cortisol reactivity in young infants

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REVIEW

Cortisol reactivity in young infants

Jarno Jansen *, Roseriet Beijers, Marianne Riksen-Walraven,Carolina de Weerth

Department of Developmental Psychology, Behavioural Science Institute, Radboud University Nijmegen,PO Box 9104, 6500 HE, Nijmegen, The Netherlands

Received 27 April 2009; received in revised form 10 July 2009; accepted 10 July 2009

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3302. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

2.1. Selection of papers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3302.2. Presentation of results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3313.1. Infant age and cortisol reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3313.2. Stressor type and cortisol reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3313.3. Interaction of age and stressor type and cortisol reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3313.4. Studies reporting no cortisol reactivity in response to pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Psychoneuroendocrinology (2010) 35, 329—338

KEYWORDSInfant;Human;Stress;Reactivity;Cortisol;Review

Summary In this systematic review on empirical studies of cortisol reactivity to acute stressorsin infants, we specifically focus on the role of infant age in the early development of cortisolreactivity to stressors.

Our findings indicate that many psychological stressors do not provoke a cortisol reaction, butin response to physical stressors, the infant HPA-axis mostly reacts with a moderate increase inpost-stressor cortisol. Furthermore, for physical stressors only, cortisol reactivity effect sizesdecrease with infant age, although relatively little is known for infants older than 6 months.

These data provide more insight in the role of infant age in the development of cortisolreactivity in response to acute stressors. We discuss the role of caregivers in buffering the cortisolresponse to both psychological and physical stressors, and recommend extending the currentknowledge on infant cortisol reactivity.# 2009 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: +31 24 3612636; fax: +31 24 3612698.E-mail address: [email protected] (J. Jansen).

ava i lab le at www.sc ienced i rect .com

journa l homepage: www.e l sev ie r.com/locate/psyneuen

0306-4530/$ — see front matter # 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.psyneuen.2009.07.008


1. Introduction

Human infants are born with a well-functioning stress systemthat allows them to react to changes in the internal orexternal environment. Physiological measurements of infantstress reactivity have become of increasing interest in bothscience and society, as the nature of the stress reaction maypredict future development (reviews by Gunnar and Que-vedo, 2007; Beauchaine et al., 2007). When quantifyingstress reactivity, many studies have focused on reactivityof the hypothalamus—pituitary—adrenal axis (HPA-axis),which can be assessed by the pre- to post-stressor changein salivary cortisol concentrations.

In a review on psychological lab stressors in human adults,Dickerson and Kemeny (2004) show that stimuli characterizedby unpredictability, uncontrollability, and social-evaluativethreat result in the strongest cortisol reaction. However, it isunclear whether these findings are true for infants. In anextensive review, Gunnar et al. (2009) summarize the find-ings of studies on cortisol reactivity in children aged 0—18years. The authors describe how different types of stressfulstimuli affect cortisol reactivity, clearly showing that manytheoretically stressful stimuli do not result in a reaction.

In the present systematic review we extend previousfindings by expanding the number of papers and quantifyingthe effect sizes of the cortisol reaction in infants of up to 2years of age. By quantifying cortisol reactivity in response todifferent types of stressors and by looking at how effect sizeschange with the age of assessment, we give a more detailedaccount of how the magnitude of the cortisol reaction maychange in the first two postnatal years. Based on this detailedsummary of the empirical data on cortisol reactivity in younginfants, we will discuss the role of infant development instress reactivity, and call attention to existing gaps in knowl-edge and to opportunities for future research.

2. Methods

2.1. Selection of papers

A literature search in the WebSPIRS 5 databases of Medlineand Psychinfo was carried out in December of 2008 forEnglish-written papers published after 1978, the year inwhich the first study on the measurement of cortisol in salivawas presented (Walker et al., 1978). The papers were foundby combining the search terms ‘stress*’, ‘cortisol’, and ‘babyor infant’.

The initial search yielded 409 records, the abstracts ofwhich were read by the first and second author. Papers weredeemed suitable for inclusion in our dataset if they reportedpre- and post-stressor concentrations in salivary cortisol inresponse to a hypothetically stressful stimulus in infantsyounger than 24 months. Because of the focus on agechanges, data were only included if the age of cortisolassessment was restricted to a 2-month range (e.g., studiescombining data on children ages 4 months to 2 years wereexcluded; 3 studies excluded). Longitudinal studies thatassessed cortisol reactivity at multiple ages were includedif the age range of each individual assessment was 2 monthsor smaller. Furthermore, we only included studies in low risksamples (5 studies excluded) larger than 10 subjects (2

studies excluded). In studies presenting the potential effectof an intervention, only the results of the non-interventioncontrol group were included. Finally, studies presentingpreviously reported data were omitted (10 studies). The firstand second author then independently read the selectedpapers and noted the pre- and post-stressor cortisol concen-trations and standard deviations. If pre- or post-stressorconcentrations of salivary cortisol were not reported, orcould not be assessed because of missing information, thecorresponding author was contacted (up to two times) with arequest for further information. Papers were excluded if wedid not receive the requested information (4 studies wereexcluded for this reason).

