation. On the first day of thechallenge, increasing amounts (1, 5, 10,50, and 100 ml) of the allocated chal-lenge formula were given at 15- to 30-minute intervals until intake appropriatefor age was reached. The placebo formu-la was the amino acid-derived Neocate

(SHS Int., Liverpool, U.K.), and the testformula consisted of Neocate and 100gm cows milk powder/L. As previouslydescribed,4,6 a computerized randomiza-

tion schedule was used to fix the se-quence of the challenges. The nursingstaff, pediatricians, parents, and investi-gators were unaware of the administeredformulas nature. For open challenge anadapted infant formula was used.4 Thechallenge period was 1 week for both

1005

Fig. 1. Growth during first 24 months of infancy in patients with cows milk allergy, during symptomaticperiod before diagnosis, and during therapeutic elimination diet, and in control group. Length-for-age in

SDS is shown at 1, 3, 6, 10, 12, 18, and 24 months of age.Open circles represent mean of measurements in

early onset group with mean (95% CI) age at onset of symptoms 2.7 months (2.3 to 3.1 months) and at

start of elimination diet, 4.6 months (4.2 to 5.1 months).Open squares represent mean of measurements in

older onset group with mean (95% CI) age at onset of symptoms 6.5 months (4.7 to 8.3 months) and at

start of elimination diet, 12.5 months (11.5 to 13.5 months). Solid circles represent measurements in healthy

control group. Intersecting vertical lines show 95% CI. Inset: SDS in subgroup of patients with early onset of

symptoms in whom dietary intake was evaluated. Barred circles represent mean of measurements. Intersect-

ing vertical lines show 95% CI.


3/6

ISOLAURI ET AL. THE JOURNAL OF PEDIATRICS

JUNE 1998

placebo and test formula and for openchallenge. Cows milk allergy was de-fined as an unequivocal adverse reaction

to challenge. To judge long-term toler-ance and reveal any false-negative resultof challenge, all patients negative to chal-lenge continued to consume cows milk.

All patients were seen 1 month after thechallenge was commenced, when the di-

agnosis was confirmed, as previously de-scribed.4

Evaluation of the GrowthTo characterize the effects on growth

of clinical factors, the length and weightof the patients were analyzed during thefirst 24 months of age. The idea was todepict growth in length and weight dur-ing the first 24 months of life in infants

with cows milk allergy, during the symp-tomatic period before diagnosis, and dur-ing the therapeutic elimination diet. The

schedule for the follow-up mimicked thatused in the well-baby clinics in Finland,

with more frequent measures in theyoungest infants (Fig. 1). The growth ofinfants in the healthy control group isshown for comparison. The length and

weight of the patients were measuredwith a recumbent infant length boardand an electronic scale. As described pre-

viously,6 the most recent Finnish stan-dards were used for recording length-

concentrations of albumin, prealbumin,transferrin, urea, alkaline phosphatase,zinc, and vitamin A in serum were mea-sured. Serum samples from members of ahealthy age-matched control group weredetermined for comparison. Fatty acidcomposition in serum phospholipids was

determined, and the results were com-pared with normal values obtained from87 healthy 14-month-old infants (SaloMK, unpublished results).

Determination of Serum FattyAcid Composition

Plasma lipids were extracted withchloroform methanol (2:1) and fraction-ated into phospholipids and nonpolarlipids by thin-layer chromatography.20

Phospholipid fatty acids were transester-ified in 2% H

2SO

4in dry methanol.

Fatty acid methyl esters were extractedinto petroleum spirit and analyzed with aHewlett-Packard 5890A gas chromato-graph equipped with a 25 m 0.32 mm in-side diameter NB-351 (HNU-NordionLtd Oy, Helsinki, Finland) fused silicacapillary column and flame ionization de-

tector. The results are expressed as per-centages of the total area of 24 majorfatty acids with 14 to 24 carbon atoms.

Statistics

Means are presented with ranges orwith 95% CI in parentheses. Because ofthe skewed distribution of serum totalIgE concentration, logarithmic (ln)

transformation was used. Analysis ofvariance, ANOVA for repeated measure-ments, and the chi-squared test wereused in statistical comparisons. The cor-relation coefficient was calculated to de-

termine the association between the clin-ical factors and growth.

