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ARTICLE

Antenatal Betamethasone and Fetal Growth in

Prematurely Born Children: Implications for

Temperament Traits at the Age of 2 Years

Anu-Katriina Pesonen, PhDa, Katri Ra¨ikko¨nen, PhDa, Aulikki Lano, MD, PhDb, Outi Peltoniemi, MD, PhDc, Mikko Hallman, MD, PhDc, M. Anneli Kari, MD, PhDb

aDepartment of Psychology, University of Helsinki, Helsinki, Finland;bHospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland; cDepartment of Pediatrics, Biocenter Oulu, University of Oulu, Oulu, Finland

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject

Previous randomized, controlled trials on antenatal betamethasone have examined child psychiatric profiles but not the behavior at a more general level.

What This Study Adds

We showed that duration of exposure is associated with child impulsivity at the age of 2 and that fetal growth as a continuous measure predicts temperament traits within a premature sample.

ABSTRACT

OBJECTIVE.We explored whether repeated dose of antenatal betamethasone and vari-ation in intrauterine growth of prematurely born children predict temperament characteristics at the age of 2 years.

PATIENTS AND METHODS.The patients (n⫽142) were prematurely born children (mean gestational age: 31.0 weeks; range: 24.6 –35.0 weeks) who participated in a random-ized and blinded trial testing the effects of a repeated dose of antenatal betametha-sone in imminent preterm birth. Fetal growth was estimated as weight, length, and head circumference in SDs according to Finnish growth charts. Parents assessed their toddlers’ temperament with 201 items of the Early Childhood Temperament Ques-tionnaire (mean child corrected age: 2.1 years).

RESULTS.No significant main effects of repeated betamethasone on toddler tempera-ment existed. However, a significant interaction between study group and duration of exposure to betamethasone emerged; those exposed to a repeated dose for⬎24 hours before delivery were more impulsive. One-SD increases in weight, length, and head circumference at birth were associated with 0.14- to 0.19-SD lower levels of negative affectivity (fearfulness, anger proneness, and sadness); 1-SD increases in length, weight, and head circumference at birth were associated with 0.14- to 0.18-SD higher levels of effortful control (self-regulation).

CONCLUSIONS.Repeated antenatal betamethasone did not induce alterations in toddler temperament. The results, however, suggest that a longer duration of exposure is associated with higher impulsivity scores. Regardless of betamethasone exposure, slower fetal growth exerted influences on temperament. Our findings indicate prenatal programming of psychological development and imply that more attention is needed to support the development of infants born at the lower end of the fetal growth distribution.Pediatrics2009;123:e31–e37

A

LTHOUGH THE BENEFITS of a single course of antenatal corticosteroid treatment are evident in decreasing morbidity of preterm infants,1 the effects of repeat courses of corticosteroids are far less clear.2–4 In recent

randomized, controlled trials, repeat courses of antenatal corticosteroids have reduced the risk for respiratory distress syndrome2 and severe lung disease2,4 but had no impact on other neonatal morbidities.4 We have demonstrated

previously that a single repeat dose of betamethasone increased the risk for respiratory distress syndrome requiring surfactant treatment.3Earlier studies have also observed reductions in birth weight or in head circumference among

children exposed to weekly repeat courses of corticosteroids.2,4

Follow-up data on humans have only recently allowed exploration of the long-term outcomes of repeat courses of corticosteroids. Exposure to repeat betamethasone has not been shown to affect postnatal growth or child health status at 2 to 3 age-corrected years.5–7 With regard to cognitive and behavioral development, children exposed to

repeat betamethasone have not differed in cognitive abilities from children in a placebo group at the corrected ages of 2 and 3 years,7,8nor did differences emerge in behavior problems in early childhood, except that children exposed

www.pediatrics.org/cgi/doi/10.1542/ peds.2008-1809

doi:10.1542/peds.2008-1809

This trial has been registered at www.clinicaltrials.gov (identifier 00295464).

Key Words

birth weight, corticosteroids, developmental outcomes, prematurity, randomized, controlled trial

Accepted for publication Sep 22, 2008

Address correspondence to Katri Ra¨ikko¨nen, PhD, University of Helsinki, Department of Psychology, PO Box 9, 00014 Helsinki, Finland. E-mail: katri.raikkonen@helsinki.fi

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to repeat antenatal betamethasone showed more atten-tion,5hyperkinetic,8and aggression8problems than

chil-dren in the placebo group.

