Archives ofDisease in Childhood 1993; 68: 240-245

CURRENT TOPIC

Cows' milk induced intestinal bleeding in infancy

Peter B Sullivan

Current United Kingdom Department ofHealthrecommendations on infant feeding state that'milks considered suitable for inclusion in thediet of infants from the sixth month are humanmilk, infant formulas, follow-up milks andwhole pasteurised cow milk'.' Recently, how-ever, controversy has arisen as it has beensuggested that ordinary cows' milk should notbe given before 1 year of age because of itsrelatively low iron and vitamin content,2 andbecause it is said to be associated with subclinicalbut appreciable gastrointestinal bleeding ininfancy.3

This review aims to examine published workrelating to the association between feedingcows' milk to infants and small children and thesubsequent development in them of blood lossfrom the gastrointestinal tract.

It has been established that normal infantslose small amounts of blood in their stools; ithas been estimated that the average 'physio-logical' loss of blood is 0-64 ml/day (range0-17-2-5 ml/day).4 Although the presence ofgross blood in the stool (haematochezia) isobvious, detection of occult gastrointestinalblood loss is more difficult. Interpretation of theavailable published reports is complicated bythe application of tests of differing sensitivityand specificity. One of the most sensitivemethods for the identification of occult entericblood loss detects chromium-51 (5'Cr) labellederythrocytes in incinerated faeces.±7 Otherworkers have used the orthotolidine reaction todetect faecal occult blood.8 9 Most workers,however, have used the guaiac test; orthotolidinegives a positive result with blood in a 1:20 000dilution with saline, whereas guaiac gives apositive result in a 1:100 to 1:5000 dilution.Guaiac is a colourless leucodye that becomescoloured in the presence of hydrogen peroxideand haemoglobin. Unfortunately, this test reactswith many non-haemoglobin substances andpoor sensitivity and specificity may confoundinterpretation; the commerical guaiacHemoccult test3 10 is known to underestimateblood loss in stools." On the other hand, thehighly sensitive tests may not be specific andcarry a high false positive rate.

Specific and quantitative tests for the de-termination of faecal haemoglobin (forexample, the HemoQuant test) have beendeveloped'2 and used to measure blood lossfrom the gastrointestinal tract of infants.3HemoQuant is a quantitative, exquisitely sensi-tive test specific for faecal haem which utilisespurification methods that remove non-hae-moglobin porphyrin derivatives (for example,chlorophyll). The assay is based on the chemical

conversion of non-fluorescing haem to intenselyfluorescent porphyrins. Proof that a positiveresult represents haem derived porphyrin isbased on its solubility, characteristic spectraland chromatographic properties, and on thefinding that it increases proportionately withingested blood. 2 Alquist et al, in a comparativestudy, found the HemoQuant test to be con-siderably more sensitive and specific in thedetection of faecal occult blood than theHemoccult test. '3 HemeSelect (SmithKlineDiagnostics), the latest addition to the Europeanmarket, is a sensitive and specific immunologicaltest for faecal occult blood based on reversepassive haemagglutination which has yet to beapplied to the study of occult blood loss inchildren.

Iron deficiency anaemia and gastrointestinalblood lossThe fact that some infants with iron deficiencyanaemia have an increased gastrointestinal bloodloss has been recognised for many years. Raschet al using chromium-51 labelled erythrocytes,showed that anaemic infants (aged 8-23 months)had a greater gastrointestinal blood loss thannon-anaemic infants.5 In subsequent earlystudies approximately half the number of casesof infants with iron deficiency anaemia werefound to have occult blood in their faeces:Wilson et al, revised their initial figure of 40%'4based on the guaiac test to 50% in an extendedstudy in which they used the 5"Cr erythrocytelabelling technique.7 Hoag et al, reported that37/64 (58%) of iron deficient patients (aged 7-17months) had positive guaiac tests comparedwith only 5/65 (8%) of normal subjects; further-more, using faecal recovery of intravenouslyadministered radioactive iron (59Fe), theseworkers calculated that over the three to fourweek period of observation anaemic infantswere losing a mean of 41 ml of blood in theirstools and they concluded that occult blood lossappeared to be a significant factor in thedevelopment of iron deficiency in early child-hood. '5

Iron deficiency anaemia, gastrointestinalblood loss, and cows' milkThe association between gastrointestinal bloodloss, iron deficiency anaemia, and ingestion ofwhole cows' milk was suggested by several early

9116 17 16studies.6 Gryboski, in a seminal study,examined 21 children (age range 2 days to 30months) with chronic diarrhoea whose diagnosisof gastrointestinal milk allergy fulfilled the

Department ofPaediatrics,The Chinese Universityof Hong Kong,Prince of Wales Hospital,Shatin,New Territories,Hong KongCorrespondence to:Dr Sullivan.

