Archives ofDisease in Childhood 1990; 65: 411-415

Food and drug reactions, wheezing, and eczema inpreterm infants

A Lucas, 0 G Brooke, T J Cole, R Morley, M F Bamford

AbstractAllergic reactions were investigated in 777preterm infants who were randomly assignedto early diet and followed up to 18 monthspost term. Wheezing or asthma was common(incidence 23%); it was associated with neona-tal ventilation, maternal smoking, and a familyhistory of atopy and was unexpectedlyreduced in babies born by caesarean section.Even in non-ventilated infants, the incidenceof subsequent wheezing was 18%, rising to anestimated 44% (using logistic regression)when the foregoing risk factors (excludingventilation) were present. Eczema occurred in151 infants (19%) and was strongly associatedwith multiple pregnancy (30% incidence intwins or triplets). Reactions to cows' milk(incidence: 4 4% from detailed history; 0-8%confirmed by challenge), other foods (10%),and drugs (5%) were within the range reportedin full term infants. Milk and food reactionswere associated with multiple pregnancy(19%) and a family history of atopy. Reactionsto drugs were least likely to occur in infantswho had been ventilated and were on multiplemedications in the neonatal period, suggest-ing that drug tolerance may have developed.We speculate that preterm infants may be ahigh rsk group for asthma and eczema, whichcould imply an association between atopy andprematurity.

MRC Dunn NutritionUnit and UniversityDepartment ofPaediatrics,CambridgeA Lucas0 G BrookeT J ColeR MorleyIpswich Hospital,SuffolkM F BamfordCorrespondence to:Dr A Lucas,Dunn NutritionalLaboratory,Downhams Lane,Milton Road,Cambridge CB4 1XJ.Accepted 8 November 1989

It is reasonable to suppose that preterm infantswould be vulnerable to an increased incidenceof later allergic reactions. They are commonlyexposed to cows' milk antigens at a time whenexclusion of whole antigenic proteins by the gutis poor,' and they are vulnerable to milk aspira-tion, a potent source of sensitisation.2 They mayalso consume a greater load of food antigens fortheir size than mature infants, and have pre-viously been shown to develop latent anaphylac-tic sensitisation to cows' milk.3 Moreover,premature babies are often heavily exposed tonumerous drugs to which they might be sensi-tised. On the other hand, there is some evidencethat preterm infants may be less liable to clinicalsensitisation than more mature infants. Forexample, IgE production does not seem to occurbefore about 36 weeks' gestation.4 It is possiblethat increased antigen absorption from the gutmay act as a suppressant to antibodyproduction,5 a proposal supported by work inlower primates6 and by the finding of an

increased population of suppressor T cells.7Infants born very prematurely may also haveless exposure to maternal anti-idiotype anti-

bodies, which are thought to be important inthe pathogenesis of childhood atopy.8 9 Despitethese considerations, allergic reactions and thefactors relating to them have been poorly docu-mented in such infants. This paper reports dataon allergic reactions in 777 infants born pretermwho were followed up to 18 months of correctedage.

Subjects and methodsThe subjects in this investigation are currentlytaking part in a five centre study designed toinvestigate the effects of early diet on later out-come in preterm infants. The overall objectives,study population, and design of this study havealready been described.'0 We report here theincidence of atopic or allergic disease in 777infants who have been followed up until 18months after the expected date of delivery.

Infants were recruited, with informed paren-tal consent, in Cambridge, Ipswich, KingsLynn, Norwich, and Sheffield. All infantsweighed less than 1850 g at birth and were with-out major congenital abnormality. Mean (SD)birth weight was 1397 (298) g and mean gesta-tion 31-0 (2-7) weeks. Details of atopic or aller-gic disease in the family were recorded while theinfant was in the neonatal unit.

Infants in centres 1-3 were first seen forfollow up at 9 (1) months' corrected age, andinfants in all five centres were seen at 18 (1)months' corrected age. At the follow up exami-nations information was collected on eczema,wheezing (asthma), and food or drug sensitivi-ties (see below). The history was supported asfar as possible by clinical examination.A single observer (RM) recorded the histori-

cal data in centres 1-4, achieving a follow uprate of over 95%. While other observers wereinvolved at centre 5, in all cases they were blindto the infants' clinical course and managementduring the neonatal period.