RESULTS

Clinical Characteristics atDiagnosis

The diagnosis of cows milk allergy wasmade at 7 months (6 to 8 months) of age(mean 95% CI). The reactions involved

pruritus, urticaria, morbilliform exanthe-ma, or reactions of eczematous type. Thereactions were confined to the skin in 80%of the patients. Vomiting, loose stools, anddiarrhea occurred in 20% of the patients.

1006

for-age in SD score and weight-for-length by expressing weight as percent-age of the mean weight-for-length in thenormal Finnish population with samesex.14 SDS was calculated by a formula:SDS = (Measured length Mean lengthfor age)/SD of normal Finnish popula-

tion of the same age and sex.

Calculation of Dietary IntakeThe parents completed home recordsof nutrient intake for 3 consecutive days,

the quantities of solid and liquid ingestedbeing estimated with household mea-sures. The records were reviewed by aclinical nutritionist (R. I.). Calculationsof nutrient intake were made with the

AIVO computer program and were com-piled from Finnish nutrient databases15

and manufacturers data. Daily intake ofnutrients was expressed as mean with95% confidence interval. The nutrient in-

take of the patients was compared withthat of healthy infants of this age groupin Finland.16-19

SamplesAt the initial challenge the serum total

IgE (Phadebas IgE Prist, Pharmacia,Uppsala, Sweden) and cows milkspecif-ic IgE (RAST, Pharmacia) were mea-sured; at the time of rechallenge the serum

total IgE, cows milkspecific IgE, and

Early onset group Later onset group

(n = 70) (n = 30) Statistics

Total breast-feeding 5.8 9.9 F= 24.02

(mo)*

(4.9-6.8) (8.6-11.1) p < 0.0001Exclusive breast-feeding 2.6 3.7 F= 11.46(mo)* (2.3-3.0) (3.2-4.2) p = 0.001First intake of infant formula 3.0 6.1 F= 29.96(mo)* (2.5-3.6) (4.9-7.3) p < 0.0001Family history 88 67 2 = 5.80of allergy (%) p = 0.01Total IgE in serum 24 21 F= 0.05(kU/L) (11-55) (6-71) p = 0.83Elimination of cereals 76 67 2 = 0.87(%) p = 0.35Elimination of citrus 69 73 2 = 0.23

fruits and vegetables (%) p = 0.63

*Mean (95% CI).

Table I. Clinical characteristics of patients with cow milk allergy diagnosed before 9months of age (early onset group) and after 9 months of age (later onset group)


4/6


VOLUME 132,NUMBER 6

Cows milkspecific RAST was positive(0.4 kU/L) in 41%, and skin prick testfor cows milk was positive in 36%. Skin

prick tests for egg, cereals (wheat, barley,rye, oats), and various fruits and vegeta-bles were positive in 51%, 51%, and 53%of cases, respectively. Polysensitization

(more than two positive skin test resultsfor these food groups) was detected in

41% of the patients.Seventy patients who were younger

than 9 months of age when the diagnosisof cows milk allergy was made and treat-ment started, and 30 were older than 9months (Table I). There were more fami-ly members with atopic disorders in theearly onset group, 41%, than in the lateronset group, 33%. When only one mem-ber was affected, it was more frequently

the mother in the early onset group, 34%,than in the later onset group, 10%; chisquare = 11.76,p = 0.01.

Growth During EliminationDiets

The relative length of patients de-creased compared with the healthycontrol group (F= 11.63,p < 0.0001). Thefall in relative length coincided with theonset of the symptoms suggestive of cowsmilk allergy and the start of the elimina-

tion diet: between 3 and 6 months of age

in the early onset group (F = 9.78, p =0.003) and between 6 and 10 months ofage in the later onset group (F= 8.07,p =0.009). No catch-up was seen by 24months of age. The relative weight in pa-

tients (Fig. 2) continued to fall comparedwith that in the control group (F= 2.42,p = 0.03). In the subgroup of patients inwhom the symptoms of cows milk allergyappeared at the age of 2.7 months (2.2 to3.1 months) (mean 95% CI), the rate and

the pattern of growth was consistent withthe total study population (Figs. 1 and 2).

