1100.full

DOI: 10.1542/peds.2011-1712; originally published online November 28, 2011; 2011;128;1100Pediatrics

Linda Franck, Caryl L. Gay, Mary Lynch and Kathryn A. LeeAcetaminophen

Infant Sleep After Immunization: Randomized Controlled Trial of Prophylactic

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

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Infant Sleep After Immunization: RandomizedControlled Trial of Prophylactic Acetaminophen

WHAT’S KNOWN ON THIS SUBJECT: For adults, sleep deprivationbefore or after immunization is associated with decreasedantigen-specific antibody formation, but little is known aboutinfant sleep before and after immunization or the effects ofprophylactic acetaminophen treatment on infant sleep.

WHAT THIS STUDY ADDS: Infants demonstrated increased sleepduration in the 24 hours after immunization, particularly if theywere immunized after 1:30 PM and had elevated temperatures.Acetaminophen use was associated with smaller increases insleep duration but not when other factors were controlled.

abstractOBJECTIVE: To determine the effects of acetaminophen and axillarytemperature responses on infant sleep duration after immunization.

METHODS: We conducted a prospective, randomized controlled trial tocompare the sleep of 70 infants monitored by using ankle actigraphyfor 24 hours before and after their first immunization series at �2months of age. Mothers of infants in the control group received stan-dard care instructions from their infants’ health care provider, andmothers of infants in the intervention group were provided with pre-dosed acetaminophen and instructed to administer a dose 30 minutesbefore the scheduled immunization and every 4 hours thereafter, for atotal of 5 doses. Infant age and birth weight and immunization factors,such as acetaminophen use and timing of administration, were evalu-ated for changes in infant sleep times after immunization.

RESULTS: Sleep duration in the first 24 hours after immunization wasincreased, particularly for infants who received their immunizationsafter 1:30 PM and for those who experienced elevated temperatures inresponse to the vaccines. Infants who received acetaminophen at orafter immunization had smaller increases in sleep duration than didinfants who did not. However, acetaminophen use was not a significantpredictor of sleep duration when other factors were controlled.

CONCLUSIONS: If further research confirms the relationship betweentime of day of vaccine administration, increased sleep duration afterimmunization, and antibody responses, then our findings suggest thatafternoon immunizations should be recommended to facilitate in-creased sleep in the 24 hours after immunization, regardless of acet-aminophen administration. Pediatrics 2011;128:1100–1108

AUTHORS: Linda Franck, RN, PhD, Caryl L. Gay, PhD, MaryLynch, RN, MS, MPH, CPNP, and Kathryn A. Lee, RN, PhD

Department of Family Health Care Nursing, School of Nursing,University of California, San Francisco, California

KEY WORDSimmunization, infant, sleep, acetaminophen, actigraphy

ABBREVIATIONRCT—randomized controlled trial

This trial has been registered at www.clinicaltrials.gov (identi-fier NCT01321710).

www.pediatrics.org/cgi/doi/10.1542/peds.2011-1712

doi:10.1542/peds.2011-1712

Accepted for publication Aug 26, 2011

Address correspondence to Linda Franck, RN, PhD, School ofNursing, Box 0606, University of California, San Francisco, 2Koret Way, Room N415Y, San Francisco, CA 94143-0606. E-mail:[email protected]

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

Copyright © 2011 by the American Academy of Pediatrics

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

Funded by the National Institutes of Health (NIH).

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Irritability and elevated temperatureare expected reactions to infant immu-nizations.1,2 Anecdotal parent reportsof infant sleep changes after immuni-zation also are common. However, theinfluence of immunization on infantsleep has received little research at-tention. For adults, sleep deprivationbefore immunization3 or the night af-ter immunization4 was associated withdecreased antigen-specific antibodyformation. Loy et al5 studied the effectsof immunization on infant sleep andfound no differences in sleep durationor numbers of awakenings for 14 in-fants during 5-hour observation peri-ods the day before and the day afterimmunization. Parent-completed sleepdiaries for 11 of the infants alsoshowed no sleep differences.5

Before 2009, infants commonly re-ceived prophylactic acetaminophentreatment to prevent immunizationdiscomfort and fever, although there isa low level of evidence for effective-ness.6–8 In 2009, Prymula et al9 pub-lished data from a randomized con-trolled trial (RCT) that showed reducedimmunogenicity when infants (3–5months of age) received 3 doses ofacetaminophen in the first 24 hoursafter primary vaccines. This ledsome authors to reconsider thepractice,10 whereas others advo-cated maintaining the current prac-tice.11,12 All agreed, however, that ad-ditional research is needed. Thereare no published data on how acet-aminophen affects postimmuniza-tion sleep in this age group.