The final data set consisted of 48 peer-reviewed studies,presenting 77 unique data pairs of pre- and post-stressorconcentrations of salivary cortisol at different ages. Thirtypapers present one data pair (set of pre- and post-stressormeans), 13 present two data pairs of either two differentstressors or two different ages, two present three data pairs,two present four data pairs, and one presents seven datapairs. A full list of all records can be obtained from the firstauthor.

2.2. Presentation of results

Salivary cortisol concentrations were noted as nmol/L (SIunits, see Jessop and Turner-Cobb, 2008). If values werepresented in mg, they were recalculated to nmol by dividingthe initial concentration by the molecular weight of cortisol(362.465), and multiplying the result with 1000. Standarddeviations were noted or recalculated from standard errorsbased on the available information on the sample size used.When cortisol scores were presented for different groupsseparately (e.g. based on method of delivery), these groupswere combined and a weighted average and standard devia-tionwere calculated if the groups did not significantly differ intheir response. If they did differ, scores from the control groupare presented. HPA reactivity was calculated as the pre- topost-stressor difference in concentrations of salivary cortisol,expressed inunits ofpre-stressordeviation (effect size).Effectsizes were calculated as Cohen’s d weighted for sample sizeðd ¼ ðððM2

post �M2preÞ=ð

ffiffiffi

2p

SD2 � ðn� 1ÞÞÞ=2n� 2Þ; Lipsey andWilson, 2001), where M indicates the sample mean, SD is thesample standard deviation, and n refers to the sample size.

Cohen’s d was calculated using only the pre-stressorstandard deviation and sample size. Because our initialexploration of the data indicated that deviation scoresoften approached or exceeded cortisol means, expressingthe effect size in terms of both pre- and post-stressordeviation would have confounded potential findings ondifferences between stressors, as a larger absoluteincrease in cortisol would be cancelled out by a corre-sponding increase in post-stressor deviation. By only takinginto account the pre-stressor standard deviations, varia-tion caused by differing responses to different stressortypes is avoided. Because the distribution of effect sizeswas positively skewed, we normalized the effect sized bycalculating r (r = d/H(d2 + 4)) for use in figures. In tablesand text referring to tables, Cohen’s d was used; in figuresand text referring to figures we used r. For further inter-pretation of these effect sizes, we employed Cohen’s rule-of-thumb (Cohen, 1988) of d � 0.2 for a small effect,

330 J. Jansen et al.


d � 0.5 for a moderate effect, and d � 0.8 for a largeeffect (or r � 0.1, 0.25, and 0.4, respectively).

For discussion purposes, age of assessment was clusteredinto three groups (0—3 months, 4—6 months, and 7—24months), based on the categorization in Gunnar et al. (2009)and the available data. The stimuli presented in the paperswere categorized based on stressor type. In accordance withthe classification of Gunnar et al. (2009), stressor type wasscored as ‘pain’ when it involved a serious breach of thephysical integrity of the subject (heelstick procedure or vac-cination), ‘mildphysical’ if it involvedamildphysical challenge(e.g. examination), ‘separation’ if it involved the temporaryunavailability of the mother (e.g. maternal separation), or‘anger/fear/novelty’ if it entailed a situation intended toprovoke an anger or fear response (e.g. response to frustrationor novelty). Please note that these categories are notmutuallyexclusive. Any physical stressor will have a psychological com-ponent to it, and many psychological stressors include somedegree of handling of the infant. This categorization wasmadebased on what component, in our opinion, was the main causeof a potential stress response. Each individual data pair is onlypresented in one stressor category.

3. Results

Table 1 presents an overview of pre- and post-stressor con-centrations of salivary cortisol and effect sizes d for the 48empirical studies included in this review. The papers areordered by stressor type and age. Table 1 is mainly a refer-ence table and will be used as the basis for all further figuresand tables.

3.1. Infant age and cortisol reactivity

Fig. 1 presents the effect sizes of the cortisol reactions of thereviewed studies, collapsed across stressor type, plottedagainst the infants’ age at the time of the study.

Changes in effect sizes over age become apparent by moreclosely inspecting the different age periods. During the firstthree postnatal months (first 13 weeks), the average cortisolreactivity effect size r is 0.39 and ranges from r = �0.1 tor = 0.9. In 26 out of 32 data pairs (81%) the effect size r is�0.1(indicating a small effect (Cohen, 1988); equivalent tod � 0.2).

Between 3 and 6 months of age (weeks 14—26), the meancortisol reactivity effect size r is 0.26, with a range of�0.1 to0.8. Thirteen out of 21 data pairs (62%) present an effect sizer � 0.1.

