Validating Current Immunization Practice With Young Infants

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PEDIATRICS Vol. 90 No. 5 November 1992 771

EXPERIENCE

AND

REASON-Briefly

Recorded

In Medicine one must pay attention not to plausible theorizing but to experience and reason together. ... I

agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions

from what is observed. . ..But conclusions drawn from unaided reason can hardly be serviceable; only those

drawn from observed fact.” Hippocrates: Precepts. (Short communications of factual material are published here.

Comments and criticisms appear as letters to the Editor.)

Validating

Current

Immunization

Practice

With

Young

Infants

A recent change in standard pediatric practice on

immunization of young infants has involved the

ad-ministration of two injections during the same office visit as opposed to one injection per office visit. In the past, infants received a single injection at 2, 4, and 6 months of age, to immunize against diphtheria,

tetanus, and pertussis. Now, young infants also

re-ceive a second injection, to immunize against

Hae-mophilus influenzae type b. This change in procedure

raises the question whether two injections during the

same visit might be too stressful for young infants. A

clear demonstration that two injections are no more

stressful than one could provide sufficient evidence to allow pediatricians to feel confident that this new procedure is appropriate. In this report, we compare the different amounts of stress, if any, in

2-month-old infants receiving either one or two injections. It

was of interest to test for a difference between the

two protocols at 2 months of age, when infants

re-ceive their first inoculation and when they might be

most likely to show a difference between the two

protocols given the evidence that inoculation is less

stressful for 4- and 6-month-old infants.’

The research literature indicates that adrenocortical reactivity, specifically the magnitude of cortisol in-crease over basal levels, provides a reliable index of stress in infants, children, and adults as well as

ani-mals.25 There is reason to believe that cortisol

re-sponse should prove sensitive in indicating a differ-ence in infants’ stress response to one vs two inocu-lations. Various maternal and pediatric staff attempts to reduce or eliminate infants’ behavioral manifesta-tions of stress may not affect their cortisol response.

In this regard, Gunnar2 reported that soothing

neo-nates during circumcision did reduce crying but had

no effect on cortisol response. Past research has found

that local anesthetic during circumcision reduced

crying but did not always affect cortisol response.6’7 More generally, the absence of a behavioral response

does not necessarily mean that infants are not

stressed, whereas some stress-related cortisol

re-sponse might be expected. Thus, the present study

Received for publication Oct 30, 1991; accepted Jun 23, 1992

Reprint requests to (ML.) Institute for the Study of Child Development, Department of Pediatrics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 97 Paterson St. CN 19, New Brunswick, NJ 08903-0019.

relied on adrenocortical reactivity to index infants’

stress response. Nonetheless, inasmuch as infants’

state prior to the perturbation might well affect their cortisol response, infants’ preinoculation affective be-havior was rated to ensure that it did not confound

the comparison between cortisol response to one vs

two inoculations.

Research on infant adrenocortical reactivity has

often relied on assays of blood.69 Because drawing

blood is itself a painful procedure, baseline respon-siveness was typically established for different

sub-jects from those responding to the stressor. In our

research on infants’ adrenocortical reactivity to inoc-ulation,’ assays of saliva are used to determine base-line and response cortisol levels for the same infants

to derive measures of individual subject response to

stress. In our experience, the saliva collection

proce-dure does not lead to behavioral manifestations of

stress in young infants. Thus, it is unlikely that this

procedure causes a cortisol response that would be

confounded with infants’ subsequent cortisol

re-sponse to the inoculation(s). In any case, because this

procedure is comparable for the one- vs

two-inocu-lation groups, a difference in subsequent cortisol

re-sponse between the two groups would reflect a group

difference in response to inoculation.

Subjects

METHODS

Subjects were 40 two-month-old infants: 20 received only the

diphtheria, tetanus, and pertussis inoculation, and 20 received both

the diphtheria, tetanus, and pertussis and the H influenzae type b

inoculation. Informed consent was obtained from infants’ mothers

prior to the study.

Procedure

The study was conducted in the waiting rooms of three different

pediatricians’ offices. Saliva was collected from infants both

im-mediately after arrival at the office and approximately 20 minutes after the inoculation(s), thus giving enough time to see the rise in

cortisol level in response to inoculation. This delay was chosen

based on our research indicating that this interval is approximately the time required to detect reliably the peak cortisol increase to the perturbation in most infants.t For subjects in the one-inoculation

group, poststress saliva was collected approximately 18 minutes

(range 15 to 20 minutes) after the injection. For subjects in the two-inoculation group, poststress saliva was collected 20 minutes after the first injection. Inasmuch as the two injections were typically

given within 2 minutes of each other, the interval between the injection(s) and the collection of the poststress saliva sample was quite comparable for the two groups.