In this study, we focused on more detailed aspects of behavior in the context of daily functioning. Tempera-mental profiles of 2-year-old children exposed to repeat antenatal betamethasone were compared with profiles of children belonging to a placebo group. By tempera-ment, we refer to biologically based, individual differ-ences in children’s emotional reactivity and self-regula-tion, which manifest as various behaviors in different daily situations.9,10In particular, emotional reactivity

re-fers to excitability, responsivity, or arousability of behav-ioral and physiologic systems of the organism, whereas self-regulation refers to neural and behavioral processes that modulate the underlying reactivity.9 There is a

growing body of evidence showing that certain early temperament characteristics, namely, high levels of emotional reactivity and low levels of self-regulation,11,12

form a major risk for later psychopathology.11–15

We hypothesized that exposure to repeat betametha-sone would be associated with traits reflecting higher emotional reactivity and lower self-regulation. We also explored whether a longer delay from treatment to de-livery, that is, longer duration of exposure, would be associated with temperament outcomes. A secondary aim was to test whether fetal growth in weight, length, and head circumference in prematurely born children would predict temperament outcome and whether these associations would be explained by repeat betametha-sone exposure.

METHODS

Experimental Betamethasone

All of the participants (n⫽178) came from the Helsinki University Central Hospital, which is 1 of 8 hospitals participating in a multicenter, blinded, randomized clin-ical trial on a repeated dose of antenatal betamethasone.3

This study aimed at investigating whether a single addi-tional dose of betamethasone exposure given in immi-nent preterm birth would improve the proportion of infants surviving without respiratory distress syndrome or severe intraventricular hemorrhage.3The participants

in our study represented 71% of the original sample. For the 7 other recruiting hospitals, together representing 29% of the original sample, we lacked the necessary resources for measuring temperament at the age of 2 years. Pregnant women with a heightened risk for im-minent premature delivery were recruited from May 2001 to March 2005.3These women were eligible for the

study if they had received their first complete course of prenatal corticosteroid treatment (12 mg of betametha-sone given twice) ⱖ7 days before trial entry, with pre-term birth before 34 weeks of pregnancy being immi-nent. The inclusion criterion for the second course of corticosteroid/placebo was elective delivery or a very high risk for spontaneous delivery within 48 hours. Ex-clusion criteria were maternal long-term systematic cor-ticosteroid therapy, clinical chorioamnionitis, or lethal disease of the fetus. The eligible mothers received either

one 12-mg dose of betamethasone or isotonic saline administered intramuscularly.

Of the 178 children, 167 survived. From this sample, we recruited all of the traceable mother-infant pairs who lived within a reasonable distance of the research hos-pital (n⫽159, 95% of survivors;n⫽1 not traceable;n

7 lived too far away) to the clinical follow-up at 2 years of corrected age. Of those invited, 151 (95%) partici-pated, and 142 (94% of participants and 89% of those invited) returned the temperament questionnaire. Non-participation in the study, compared with all of the survivors, was unrelated to body size at birth or gesta-tional length (P⬎.11) but was related to lower educa-tional attainment of the mother (␹2⫽12.9;P.01; for other maternal characteristics, all of the P values were

⬎0.23; data not shown).

As in the original study,3women in the present

ex-perimental group were older on average compared with women in the placebo group. Unlike in the original study, however, they had multiple pregnancies less often (Table 1). One mother in each group had diabetes mel-litus and gestational diabetes. No significant differences were present in neonates (Table 2). Severe retinopathy of prematurity requiring laser treatment was observed in 2 children in the repeated betamethasone study group (␹2⫽2.8;P.25). There were significantly more post-natal dexamethasone-treated children in the repeat be-tamethasone group (P⫽.01). At the 2-year follow-up, the groups did not differ significantly with regard to medical history after the discharge from the NICU (Table 2). Three children, 1 in the experimental and 2 in the placebo group, were diagnosed as having hemiplegic cerebral palsy (␹2 ⫽0.13; P.72), and 4 children in both groups had gastroesophageal reflux (␹2⫽0.14;P⫽ .73).

Study Variables

Birth- and pregnancy-related variables, as well as vari-ables associated with growth and health at the 2-year follow-up, were derived from hospital records and clas-sified as described elsewhere.3Gestational age was

as-sessed from the mother’s last menstrual period and was confirmed with ultrasonography before 20 weeks of ges-tation. We used Finnish growth charts16 in calculating

TABLE 1 Demographic Characteristics and Major Morbidity of Pregnant Women

Characteristic Repeated

Betamethasone

Placebo P

Pregnant women,N 52 57

Age, mean (SD), y 33.6 (5.9) 31.2 (6.1) .04

PROM, % 42.3 38.6 .70

Preeclampsia, % 23.1 19.3 .65

Vaginal delivery, % 42.3 38.6 .70

Multiple pregnancy, % 15.4 35.1 .03

Maternal education, % .77

Elementary school 5.8 7.0

High school/community college 59.6 54.4

University degree 34.6 38.6

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weight, length, and head circumference at birth in con-tinuous SD units. Growth at 2 years of corrected age was measured during the clinical visit. We calculated SD units according to World Health Organization growth charts.17