Between 6 and 12 months of age (weeks 27—52), theaverage effect size r is 0.07, with a range of �0.45 to 0.4.In six out of 11 data pairs (55%) the effect size r is �0.1.

Finally, between 12 and 24months of age (weeks 53—104),mean cortisol reactivity effect size r is 0.04, ranging from�0.2 to 0.5. The effect size r is �0.1 in four out of 13 of thepresented data pairs (31%).

Taken together, these findings indicate that cortisol reac-tivity appears to decrease with age, when data are collapsedacross stressor type. Because of this decrease, acute stres-sors provoke a small to moderate cortisol reaction only ininfants younger than 6 months. After 6 months of age, meancortisol reactivity effect sizes are lower than r = 0.1, signify-ing no effect.

3.2. Stressor type and cortisol reactivity

Table 2 presents themean effect sizes per stressor type (maincategories and sub-types), collapsed across age, togetherwith the percentage of studies showing more than a smalleffect according to Cohen (1988). As can be seen in Table 2,mild physical and painful stressors mostly result in a cortisolreaction (69% and 80% of the data pairs for mild physical andpainful stressors respectively), but the effect of separationon reactivity is more uncertain (63% reporting an effect).Fear (0%), anger (22%), and novelty (0%) stressors are unlikelyto provoke a cortisol reaction.

3.3. Interaction of age and stressor type andcortisol reactivity

The effects of different stressor types may change withage, and different stressor types have been utilized atdifferent ages. We therefore divided the data presented inFig. 1 by stressor type and plotted the results in Fig. 2a—d.

Fig. 2a presents 16 data pairs on cortisol reactivity inresponse tomild physical stressors. The effect ofmild physicalstressors on cortisol reactivity decreases with age. Out of 14studies on mild physical stressors in infants aged 13 weeks orless, 12 report an increase in post-stressor salivary cortisolconcentrations with an effect size r greater than 0.1 (79%).After 13 weeks of age, only a longitudinal study by Gunnaret al. (1996a) investigated theeffect of amildphysical stressoron cortisol reactivity, and found no effect of a physical exam-ination at 17 or 26 weeks.

Fig. 2b presents 35 data pairs on cortisol reactivity inresponse to a painful stimulus at different ages. Before 13weeks of age, 15 out of 17 (88%) data pairs show anincrease in post-stressor concentrations of salivary cortisol(r � 0.1); between 14 and 26 weeks of age, this is the casein 12 out of 13 (92%) data pairs. With age, the averageeffect size does decrease from 0.5 (range 0.1—0.9) innewborns to 0.3 (range 0.2—0.6) in infants aged 26 weeks.Between 26 and 104 weeks of age, only five data pairs existon cortisol reactivity to a painful stimulus, with varyingoutcomes.

Fig. 2c presents eight data pairs on cortisol reactivity inresponse to a separation at different ages. Across studies,mother—infant separation results in a small cortisol reaction.Two 30-min separations at 40 and 41 weeks of age provoked acortisol reaction, while one at 54 weeks did not. The strangesituation procedure did not provoke a cortisol reaction, withthe exception of one study (Van Bakel and Riksen-Walraven,2004) in which infants were subjected to an adapted versionof the strange situation and were acclimatized to the novelsurroundings prior to pre-stressor sample collection (as sug-gested by Gunnar et al., 2009).

As can be seen from the data presented in Fig. 2d, anger,fear, and novelty stressors rarely provoke a cortisol reaction,and this does not appear to change with age. Before 26 weeksof age, only one out of seven data pairs shows an effect(Haley and Stansbury, 2003; note that they utilize a 30-minacclimatization protocol prior to collecting a pre-stressorsample). After 26 weeks of age, only three out of 11 datapairs show a small increase in post-stressor cortisol.

Thus, the empirical data reflect a normative decrease incortisol responsiveness to painful andmild physical stressors in

‘Cortisol reactivity in young infants’ 331


Table 1 Pre- and post-stressor cortisol in response to acute stressors.

