[journal] fever after imunization-original

DOI: 10.1542/peds.2009-1911 2010;125;e1448-e1452; originally published online May 17, 2010; Pediatrics

Michele and Ugo Vairo Alfredo Pisacane, Paola Continisio, Orsola Palma, Stefania Cataldo, Fabiola De

Breastfeeding and Risk for Fever After Immunization

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WHATS KNOWN ON THIS SUBJECT: Immune response to somevaccines is different among breastfed infants compared withthose who are not breastfed.

WHAT THIS STUDY ADDS: Breastfed infants are less likely tohave fever after routine immunizations.

abstractOBJECTIVE: The objective of this study was to evaluate the effects ofbreastfeeding on the risk for fever after routine immunizations.

METHODS: A prospective cohort study was conducted at a pediatricvaccination center in Naples, Italy. The mothers of the infants sched-uled to receive routine immunizations were instructed on how to mea-sure and record infant temperature on the evening of the vaccinationand for the subsequent 3 days. The information about the incidence offever was obtained by telephone on the third day after vaccination. Therelative risk for fever in relation to the type of breastfeeding wasestimated in multivariate analyses that adjusted for vaccine dose, ma-ternal education and smoking, and number of other children in thehousehold.

RESULTS: A total of 460 infants were recruited, and information on theoutcome was obtained for 450 (98%). Fever was reported for 30 (25%),48 (31%), and 94 (53%) of the infants who were being exclusivelybreastfed, partially breastfed, or not breastfed at all, respectively (P.01). The relative risk for fever among infants who were exclusively andpartially breastfed was 0.46 (95% condence interval: 0.330.66) and0.58 (95% condence interval: 0.440.77), respectively. The protectionconferred by breastfeeding persisted even when considering the roleof several potential confounders.

CONCLUSIONS: In this study, breastfeeding was associated with a de-creased incidence of fever after immunizations. Pediatrics 2010;125:e1448e1452

AUTHORS: Alfredo Pisacane, MD,a Paola Continisio, PhD,a

Orsola Palma, RN,b Stefania Cataldo, RN,a Fabiola DeMichele, MD,b and Ugo Vairo, MDb

aDipartimento di Pediatria, Universita` Federico II, Napoli, Italy;and bAzienda Sanitaria Locale, Napoli 1 Centro, Napoli, Italy

KEY WORDSbreastfeeding, fever, immunization

ABBREVIATIONCIcondence interval

www.pediatrics.org/cgi/doi/10.1542/peds.2009-1911

doi:10.1542/peds.2009-1911

Accepted for publication Jan 22, 2010

Address correspondence to Alfredo Pisacane, MD, Dipartimentodi Pediatria, Universita` Federico II, Via S. Pansini 5, Napoli 80131,Italy. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno nancial relationships relevant to this article to disclose.

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Fever is 1 of themost common adverseeffects after infant immunizations,1,2

and it is triggered by immune and in-ammatory responses to vaccine com-ponents. Fever associated with vacci-nations is usually mild and of shortduration; nonetheless, it would be use-ful to know whether preventive mea-sures are available. Breastfed infantshave different immune responses todisease as well as to some vaccines3,4

compared with infants who are notbreastfed. Such different responsesmight be attributable to the severalanti-inammatory and immunomodu-latory factors that are present inbreast milk.5,6 Nevertheless, becauseno data have been published on reac-togenicity to vaccines according tofeeding habits, the objective of thisstudy was to investigate the incidenceof fever after immunizations amongbreastfed and nonbreastfed infants.

METHODS

Study Design

We conducted a cohort study to com-pare the incidence of fever during the3 days after immunizations amongbreastfed and nonbreastfed infants.

Setting

The study was conducted at the vacci-nation center of District 49 of Naplesbetween October 1, 2008, and May 31,2009.