To collect each saliva sample, unsweetened lemon crystals were

placed on an absorbent dental cotton roll. This roll was applied to

the tongue, cheeks, and gums of the infants. The lemon crystals

were used to promote salivation. After saliva was absorbed by the

cotton, the dampened cotton roll was placed into the barrel of a

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772 EXPERIENCE AND REASON

clean 5-mL syringe, and the plunger was used to express the saliva into labeled test tubes. Usually, the application of only one cotton roll was necessary for collection of a sufficient quantity of saliva

for analysis. Each sample collection did not take longer than 2

minutes. Infants did not show any sign of upset with the collection

procedure, although a few infants did grimace in response, in all

likelihood to the taste of the unsweetened lemon crystals. Preinocu-lation and postinoculation saliva samples were immediately

refrig-erated and then frozen for storage. Individuals collecting the saliva

samples as well as infants’ mothers and pediatric staff involved in

the inoculation were not aware of the specific objective of this

study (ie, difference in cortisol response to one vs two inoculations).

The frozen cortisol samples were shipped in dried ice to Hazelton

Laboratories, Vienna, VA, for radioimmunoassay for unbound

salivary cortisol. Laboratory quality control procedures have been

described previously.’

Preinoculation state was evaluated to ensure that it was not a

confounding factor in the comparison between the two groups in

cortisol response. Infants’ peak negative affect (both facial and

vocal) was rated on a 6-point scale (0 = no sign of distress; 6 = full

distress) during the 5-second interval before the inoculation (see

references I and 10 for a more complete description of this scale). This rating was made by observers (interobserver reliability greater

than 0.96) with no knowledge of infants’ group membership or

cortisol response. Preinoculation negative affect did not differ

significantly between the two groups by one-way (group) analysis

of variance (mean = 1 .94, SD = 2.54 for the one-inoculation group;

mean = 2.10, SD = 2.40 for the two-inoculation group). (A one-way [group] analysis of covariance was performed on the difference

between preinoculation and postinoculation cortisol level with

preinoculation negative affect as the covariate. There was no

sig-nificant group or covariate effect in this analysis of covariance. Thus, the absence of group differences in cortisol response was not due to any confounding of preinoculation state on this response.)

RESULTS AND DISCUSSION

The Table shows the preinoculation and

postinocu-lation cortisol levels for the two inoculation groups.

A repeated-measure (saliva sample: preinoculation vs

postinoculation) analysis of variance with one

be-tween-subjects factor (group: one vs two inoculations) was performed on these data. The analysis of variance

yielded a significant main effect of sample, F(1, 38)

= 1 1.95, P < .001, indicating a reliable preinoculation to postinoculation increase in cortisol level. This in-crease indicates that the inoculation procedures were

stressful to the infants. Neither the main effect of

group, nor the group by sample interaction, was

significant in this analysis of variance. Thus, the

cortisol increase was comparable for the two groups

of infants. The proportion of infants showing a

cor-tisol increase did not differ significantly between the

two groups by x2 test (0.75 [15 of 20] for the

one-inoculation group; 0.70 [14 of 20] for the two-inocu-lation group).

These findings suggest that 2-month-old infants

are no more likely stressed by two inoculations than

by one. Although the power for detecting a difference

TABLE. Cortisol Level in 2-Month-Old Infants Receiving One

Inoculation or Two lnoculations*

Cortisol Level, .g/dL

Baseline Response

One inoculation: DTP 0.74

(0.42)

1.34

(0.71)

Two inoculations: DTP and Hib 0.74

(0.56)

1.06

(0.51)

SStandard deviation in parentheses. DTP, diphtheria, tetanus, and

pertussis; Hib, Haemophilus influenzae type b.

in cortisol response between the one- and

two-inoc-ulation groups was relatively low in this study, the

trend in the data was in the unexpected direction for

a greater cortisol response in the one- than

two-inoculation group. Thus, it is unlikely that the use of a larger sample size than the one in this study would have led to a finding for a greater cortisol response in the two-inoculation group.

Despite the reliability and validity of cortisol release as an index of infant stress, the present results do not rule out differences in behavioral stress response

be-tween the one- and two-inoculation groups at this

age. In this regard, measures of intensity of behavioral

response cannot be used to compare the two groups

because intensity of behavioral response and duration

of the perturbation are confounded. However,

in-fants’ quieting behavior following the perturbation (that is, after the single inoculation for the one-inoc-ulation group and after the second inoculation for the

two-inoculation group) can be used for this

compar-ison. We are currently investigating this possibility.

The postinoculation saliva collection used in this

study was chosen to assess infants’ peak adrenocor-tical response to the inoculation(s). The present results

do not rule out differences between the two groups

in other aspects of adrenocortical reactivity. In partic-ular, the two groups might differ in cortisol recovery time to baseline levels following the perturbation. Investigation of this issue would require, of course, the collection of successive saliva samples at regular intervals after the inoculation(s).