Authors + year Agea Stressor: mildphysical

N Pre-stressorb Post-stressorb Cohen’s d c

Catelin et al. (2005) 0 Weighing 15 3.2 (1.3) 5.4 (4.9) 1.69Davis and Emory (1995) 0 Examination 36 29.8 (34.8) 49.7 (35.9) 0.57Emory et al. (1996) 0 Examination 35 22.9 (22.6) 24.6 (18.5) 0.08Gunnar et al. (1991)d 0 Examination 22 15.4 (10.4) 25.1 (12.9) 0.93Gunnar et al. (1991)d 0 Examination 22 12.7 (12.9) 17.9 (11.7) 0.40Keenan et al. (2002)d 0 Examination 62 11.6 (11.0) 15.4 (13.8) 0.35Morelius et al. (2006)d 0 Diaper change 30 15.8 (41.2) 13.6 (22.9) �0.05Spangler and Scheubeck (1993)d 0 Examination 25 19.0 (11.7) 27.1 (18.2) 0.70Spangler and Scheubeck (1993)d 0 Examination+e 25 19.0 (11.7) 27.1 (18.2) 0.70De Weerth and Buitelaar (2007)d 2 Examination 108 10.4 (4.7) 17.3 (9.1) 1.47Morelius et al. (2006)d 2 Diaper change 30 8.2 (17.5) 9.9 (17.3) 0.10Gunnar et al. (1996a)d 9 Examination 18 9.9 (7.0) 19.9 (10.5) 1.43Prudhomme White et al. (2000) 9 Examination 20 5.0 (9.9) 9.1 (8.6) 0.41Albers et al. (2008) 12 Bathing episode 64 6.8 (7.2) 9.9 (8.0) 0.43Gunnar et al. (1996a)d 17 Examination 18 13.2 (7.0) 13.0 (8.2) �0.03Gunnar et al. (1996a)d 26 Examination 18 11.9 (7.0) 11.9 (7.0) 0

Authors + year Agea Stressor: pain N Pre-stressorb Post-stressorb Cohen’s d c

Gunnar et al. (1991)d 0 Heelstick 18 17.1 (9.4) 32.0 (16.4) 1.59Gunnar et al. (1991)d 0 Heelstick 18 13.8 (9.4) 40.0 (22.2) 2.79Gunnar et al. (1995) 0 Heelstick 48 11.0 (5.5) 34.2 (22.1) 4.22Keenan et al. (2002)d 0 Heelstick 64 17.1 (19.3) 22.6 (22.1) 0.28Rice and Records (2008) 0 Heelstick 16 33.4 (19.8) 30.0 (10.3) �0.17Takai-Kawakami et al. (1995) 0 Heelstick 34 22.6 (16.8) 38.1 (25.1) 0.92De Weerth and Buitelaar (2007)d 8 Vaccination 81 12.0 (6.5) 17.1 (7.1) 0.78Taylor et al. (2000) 8 Vaccination 76 1.3 (1.3) 2.4 (NR) 0.85Davis and Granger (2009)d 9 Vaccination 22 9.4 (6.5) 22.1 (10.4) 1.95Gunnar et al. (1996a)d 9 Vaccination 83 12.1 (3.9) 25.4 (12.4) 3.41Lewis and Ramsay (1995a)d 9 Vaccination 64 19.9 (15.4) 28.4 (15.4) 0.55Lewis and Thomas (1990)d 9 Vaccination 20 20.4 (11.6) 37.2 (NR) 1.45Lewis et al. (1992) 9 Vaccination 20 20.4 (13.5) 33.1 (16.9) 0.94Miller et al. (2004)d 9 Vaccination 161 5.0 (4.4) 14.3 (NR) 2.11Ramsay and Lewis (1994)d 9 Vaccination 40 20.4 (11.9) 33.4 (13.5) 1.09Wilson et al. (2003)d 9 Vaccination 27 8.3 (6.6) 16.8 (9.7) 1.29Morelius et al. (2009) 13 Vaccination 98 9.1 (28.6) 11.0 (38.3) 0.07Braarud and Stormark (2006) 14 Vaccination 37 4.2 (1.1) 6.5 (1.1) 2.09Gunnar et al. (1996a)d 17 Vaccination 83 11.9 (5.5) 18.2 (7.2) 1.15Lewis and Ramsay (1995a)d 17 Vaccination 64 13.0 (13.2) 25.4 (13.2) 0.94Lewis and Thomas (1990)d 17 Vaccination 25 26.5 (18.2) 27.6 (NR) 0.06Miller et al. (2004)d 17 Vaccination 152 6.1 (5.0) 12.3 (NR) 1.24Wilson et al. (2003)d 17 Vaccination 27 0.8 (3.8) 12.7 (5.8) 3.13Lewis et al. (1993)d, f 20 Vaccination 31 23.5 (17.7) 27.0 (11.9) 0.20Lewis et al. (1993)d, g 20 Vaccination 30 26.8 (27.6) 40.0 (31.5) 0.48Davis and Granger (2009)d 26 Vaccination 19 5.5 (3.6) 11.0 (4.8) 1.53Gunnar et al. (1996a)d 26 Vaccination 83 14.3 (8.6) 17.1 (6.6) 0.33Lewis and Ramsay (1995a)d 26 Vaccination 64 11.6 (11.0) 19.3 (13.2) 0.70Lewis and Thomas (1990)d 26 Vaccination 24 19.9 (15.7) 25.4 (NR) 0.35Ramsay and Lewis (1994)d 26 Vaccination 40 15.4 (10.5) 24.8 (10.2) 0.90Ball et al. (2006) 28 Vaccination 43 7.4 (7.2) 6.9 (7.2) �0.07Davis and Granger (2009)d 52 Vaccination 22 8.3 (6.5) 12.4 (12.9) 0.63Gunnar et al. (1996b) 65 Vaccination 72 8.3 (4.1) 8.3 (4.1) 0Lewis and Ramsay (1995b) 78 Vaccination 33 16.0 (10.5) 19.3 (16.0) 0.31Davis and Granger (2009)d 104 Vaccination 22 5.0 (3.9) 4.4 (3.9) �0.15