Participants

All infants who were scheduled to re-ceive the rst or second dose of ahexavalent combination vaccine (diph-theria, tetanus, acellular pertussis,hepatitis B, inactivated polio virus, andHaemophilus inuenzae type b), co-administered with a heptavalent pneu-mococcal conjugate vaccine, were en-rolled. Infants were excluded whentheir birth weight was2500 g, whenthey hadmajor congenital defect or se-rious chronic illness, and when they

had had acute febrile illness in theweek before the vaccination. No infantwas included twice during the studyperiod. After informing the parentsand obtaining their written consent,data were collected about socioeco-nomic characteristics, and the type ofinfant feeding was investigated bymeans of a 24-hour dietary recall. Themothers were then instructed on howto measure infant rectal temperatureand to record the exact values on adiary card. Parents were asked tomeasure body temperature on theevening of the vaccination and twice aday for the subsequent 3 days, once inthe morning and once in the afternoonbefore meals,7,8 and whenever feverwas suspected. A standard thermome-ter (Pic-Artsana, Como, Italy) and a fe-ver diary card were provided to themothers. One of the authors, unaware ofthe feeding habits of the infants, con-tacted all of the families by telephone onthe third day after vaccination. The studywas approved by the institutional reviewboard of the ASL Napoli 1.

Denition of Exposure

We used the 24-hour dietary recallmethod recommended by the WorldHealth Organization to dene exclusive(no other food or uids given) and par-tial (food and nutritive uids, includingformula milk, added to breast milk)breastfeeding.9

Denition and Assessment ofOutcome

The main outcome of this study wasfever, dened as body temperature of38C10, when temperature was ob-tained by rectal route and using thethermometer provided to the familiesby the study team. The mothers werecontacted by telephone and wereasked to read the information that theyhad recorded on diary cards. For eachinfant, information was obtained onhow many times temperature hadbeen recorded, how and when it was

measured, and the exact values in de-grees centigrade.

Potential Confounders

In this study we considered maternaleducation and smoking, the number ofother children in the household, andthe vaccine dose as potential con-founders of the association betweenbreastfeeding and fever. The informa-tion about such variables was ob-tained from the mothers at the time ofthe vaccination.

Vaccines and Vaccinators

Vaccines used were Infanrix HeXa(GlaxoSmithKline) and Prevnar (WyethLederle Vaccines SA). The vaccineswere administered via intramuscularinjection into the anterolateral aspectof thighs by using a 16-mm-long nee-dle. A pediatrician (Dr De Michele) anda pediatric nurse (Ms Palma) were theonly vaccinators during the studyperiod.

Statistical Analysis

Comparison between groups was per-formed by means of the 2 test. Therelative riskwith 95% condence inter-vals (CIs) was used to compare the in-cidence of fever among the feedinggroups. Stratied analysis was per-formed to investigate the role of con-founding and effect modication ofvariables that were considered as po-tential confounders or effect modiersof the association between breastfeed-ing and fever. As in this study the prev-alence of the outcome is high (10%),to estimate the relative risk or risk ra-tio adjusted for potential confounders,we used SAS software PROC GENMODslog-binomial regression11 (SAS Insti-tute, Inc, Cary, NC).

Sample Size

Preliminary unpublished data of ourgroup suggested that the incidence offever after heptavalent immunizationamong nonbreastfed infants was

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40%. Assuming a 20% loss to follow-up, we calculated that we would re-quire 110 infants in each feedinggroup to detect a statistically signi-cant decrease of 50% ( .05, 1 80%) in the rate of fever afterimmunization.

RESULTS

Participants

A total of 485 motherinfant pairswere assessed for eligibility. Amongthem, 25were excluded (19 infants had

low birth weight, and 6 had fever in theweek before immunization). All moth-ers recruited (n 460) accepted toparticipate in the study, and data foranalysis were available for 450 (98%;Fig 1). Ten mothers were lost to follow-up: 4 of them did not answer 3 consec-utive telephone calls, and 6 did not col-lect and record information on infantbody temperature. Of these 10 chil-dren, 2 were exclusively breastfed, 4were partially breastfed, and 4 werenot breastfed.

Characteristics of StudyParticipants

Table 1 shows some baseline charac-teristics of themothers and infants en-rolled in the study. A total of 206 infants(46%) received the rst vaccine doseand 244 (54%) the second 1; theirmean ageswere 101 days (SD: 90 days)and 176 days (SD: 86 days), respec-

tively. The infants who received therst dose were signicantly more ex-clusively breastfed compared withthose who received the second dose(41% vs 15%; P .01).

Potential Confounders

Table 2 provides information on thedistribution of some potential con-founders among feeding groups. Ma-ternal smoking and education, thenumber of other children in the house-hold, and vaccine dose were associ-ated with breastfeeding (Table 2), aswell with fever (Table 3), and couldthen confound the association be-tween breastfeeding and fever.