240

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from

241Cows' milk induced intestinal bleeding in infancy

criteria of Goldman et al, which require that thesymptoms must subside after the elimination ofmilk from the diet; they must recur within 48hours after a trial of feeding milk; threechallenges must be positive and similar; and thesymptoms must subside again after eachchallenge reaction.'8 All the children in thisstudy had either occult (method not stated) orgross blood in their stools as well as evidence ofa microcytic, hypochromic anaemia. Rectalbiopsy in eight infants showed a proctitis whichreverted to normal after milk elimination.Morton et al found that the introduction ofwhole cows' milk before the age of 6 monthswas associated with iron deficiency at this ageand at 1 year, though they were unable to showa correlation between occult blood loss in thestool and iron status in infants of 1 year of age. 9These studies, though suggesting that whole

cows' milk can induce faecal blood loss ofsufficient magnitude to contribute to irondeficiency in anaemic infants, do not addressthe question of whether substantial blood losscan be caused by feeding whole cows' milk tonormal infants. The answer to this was soughtby Ziegler et al, who undertook a prospectivestudy of normal infants to quantify intestinalblood loss and iron nutritional status.3 Fifty twoinfants entered the trial at 168 days of age andwere assigned at random to receive eitherpasteurised cows' milk or a milk based formula.Initially, 31 infants had been breast fed and 21had been formula fed. With the feeding ofwhole cows' milk, the proportion of guaiacpositive stools increased from 3% at baseline to30% during the first 28 days of the trial(p<0 01), whereas the proportion of guaiacpositive stools remained low (5%) with thefeeding of formula milk. Although the propor-tion of guaiac positive stools among whole cows'milk fed infants decreased later, it remainedsignificantly greater for the entire trial (p<001).Stool haemoglobin concentration increasedmarkedly with the introduction of whole cows'milk, increasing from a mean (SD) of 622 (527)gg/g dry stool at baseline to 3598 (10 479) lig/gdry stool (p<0 01) during the first 28 days ofingestion of whole cows' milk. Among infantsfed formula milk, stool haemoglobin did notincrease and was significantly less than in thegroup fed with whole cows' milk (p<0 01). Ininfants fed whole cows' milk, the increase inhaemoglobin concentration tended to be greaterfor those who had initially been fed human milkthan for those who had initially been fedformula milk. Notably, iron nutritional statuswas not significantly different between the twofeeding groups, although one infant becameiron deficient after four weeks of ingestingwhole cows' milk. Ziegler et al concluded thatnormal infants lose measurable amounts ofblood in their faeces at all times and that feedingwith pasteurised cows' milk leads to increasedintestinal tract blood loss in a large proportionof normal infants.3 Moreover, some infantsappear to be sensitive to pasteurised cows' milkand may lose large amounts of blood such thatthe amount of iron lost is nutritionally impor-tant. In the absence of gastrointestinal bloodloss, the estimated requirement for absorbed

iron is about 0-6 mg/day during the first year oflife and Fomon et al calculated that entericblood loss of 3 ml/day in anaemic subjectsrepresented a loss of iron of 0-9 mg/day.20The findings of Ziegler et a13 contrast with

those of a much larger study by Thomas et al.2'These workers, who also used faecal haemo-globin concentration in an assay which coulddetect as little as 1 mg of haemoglobin per gramof stool, found similar levels of enteric bloodloss in infants receiving whole cows' milk (4/140(3%)), human milk (7/338 (2%)), and formulamilk (6/314 (2%)). Thomas et al thus concludedthat the prevalence of intestinal bleeding inhealthy 6-12 month old infants receiving freshwhole cows' milk and other supplementaryfoods is low.