Authors + year Agea Stressor: separation N Pre-stressorb Post-stressorb Cohen’s d c

Gunnar et al. (1992) 40 30-min separation 38 11.3 (4.8) 13.8 (NR) 0.52Larson et al. (1991) 41 30-min separation 27 8.8 (4.4) 12.4 (5.8) 0.82



the first 26 weeks after birth, but more studies are needed toclarify the normative response after 26 weeks of age. Incontrast, age-related changes in cortisol reactivity in responsetomother—infant separations are more unclear, as the studiesare few and the results inconclusive. Fear/anger/noveltystressors appear to have no effect on cortisol reactivity.

3.4. Studies reporting no cortisol reactivity inresponse to pain

Even though most studies report that painful stressors resultin a cortisol reaction in infants, some studies do not find this

increase in post-stressor cortisol concentrations. In this sec-tion, we will discuss these studies and evaluate whethermethodological factors could be responsible for the null-findings presented in these studies.

Sampling time can be an important factor determining themagnitude of the response found. It has been empiricallyshown that in response to a vaccination, salivary cortisolconcentrations increase to peak levels at 20—25 min post-vaccination in the majority of the infant population (Ramsayand Lewis, 2003). Indeed, most studies referred to in thisreview have collected post-stressor samples at approxi-mately 20—25 min after onset of the stressor. However, of

Table 1 (Continued )

Authors + year Agea Stressor: separation N Pre-stressorb Post-stressorb Cohen’s d c

Spangler and Grossmann (1993) 52 Strange situationh 41 11.6 (5.5) 13.0 (6.3) 0.25Spangler and Schieche (1998) 52 Strange situationh 106 6.9 (6.0) 6.9 (7.7) 0Gunnar and Nelson (1994)d 54 30-min separation 49 11.3 (5.8) 10.8 (5.8) �0.09Gunnar et al. (1989)d 57 Strange situationh 66 13.8 (4.5) 15.2 (4.5) 0.31Van Bakel and Riksen-Walraven (2004) 65 Strange situation i 85 5.2 (2.5) 8.0 (6.1) 1.12Nachmias et al. (1996)d 78 Strange situationh 77 11.9 (29.1) 11.6 (26.6) �0.01

Authors + year Agea Stressor: anger N Pre-stressorb Post-stressorb Cohen’s d c

Lewis and Ramsay (2005)d 17 Frustration 56 19.3 (9.7) 19.6 (8.6) 0.03Azar et al. (2007) 19 Frustration 126 7.2 (5.5) 6.6 (5.5) �0.11Haley and Stansbury (2003) 24 Still face j 43 6.1 (5.5) 9.1 (11.9) 0.55Blair et al. (2006) 26 Novelty/frustration 1292 5.5 (4.9) 6.2 (5.3) 0.14Huot et al. (2004) 26 Frustration 85 14..6 (11.9) 14.8 (11.2) 0.02Lewis and Ramsay (2005)d 26 Still face j 84 15.4 (9.7) 16.6 (11.3) 0.12Schuetze et al. (2008) 30 Frustration 40 8.3 (9.4) 6.6 (6.3) �0.18Gunnar et al. (1989)d 39 Novelty/frustration 66 11.6 (6.7) 14.1 (4.5) 0.37Blair et al. (2008) 65 Novelty/frustration 1292 5.3 (5.8) 6.5 (7.6) 0.21

Authors + year Agea Stressor: fear N Pre-stressorb Post-stressorb Cohen’s d c

Nachmias et al. (1996)d 78 Strange environment 77 9.7 (21.8) 11.0 (19.4) 0.06Ouellet-Morin et al. (2008) 83 Strange environment 418 10.8 (8.3) 10.2 (6.9) �0.07Fortunato et al. (2008) 104 Strange environment 111 6.3 (6.6) 4.1 (3.0) �0.33Buss et al. (2004)d 104 Stranger approach 58 9.7 (13.8) 10.2 (22.3) 0.04Buss et al. (2004)d 104 Risk roomk 50 9.4 (13.0) 7.7 (14.3) �0.13