Given the paucity of research regard-ing sleep after immunization, we exam-ined infant sleep at the first immuniza-tion series. For this RCT, we had 3hypotheses: (1) infants would sleepmore in the 24-hour period after im-munization compared with the 24-hourperiod before immunization; (2) ahigher temperature response to im-munization would be associated with

more sleep; and (3) the group as-signed randomly to receive prophylac-tic acetaminophen treatment wouldhave an altered temperature responseand increased postimmunization sleepduration.

METHODS

Participants and Procedures

This study was approved by the institu-tion’s committee on human research.As part of a larger RCT,13 expectantmothers were recruited from child-birth education classes and prenatalclinics between 2004 and 2008. Eligiblewomen were expecting their first sin-gleton birth, were �18 years of age,andwere able to read and to write Eng-lish. Women were excluded if theyworked nights, had a diagnosed sleep

or mood disorder, or took medicationthat affected sleep. Of the 198 womenscreened for eligibility, 152 enrolled inthe study (Fig 1).

Each woman provided written in-formed consent for herself and herinfant, and women were paid for par-ticipation. Women were enrolled be-ginning at 36weeks of gestation; there-fore, all infants had gestational ages of�37 weeks at birth. Women were as-sessed in their homes during latepregnancy and at 1, 2, and 3 monthsafter the birth. The 2-month assess-ment was coordinated with infant im-munizations and included an assess-ment of infant sleep.

The mother-focused sleep hygiene in-tervention in the larger study was not

Nutritional intervention(control)(n = 50)

Sleep hygiene intervention(experimental)

(n = 102)

Complete actigraphy (n = 21)

Ineligible (n = 13)(n = 16)

(n = 17)DeclinedDelivered early

No immunization at T2 (n = 3)Missed T2 visit (n = 9)

No immunization at T2 (n = 7)Missed T2 visit (n = 8)

Prophylactic acetaminophen (experimental)

(n = 44)

Standard care(control)(n = 43)

Standard care(control)(n = 38)



Screened for eligibility(N = 198)

No actigraphya (n = 17)

No actigraphya (n = 19)

Final sample included in analysis(n = 70)

Enrollment and maternal random assignment(n = 152)

Infant immunization random assignment(n = 87)

No actigraphya (n = 19)=

FIGURE 1Consolidated Standards of Reporting Trials (CONSORT) diagram of participant flow. T2 indicates thestudy visit 2months after birth. a Actigraphic dataweremissing (mother declined), invalid (actigraphyerror), or incomplete (�24 hours of continuous data immediately before and after immunization).

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the primary interest in this analysis,but random group assignment wasconsidered a covariate. Mothers as-signed randomly to the sleep hygieneintervention group were given strate-gies for improving their own sleepwhile providing nighttime infant carein the first 3 months.13 Mothers as-signed randomly to the control groupwere given dietary information for pro-moting sleep.

The infant-focused intervention wasdesigned to minimize infant sleepdisruption after immunization at 2months of age (Fig 1). Each infant wasweighed, and mothers of infants as-signed randomly to the interventionwere provided with predosed acet-aminophen appropriate for weight (Ta-ble 1). Mothers were instructed to ad-minister a dose 30 minutes beforeimmunization and every 4 hours there-after, for a total of 5 doses.14 Mothersassigned to the control group receivedstandard immunization care instruc-tions from the infant’s health care pro-vider. Some providers administered asingle prophylactic dose of acetamino-phen as standard care, whereas otherproviders recommended that mothersadminister acetaminophen in theevent of infant fever or discomfort af-ter immunization.