Reactions to specific foods were classified asfollows. (1) Cases with a convincing history ofreaction(s) to a specific agent, resulting in itsexclusion from the diet on professional advice.Such reactions were usually gastrointestinal ordermatological. (2) Cases where specific symp-toms recurred on challenge conducted undercontrolled conditions. Reactions to drugs andhousehold agents, mainly dermatological, wererecorded similarly.There has been much debate on the definition

of asthma in infancy and childhood." Godfreysuggests that the diagnosis should be based onintermittent cough or wheeze that can bereversed, largely or completely, by bronchodila-

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tors or steroids.12 It is uncertain, however,whether recurrent untreated wheezing shouldbe classified as asthma. We have used threecategories: (a) 'recurrent wheezing', whichrefers to infants with at least three episodes ofwheezing recorded by careful history, butwhere no drug treatment has been used; (b)'moderate asthma': cough and wheeze requiringdrug treatment either intermittently or contin-uously; and (c) 'severe asthma': cases requiringone or more hospital admissions for acuteasthma. Other respiratory conditions charac-terised by noisy breathing, for example mucousrattling, were as far as possible excluded.

Atopic eczema was diagnosed from a clearhistory of itchy dermatitis with characteristicdistribution, confirmed by clinical examinationwhen active at the time of interview (60% ofcases). Seborrhoeic dermatitis was not classifiedas eczema. Disease severity was classified asmild, requiring no treatment, moderate, requir-ing intermittent treatment (for example, steroidapplications), and severe, reflecting the need forintensive treatment, usually after specialistreferral.

Statistical analysis was by x2 test and multiplelogistic regression analysis.The study was approved by the local health

authority ethics committee at each of the fivehospitals and the Dunn Nutrition Unit.

ResultsINCIDENCE OF ATOPIC OR ALLERGIC DISEASETable 1 shows the prevalence of atopic/allergicdiseases in the 777 infants at 18 months'corrected age. Overall incidence of wheezing bythis age was 22-5% (175/777) and of eczema19-4% (151/777). Reactions to foods occurred in10% (81/777) and to drugs in 5% (42/777). Inall, 341 infants (44%) had had one or moremanifestations of 'allergic' or atopic disease by18 months of age.

All the atopic or allergic conditions investi-gated were highly correlated with one another.

Table I Incidence of wheezing or asthma, eczema, andfood and drug reactions at 18 months' corrected age in 777infants born preterm

No of Incidence (%)cases

Asthma or wheezing*:All cases 175 22 5

Intermittent wheezing 117 15-1Moderate asthma 46 5 9Severe asthma 12 1.5

Eczema*:All cases 151 19-4

Mild 48 6-2Moderate 97 12-5Severe 6 0-8

Food reactions:All casest (one or more food) 81 10-4Cows' milk

Positive history 34 4-4Confirmed by challenge 6 0-8

Egg 14 1-8Other foods (including additives) 39 5 0

Drug reactions:All cases 42 5 4Penicillin 25 3-2

One or more of the above conditionsor reactions: 341 43-9

*For definitions see text.tReported reactions to foods where usually specific to one food;only six cases reacted to two foods and none to more than two.

Children with eczema were more than twice aslikely to experience food reactions as childrenwithout eczema (27/151 (18%) compared with54/626 (9%); p<0-001), and significantly morelikely to have asthma or wheezing (47/175 (27%)compared with 104/602 (17%); p<0 005.)

FACTORS ASSOCIATED WITH THE DEVELOPMENTOF ATOPIC OR ALLERGIC DISEASE(a) Wheezing or asthmaUsing logistic regression, factors examined foran independent association with wheezing orasthma (dependent variable) were: sex, birthweight, gestation, mode of delivery (vaginal orcaesarean), days of mechanical ventilation (logtransformed and +1 to avoid log 0), multiplepregnancy (twins or triplets), maternal steroidsbefore delivery, small for gestational age (birthweight < 10th centile), pregnancy inducedhypertension (systolic blood pressure > 140mmHg, diastolic blood pressure >90 mmHg),social class of parents, number of cigarettessmoked by mother and father, and number offirst degree relatives with a history of allergicdisease (asthma, eczema, hay fever, drug reac-tions, or proved food sensitivities). The onlyfactors to emerge as independently related towheezing or asthma were: duration of mechani-cal ventilation (p<0-001), mode of delivery(p<O-Ol), family history of allergy (p<0-01),and maternal smoking (p<0-01). The odds ratioof the infant developing wheezing or asthma inassociation with each factor is shown in table 2.The constant in the regression model shown wasset as the 'best case' (lowest incidence ofwheezing), which occurred in babies born bycaesarean section from non-smoking mothers,who had no close family history of allergy andrequired no ventilation (relative risk 0-13:1;equivalent to an incidence of 11 -5%). From theregression equation presented, the absolute riskof wheezing, based on the 'risk factors' shown,can be estimated from the constant and indi-vidual regression coefficients. Thus a non-ventilated infant with two atopic first degreerelatives and who was delivered vaginally to amother smoking 20 cigarettes per day, wouldhave a relative risk of 0-8:1 (equivalent to 44%incidence). Table 3 shows raw data for theincidence and prevalence of wheezing or asthmabroken down into categories for each of thesignificantly associated factors identified by theregression analysis. Notably 38% of infantsventilated for 10 days or more developed wheez-ing or asthma subsequently. No correlation atall was found between birth month and thedevelopment of asthma, in contrast to the find-ings in full term infants.'3 14