Authors + year Agea Stressor: novelty N Pre-stressorb Post-stressorb Cohen’s d c

Oberlander et al. (2008) 13 Processing task l 45 9.4 (8.0) 10.8 (14.1) 0.18Grunau et al. (2004) 35 Novel toy play 22 5.2 (2.6) 5.8 (2.6) 0.23Hertsgaard et al. (1992) 43 First swim 31 8.8 (4.6) 4.1 (4.6) �1.02Gunnar and Nelson (1994)d 52 ERP testm 49 9.7 (5.8) 9.9 (5.8) 0.03a Age is expressed in weeks. Age = 0 indicates newborn infants.b Pre- and post-stressor cortisol concentrations in nmol/L; cortisol values indicate means (SD).c For Cohen’s d, d > 0.2, >0.5, and >0.8 indicate a small, moderate, and large effect, respectively.d A number of studies report more than 1 data pair. These studies are referred to more than once in this table.e Examination+ refers to a physical exam and the attachment of Heart Rate monitoring equipment.f American infants, in the same study Japanese immigrant infants were studied.g Japanese infants, in the same study American infants were studied.h Strange situation (Ainsworth et al., 1978) is a 20-min lab situation of increasing stressfulness, including two short mother—infant

separations.i Modified strange situation, including fear-evoking stimuli.j The still face paradigm (Tronick et al., 1978) is a face-to-face mother—infant interaction, characterized by alternating episodes of maternal

availability and unavailability.k In the risk room, the infant was challenged by the experimenter to perform a series of challenging tasks.l During the processing task (Mayes et al., 1995), carried out in a laboratory environment, infants were required to look at a neutral stimulus

presented on a TV screen.m In the ERP test, electrodes were attached to the infant’s head before subjecting the infant to a series of visual stimuli.



the studies presenting null-findings, two report collectinginfant saliva at atypical time points. First, Rice and Records(2008) collected newborn saliva at 5 and 20—25 min after theheelstick procedure. Because the heelstick procedure waspreceded by an initial examination and by connecting equip-ment intended to measure heart rate and oxygen saturation,it is possible that pre-stressor cortisol concentrations do notreflect a baseline cortisol measure, but a cortisol reaction tohandling. Support for this idea comes from the fact that thepre-stressor cortisol concentration reported in this study(33.4 � 19.8 nmol/L) is higher than most post-stressor con-centrations reported in other studies. Second, Ball et al.(2006) report collecting saliva samples in 28-week oldsbefore and 10 min after a vaccination. It is therefore likelythat Ball et al. (2006), by sampling only 10 min post-vaccina-tion, missed the peak cortisol response in their population.

As the effect size of a reaction is expressed in terms ofstandard deviations, a very high deviation score will reducethe effect size of a response. In the study by Morelius et al.(2009), 13-week-old infants were found to respond to a

vaccination with a small (2 nmol/L) increase in salivarycortisol concentrations. This absolute increase is comparableto the 2.3 nmol/L increase reported in Braarud and Stormark(2006) in 14-week-old infants. However, in contrast with thelarge effect size reported by the latter (Cohen’s d = 2.09),the effect size reported by Morelius et al. (2009) is only 0.07,because the reported deviation score of 28.6 is more thanthree times as large as the reported average concentration.We could find no methodological reasons why the deviationscores presented are this large, as many procedures pre-sented have been utilized in previously published papers.Interestingly, the deviation scores reported in Morelius et al.(2006) are also very high, as are salivary cortisol rangespresented in Morelius et al. (2004). Because Morelius andcolleagues report analyzing their saliva samples with an in-house immunoassay (Nelson et al., 2001), it may be that thehigh deviation scores are associated with this particularmethod. In a recent review, Hansen et al. (2008) presentsseveral methodological factors associated with variation insalivary cortisol, and they urge that assay validity should beconfirmed in different, independent labs.

At 17 and 20 weeks of age, two studies have reported thatvaccinations do not result in a relevant cortisol reaction(Lewis and Thomas, 1990 and Lewis et al., 1993, respec-tively). This is surprising as, using the same methodology andage-groups, these researchers have reported cortisol reac-tions to vaccinations in other studies (e.g. Lewis and Ramsay,1995a; Ramsay and Lewis, 1994). The only potential cause ofthe lacking increase in post-vaccination cortisol is the rela-tively high pre-stressor cortisol concentration. Variousauthors, first and foremost Lewis and Ramsay themselves,report how in response to painful stressors, the infant cortisolreaction may be subject to the law of initial values (Lewis andRamsay, 1995a). The LIV (Wilder, 1956; Myrtek and Foerster,1986; Jin, 1992) states that the magnitude of any physiolo-gical reaction is negatively correlated with the initial value.While proposed on an individual level, the law of initial valuealso applies on a population level for the infant cortisolreaction to painful stressors (Jansen et al., unpublisheddata). Therefore, the lower effect sizes reported in Lewisand Thomas (1990) and Lewis et al. (1993) may be the resultof higher pre-stressor cortisol concentrations.

Finally, the null findings reported by Gunnar et al. (1996b)in 15-month-old infants, and Davis and Granger (2009) in 2-year-old children are difficult to interpret. In these long-itudinal studies, the authors report significant cortisol reac-tivity at younger ages. It may therefore be that, after 1 yearof age, the cortisol reaction to painful stressors is reduced,although more studies are needed to confirm this.