Both mother and infant randomizationsequences were generated randomly,in blocks of 6, by the project statisti-cian. The mother-focused interventionhad a 2:1 ratio (experimental group/control group) to allow for an ade-quately sized group eligible for theinfant-focused intervention. Only in-

fants with mothers assigned to thesleep hygiene intervention were eligi-ble for the infant-focused intervention,and they were assigned randomly in a1:1 ratio. Research assistants were in-formed of randomization assignmentsimmediately before each study visitand were responsible for implement-ing the intervention procedures. Par-ticipants and outcome assessors wereblinded to group assignment.

Measures

Demographic and ImmunizationInformation

Demographic information was pro-vided through maternal report, aswere infants’ birth history and immu-nization information.

Actigraphy

For objective estimation of sleep quan-tity, each infant wore an actigraph(Ambulatory Monitoring, Ardsley, NY)around 1 ankle for 24 hours before andafter the 2-month immunization. Theactigraph provides continuous motiondata by using a microprocessor with apiezoelectric linear accelerometer.Data were analyzed by using the SadehInfant Algorithm autoscoring programin Action4 software (Ambulatory Moni-toring), with established validity andreliability for infants.15,16 Sleep out-comes included active sleep time,quiet sleep time, and total sleep time(active sleep time plus quiet sleeptime). Measures were computedacross 2 time periods, namely, 24hours before immunization and 24hours after immunization.

Daily Sleep Diaries

Mothers used sleep diaries to recordtheir infants’ time spent asleep, whichwere used to facilitate interpretationof actigraphic data. Infant medicationdoses, feeding type, and sleep loca-tions also were recorded.

Infant Temperature

Mothers were given digital thermome-ters (Write Temp 3-in-1 digital ther-mometer [Safety 1st, Columbus, IN])and instructed to record their infants’axillary temperature in the diary eachmorning and evening throughout the72-hour monitoring period.

Analyses

Without previous data to estimate thesample size needed for statistical sig-nificance, we used a clinically mean-ingful effect size difference of 1.0 SDunit between the prophylactic acet-aminophen treatment group and thecontrol groups. This effect size (d) re-quired a minimum of 17 infants pergroup for 80% power to test our thirdhypothesis with a significant differ-ence (2-tailed P� .05) between infantsreceiving prophylactic acetaminophentreatment and infants receiving stan-dard care.17

To evaluate the effect of immunization,paired t tests were used to comparesleep and temperaturemeasurementsbefore and after immunization. To con-trol for individual differences in infantsleep, the main outcome variable usedin subsequent analyses was the differ-ence in total sleep time for 24 hoursbefore and 24 hours after immuniza-tion, with positive values indicatingmore sleep after immunization;changes of �5 hours (n � 3) weretruncated to 300 minutes to normalizethe distribution. Morning and eveningtemperatures were correlated (r �0.46 before immunization and r� 0.52after immunization) and were notsignificantly different. Therefore, av-

TABLE 1 Intervention Group (N� 25) Predosed Acetaminophen Doses Based on Infant Weight

Weight, Range, kg Dose to Administer, mg Dose, Range, mg/kg

3.80–4.44 51 11.49–13.424.45–5.20 60 11.54–13.485.21–6.05 70 11.57–13.446.06–6.95 80 11.51–13.206.96–7.80 90 11.54–12.93

The target dosewas 11.5 to 13.5mg/kg, to be administered 30minutes before the scheduled immunization and every 4 hoursthereafter, for a total of 5 doses.14



erage temperatures for 24 hours be-fore immunization and for 24 hoursafter immunization were used, anddifferences between preimmuniza-tion and postimmunization tempera-tures were calculated.

Independent t tests, analyses of vari-ance, and �2 tests were used to iden-tify group differences in infant charac-teristics, immunization factors, andsleep and temperature changes. Pro-phylactic acetaminophen usewas eval-uated through intention-to-treat analy-sis, as well as analyses of actual useand timing of administration. Becauseof the small sample sizes for somegroup comparisons, type II error wasevaluated by calculating effect sizes(d). Pearson correlations were used todetermine the relationship betweensleep measures and infant immuniza-tion factors.