Outcome Data

Table 4 shows the frequency of feveramong feeding groups. Among the in-fants who were exclusively breastfed,partially breastfed and not breastfed,the incidence of fever was, respec-

Mother-infant couples assessed for eligibility n= 485

Excluded n=25

low birth weight: n= 19 fever on the previous week: n=6

Total recruited: n= 460

Lost to follow up n=10 did not answer phone: n=4

did not check temperature: n= 6

Data available for analysis: n= 450

FIGURE 1Flow diagram of the study.

TABLE 1 Characteristics of Infants Enrolled inthe Study (n 450)

Characteristics Value

Gender, M/F 220/230Presence of other children in the

household, n (%)224 (50)

Maternal education8 y, n (%) 172 (38)Maternal smoking, n (%) 118 (26)Fever in family members in the 3 d

before immunization, n (%)14 (3)

First vaccine dose, n (%) 206 (46)Age, mean (SD), d 101 (90)Breastfeeding, n (%)Exclusive 84 (41)Partial 60 (29)None 62 (30)

Second vaccine dose, n (%) 244 (54)Age, mean (SD), d 176 (86)Breastfeeding, n (%)Exclusive 36 (15)Partial 94 (38)None 114 (47)

TABLE 2 Association of Some Potential Confounders With Exposure

Characteristics ExclusiveBreastfeeding(n 120)

PartialBreastfeeding(n 154)

NoBreastfeeding(n 176)

P

Maternal education8 y 34 (28) 44 (28) 94 (53) .01Maternal smoking 14 (12) 30 (19) 74 (42) .01Other children in the household 54 (45) 70 (45) 100 (57) .05First vaccine dose 84 (70)a 60 (39) 62 (35) .01a Exclusive but not partial breastfeeding was associated with vaccine dose.

TABLE 3 Association of Some PotentialConfounders With Outcome

Characteristic Infants WithFever (n 172)

P

Maternal education, y8 (n 172) 77 (45) .058 (n 278) 95 (34)

Maternal smokingYes (n 118) 59 (50) .01No (n 332) 113 (34)

Other children in thehousehold

Yes (n 224) 98 (44) .05No (n 226) 74 (33)

First vaccine dose(n 206)

54 (26) .01

Second vaccine dose(n 244)

118 (48)

Data are n (%).


tively, 25%, 31%, and 53% (P .01).Compared with the infants who werenot breastfed, those who were exclu-sively breastfed had a relative risk forfever of 0.46 (95% CI: 0.330.66) andthose who were partially breastfed of0.58 (95% CI: 0.440.77). None of thevariables investigated turned out to beeither an effect modier (Table 5) or aconfounder of the association between

breastfeeding and fever; actually, theadjusted relative risks, when consider-ing all of the potential confounders, re-sulted 0.38 (95%CI: 0.210.73) and 0.46(95% CI: 0.270.84), respectively, forexclusive and partial breastfeeding(Table 4).

Table 6 shows the distribution of tem-peraturemeasurements and themean

peak temperatures during the rst dayafter the vaccination. The choice of thisday was suggested by the observationthat, for 155 (90%) of the 172 infants,fever was reported to have occurredduring the rst day after vaccination.Fever was for most children of shortduration (75% of the infants had a1-day duration of fever), and durationwas not associated with the type offeeding. Body temperature 39.0Coccurred in 8 (1.7%) infants; 4 werepartially breastfed, and 4 were notbreastfed.

DISCUSSION

This study suggests that breastfed in-fants are less likely to have fever afterimmunization compared with thosewho are not breastfed. Actually, a sig-nicant difference of risk is stillpresent after controlling for severalpotential confounders, and also themean peak temperature is differentamong feeding groups on the rst dayafter vaccination.

This study has several limitations. Oneis that body temperatures were takenby the mothers rather than by healthprofessionals. Even if the motherswere accurately trained on how tomeasure rectal temperature, wereprovided a standard thermometer,and were compliant with taking andrecording temperatures, it is not pos-sible to exclude a bias in the assess-ment of fever. Actually, breastfeedingmothers had a higher education leveland could have been more accurate indetecting fever; however, fever wasless frequent among breastfed infants,and it is unlikely that mothers of lowereducation systematically reported bi-ased body temperatures. A second lim-itation is that fever after immunizationcould be an infective episode. Even if itis not easy to deal with this potentialconfounder, that fever was usually ofshort duration and occurred duringthe 24 hours after immunization rules

TABLE 4 Distribution of Fever According to Type of Feeding

Type of Feeding Infants WithFever, n (%)

RR (95% CI) Adjusted RR(95% CI)a

Exclusive breastfeeding (n 120) 30 (25) 0.46 (0.33 to 0.66) 0.38 (0.21 to 0.73)Partial breastfeeding (n 154) 48 (31) 0.58 (0.44 to 0.77) 0.46 (0.27 to 0.84)No breastfeeding (n 176) 94 (53) 1.0

RR indicates risk ratio.a Risk adjusted for maternal education, smoking, presence of other children in the household, and vaccine dose.