(b) EczemaUsing logistic regression (table 2), with inde-pendent variables as described above, the onlyfactor found to be independently related to theincidence of eczema was multiple pregnancy(twins or triplets), which increased the relativeodds by 2-1:1 (p<0-001). Raw data (table 3)show an incidence of eczema of 30% in twins ortriplets (39/130 cases) compared with 17% insingletons (p<0O005).

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Food and drug reactions, wheezing, and eczema in preterm infants

Table 2 Relative odds of (a) wheezing or asthma or (b) eczema for each significantly associated factor identified by multiplelogistic regression

Factor Regression SE Relative oddscoefficient

(a) Wheezing or asthmaVaginal delivery 0-50 0 18'' 1 6:111Duration of ventilation 0-34t 0-08' 1-6:1 for 3 1

2-0:1 for 7 days2-6:1 for 15 J

Cigarettes smoked by mother/day 0-04 0 01 '' 1-2:1 for 51-5:1 for 10 cigarettes/day2-3:1 for 20 1

No of first degree relatives with history of allergyt 0 25 0 10' 13:1 for 1 relative2-1:1 for 2 1rltv

Constant (best case)§ -2-03 0-13:1

(b) EczemaMultiple birth 0-72 0 22'' 2-0:1Constant (best case)§ -1-56 0-21:1

'p<002, **p<0.01, ***p<0001.tRegression coefficient derived using log transformed data: log,( (days of ventilation +1).1Eczema, asthma, hay fever, or proved reactions to foods in first degree relatives.6Constant set for lowest risk cases.IIRelative odds (odds ratio) for each factor are derived from the antilog of the regression coefficient and represent the odds relative to thecorresponding lowest risk category.

Table 3 Raw data on overall incidence and prevalence at18 months of wheezing, eczema, and food sensitivities,broken down by factors shown to be signiftcantly relatedusing logistic regression analysis (see table 2)

Proportion of cases p Value(% incidence)

Asthma or wheezing:(a) VentilationNone 72/410 (18)1-9 days 75/294 (26) <0 0001>10 days 28/73 (38)

(b) Parental smokingNo 107/545 (20) <0-005Yes 68/232 (29)

(c) Caesaerean sectionNo 103/382 (27) <0o-o5Yes 72/395 (18)

(d) Family history of allergy'(i) All cases

No 104/577 (22) >0-05Yes 51/200 (26)(ii) Cases still symptomatic

at 18 monthsNo 82/577 (14) 0 01Yes 45/200 (23) <

Eczema:Multiple pregnancyNo 112/647 (17) <0-005Yes 39/130 (30)

Food sensitivities:Multiple pregnancyNo 57/647 (9) <0-005Yes 24/130 (19)

Family history of allergiesNo 51/577 (9) <02Yes 30/200 (15) <0-02

.Family history was a significant factor for overall incidence ofasthma when confounding factors were adjusted for - see table 2.

(c) Reactions to foods and drugsAnalysis of raw data showed reactions to foodswere more common in twins or triplets(p<0-005) and in infants who had a family his-tory of allergy or atopy (p<0 02) (table 3).These findings were confirmed by logisticregression analysis as above. Regression analysisalso showed that drug reactions were appreci-ably more common in infants who were not ven-tilated (relative risk compared with ventilatedinfants, 2 5:1), despite lower drug exposure inthe neonatal period in this group. There was atrend towards a lower incidence of reactions topenicillin by 18 months in those who hadreceived penicillin in the neonatal period (2-3%;11/473 cases) compared with those who had not(4-6%; 14/304).The influence of early diet on later allergic

disease is an important area in its own rightwhich is not considered in this paper andwill be published separately. As describedpreviously,'1 infants were assigned in threecentres to preterm formula and compared withdonor breast milk (either as sole diets or as sup-plements to maternal milk). In the remainingtwo centres infants were assigned to a standardterm formula and compared with a preterm for-mula (as sole diets or as supplements to mater-nal milk). For the purpose of interpretingresults in this paper, however, our (unpub-lished) data show that while dietary effects onlater allergy emerged in subgroup analyses,there was no overall effect of early diet on laterallergic or atopic disease. Thus the conclusionspresented here would not be altered if the pro-portions of infants on each diet were different tothose in this study.