4. Discussion

In this review, we set out to quantify age-related changes incortisol reactivity in response to different stressor types ininfants between 0 and 24 months of age. We found that thenormative response to stressors decreases with age. Further-more, both painful and mild physical stressors result in astronger reaction than stressors subjecting the infant tomaternal separations, or stressors aimed at evoking a fearor anger response. The findings on cortisol reactivity effectsizes in response to psychological stressors (mother—infantseparations and anger/fear/novelty) mirror the data pro-

Figure 1 Effect sizes of studies on infant cortisol reactivity toacute stressors at different ages. Line indicates cut-off for smalleffect size (Cohen, 1988). For aesthetic reasons, the study byHertsgaard et al. (1992) on cortisol reactivity to novelty(r = �0.45) was not included in the figure.

Table 2 Average cortisol reactivity effect sizes (d) per stressortype.

# Data pairs Mean d # d � 0.2 (%)

Mild physical 16 0.62 11 (69)

Examination 13 0.72 10 (77)Diaper change 2 0.02 0 (0)Bathing routine 1 0.43 1 (100)

Pain 35 1.10 28 (80)

Heelstick 6 1.60 5 (83)Vaccination 29 0.98 23 (79)

Separation 8 0.37 5 (63)

30 min separation 3 0.42 2 (67)Strange situation 5 0.34 3 (60)

Anger 9 0.13 2 (22)

Fear 5 �0.09 0 (0)

Novelty 4 �0.15 0 (0)

Text in bold refers to main stressor types; text in italics indicatesstressor subtypes.



vided by Gunnar et al. (2009), indicating that, on average,these stimuli mostly do not provoke a cortisol reaction inyoung infants, irrespective of age.

In the last 30 years, 48 studies have been published thatpresent unique data on cortisol reactivity in response to apotentially stressful stimulus in infants younger than 2 yearsof age. Although this appears to be a substantial amount, wenote that these studies have mostly been clustered aroundcertain ages for each different stressor type. Studies on thecortisol response to physical stressors (both mild physical andpainful) have focused on infants younger than 6 months,while studies on the effects of mother—infant separationhave only been done in infants aged between 9 and 18months. Only studies focusing on the cortisol reaction inresponse to anger/fear/novelty have made use of a broaderage range (3—24 months). In addition to the proposal byGunnar et al. (2009) that the factors triggering a cortisolresponse need to be further investigated, we therefore urgethat we expand the age range at which infants are subjectedto different stressor paradigms.

Most psychological stressors do not provoke a mean corti-sol reaction for the group as a whole. However, this does notimply that the measurement of the cortisol reaction inresponse to these stimuli is redundant. As Gunnar and col-leagues have shown in several elegant studies on the cortisolreaction to psychological stressors (e.g. Hertsgaard et al.,1995; Nachmias et al., 1996; Gunnar et al., 1996b), while thewhole group does not react with an increase in post-stressor

cortisol, certain individuals do show a cortisol response.These individual differences in infant cortisol reactivity inresponse to psychological stressors, in turn, bring to lightpotential risk factors that may adversely affect infant devel-opment. As an example, Nachmias et al. (1996) show thatwhile the exposure of 18-month-old infants to a strangeenvironment does not result in a cortisol reaction at thegroup level, fearful individuals in an insecure attachmentrelationship do show an increase in post-stressor cortisol.

In contrast with psychological stressors, younger infantsshow a considerable cortisol reaction in response to physicalstressors. With age, this response decreases in magnitude.Although the scarcity of data after 6 months of age calls forsome caution, it is interesting to theorize on the cause of thisnormative decrease. In order to address this issue, we needto shortly introduce the infant behavioral response to stress.In response to an acute stressor, human infants are likely tofuss or cry, signaling their distress to caregivers and invitingsoothing (for an excellent review on the function of infantcrying, read Zeifman, 2001). Studies have suggested thatwhile cortisol reactivity in response to physical stressorsdecreases with age, the crying response does not (e.g. Lewisand Ramsay, 1995a; reviewed by Gunnar and Donzella, 1999).

The apparent dissociation between the cry and cortisolresponse to a stressor, beginning after approximately 26weeks of age, has led to a hypothesis of a developmentalperiod of reduced HPA-reactivity (Tarullo and Gunnar, 2006;Gunnar and Quevedo, 2007). Indeed, Lashansky et al.’s

Figure 2 Effect sizes of studies on infant cortisol reactivity to acute stressors at different ages and by stressor type. Line indicatescut-off for small effect size (Cohen, 1988). For aesthetic reasons, the study by Hertsgaard et al. (1992) on cortisol reactivity to novelty(r = �0.45) was not included in (d).