Nutrient Intake DuringElimination Diets

A homogenous subgroup of patientswith early onset of symptoms in whomthe elimination diet was commenced atthe age of 6 months was evaluated (TableII). The children were receiving an elimi-nation diet containing 11% (95% CI, 10%

to 12%) and 34% (95% CI, 31% to 37%)of energy as protein and fat, respectively.

The amount of substitute formula con-sumed by the patients daily was 570 ml(95% CI, 490 to 650 ml). This was a

major source of nutrient intake, particu-larly fat intake, at the age of 12 months.

Clinical Characteristics AfterElimination Diet

A cow milk rechallenge was scheduled13 months (12 to 14 months) (mean 95%CI) after the diagnostic challenge. Themean (95% CI) age of the patients was21 months (20 to 23 months). At this

time 15 of 100 of the patients, 11 (16%)of 70 of the early onset group and 4(13%) of 30 of the later onset group, had

attained clinical tolerance to cows milk;chi square = 0.09, p = 0.76. The serum

total IgE concentration was 38 kU/L(range 0 to 3598 kU/L), and cowsmilkspecific RAST was positive (0.4kU/ L) in 33% of the patients.

Nutritional Balance AfterElimination Diet

The mean (95% CI) concentration ofalbumin in serum was lower in patients,

1007

41 gm/L (40 to 43 gm/L) than in the con-trol group, 46 gm/L (44 to 48 gm/L);F=11.24,p = 0.001. A total of 6 (6%) of 96

patients had values below the normal ref-erence values (36 to 50 gm/L). Likewise,the proportion of patients with an abnor-mal serum urea concentration was 24%(low levels in 18% and elevated levels in6%), whereas none of the members of thecontrol group had abnormal serum ureaconcentrations (reference value 2.7 to6.0 gm/L). The mean (95% CI) serumurea concentration in patients, 3.81mmol/L (3.47 to 4.14 mmol/L), was notdifferent from that in the control group,3.95 mmol/L (3.42 to 4.49 mmol/L). The

remaining nutritional parameters tested,prealbumin, transferrin, alkaline phos-phatase, zinc, and vitamin A, were with-in normal values.

The relative amount of linoleic acid inserum phospholipids was normal in all

patients (normal range 16.7% to 26.7%),but 9% of the patients (11% of the earlyonset group and 6% of the later onsetgroup) had a level of -linolenic acidbelow the normal range (0.17% to

Fig. 2.Weight gain during first 24 months of infancy.Weight indexes are shown at 1, 3, 6, 10, 12, 18, and24 months of age. Open circles represent mean of measurements in early onset group, open squares in later

onset group, and solid circlesthose in healthy control group. Intersecting vertical lines show 95% CI. Inset:

weight index in subgroup of patients with ear ly onset of symptoms in whom dietary intake was evaluated.

Barred circles represent mean of measurements. Intersecting vertical lines show 95% CI.


5/6

ISOLAURI ET AL. THE JOURNAL OF PEDIATRICS

JUNE 1998

0.53%). Five percent of the patients hadan abnormally low and 13% an abnor-mally high percentage of arachidonicacid (normal range 6.6% to 12.0%); 8%of the patients had low docosahexaenoicacid (1.9% to 5.8%).

Clinical Factors Affecting theGrowth and Nutrition in PatientsWith Cows Milk Allergy

The factors independently contribut-ing to the growth of patients with cowsmilk allergy were the age at onset ofsymptoms and the diet. Lag in growth

was more pronounced in the early onsetgroup than in the later onset group;F=6.65,p < 0.0001 (Fig. 1). In contrast, the

extent of dietary restriction in terms ofnumber of foods eliminated (cereals andvegetables) from the diet and substitutedby other foods of the same group did notexplain the lag in growth (p = 0.20 and

p = 0.70, respectively), nor did polysensi-tization or the presence of gastrointesti-nal manifestations affect the growth of

these patients (p = 0.35 andp = 0.70, re-spectively).

A disproportionate amount of nutri-ents deriving from the substitute formulaat the expense of introduction of solid

foods was one factor contributing topoor growth. During the follow-up aninverse correlation was found between

the amount of protein intake derivedfrom the substitute formula and the rateof growth in length (r = 0.37,p = 0.05)and in weight (r = 0.43,p = 0.02).