TABLE 5 Association Between Breastfeeding and Fever Stratied by Potential Confounders

Confounder Breastfeeding Relative Riskfor Fever

95% CI

Maternal smokingYes Exclusive 0.23 0.07 to 0.80

Partial 0.57 0.33 to 0.97No Exclusive 0.56 0.38 to 0.81

Partial 0.64 0.45 to 0.89Other children at homeYes Exclusive 0.66 0.44 to 0.97


Partial 0.62 0.42 to 0.91Maternal education8 yYes Exclusive 0.51 0.30 to 0.88


Partial 0.73 0.51 to 1.00First vaccine doseYes Exclusive 0.48 0.30 to 0.80


Partial 0.66 0.49 to 0.88

Mantel-Haenszel adjusted risk ratio for exclusive breastfeeding 0.50 (95%CI: 0.42 to 0.60); Breslow-Day test for interactionover strata: P .48. Mantel-Haenszel adjusted risk ratio for partial breastfeeding 0.59 (95% CI: 0.52 to 0.68); Breslow-Daytest for interaction over strata: P .66.

TABLE 6 Frequency of Temperatures Recorded and Mean Peak Temperature on the First Day AfterVaccination According to the Type of Feeding

Parameter Exclusive Breastfeeding(n 120)

Partial Breastfeeding(n 154)

No Breastfeeding(n 176)

No. of temperature checks reported56 105 (88) 129 (84) 150 (85)34 12 (10) 18 (12) 24 (14)12 3 (2) 7 (4) 2 (1)

Peak temperature mean (SD), Ca 37.10 (0.84) 37.20 (0.88) 37.50 (0.89)a Analysis of variance: F 8.74, P .001.

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out most infections; however, the limi-tations of our study are common toother investigations performed on thistopic and reect the difculty of ob-taining outcome data by means ofhealth professionals.

Any explanation for an association be-tween breastfeeding and fever afterimmunization must be conjectural. Dif-ferent responses to Haemophilus in-uenzae type b and pneumococcal3,4 aswell as tomeasles-mumps-rubella vac-cine12 have been reported amongbreastfed infants compared withthose who were not breastfed; it isthen conceivable that reactogenicitycould be different, too.5,6 Becauseproinammatory cytokines act as en-dogenous pyrogens, some antimicro-bial or anti-inammatory componentsof breast milk could reduce fever bydecreasing the production of such in-

terleukins or of Toll-like receptor andtheir effects on the vascular networksupplying the thermoregulatory cen-ter in the anterior hypothalamus.13,14

The production of proinammatory cy-tokines could be reduced not only bycomponents of breast milk but also bybreastfeeding itself. Actually, breast-feeding fullls the function of meetingthe infants emotional needs, and it isconceivable that sick infants fre-quently breastfeed to reduce discom-fort and to get emotional support fromthe intimate contact with their moth-ers. This could be a reason that a re-duced caloric intake after immuniza-tion has been reported among infantswho are not breastfed but not amongthose who are breastfed. Such re-duced caloric intake has been associ-ated with an increase of serum leptinand of proinammatory interleukin 1

and tumor necrosis factor 15 andcould be 1 of the reasons that non-breastfed infants are at more risk forfever; however, breastfed infantscould be less prone to illness-inducedanorexia also because of the presenceof docosahexaenoic acid in breastmilk.16

CONCLUSIONS

Breastfeeding seems to be associatedwith a reduced risk for fever afterimmunization, but additional, well-organized studies are needed. The de-sign of such studies should includemore objective research methods,such as measurements taken byhealth care professionals at the sametime of the day or night, and shouldevaluate the role of mild intercurrentinfections by medical monitoring.

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DOI: 10.1542/peds.2009-1911 2010;125;e1448-e1452; originally published online May 17, 2010; Pediatrics

Michele and Ugo Vairo Alfredo Pisacane, Paola Continisio, Orsola Palma, Stefania Cataldo, Fabiola De


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