Whole cows' milk and heat treated cows' milkIn many of the early studies referred to, younginfants were fed homogenised, pasteurised wholecows' milk. Wilson et al, using the 51Cr labelledred blood cell technique, showed abnormalgastrointestinal bleeding in 17/34 anaemicchildren (aged 6-25 months) fed with wholecows' milk.7 There was, unfortunately, nosearch for the site of bleeding or rectal histologyperformed in this otherwise well conductedstudy. In eight of their infants the whole cows'milk induced bleeding did not decrease despiteiron treatment as long as whole cows' milk wasingested.Wilson et al also observed a dose dependent

effect wherein the amount of whole cows' milkingested was proportional to the amount offaecal occult blood loss; in one patient faecalblood loss of 9-3 ml/day was observed when thesubject was consuming 2230 ml/day of milk andthis decreased to a loss of 1 -2 ml/day whenconsumption was reduced to 300 ml/day. Thisdose dependent effect might imply that themechanism of damage could be via some direct'toxic' effect of whole cows' milk on the gut22especially as, at this stage, no classical immuno-logical mechanism had been shown to accountfor the phenomenon. The likelihood of anantigenic effect ofwhole cows' milk was indicatedby Wilson et al, who also noted that feeding aheat processed cows' milk proprietary formulastopped abnormal enteric bleeding, leadingthem to speculate that heat labile proteins suchas bovine serum albumin in whole cows' milkmay be the aetiological factor responsible for thebleeding.7 Kilshaw et al showed that animalsfed heat treated milk (121°C for 20 minutes)produced circulating antibodies to ,B lactoglo-bulin and casein, although titres were lowerthan for unheated milk.23 In this study x caseinwas unaffected by heat treatment whereas ,Blactoglobulin and a lactalbumin were denatured.May et al, also found that heat treatmentsignificantly decreased the serum antibodyresponse to ingested whole cows' milk; howeverno clinical nor immunological disorders werenoted by these workers in infants with antibodyresponses to whole cows' milk.24 It is probablethat methods of preparation and manufacture ofmilk formulas alter their antigenicity; SMAliquid, which is sterilised, is less sensitising thanSMA powder, which is spray dried.25

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from

Sullivan

Other reports have underlined the differencebetween whole cows' milk and heat treatedformula. Using albumin turnover following theintravenous injection of 4-44 kBq of [131I]albumin Woodruff and Clark showed an exuda-tive enteropathy in 7/12 anaemic children (aged7-17 months) fed whole cows' milk for at leastthree months.26 Feeding evaporated milk insteadof whole cows' milk was followed by a lengthen-ing of albumin turnover half times in four offive patients. In a companion study, Woodruffet al reported a significant degree of microcytosisand lower concentrations of haemoglobin andserum iron (p<0-01 at 6 months; p<0.05 at9 months; and not significant at 12 months) in13 infants fed whole cows' milk compared with25 infants fed with prepared formula (Sjiiniacwithout iron).27 In the study of Fomon et al,15/38 (40%) children (aged 4-7 months) fedwhole cows' milk compared with 4/43 (9%) chil-dren fed heat treated (three and a half minutesat 269°F or five minutes at 260°F) formula(Enfamil) had occult blood (Hemoccult) in thestool (p<0.001).20 Similarly, infants fed wholecows' milk had a significantly greater (p<0-001)number of stools positive for occult blood thandid the other infants. These differences dis-appeared in infants aged more than 140 days.All subjects in this study received iron supple-ments which may account for the fact that no

difference was observed between the two groups

in terms of haemoglobin concentration, packedcell volume, serum iron, and total iron bindingcapacity. Fomon et al concluded that pasteurisedcows' milk should not be fed to infants before140 days of age.20 The differences betweenwhole cows' milk and heat treated formulamilks have led to suggestions2 28 that wholecows' milk should not be given to childrenunder 12 months of age and that so called'follow on' formula milks should be used in thesecond half of infancy in preference to wholecows' milk. There is no direct evidence fromcontrolled studies that such formulas do indeedprevent blood loss from the gastrointestinaltract.

Age of ingestion of whole cows' milkOne of the major criticisms of many of the earlystudies which purported to show an associationbetween whole cows' milk consumption andiron deficiency anaemia is the rather young age(<4 months in many studies) at which some ofthe infants were given whole cows' milk.6 9 16 17

In the studies of Woodruff et al, for instance,some infants received whole cows' milk from2 months of age when it is possible that thedeveloping gut might be more vulnerable to the