Logistic regression was used to iden-tify predictors of changes in sleeptimes after immunization. Variablesthat were associated with postimmu-nization sleep changes in univariateanalyses (P � .10) were included inthe multivariate model. Because thisstudy was a RCT, group assignmentwas included in the model regard-less of its relationship to infantsleep. Analyses were conducted byusing SPSS for Windows 18.0 (SPSSInc, Chicago, IL). A 2-tailed � level of.05 was used.

RESULTS

Study Group

Of the 152 mother-infant dyads en-rolled in the study, 70 infants had com-plete actigraphic data for 24 hours be-fore and after immunization and wereincluded in the analyses (Fig 1). The 82infants not included did not differ fromthe final sample with respect to mater-nal or infant age, infant gender, birthweight, feeding type, sleep location,acetaminophen use, or group assign-ment. The mothers in the final sample

had a mean age of 26.8 � 6.9 years(range: 18–47), and the sample wasdiverse (31% Asian, 26% white, 23%Hispanic, 11% black, and 9% mixed orother race). Most mothers (90%) hadfinished high school, and 29% hadcompleted college. Approximately 36%were employed, but only 9% wereworking at the 2-month assessment.Infant characteristics and immuniza-tion factors are reported in Table 2.Sixty-six infants (94%) had tempera-tures recorded for 24 hours before im-munization, 68 (97%) had tempera-tures recorded for 24 hours afterimmunization, and 65 (93%) had both.

Immunizations

The majority of infants (80%) receivedall recommended immunizations, in-cluding pneumococcal conjugate vac-cine, diphtheria-tetanus-pertussis vac-cine, Haemophilus influenzae type bvaccine, inactivated poliovirus vaccine,and hepatitis B vaccine.18–20 Rotavirusvaccine became available in February2006,21 and approximately one-half ofthe infants received this orally admin-istered vaccine in addition to the in-jected vaccines. Of the 7 infants (10%)who did not receive 1 or 2 of the rec-ommended immunizations, 5 did notreceive hepatitis B vaccine, 2 did notreceive H influenzae type b vaccine, 1did not receive diphtheria-tetanus-pertussis vaccine, and 1 did not re-ceive inactivated poliovirus vaccine.Because some vaccines were adminis-tered in combination, the number ofinjections ranged between 2 and 5,with 96% of infants receiving 3 or 4injections. Seven mothers (10%) didnot know which immunizations theirinfants had received and could not findthe immunization records, but they didrecall their infants receiving 3 or 4 in-jections, which suggests that the in-fants likely received most or allvaccines.

Acetaminophen Use

Most infants (80%) received acetamin-ophen either prophylactically at thetime of immunization or to managesymptoms that appeared later, re-gardless of group assignment (Table2). Infants in the prophylactic acet-aminophen intervention group weremore likely to have received the firstdose at the time of immunization, andinfants in the control group weremorelikely to have received the first doseafter symptoms (eg, fever or discom-fort) appeared. No adverse eventswere reported.

Infant Axillary Temperature AfterImmunization

There were small but significantchanges in infant temperature afterimmunization (Table 3). The mean axil-lary temperature for the 24 hours afterimmunization was 0.23°C � 0.41°Chigher than the mean temperature forthe 24 hours before immunization. Ofthe 65 infants with temperature databefore and after immunization, 28 re-ceived acetaminophen within 1 hourafter immunization and had minimaltemperature increases after immuni-zation (0.09°C � 0.40°C), comparedwith 14 infants who received no acet-aminophen (0.38°C � 0.31°C; effectsize: 0.767) and 25 infants who re-ceived acetaminophen later (0.31°C�0.44°C; effect size: 0.520). The results ofa comparison of all 3 groups were notstatistically significant (F2,62 � 3.09;P � .053); effect sizes were �0.50 SDunits but less than the 1.0 SD unit onwhich statistical power was based.