The proportion of energy derived fromthe subst itute formula correlated nega-tively with the sum of n-3 polyunsaturat-ed fatty acids (r = 0.41, p = 0.04). The

duration of breast-feeding correlatedpositively with the sum of n-3 polyunsat-urated fatty acids (r = 0.39, p = 0.001)and with the relative amount of docosa-hexaenoic acid (r = 0.36,p = 0.002).

DISCUSSION

The use of elimination diets has becomean accepted adjunct in attempts at both

prevention and treatment of allergy inearly childhood. Despite the persuasiverationale of decreasing exposure to themost important source of antigens earlyin life, the results have been conflicting.Moreover, knowledge of the nutritional

repercussions of exceptional diets is frag-mentary. Our results substantiate a deli-cate balance between the benefits andrisks. Therapeutic elimination diets re-sulted in clinical control of symptoms inall patients and reduction in antigen-spe-cific IgE and in acquisition of clinical tol-erance in 15% of the patients during fol-low-up. At the same time a constant riskof nutritional inadequacy was demon-strated. Growth in allergic patients dif-fered from that expected for the agegroup, and it was reduced compared with

that in our healthy control group.It is unlikely that poor growth was as-

sociated with the allergic state per se;previous studies demonstrated thatcatch-up growth could be achieved in anidentical patient population with rigor-ous elimination diets supplemented withan amino acid-derived formula.6,10 Be-cause protein hydrolysates have beenshown to support normal growth,6 thehypothesis that such formulas are nutri-

tionally inadequate can be rejected. In-adequate nutrient intake also does notexplain the growth disturbance. The in-

take of the substi tute formula was ade-quate, and the total energy and proteinintakes achieved during elimination dietscorresponded to the recommended di-

etary allowances. Nutrient intake andgrowth of healthy infants of this agegroup in Finland were evaluated during

the study period.16-19 These studies con-stantly demonstrate normal growth inhealthy infants receiving this level of en-ergy and protein intake. Thus the hy-

pothesis that dietary recommendationsare inadequate can be rejected. Howev-er, we have shown that the younger thechild is at the onset of symptoms andstart of the diet, the more significant therisk of poor growth is, perhaps resultingin an inability to increase the amount ofsolid foods in the diet at the rate ofhealthy children.18 Certain families maybe very timid in introducing new foods,21

and children with food allergies mayhave developed food aversions during

the symptomatic period of the disease,increasing the risk for undernutrition.

The most plausible explanation for thedemonstrated nutritional hazards could be

poor use or loss of nutrients caused by sus-tained allergic inflammation. Persistent

unnoticed inflammation in the target or-gans (skin or gut) may cause ongoing nu-trient loss. A positive cows milk challengeresults in albumin secretion into the gut22

and increased fecal -1 antitrypsin andtumor necrosis factor- concentrations.8

Taken together with the demonstrated lowserum albumin in some patients, the no-

tion of low-degree loss of protein may besupported. The demonstrated low ureaconcentration may reflect malnutritionand elevated urea concentration or pooruse of amino acids or peptides.23,24 It is im-

portant that active inflammation by re-lease of proinflammatory cytokines direct-ly impairs linear bone growth independentof nutritional intake.25

What could be the cause of sustained al-lergic inflammation in atopic infants withfood allergies during elimination diets?First, the substitute formulas render

them hypoallergenic but not nonaller-genic.6,9,10 The result may be continuedlow-grade antigen challenge, particularly

1008

Intake per kg body Percentage derived

Intake per day weight per day from the formula

Total energykcal 1002 (910-1094) 112 (101-122) 40 (34-45)kJ 4197 (3811-4582) 467 (423-511)

Protein (gm) 28 (24-31) 3 (2.7-3.4) 41 (35-47)Fat (gm) 38 (33-45 ) 4 (3.6-5) 52 (44-60 )Carbohydrates (gm) 132 (120-144) 15 (13-16) 35 (29-41)

Mean (95% CI).