2627

effects of ingested foreign protein. Levels ofmilk and soy agglutinins have been shown to beconsiderably higher in infants fed milk and soyformulas within the first three months than inthose introduced to these protein antigens after3 months of age.29 This situation prompted theAmerican Academy of Pediatrics to ask: 'Canthe change to cows' milk when the infant is 6months old produce anemia from occult bloodloss when the milk is fed in excessive amountsand there is no iron supplementation?' and to

conclude that '. . . there is at present no con-

vincing evidence from well-designed researchstudies that feeding whole cows' milk after6 months of age is harmful if adequate supple-mentary feedings are given.'30 The assumptionbehind this statement, namely, that adequateiron would be available to infants who consumedan appropriate variety of supplemental foodswas refuted by Penrod et al, who showed anincreased occurrence of iron deficiency in infantsfed whole cows' milk during the second sixmonths of life, although these workers did notlook for evidence of enteric blood loss.3' Wilson,in an attempt to answer the question posed bythe American Academy of Pediatrics, revieweddetailed dietary histories from the records of his1974 report and found that 6/17 (35%) of hisreported cases of whole cows' milk inducedenteric bleeding received whole cows' milk forthe first time after 6 months of age or later.32 Heconcluded that 6-12 months of age for thedietary introduction of whole cows' milk may bea vulnerable time for some and that 12 monthsor older may be a safer age.

Using more sensitive tests for the detection ofiron depletion, Sadowitz and Oski were able toassess further the effect of the introduction ofwhole cows' milk into the diet of infants atdifferent ages.33 One of the estimations made,erythrocyte protoporphyin, utilises the fact thatthere is an accumulation of protoporphyrin inred blood cells when insufficient iron is availableto combine with protoporphyrin to form haem.Erythrocyte protoporphyrin can be measuredfluorometrically from small samples of blood.In addition to erythrocyte protoporphyrin (ameasure of iron deficiency), Sadowitz and Oskimeasured haemoglobin, red blood cell indices,and serum ferritin (a measure of iron depletion)in 217 infants, aged 9 to 12 months, attending awell baby clinic in whom complete dietaryhistory was available. The introduction of wholecows' milk into the diet had occurred before 6months of age in 66/217 (30%) infants, and 41/66 (62%) of these had laboratory evidence ofnutritional iron inadequacy compared with only33/151 (22%) of those with iron deficiencies fedwhole cows' milk after 6 months ofage (p<0-01).In this study, 19/21 (91%) infants with irondeficiency anaemia had been fed whole cows'milk before 6 months of age. These results wereconfirmed in subsequent work.'0 3' Tunnessenand Oski found that 22% of infants fed wholecows' milk after 6 months of age had evidence ofiron insufficiency (lower mean corpuscularvolume, lower ferritin levels, and higher freeerythrocyte protoporphyrin levels) at 12 monthsof age.'0 In this study, however, there wasno significant difference in the proportion ofguaiac positive stools in infants fed whole cows'milk compared with those fed iron fortifiedformula milk. Thus, Tunnessen and Oski con-cluded that 'the results of our study of infantsbetween 6 and 12 months of age indicate thatnot occult gastrointestinal blood loss but lowiron content of whole cows' milk was theprimary factor responsible for iron inadequacyin the cow milk group.'"0

Duration of sensitivity to whole cows' milkCow's milk induced intestinal tract blood loss

242

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from

243Cows' milk induced intestinal bleeding in infancy

seems to occur predominantly during infancyand early childhood. Even sensitive infants maytolerate cows' milk later in life without adverseconsequences. A 6 week old breast fed infantwith rectal bleeding induced by maternal inges-tion of whole cows' milk34 was found to becompletely well and tolerating whole cows' milkat 2 years of age. Wilson et al reported foursubjects with proved whole cows' milk inducedgastrointestinal bleeding in infancy who were

able to ingest whole cows' milk without entericbleeding when seen at follow up aged 2-3years.7 Most of the 12 children with cows' milkrelated colitis described by Hill and Milla were

tolerating whole cows' milk by the age of 5

years.35 Conversely, there have been occasionalreports of persistence of milk intolerance.Samuelsson and Werner, for instance, describea 16 year old boy with a history of watery,sometimes bloody, stools since the introductionof whole cows' milk at 3 months of age whosesymptoms resolved on a milk free diet.' Thepotential relation between early cows' milksensitivity, whatever its manifestation, and thesubsequent development of ulcerative colitis hasbeen suggested for 30 years, but remainsunresolved.37

Rectal bleeding in exclusively breast fedinfantsThere have been numerous case reports of rectalbleeding in exclusively breast fed infants whichhas resolved when either the nursing motherhad eliminated whole cows' milk protein fromher diet or breast milk has been replaced by a

casein hydrolysate formula.' 3-3 In the largestseries six neonates with rectal bleeding respondedclinically to the substitution of breast milk bya hydrolysed casein or a soy protein basedformula.38 Breast feeding was subsequentlyresumed in five of six infants; all experienced an

immediate recurrence of symptoms. Elimina-tion of whole cows' milk protein from thematernal diet led to a tolerance of breastfeeding in two infants but there was no changein the other three. The possibility of prenatalsensitisation to whole cows' milk was suggestedby Wilson et al, who reported eosinophiliccolitis in a 4 day old neonate who presented withprofuse rectal bleeding.43 This infant had beenexclusively breast fed from birth but her motherhad been drinking four to five glasses per day ofwhole cows' milk. Prick puncture skin testingof the infant and a serum radioallergosorbenttest were positive for cows' milk protein.