Changes in Infant Sleep AfterImmunization

Infants slept an average of 69 minutesmore (95% confidence interval: 32–105minutes) in the 24-hour period afterimmunization than in the 24-hour pe-riod before immunization (Table 3).Most of the additional sleep was active

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sleep, whereas quiet sleep time in-creased only slightly. To verify thatthese results were not influenced bythe prophylactic acetaminophen inter-vention, analyses were repeated with

only the 45 infants assigned to the con-trol group, and results were the same.Although most infants slept more inthe 24 hours after immunization, com-pared with the 24 hours before immu-

nization, 37% slept less afterimmunization.

Predictors of Increased SleepDuration After Immunization

The change in infant sleep durationwas unrelated to infant age (r �0.081), birth weight (r � 0.018), ornumber of acetaminophen doses(r � �0.189). Postimmunizationsleep increase was significantly cor-related with higher mean tempera-ture in the 24 hours after immuniza-tion (r� 0.315; P� .009). There wasa significant correlation between the

TABLE 2 Infant Characteristics and Immunization Factors According to Treatment Group (N� 70)

Total Sample(N� 70)

StandardImmunizationCare(N� 45)

ProphylacticAcetaminophenIntervention(N� 25)

Statistics

Infant characteristicsAge, wk NSMean� SD 8.7� 1.2 8.9� 1.1 8.4� 1.3Range 6.1–11.3 6.3–11.3 6.1–11.0Male, % (n) 57 (40) 58 (26) 56 (14) NSDelivery type, % (n) NSVaginal 61 (43) 64 (29) 56 (14)Cesarean 39 (27) 36 (16) 44 (11)Birth weight, kg NSMean� SD 3.41� 0.5 3.37� 0.53 3.48� 0.47Range 2.49–4.99 2.49–4.99 2.66–4.88Feeding type, % (n) NSBreast milk only 47 (33) 51 (23) 40 (10)Combination of breast milk and formula 23 (16) 20 (9) 28 (7)Formula only 30 (21) 29 (13) 32 (8)Usual sleep arrangement (N� 69), % (n) NSParent/infant bed-sharing 45 (31) 41 (18) 52 (13)Parent/infant room-sharing 51 (35) 52 (23) 48 (12)Separate room 4 (3) 7 (3) 0 (0)

Immunization factorsVaccines received, % (n) NSAll recommended vaccinesa 80 (56) 80 (36) 80 (20)All except 1 or 2 recommended vaccines 10 (7) 11 (5) 8 (2)Unsure of specific vaccines received 10 (7) 9 (4) 12 (3)No. of injections (N� 69) NSMean� SD 3.42� 0.58 3.38� 0.54 3.50� 0.66Range 2–5 3–5 2–5Time of immunization NSMean� SD 1:21 PM� 145 min 1:18 PM� 140 min 1:27 PM� 157 minRange 9:00 AM to 7:30 PM 9:00 AM to 6:30 PM 9:00 AM to 7:30 PM

Acetaminophen useAny acetaminophen administered, % (n) 80 (56) 71 (32) 96 (24) �1

2� 6.22; P� .013Timing of first dose, % (n) �2

2� 27.0; P� .001None 20 (14) 29 (13) 4 (1)Within 1 h of immunization 43 (30) 20 (9) 84 (21)�1 h after immunization 37 (26) 51 (23) 12 (3)

Total No. of doses t69� 3.89; P� .001Mean� SD 2.80� 2.11 2.13� 2.09 4.00� 1.58Range 0–9 0–9 0–6

NS indicates nonsignificant.a At the time the study data were collected, the vaccines recommended at 2 months of age were diphtheria-tetanus-pertussis vaccine, H influenzae type b vaccine, pneumococcal conjugatevaccine, inactivated poliovirus vaccine, and hepatitis B vaccine. An oral rotavirus vaccine was added to the immunization schedule in February 2006.

TABLE 3 Comparison of Infant Sleep Measures and Temperature Readings Before and AfterImmunization

Sleep Outcome Before Immunization After Immunization Statistics

Infant sleep over 24 h, N 70 70 —Total sleep, mean� SD, h 11.8� 2.2 13.0� 2.6 t69� 3.77; P� .001Active sleep, mean� SD, h 7.1� 1.3 7.9� 1.8 t69� 4.07; P�.001Quiet sleep, mean� SD, h 4.7� 1.6 5.0� 1.8 NSInfant axillary temperature, N 65 65 —Temperature, mean� SD, °C 36.60� 0.32 36.84� 0.46 t64� 4.55; P�.001

NS indicates nonsignificant.



time of day of immunization andchanges in infant sleep quantity (r�0.303; P � .011). Infants immunizedlater in the day had larger increasesin sleep duration in the 24 hours af-ter immunization. Infants immunizedearlier in the day not only hadsmaller increases in sleep, many ofthem slept less than they had in theprevious 24 hours (Fig 2).