Finally, it is possible that there might be a difference

in cortisol or behavioral response between one vs two

inoculations at older ages (eg, 4 and 6 months of age). We believe that such a difference is unlikely because various cortisol and behavioral measures of response

to inoculation decrease between 2 and 6 months of

age.’ From the point of view of clinical procedures, therefore, our results support the current practice of giving two injections during the same visit.

ACKNOWLEDGMENTS

This research was supported by National Science Foundation

grant BNS 8919377 to Dr Lewis and by the Intramural Research

Program of the National Institute of Child Health and Human

Development to Dr Suomi.

MICHAEL LEWIS, PHD

DOUGLAS S. RAMSAY, PHD

Institute for the Study of Child

Development

Robert Wood Johnson Medical

School

New Brunswick, NJ

STEPHEN J. SUOMI, PHD

Laboratory of Comparative Ethology

National Institute of Child Health

and Human Development

REFERENCES

I. Lewis M, Thomas D. Cortisol release in infants in response to inoculation. Child Der 1990;61:50-59

2. Cunnar MR. Human developmental psychoneuroendocrinology: a

re-view of research on neuroendocrine response to challenge and threat in infancy and childhood. In: Lamb ME, Brown SL, Rogoff B, eds. Advances

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EXPERIENCE AND REASON 773

in Developmental Psychology. Vol. 4. Hillsdale, NJ: Erlbaum; 1986;4:51-103

3. Levine S. A psychobiological approach to the ontogeny of coping. In: Carmezy N, Rutter M, eds. Stress, Coping, and Development in Children.

New York, NY: McCraw-Hill; 1983:107-131

4. Levine 5, Wiener SC. Coping with uncertainty: a paradox. In: Palermo

DS, ed. Coping With Uncertainty: Behavioral and Developmental Perspec-tives. Hillsdale, NJ: Erlbaum: 1989:1-16

5. Suomi S. Primate separation models of affective disorders. In: Madden

J, ed. Neurobiology of Learning. Emotion, and Affect. New York, NY: Raven

Press; 1991:195-213

6. Williamson PS, Evans ND. Neonatal cortisol response to circumcision with anesthesia. Clio, Pediatr (Phila). 1986;25:412-415

7. Stang HJ, Cunnar MR. Snellman L, Condon LM, Kestenbaum R. Local anesthesia for neonatal circumcision: effects on distress and cortisol

response.JAMA. 1988;259:1507-1511

8. Anders T, Schacher E, Kream J, Roffwarg H, Hellman J. Behavioral state

and plasma control response in the human newborn. Pediatrics.

I 970;46:532-537

9. Tennes K, Carter D. Plasma cortisol levels and behavioral states in early infancy. Psychosom Med. I 973;35: I 21-128

10. Worobey J,Lewis M. Individual differences in the reactivity of young infants. Dev Psycho!. I 989;25:663-667

PRESCHOOL AROUND THE GLOBE

JAPAN.The Japanese have created a two-tier system of preschools: yochien for

the children of mothers who do not work and hoikuen for the children of working

parents. About 95% of youngsters enroll in one or the other. Run by the Ministry

of Education, yochien are for kids age 3 to 6, who attend four hours a day. Hoikuen,

supervised by the Ministry of Health and Welfare, takes infants and toddlers as

well. Even though hoikuen are considered less prestigious than yochien, tuition is

higher-about $45 a month, based on family income, vs. $37-because the children

are cared for all day.

DENMARK.Today working parents have a wide choice of public day care, and

nearly 70% of children from 3 to 6 attend preschools. Programs are funded and

operated by the government, although parents make a small contribution (average

amount: $140 a month).

A typical preschool has two teachers and one assistant for every 20 children.

Instructors receive three years of training in teachers’ colleges. Most schools open

at 6:30 A.M., and kids who arrive before 8 can have a breakfast of cereal and milk

or yogurt. Parents retrieve their children between 2:30 and 5 P.M. Danish youngsters

get an early introduction to egalitarianism. As a rule, preschoolers aren’t taught to

read or write, so as not to put at a disadvantage the 30% of children who do not

attend such programs. Another reason for the easygoing approach may be that

Danish educators believe children should be allowed to-as one of them put

it-“finish playing.”

FRANCE.The French pay starting preschool teachers $17,480 a year (vs. about $1 1,000 in the U.S.). . . Most children from 3 to 6 enroll in public classes run by the

Ministry of Education. To accommodate working parents, preschools offer activities

before and after school, during vacations, and on Wednesdays, when school is not

in session. Parents pay about $210 a year for this additional service.

The French government subsidizes two kinds of day care programs for the infants

and toddlers of working parents. Family day care, a collection of home-based

caregivers, costs from $1 1 to $1 8 a day. Larger day care centers charge somewhat less.

Caminiti S. Preschool around the globe. Fortune. October 21, 1991:148-158.

Noted by J.F.L., MD

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1992;90;771

Pediatrics

MICHAEL LEWIS, DOUGLAS S. RAMSAY and STEPHEN J. SUOMI