Berezin et al in an attempt to define more

precisely the clinical characteristics and course

of milk protein intolerance, studied 22 infants(aged 2-16 weeks), all of whom presented withhaematochezia.4' Of these 11 were receivingcows' milk, four soy protein, two cows' milkand soy milk, and five were breast fed. Allmothers of breast fed infants ingested wholecows' milk during lactation. Rectal bleedingstopped in 19/22 infants within one week oftransfer to a protein hydrolysate formula(Nutramigen). In three breast fed infants,breast feeding was continued; each mother,however, was placed on a whole cows' milk free

diet. Within two weeks symptoms resolved inthese infants. Two months after symptomresolution, 17 formula fed infants were re-challenged with cows' or soy formula. In allinstances a recrudescence of the presentingclinical findings was heralded by the reappear-ance of blood in the stools. In every instancesymptom resolution and blood free stools wererapidly achieved after reinstitution of the proteinhydrolysate formula feedings. Although theseworkers went to great lengths, by the process ofelimination-challenge-elimination in a similarmanner to that initially advocated by Goldmanet al,'8 to confirm the diagnosis of proteinintolerance in their patients, it is not clear fromtheir report whether infants received wholecows' milk or a heat treated formula.

Histological appearances of the colon ininfants with gastrointestinal bleedingAn important feature of the study by Berezin etal was the demonstration of the histologicalabnormality associated with rectal bleeding ininfants.4' Moreover, one of their most impor-tant contributions was to examine the mucosalresponse to elimination and challenge. Typicallesions, manifested by patchy aphthoid ulcer-ations, were observed by colonoscopy in therectosigmoid colon in 19/22 infants. Histologicalfindings included surface ulcerations and as-sociated inflammation of the lamina propria andsubmucosa, marked by substantial eosinophilicinfiltration. These appearances had resolvedwhen subjects were re-examined two weeksafter elimination of cows' milk or soy protein, orboth, from the diet. Furthermore, the charac-teristic mucosal appearances recurred followingchallenge with either cows' milk or soy protein.They concluded that in an infant with haemato-chezia and negative stool culture findings, aninitial colonoscopy can identify the characteristicfindings of milk induced colitis."

Atopy, allergy, and cows' milk induced entericblood lossThis has long been a contentious subject;three aspects, however, stand out from pub-lished reports. Firstly, eosinophilic colitis is amanifestation of food allergy and not of cows'milk intolerance per se; several workers havedescribed similar appearances in associationwith a wide variety of foods other than wholecows' milk including soy, beef, wheat, egg, andpork.35 4 Secondly, gastrointestinal blood lossis, in many instances, only one of several symp-toms attributable to an allergic reaction; suchassociated symptoms include chronic diar-

16 34 35 38 46 16 46448 coiic 6 38 42rhoea,' vomiting, coicdermatitis,38 and irritability and weight loss.'7Thirdly, milk induced colitis with gastrointest-inal blood loss is more likely to occur in childrenwith a personal or family history of atopy orother allergy.'7 35 45 47-49 In Gryboski's series,14/21 had a positive family history of allergy.'6Jenkins et al found that allergic symptoms weremore common in milk induced colitis than inselected controls as was a positive family historyof atopy related disease (p<0-006; Fisher's

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from

244

exact test)45 and, in the series reported by Hilland Milla, 690/o of patients and 92% of firstdegree relatives were atopic.

Pathophysiological basis ofcows' milkinduced enteric blood lossThe pathogenic mechanisms that underlyadverse reactions to whole cows' milk remainundefined. The association between these re-actions and an allergic/atopic diathesis, asindicated above, suggest that immunologicalmechanisms probably play a part. Attempts todefine such mechanisms in cows' milk intoler-ance have produced conflicting results. In somestudies, for instance, increased serum antibodiesto food proteins were thought to correlate withpositive responses to oral cows' milkchallenge'4 50 51 whereas in other studies52 53no difference in serum antibodies was foundbetween milk sensitive and normal infants.Similarly inconclusive results have arisen frommeasurements of lymphocyte transformationand lymphokine production in response to foodantigens.54 These contradictory findings may beaccounted for, in part, by the heterogeneity ofthe populations studied: some have includedthose with cutaneous and respiratory as well asgastrointestinal symptoms and children ofdifferent ages.Whole cows' milk induced intestinal tract

blood loss seems to occur predominantly ininfancy and, as has been pointed out, evensensitive infants appear to tolerate whole cows'milk later in life without adverse consequences.Adverse reactions to whole cows' milk may berelated to antigenic challenge of the gut mucosabefore adequate development of oral immunetolerance to ingested foreign proteins.