Table II. Intake of energy, protein, fat, and carbohydrates and respective percentages de-rived from substitute formula in infants with cow milk allergy


6/6


VOLUME 132,NUMBER 6

1009

in patients with multiple food allergies.6,10

Indeed, the level of antigenicity distin-guishes the amino acid-derived formulas

with the ability to promote catch-upgrowth in patients with multiple food al-lergies from protein hydrolysates.6,10 Sec-ond, any degree of noncompliance with

extensive dietary limitations would resultin persistent antigen challenge in these pa-

tients.26,27 More rigorous adherence tothe elimination diet may be achieved if inaddition to clinical follow-up, markers ofinflammation are also monitored.

Our results also emphasize the necessityfor development of improved formulas for

these patients, especially in the group ofpatients identifiable by maternal atopicpredisposition, short duration of breast-feeding, and early onset of symptoms in

whom the formula furnishes the majorsource of protein even beyond the formu-la age.6 First, the quality of proteins hasbeen manipulated in producing less aller-genic formulas; however, knowledge of thenutritional repercussions is scanty. Thereare lower amino acid concentrations in the

plasma of atopic patients with cows milkallergy treated with extensively hy-drolyzed formula than in age-matchedhealthy breast-fed infants.6 Second, thesubstitute formulas are significantly differ-ent in fatty acid composition compared

with breast milk. Low serum -linolenicacid, phospholipid arachidonic acid, anddocosahexaenoic acid concentrations wereobserved. Low serum and tissue arachi-donic acid content has been associated

with poor growth.28 Our result further im-plies that the use of special formulas in-volves a risk of abnormally low tissue lev-els of docosahexaenoic acid; this fatty acidis required during rapid brain growth.

As the understanding of the impor-tance of early nutrition on later develop-

ment and immunocompetence is extend-ed,11,12,29the necessity for coordinateddietetic and pediatric evaluation of aller-gic patients is underlined. Such evalua-

tion should include meticulous diagnosisof food allergy to avoid unnecessaryelimination diets and encourage compli-ance to the individually tailored elimina-

tion diets.

We thank Eija-Liisa Ala-Laurila, MD, for helpin evaluating the control patients, and Tuija

Poussa, MSc, for able statistical consultations.We thank Ms. Kaarina Katajisto and Ms. Marjo

Leponiemi for their assistance.

REFERENCES1. Schultz-Larsen F, Hanifin JH. Secular

change in the occurrence of atopic der-matitis. Acta Derm Venereol (Stockh)1992;176:7-12.

2. Nakagomi T, Itaya H, Tominaga T, Ya-maki M, Hisamatsu S, Nakagomi O. Isatopy increasing? Lancet 1994;343:121-2.

3. Sampson HA, McCaskill CC. Food hy-persensitivity and atopic dermatitis: eval-uation of 113 patients. J Pediatr 1985;107:669-75.

4. Isolauri E, Turjanmaa K. Combined skinprick and patch testing enhances identifi-cation of food allergy in infants withatopic dermatitis. J Allergy Clin Im-munol 1995;97:9-15.

5. Agata H, Kondo N, Fukutomi O, Shino-da S, Orii T. Effect of elimination dietson food-specific IgE antibodies and lym-

phocyte proliferative responses to foodantigens in atopic dermatitis patients ex-hibiting sensitivity to food allergens. J

Allergy Clin Immunol 1993;91:668-79.6. Isolauri E, Stas Y, Mkinen-Kiljunen S,

Oja SS, Isosomppi R, Turjanmaa K. Effi-cacy and safety of hydrolysed cow milkand amino acid-derived formulas in in-fants with cow milk allergy. J Pediatr1995;127:550-7.

7. Mabin DC, Sykes AE, David TJ. Con-trolled trial of a few foods diet in severeatopic dermatitis. Arch Dis Child 1995;73:202-7.

8. Majamaa H, Miettinen A, Laine S,

Isolauri E. Intestinal inflammation inchildren with atopic eczema: faecaleosinophil cationic protein and tumornecrosis factor- as noninvasive indica-

tors of food allergy. Clin Exp Allergy1996;26:181-7.

9. Sampson HA, Bernhisel-Broadbent J,Yang E, Scanlon SM. Safety of caseinhydrolysate formula in children with cowmilk allergy. J Pediatr 1991;118:520-5.