DiscussionIn this study we have documented asthma orwheezing, eczema, and food or drug reactions at18 months post term in nearly 800 infants bornpreterm. A number of important associationswith these outcomes have been identified whichmay have broader significance for the aetiologyof childhood atopy. As we suggest below,however, preterm infants may be, in certainrespects, a special group in terms of the evolu-tion of their atopic disease. The apparently highincidence of asthma and wheezing, which wasintercorrelated with the incidence of eczema hasled us to explore and develop the hypothesisthat prematurity may be linked to atopicdisease.Our multicentre study was designed to inves-

tigate the effects of early diet (not reported here)on later outcome, including allergic reactions.The experimental design did not require fullterm control infants, as it was the differencebetween randomised groups of prematurebabies that was of importance. The principalpurpose in this paper was to explore factors thatrelate to the development of allergic reactionswithin our population of preterm infants; againsuch analyses do not require full term controlbabies. It was also considered, however, that

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our overall incidence figures for allergic reac-tions in infants born preterm should be pre-sented here, though it must be emphasised thatwithout using the same data collection proce-dure on infants born at term any comparison ofour incidence figures with those published interm infants are of speculative significance.Nevertheless, such data have been collected inmany studies using apparently similar diagnos-tic criteria to the ones used by us.

It is also reasonable to challenge the reliabilityof data on food reactions obtained mainly byclinical history. In this large multicentre studydetailed immunological tests would have beenimpracticable and their value controversial. Ourstudy is comparable with others,' 5-17 and hasthe advantage over several questionnaire basedstudies'3 1120 that a careful and consistent his-tory was taken, in four centres, by one observer.The incidence of wheezing or asthma

appeared high. A diagnosis of intermittentwheezing was made at follow up after carefulhistory by an experienced clinician, andmoderate or severe 'asthma', requiring drugtreatment, had usually been diagnosed by apaediatrician. The incidence of asthma in child-hood has been reported to be between 0-1% and19%, and even higher (up to 25%) if occasionalwheezing is included.2' However, such highfigures have not been reported for infants under2 years of age. For example, data from the 1970British cohort study using a questionnaire withless stringent diagnostic criteria than employedhere,22 showed that by 5 years 21% of all chil-dren had had at least one wheezing episode; yetat 1 year the incidence was only 8 5%, and by 2years, 11-5% (1318/11 465 cases). From pub-lished reports it seems unlikely that intermittentwheezing or frank asthma before 2 years wouldoccur in more than 12% of infants born at term.Thus our 23% overall incidence at 18 monthsstrongly suggests an excess in infants born pre-term over that in the normal population.

It might be argued that the high rate ofwheezing or asthma in infants born preterm isnot an atopic manifestation but reflects lungdamage after mechanical ventilation for earlyrespiratory disease. Indeed, we found durationof ventilation was strongly associated with laterwheezing or asthma, which occurred in nearly40% of infants ventilated for 10 days or more.However, we suggest that ventilation was notthe sole reason for this excess of cases. Firstly,wheezing or asthma was very common even ininfants who received no mechanical ventilationat all, with an 18% overall incidence in this sub-group, rising to an estimated 44% in the 'worstcase' for non-ventilated infants with other riskfactors (see below). Secondly, wheeziness orasthma in this study was strongly associatedwith a family history of atopy, though only inthe case of infants whose wheezing was stillproblematic at the time of the 18 month followup. Finally, the incidence of wheezing orasthma was intercorrelated with that of eczema,generally regarded as an atopic disease. We haveconsidered whether our incidence figure foreczema of 19-4% should be regarded as high.Kjellman'8 and Croner et al,'9 who collectedtheir data in a similar way to ours, reported inci-

dence rates of only 7-6% and 5-7% in prospec-tive studies of European (Swedish) term infants.The incidence figures for eczema reported inthis country have, however, risen in recentyears, from 5% in the 1946 national birth cohortto 12% in the 1970 cohort,23 though thesefigures represent incidence up to 6 years of ageand cannot be compared with our 18 monthincidence. More recent data (1981) from NewZealand, however, showed an incidence of 12%in 2 year old infants with no atopic family his-tory (compared with 18% in our study).24Interestingly, though, this study demonstratedthat in the subgroup of children with a positiveatopic family history, the incidence of eczema(24%) was similar to ours (25%). Further study,comparing preterm and term infants using thesame data collection procedure, would beneeded to examine the possibility raised here,that preterm infants are a high risk group foreczema.The hypothesis presented that wheezing or