ConclusionsOn the evidence so far available it is not possibleto give an estimate of the true prevalence ofcows' milk induced gastrointestinal bleeding ininfancy, nor has it been defmnitively establishedwhether or not nutritionally significant entericblood loss represents a relatively rare idio-syncratic reaction in certain susceptible infants.The Office of Population Censuses and Surveysmost recent survey of infant feeding practices inthe United Kingdom' found that 5% of infantswere being given liquid cows' milk as a maindrink at 4-5 months and this figure hadincreased to 60% at 9-10 months. This latterstatistic represents about 72 000 infants, andassuming that a third of infants fed whole cows'milk might develop gastrointestinal bleeding,3this represents 24 000 infants; there is noevidence that whole cows' milk induced entericblood loss, with or without anaemia, is so highlyprevalent in this country.Whole cows' milk does contain proteins

which can provoke an allergic eosinophiliccolitis but this occurs more commonly in infantswith an allergic or atopic diathesis. In somesubjects whole cows' milk induced gastro-intestinal blood loss appears sufficiently great tobe nutritionally significant and may contributeto the development of iron deficiency anaemia.

Such an anaemia, however, is more likely to besecondary to the poor concentraton and bio-availability of iron in cows' milk than to occultblood loss from the gastrointestinal tract.

Heat treatment appears to reduce but maynot entirely remove allergenic proteins in wholecows' milk. There is no evidence as yet that'follow on' milks are less likely to produceenteric blood loss than whole cows' milk inchildren, especially those who show allergicfeatures, in the second half of infancy. Those'follow on' milks currently available are producedusing the spray drying process which does notabolish antigenic sensitising potential. Whetheror not different formulations of 'follow on'milks based, for instance, on heat denaturedwhey55 may protect susceptible infants againstenteric blood loss remains to be investigated.Which of the five major whole cows' milk

proteins ((3 lactoglobulin, bovine gammaglo-bulin, casein, a lactalbumin, and bovine serumalbumin) is the prime allergen in infants withcows' milk related allergy is unknown. Whenthe antigens have been more precisely identified,questions will arise about the nature of themechanism of interaction with the host. Doesdevelopment of whole cows' milk enterocolitissuggest that a T suppressor cell population forthese antigens has not been developed-that is,an altered regulation of the immune response(oral tolerance) to milk protein? Other mech-anisms possibly playing a part in oral tolerance,including circulating antibody-antigen com-plexes and anti-idiotypic antibodies, have yet tobe explored. One approach to further elucidatemechanisms involved in development of intest-inal mediated tolerance might be to measuredirectly intestinal antigen absorption in infantswith enterocolitis and correlate this with markersof immune activity.

Results of such studies, though helping toincrease the understanding of the mechanismsinvolved in the phenomenon of whole cows'milk enteric blood loss will not assist in theformulation of recommendations about theadvisability of using cows' milk in late infancy.This issue will remain controversial until theprevalence of the phenomenon is accuratelyestablished.

This review is based in part on a report prepared for theNutritional Consultative Panel of the United Kingdom DairyIndustry.

1 DHSS. Report on health and social subjects 32: present daypractice in infant feeding: third report. London: HMSO,1988.

2 Wharton B. Milk for babies and children. BMJ 1990;301:774-5.

3 Ziegler EE, Foman SJ, Nelson SE, et al. Cow milk feeding ininfancy: further observations on blood loss from thegastrointestinal tract. J Pediatr 1990;116:11-8.

4 Elian E, Bar-Shani S, Liberman A, Matoth Y. Intestinalblood loss: a factor in calculations of body iron in lateinfancy. J Pediatr 1966;69:215-9.

5 Rasch CA, Cotton EK, Harris JW, Griggs RC. Blood loss as acontributing factor in the etiology of iron-lack anemia ofinfancy. Am J Dis Child 1960;207:627(A200).