(1991) findings suggest that the infant response to ACTH maybe reduced after 6 months of age, but this study has not yetbeen replicated. Furthermore, while cortisol reactivity isapparently reduced after 6 months of age, this may bedue to the previously noted association between stressortype and infant age. Before 6 months of age, in most studiesthe infants are subjected to a physical stressor, while after 6months of age, psychological stressors are more frequentlyutilized. Because the studies reviewed in this paper show thatcortisol reactivity is greater in response to physical thatpsychological stressors, this age-stressor bias, rather thana period of reduced cortisol reactivity, may to a large extentexplain the reduction in cortisol reactivity. This is furthersupported by the few studies that explore cortisol reactivityin response to painful stressors after 1 year of age. Althoughthe available data are limited, 2 out of the 4 studies find asmall to moderate increase in cortisol, suggesting that theinfant HPA-axis is capable of responding to stressors with asubstantial cortisol reaction.

A more likely explanation may therefore be that a broad-ening behavioral repertoire of the infant reduces thepotency of many physical stressors to provoke a (significant)cortisol reaction. The expansion of the infant’s behavioralcapabilities could explain the developmental dissociationbetween crying and HPA-reactivity: it would not necessarilymean that the HPA-axis is hypo-reactive, but that the beha-vioral response is more effective in regulating the stressor.As there is a substantial lag between the onset of the stressorand the peak cortisol response, an effective behavioralresponse may significantly reduce the magnitude of theHPA-axis reaction. The sympathetic (autonomic nervoussystem–—ANS) stress response is much faster in its onsetand is therefore less likely to be buffered by the behavioralresponse. Indeed, a recent study byDavis andGranger (2009)suggests that both the ANS-activity marker salivary alphaamylase (sAA, see Nater and Rohleder, 2009; Rohleder andNater, 2009) and cortisol increase after a painful stimulus at26weeks of age. In contrast, at 52 and 104weeks of age, HPA-reactivity decreases to non-significant levels (although at 52weeks of age, the effect size d indicates a moderateresponse, but note the sample size in Table 1), while sAAis significantly higher 5 min after the stimulus when com-pared to the baseline samples. These stimulating findingsboth renew the need for a careful re-examination of thenormative development of stress reactivity in response tophysical stimuli, focusing on a broader spectrum of reactiv-ity measures, and highlight the value of using a physicalstressor to study regulative processes.

By expanding the findings on the stress reaction to physicalstressors, both by broadening the age range and by studyingdifferent stress reactive systems (ANS, HPA, behavior), wemay gain new insights and a deeper understanding of thenormative development of stress reactivity, and reach newinsights in the development of cortisol reactivity in particu-lar. Although national immunization schedules limit the avail-able sampling ages for the reaction to vaccinations,differences between countries may allow for a broadeningof the age range. Cross-sectional studies on the response tonon-scheduled vaccinations (e.g. preventative vaccinationbefore intercontinental travel) may allow for a further broad-ening of the age range. In addition, expanding our knowledgeon the basic parameters underlying the infant cortisol

response (as proposed by Gunnar et al. (2009) may resultin novel physical stressors that are both ethically acceptableand can be carried out in infants of all ages.

Finally, the study of how infants regulate stress (i.e. theprocesses by which they seek to control the stress reaction)has not yet been given sufficient attention in the literature.Studying infant stress regulative processes is of crucial impor-tance for improving our understanding of infant development(Posner and Rothbart, 2003; Crockenberg and Leerkes, 2006;Crockenberg et al., 2008). For studying regulation, the use ofphysical stressors carries two benefits. First, physical stimuliprovoke a stress reaction in most subjects, and thereforeprovide a situation that requires regulation. Second, and incontrast with psychological stressors, the source of stress isnot directly related to the intended source of regulation. It isdifficult to study infant-caregiver co-regulation of theinfant’s stress reaction if the caregiver is also (partly) thesource of stress (such as during the still face paradigm orstrange situation procedure, where the unavailability of thecaregiver is the main source of stress). Subjecting the infantto a physical stressor permits the caregiver to assume anindependent role as co-regulator of the infant’s distress.Studying age-related changes in stress reactivity in responseto physical stressors can therefore allow us to investigateboth internal (self-) and external (caregiver) regulative pro-cesses.

In sum, our data show that the infant cortisol reaction tostressors decreases with age, but also indicates that ourknowledge of infant stress reactivity is far from complete.Further studies on infant cortisol stress reactivity, at broaderage ranges, including different physiological and behavioralreactions, and making use of different, possibly novel, stres-sors, are much needed.

Role of the funding source

This research was supported by the Netherlands Organizationfor Scientific Research (NWO), Grant number 452-04-320; theNWO had no further role in the writing of this review.

Conflict of interest

The authors have no conflicts of interest to declare.

Acknowledgments

We thank all the authors who replied to our requests foradditional data or further information on their findings.

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Further readings

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Blair, C., Granger, D.A., Kivlighan, K.T., Mills-Koonce, R., Willoughby,M., Greenberg, M.T., Hibel, L.C., Fortunato, C.K., et al., 2008.Maternal and child contributions to cortisol response to emotional



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