Group comparisonswere conducted toevaluate the effects of group assign-ment (mother and infant), categoricalinfant characteristics, and categoricalimmunization factors (Table 4). Threeimmunization-related factors weresignificantly related to changes in in-fant sleep duration in univariate anal-yses, namely, acetaminophen use,axillary temperature, and time of im-munization. Infants who received acet-aminophen had smaller increases intotal sleep duration after immuniza-tion, compared with infants who didnot receive acetaminophen, regard-less of whether the first dose was ad-ministered prophylactically or givenlater in response to symptoms such asfever or discomfort (Table 4). Infantswith a mean axillary temperatureabove themedian of 36.85°C during the24 hours after immunization hadlarger increases in sleep quantity. In-fants who were immunized after themedian time of 1:30 PM had greater in-creases in sleep quantity than did in-fants who were immunized earlier inthe day. Neither of the group assign-ments and none of the infant charac-teristics was significantly associatedwith changes in sleep quantity in the24-hour period after immunization.

Multivariate logistic regression analy-sis then was conducted to explore pre-dictors of increased sleep after immu-nization, with controlling for theeffects of other variables (Table 5).Acetaminophen use, postimmuniza-tion temperature (split at the medianof 36.85°C), and timing of immuniza-

tion (split at the median of 1:30 PM)were all included in the model on thebasis of univariate associations (P �.10) with postimmunization sleepchanges, and group assignments werealso included in the model. Higherpostimmunization axillary tempera-tures and afternoon immunizationswere the only significant predictors ofincreased sleep time in the finalmodel. The final model accounted for32.5% of the variance in increasedsleep duration after immunization.

DISCUSSION

To our knowledge, this is the first studyto investigate the effects of immuniza-tion and acetaminophen use on infantsleep duration and temperaturechanges over a 24-hour period afterimmunization. Our first hypothesiswas supported by the finding that in-fants slept longer in the first 24 hoursafter immunization, compared withthe 24 hours before immunization. Thiswas particularly true for infants whoreceived their immunizations after1:30 PM. The increased sleep time wasprimarily in active sleep rather thanquiet sleep.

Our second hypothesis also was sup-ported. Infants who had elevated tem-peratures in response to vaccines alsoslept longer in the 24 hours after im-munization than in the 24 hours beforeimmunization. Temperature increaseis considered a marker of immune re-sponses and is thought to be related torelease of endogenous pyrogens (eg,interleukin 1 and tumor necrosis fac-tor �) associated with increased T cellactivity, enhanced antigen recognition,and immune responses.22 Therefore,longer sleep duration and increasedtemperature after immunization maybe indicators of the degree of antibodyresponses.9 Studies have suggestedthat sleep quantity is a potential medi-ator of antibody responses to vaccinesin adults, perhaps through stress-relatedmodulation of cytokine produc-tion by activated T cells.23,24 Althoughantibody development can take sev-eral weeks, 2 studies demonstratedthat even relatively brief periods ofsleep restriction could disrupt adultantibody responses.4,24 It was beyondthe scope of this study to determinewhether infant sleep quantity on a sin-

FIGURE 2Changes in infants’ 24-hour sleep quantities after immunization as a function of time of day ofimmunization.

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gle night after immunization was asso-ciatedwith antibody responses. Futureresearch should address this impor-

tant question by assessing infant sleepand antibody responses over longertime frames. If relationships between

time of day of vaccine administration, in-creased sleep, and antibody responsesare substantiated, then our findings sug-gest that afternoon immunizationsshould be recommended, to facilitate in-creased infant sleep after immunization.