6 Wilson IF, Heiner DC, Lahey ME. Milk-induced gastro-intestinal bleeding in infants with hypochromic microcyticanemia. JAMA 1964;189:568-72.

7 Wilson JF, Lahey ME, Heiner DC. Studies on iron meta-bolism. V. Further observations on cows' milk inducedgastrointestinal bleeding in infants with iron deficiencyanemia. J Pediatr 1974;84:335-44.

8 Anyon CP, Clarkson KG. Occult gastro-intestinal bleeding inthe first two months of life. N Z MedJ7 1969;70:315-7.

Sullivan

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from

Cows' milk induced intestinal bleeding in infancy

9 Anyon CP, Clarkson KG. Cows' milk: a cause of iron-deficiency N Z Med J 1971;74:24-5.

10 Tunnessen WW, Oski FA. Consequences of starting wholecow milk at 6 months of age. J Pediatr 1987;111:813-6.

11 Morris DW, Hansell JR, Ostrow D, Lee C-S. Reliability ofchemical tests for fecal occult blood in hospitalized patients.DigDisSci 1976;21:845.

12 Schwartz S, Dahl J, Elleson M, Ahlquist D. The'HemoQuant' test: a specific and quantitative determina-tion of heme (hemoglobin) in feces and other materials.Clin Chem 1983;29:2061-7.

13 Ahlquist DA, McGill DB, Schwartz S, Taylor WF, EllefsonM, Owen RA. HemoQuant, a new quantitative assay forfecal hemoglobin. Ann Intern Med 1984;101:297-302.

14 Wilson JF, Heiner DC, Lahey ME. Studies on iron meta-bolism. I. Evidene of gastrointestinal dysfunction in infantswith iron deficiency. J Pediatr 1%2;60:787-800.

15 Hoag MS, Wallerstein RO, Pollycove M. Occult blood loss iniron deficiency anemia of infancy. Pediatrics 19%1;27:199-203.

16 Gryboski JD. Gastrointestinal milk allergy in infants. Pedia-trics 1%7;40:354-60.

17 Kravis LP, Donsky G, Lecks HI. Upper and lower gastro-intestinal tract bleeding induced by whole cows' milk in anatopic infant. Pediatrics 1%7;40:661-5.

18 Goldman AS, Anderson DW, Sellers WA, et al. Milk allergy.I. Oral challenge with milk and isolated milk proteins inallergic children. Pediatrics 1%3;32:425-43.

19 Morton RE, Nysenbaum A, Price K. Iron status in the firstyear of life.I Pediatr Gastroenterol Nutr 1988;7:707-12.

20 Fomon SJ, Ziegler EE, Nelson SE, Edwards BB. Cow milkfeeding in infancy: gastrointestinal blood loss and ironnutritional status. J Pediatr 1981;98:540-5.

21 Thomas DW, McGilligan KM, Carlson M, et al. Fecalalpha,-antitrypsin and hemoglobin excretion in healthyhuman milk-, formula-, or cow's milk-fed infants. Pediatrics1986;78:305-12.

22 Eastham EJ, Walker WA. Effect of ccows' milk on the gastro-intestinal tract: a persistent dilemma for the pediatrician.Pediatrics 1977;60:477-81.

23 Kilshaw PHJ, Heppell LMJ, Ford JE. Effects of heat treat-ment of cows' milk and whey on the nutritional quality andantigenic properties. Arch Dis Child 1982;57:842-7.

24 May CD, Fomon SJ, Remigio L. Immunologic consequencesof feeding infants with cow milk and soy products. ActaPaediatrScand 1982;71:43-51.

25 McLaughlan P, Anderson Kj, Widdowson EM, CoombsRRA. Effect on heat on the anaphylactic-sensitizing capacityof cows' milk, goats' milk, and various infant formulae fedto guinea-pigs. Arch Dis Child 1981;56:165-71.

26 Woodruff CW, Clark JL. The role of fresh cows' milk in irondeficiency. AmJ7 Dis Child 1972;124:18-23.

27 Woodruff CW, Wright SW, Wright RP. The role of freshcows' milk in iron deficiency. II. Comparison of fresh cows'milk with a prepared formula. Am J Dis Child 1972;124:26-30.

28 Oski FA. Is bovine milk a health hazard? Pediatrics 1985;75:182-6.

29 Eastham EJ, Lichauco T, Grady MI, Walker WA. Anti-genicity of infant formulas: role of inmmature intestine onprotein permeability. J Pediatr 1978;93:561-4.