asthma in preterm infants may often have anatopic basis requires future investigation.Indeed, the arguments presented above havesome inconsistencies: for example, while weshow that eczema and wheezing are intercorre-lated, these disease states are also to some extentindependent as evidenced by a difference in thepattern of associated factors (table 2). Neverthe-less, an atopic aetiology for wheezing in preterminfants is further supported by the data ofothers. Bertrand et al showed that preterminfants, whether ventilated or not, are subject toairways hyper-reactivity.25 The tendency towheeze after mechanical ventilation, observedalso in smaller case controlled studies byothers,25 26 could be interpreted as an exacer-bating effect of ventilation in infants predis-posed, perhaps genetically, to atopic respiratorydisease. Furthermore, the association betweenventilation and later wheezing could imply thatatopic infants are the ones most likely todevelop severe early respiratory disease andhence have an increased requirement for venti-lation.

Bertrand et al observed that not only do pre-term infants have increased 'bronchial hyper-reactivity' but so also do their mothers,25 raisingthe intriguing possibility that hyper-reactivityof the smooth muscle in the bronchi could beassociated with hyper-reactivity of that of theuterus, as a potential mechanism for pretermlabour. This concept is debated however; Chanet al were unable to substantiate Bertrand'shypothesis.27 We did not perform bronchialhyper-reactivity tests and the number ofmothers with frank asthma was too small fordetailed analysis. Nevertheless, our surprisingobservation that preterm infants delivered bycaesarean section were less likely to developlater wheeziness could be explained if it isargued that the great majority of such babieswere delivered interventively, largely for com-plications arising in pregnancy, and thereforethey constituted a different group, in terms offamilial atopy risk, to those whose mothers wentinto spontaneous preterm labour.

In contrast to the high incidence of wheezingin preterm infants, the incidence of cows' milk

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reactions (4-4% based on clinical history; 0-8%confirmed by objective challenge) and of reac-tions to foods in general (10%), was well withinthe range reported for normal children, inwhom incidence of food allergies has beenclaimed to be as high as 20-40%. 17 19 28 29Few investigators have published incidence

figures for drug reactions in early childhood,but Croner's value of 7-3% (116 cases in 1701infants) was similar to our figure of 5-4% (42/779).19 Yet, in view of the very high antibioticand drug usage in low birthweight infants a highrate of subsequent drug reactions might be pre-dicted. On the contrary, the 2 5 fold greater riskof drug reactions in well, non-ventilated com-pared with sick, ventilated infants (the latterreceiving more drugs), together with the trendtowards a lower rate of penicillin reactions ininfants who had received penicillin in theneonatal period, suggests that preterm infantsmay develop tolerance to drugs.

Aetiological factors for atopic disease andallergic reactions in preterm infants may not bethe same as those factors proposed for babiesborn at term. For instance, there was no sugges-tion that any of the outcome responses in thisstudy had a seasonal incidence, as has beenfound with atopy in full term infants.'3 14 Anunexpected independent association, whichdemands further exploration, and not describedin full term infants, is the raised incidence ofeczema and food sensitivity in twins and trip-lets: indeed for both eczema and food sensitivi-ties multiple birth emerged as the most stronglyassociated factor. Various studies have exami-ned the concordance of eczema in monozygoticand dizygotic twins30 31; but if twinning per seis associated with eczema, we may question thevalidity of such concordance studies regardingthe genetic risk for eczema in the population.Maternal smoking, as in term pregnancies,32emerged as a strongly associated independentfactor for wheezing or asthma in the infant. Theassociation between atopic disease or food sensi-tivities in the preterm baby and a family historyof atopy suggests that genetic factors were ofmajor aetiological significance.

Perhaps the most important questions raisedby our data, and requiring further explorationare: whether wheezing and eczema do indeedhave an increased incidence in preterm infants;whether or not wheezing in such infants shouldbe regarded as having principally an atopicbasis; whether prematurity is linked to atopicdisease; and finally, whether atopy has aetio-logical importance in preterm labour.

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5 Helms I, Rieger CHL. Decreased production of specific anti-bodies to cows' milk proteins in premature infants duringthe first six months of life. EurJ Pediatr 1987;146:131-4.

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13 Bisgaard H, Dalgaard P, Nyboe J. Risk factors for wheezingduring infancy. Acta Paediatr Scand 1987;76:719-26.

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