In this RCT, infants were assigned ran-domly to 3 groups, namely, controlmothers with infants who receivedusual care, intervention mothers withinfants who received usual care, andinterventionmotherswith interventioninfants, who were instructed to pro-vide prophylactic and continuingdoses of acetaminophen. Althoughgroup assignment had no effect onpostimmunization sleep in intent-to-

TABLE 4 Group Differences in Infant Sleep Changes After Immunization

Infant and Immunization Characteristics n Change in Sleep Quantities in 24 h Before andAfter Immunization, Mean� SD, mina

Statistics Effect Size(d)b

Randomization 1 NS 0.175Nutrition (control) 21 47.4� 133.3Sleep hygiene (experimental) 49 73.1� 151.8Randomization 2 NS 0.153Standard care (control) 45 57.4� 140.6Acetaminophen (experimental) 25 79.8� 157.2Infant gender NS 0.296Boys 40 46.9� 144.1Girls 30 90.0� 147.3Delivery type NS 0.398Vaginal 43 87.5� 156.2Cesarean 27 30.1� 122.7Feeding type NS 0.190Breast milk only 33 75.2� 149.4Combination 16 67.8� 162.7Formula only 21 48.0� 132.2Sleeping arrangement (N� 69) NS 0.287Bed-sharing 31 42.7� 151.4Separate beds 38 84.8� 142.5No. of injections (N� 69) NS 0.2032 or 3 41 52.1� 157.34 or 5 28 81.9� 130.4Time of immunization t68� 1.84; P�.070 0.441Before or at median of 1:30 PM 36 34.6� 142.1After median of 1:30 PM 34 97.9� 145.1Acetaminophen use t68� 2.05; P�.044 0.613Yes 56 47.9� 140.4No 14 135.4� 152.4Timing of first acetaminophen dose NS 0.003Within 1 h of immunization 30 47.7� 150.8�1 h after immunization 26 48.1� 130.2Mean temperature after immunization (N� 68) t66� 2.30; P�.024 0.559Below median of 36.85°C 34 23.7� 153.1At or above median of 36.85°C 34 103.6� 132.2

NS indicates nonsignificant.a Difference between total sleep times in the 24 hours before and after immunization, with positive values indicating more sleep after immunization.b The effect size for feeding type is based on comparisons of the breast milk-only and formula-only groups.

TABLE 5 Logistic Regression Analysis of Increased Sleep Quantities After Immunization (N� 68)

Predictors Value P �R2

Step 1: group assignments, OR (95% CI) 0.032Sleep hygiene intervention 2.82 (0.67–11.81) NSAcetaminophen intervention 1.73 (0.39–7.74) NSStep 2: acetaminophen, OR (95% CI) 0.061Acetaminophen administered 0.32 (0.62–1.60) NSStep 3: temperature, OR (95% CI) 0.095Mean temperature in 24 h after immunization ofat least median of 36.85°C

5.97 (1.58–22.62) .009

Step 4: timing of immunization, OR (95% CI) 0.137Immunization after median of 1:30 PM 5.86 (1.63–21.16) .007

Full model, �52 18.59 .002 0.325

The dependent variable was increased infant sleep in the 24 hours after immunization, compared with the 24 hours beforeimmunization. NS indicates nonsignificant.�R2 is the change in the coefficient of determination resulting from this step; �52

is the �2 statistic for the goodness of the model fit.



treat analysis, 71% in the usual-caregroup received acetaminophen and20% received it prophylactically, whichmade it more difficult to detect groupdifferences. Nevertheless, the findingssupport one aspect of our third hy-pothesis regarding the effects of pro-phylactic acetaminophen treatment oninfant temperature. The large effectsizes (with P� .053) suggest that thestudy was underpowered for anintent-to-treat analysis to detectlarge differences, when effects ofgroup contamination with acetamin-ophen administration are consid-ered. These differences would require64 infants per group for statisticalsignificance.17

In comparison with the few infantswho did not receive any acetamino-phen (n � 14), the 56 infants who re-ceived�1 dose had smaller increasesin postimmunization sleep duration,regardless of acetaminophen adminis-tration timing. The rationale forpostimmunization administration ofacetaminophen cannot be completelyexplained by group assignment, whichsuggests that these infants might haveexperienced more symptoms, forwhich they received acetaminophen.However, acetaminophen use was notsignificant in the regression analysis,which suggests that the primary

mechanism for increased sleep timemay involve higher temperature.