30 American Academy of Pediatrics, Committee on Nutrition.The use of whole cows' milk in infancy. Pediatrics 1983;72:253.

31 Penrod JC, Anderson K, Acosta PB. Impact on iron status ofintroducing cows' milk in the second six months of life.J PediatrGastroenterol Nutr 1990;10:462-7.

32 Wilson JF. Whole cows' milk, age, and gastrointestinalbleeding. Pediatncs 1984;73:879-80.

33 Sadowitz PD, Oski FA. Iron status and infant feeding prac-tices in an urban ambulatory center. Pediatrics 1983;72:33-6.

34 Chong SKF, Blackshaw AJ, Morson BC, Williams CB,Walker-Smith JA. Prospective study of colitis in infancyand early childhood. J Pediatr Gastroenterol Nutr 1986;5:352-8.

35 Hill SM, Milla PJ. Colitis caused by food allergy in infants.Arch Dis Child 1990;65:132-40.

36 Samuelsson SM, Werner I. Milk-induced colitis. Acta MedScand 1966;180:145-52.

37 Glassman MS, Newman LU, Berezin S, Gryboski JD. Cows'milk protein sensitivity during infancy in patients withinflammatory bowel disease. Am J Gastroenterol 1990;85:838-40.

38 Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast-fed infants. J Pediatr 1982;101:906-10.

39 Shmerling DH. Dietary protein-induced colitis in breast-fedinfants [letter]. J Pediatr 1983;103:500.

40 Klein E, Shvartzman P, Weizman Z. Blood-streaked stools intwo breast-fed siblings.J Fam Pract 1990;30:713-4.

41 Berezin S, Schwarz SM, Glassman M, Davidian M, NewmanLU. Gastrointestinal milk intolerance of infancy. Am J DisChild 1989;143:361-2.

42 Pittschieler K. Cows' milk protein-induced coltis in thebreast-fed infant [case report]. J Pediatr Gastroenterol Nutr1990;10:548-9.

43 Wilson NW, Self TW, Hamburger RN. Severe cows' milkinduced colitis in an exclusively breast-fed neonate. ClinPediatr(Phila) 1990;29:77-80.

44 Berezin S, Schwartz SM, Glassman M, Davidian M,Newman LU. Gastrointestinal milk intolerance of infancy.AmJ Dis Child 1990;144:17.

45 Jenkins HR, Pincott JR, Soothill JF, Milla PJ, Harries JT.Food allergy: the major cause of infantile colitis. Arch DisChild 1984;59:326-9.

46 Raafat F, Castro R, Booth IW. Eosinophilic proctitis withgiant cells: a manifestation of cows' milk protein into-lerance. J Pediatr Gastroenterol Nuir 1990;1 1 128-32.

47 Gryboski JD, Burkle F, Hillman R. Milk induced colitis inan infant. Pediatrics 1966;38:299-303.

48 Powell GK. Milk- and soy-induced enterocolitis of infancy.J Pediatr 1978;93:553-0.

49 Rubin MI. Allergic intestinal bleeding in the newborn: aclinical syndrome. Amj Med Sci 1940;200:385-90.

50 May CD, Remigio L, Bock SA. Usefulness of measurementof antibodies in serum in diagnosis of sensitivity to cowmilk and soy proteins in early childhood. Allergy 1980;35:301-10.

51 McDonald PJ, Goldblum RM, Van Sickle GJ, Powell GK.Food protein-induced entercolitis: altered antibody responseto ingested antigen. PediatrRes 1984;18:751-5.

52 Saperstein S, Anderson OW, Goldman AS, Kniker WT.Milk allergy. III. Immunological studies with sera fromallergic and normal children. Pediatrics 1963;32:580.

53 Dannaeus SG, Johansson SG, Foucard T, Ohman S. Clinicaland immunological aspects of food allergy in childhood. I.Estimation of IgG, IgA and IgE antibodies to food antigensin children with food allergy and atopic dermatitis. ActaPaediatrScand 1977;66:31.

54 Van Sickle GJ, Powell GK, McDonald PJ, Goldblum RM.Milk- and soy protein-induced enterocolitis: evidence forlymphocyte sensitization to specific food proteins. Gastro-enterology 1985;88:1915-21.

55 Heppell LMJ, Cant AJ, Kilshaw PJ. Reduction in the anti-genicity of whey proteins by heat treatment: a possiblestrategy for producing a hypoallergenic infant milk formula.Arch Dis Child 1984;51:29-36.

245

on March 13, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.68.2.240 on 1 F

ebruary 1993. Dow

nloaded from