10. Hill DJ, Cameron DJS, Francis DEM,Gonzalez-Andaya AM, Hosking CS.Challenge confirmation of late-onset re-actions to extensively hydrolyzed formu-las in infants with multiple food proteinintolerance. J Allergy Clin Immunol

1995;96:386-94.11. Lucas A, Morley R, Cole TJ, Gore SM,Lucas PJ, Crowle P, et al. Early diet in

preterm babies and developmental statusat 18 months. Lancet 1990;335:1477-81.

12. Lanting CI, Fidler V, Huisman M,Touwen BCL, Boersma ER. Neurologi-cal differences between 9-year-old chil-dren fed breast-milk or formula-milk asbabies. Lancet 1994;344:1319-22.

13. Hanifin JM. Epidemiology of atopic der-matitis. Monogr Allergy 1987;21:116-31.

14. Sorva R, Tolppanen EM, Perheentupa J.Variation of growth in length and weight

of children: I years 1 and 2. Acta Paedia-tr Scand 1990;79:490-7.

15. Rastas M, Seppnen R, Knuuts LR,Karvetti RL, Varo P. Nutrient compo-nents of foods. Helsinki: Publication of

the Social Insurance Institution, 1993.16. Rsnen L, Ylnen K. Food consump-

tion and nutrient intake of one- to two-year-old Finnish children. Acta Paediatr1992;81:7-11.

17. Lapinleimu H, Viikari J, Jokinen E,Salo P, Routi T, Leino A, et al. Prospec-

tive randomised trial in 1062 infants ofdiet low in saturated fat and cholesterol.Lancet 1995;345:471-6.

18. Salo P, Viikari J, Rnnemaa T, Hmli-nen M, Jokinen E, Vlimki I, et al. Milk

type during mixed feeding: contributionto serum cholesterol ester fatty acids inlate infancy. J Pediatr 1997;130:110-6.

19. Niinikoski H, Viikari J, Rnnemaa T, He-lenius H, Jokinen E, Lapinleimu H, et al.Regulation of growth of 7- to 36- month-old children by energy and fat intake in

the prospective, randomized STRIP baby

trial. Pediatrics 1997;100:810-6.20. Moilanen T, Nikkari T. The effect of stor-

age on the fatty acid composition of humanserum. Clin Chem Acta 1991;114:111-6.

21. Koivisto UK, Sjdn PO. Reasons for re-jection of food items in Swedish familieswith children aged 2-17. Appeti te1996;26:89-103.

22. Bengtsson U, Knutson TW, Knutson L,Dannaeus A, Hllgren R, Ahlstedt S. In-creased levels of hyaluronan and albuminafter intestinal challenge in adult patients

with cows milk intolerance. Clin Exp Al-lergy 1996;26:96-103.

23. Giovannini M, Agostini C, Fiocchi A,Bell R, Trojan S, Riva E. Antigen-re-

duced infant formulas versus humanmilk: growth and metabolic parametersin the first 6 months of life. J Am CollNutr 1994;4:357-63.

24. Rigo J, Salle BL, Putet G, Senterre J.Nutritional evaluation of various proteinhydrolysate formulae in term infants dur-ing the first month of life. Acta Paediatr1994;402:100-4.

25. Konaris SG, Fisher SE, Rubin CT,Chawla A. Experimental colitis impairslinear bone growth independent of nutri-

tional factors. J Pediatr GastroenterolNutr 1997;25:137-41.

26. Greenberg RN. Overview of patientcompliance with medication dosing: a lit-

erature review. Clin Ther 1984;6:592-9.27. Milgrom H, Bender B, Ackerson L,Bowry P, Smith B, Rand C. Noncompli-ance and treatment failure in children

with asthma. J Allergy Clin Immunol1996;98:1051-7.

28. Koletzko B, Braun M. Arachidonic acidand early human growth: is there a rela-

tion? Ann Nutr Metab 1991;35:128-31.29. Hanson L, Hahn-Zoric M, Wieder-

mann U, Lundin S, Dahlman-HglundA, Saalman R, et al. Early dietary influ-ence on later immunocompetence. NutrRev 1996;54:S23-30.

food allergy have been shown to result in remission of symptoms, a decrease in allergen- specific...

Documents