Our findings are consistent with thoseof Prymula et al9 and, taken together,suggest that antipyretic agents shouldnot be given prophylactically for infantimmunization. Therefore, research onalternative pain-management strate-gies for immunization discomfort isurgently needed. As immunizationpractices shift from single-antigento multiple-antigen vaccine delivery,sleep duration should be measured infuture studies of combination vaccineproducts, because of the potential forfever or pain responses to such prod-ucts and sleep implications.25

These findings were limited to termfirstborn infants receiving their firstimmunization series, and they may notbe applicable to premature or older in-fants and children. The small numberof infants who did not receive acet-aminophen (n� 14) and the likelihoodthat acetaminophen often was usedfor symptom relief also may limit thegeneralizability of these findings;larger, placebo-controlled trials arewarranted. Findings should be inter-preted with caution because of the lim-ited study period (ie, 24 hours beforeand after immunization) and the use ofankle movements to estimate infantsleep. Infants mature at a rapid rate,however, and comparisons of more-

proximal times around the immuniza-tion protocol are critical for under-standing how sleep is influenced.Differences in active and quiet sleeptimes should be explored further byusing polysomnography, and longitudi-nal studies of sleep and responses toimmunization are needed for a betterunderstanding of the interactions be-tween immunization time of day, activeand quiet sleep, temperature, and an-tibody responses.

CONCLUSIONS

Our findings provide new data aboutinfant sleep after immunization. Giventhe importance of sleep for a healthyimmune response, our findings sug-gest that the time of day of vaccine ad-ministration and sleep duration afterimmunization are important variablesto consider when evaluating infant an-tibody responses. If further researchconfirms relationships between thetime of day of vaccine administration,increased sleep, and antibody re-sponses, then our findings suggestthat afternoon immunizations shouldbe recommended, to facilitate in-creased infant sleep in the 24 hoursafter immunization.

ACKNOWLEDGMENTSupport was provided by National In-stitutes of Health grant R01 NR05345.

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THE GOOD DIVORCE: A friend of ours drove our daughter home recently. Aftertalking in the driveway for a few minutes, we invited her into the house for aglass of wine. During our conversation, I noticed that shewas no longer wearingher engagement or wedding rings. Also, she had started working again after along absence from the work force. We learned a fewweeks ago that she and herhusband, both good friends of ours, may be divorcing. I had seen him severaltimes over the summer, and although never with his wife, he seemed fine andhad never said anything about her. Similarly, she seemed fine and never said aword about him. This prompted me to wonder, is there such a thing as a gooddivorce? As reported in The New York Times (Fashion: October 28, 2011), it couldbe that Generation X, those born between 1965 and 1980, approach divorce a bitdifferently than previous generations. After all, Generation X entered marriagein a different way as 60% chose to live with their future spouse before marriageand almost 80% stay married for more than 10 years. Moreover, all states nowuphold joint custody of children, whereas 30 years ago only three states did.Maybe this generation is more clear-eyed both about entering and leaving amarriage. With many divorced couples sharing parental duties, energy has tobe directed on the children rather than lobbing bombs at each other. Anotherexplanation may be that divorce is easier when couples fall out of love. If thereis no passion left in the marriage, is there likely to be passion in the divorce?While “good” and “divorce” may not be a natural pairing, for our friends thedyad may apply. As for our friends, we saw them drift apart over the years. Bothseem happier and more animated now. They have enough financial power sothat while not as well off as previously, they are both doing okay. They shareschedules and pick-ups for the kids and both children seem to be adjustingwithout any major difficulties. Still, I can’t help but wonder, what happened tothe passion? I am sad for that loss.

Noted by WVR, MD



DOI: 10.1542/peds.2011-1712; originally published online November 28, 2011; 2011;128;1100Pediatrics

Linda Franck, Caryl L. Gay, Mary Lynch and Kathryn A. LeeAcetaminophen

Infant Sleep After Immunization: Randomized Controlled Trial of Prophylactic

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