To measure toddler temperament traits, we used the Early Child Behavior Questionnaire,18 which is

com-posed of 201 items describing child behavior in different daily situations. Parents were asked to assess how often during the past 2 weeks their child had behaved or reacted in the way described (1⫽never to 7⫽always). The temperament scales by Rothbart form a “gold stan-dard” in temperament research because of their excel-lent psychometric properties. The Early Child Behavior Questionnaire is composed of 18 fine-grained dimen-sions that are presented in Table 3 with short explana-tions. These 18 dimensions can be grouped into sum-mary scales that characterize the 3 major components of child temperament that are widely recognized in child temperament research (Table 3).18 The extraversion

summary scale consisted of activity level, high-intensity pleasure, impulsivity, positive anticipation, and sociabil-ity. The negative affectivity summary scale included dis-comfort, fear, frustration, motor activity, perceptual sen-sitivity, sadness, shyness, and soothability (as reversed scale). The third summary scale, effortful control, was composed of attention focusing, attention shifting, cud-dliness, inhibitory control, low-intensity pleasure, and motor activity, frustration, and soothability after first being reversed.

Statistical Analyses

We used multiple linear regression analyses to test whether exposure to repeat antenatal betamethasone versus placebo predicted temperament outcome. An in-teraction between exposure (repeat betamethasone ver-sus placebo) and duration of exposure (both as binary 0 ⫽ ⱕ24 hours, 1 ⫽ ⬎24 hours, and as a continuous variable) was applied to determine whether duration of exposure mattered in temperament outcome. Linear re-gression analyses were also used to test whether weight, length, and head circumference at birth in SD units predicted temperament outcome and whether repeat antenatal betamethasone explained any of the potential associations. We adjusted for maternal age and educa-tion, child gender, gestational age, age at assessment, multiple pregnancy, postnatal corticosteroid treatment, intraventricular hemorrhage, bronchopulmonary dys-plasia, and neonatal sepsis in all of the analyses; in the analyses of repeated betamethasone, we also adjusted for SDs in birth weight; in the analyses of fetal growth effects, we also adjusted also for repeated dose of beta-methasone. We reran the analyses with additional ad-justing for number of hospitalizations, need for contin-uous medication, and asthma and excluding children with hemiplegic cerebral palsy (n⫽2) and a child with dysmorphic features and developmental delay (n⫽1).

RESULTS

Repeated Betamethasone

Temperament profiles of children exposed to repeat an-tenatal betamethasone and placebo did not differ signif-icantly (all Pvalues ⬎.07; Table 4). Analyses to deter-mine whether duration of exposure mattered for temperament outcome revealed that children exposed to repeat betamethasone for ⬎24 hours before delivery were more impulsive at the age of 2 years than were

TABLE 2 Characteristics and Major Morbidity of Children

Characteristic Repeat

Betamethasone (n⫽62)

Placebo (n⫽80)

P

At birth

Girls, % 50.0 37.5 .17

Gestational age, mean (SD), wka 30.7 (2.6) 31.2 (2.6) .23

Birth weight, mean (SD), gb 1485.7 (494.5) 1613.1 (504.3) .13

Birth weight in SD units, mean (SD)c 1.0 (1.5) 0.9 (1.4) .47

Length at birth, mean (SD), cm 39.4 (4.2) 40.4 (3.8) .13 Length at birth in SD units, mean

(SD)c

⫺1.0 (1.7) ⫺0.7 (1.6) .26

Head circumference at birth, mean (SD), cm

28.0 (3.0) 28.5 (2.9) .27

Head circumference at birth in SD units, mean (SD)c

⫺0.7 (1.6) ⫺0.7 (1.6) .70

Apgar 1 min, mean (SD) 7.3 (2.0) 7.1 (2.0) .70 Apgar 5 min, mean (SD) 7.8 (1.6) 7.6 (1.6) .50 SGA (birth weight less than⫺2

SD), %

29.0 18.8 .17

Time between first dose and study drug of betamethasone continuous days, mean (SD)

22.4 (16.3) 23.8 (14.4) .59

Intervention to delivery, %

ⱕ24 h 79.0 82.5 .67

⬎24 h 21.0 17.5

Intervention to delivery, continuous hours, mean (SD)

18.4 (31.1) 19.8 (34.7) .80

Gestational age at intervention, mean (SD), wk

30.6 (2.6) 31.1 (2.6) .81

Neonatal sepsis, % 14.8 8.8 .29

IVH severe grade 3–4, % 5.0 3.9 .99

IVH any grade, % 18.3 11.7 .20

PVL, % 3.2 3.8 .97

BPD at 36 wk, % 12.1 8.8 .58

Postnatal corticosteroid treatment, %

Dexamethasone 8.2 0.0 .01

Hydrocortisone 11.5 8.8 .40

At 2 y corrected age

Weight, mean (SD), kg 12.2 (1.4) 12.3 (1.8) .62 Weight in SD units, mean (SD)d 0.2 (1.0) 0.3 (1.2) .82

Height, mean (SD), cm 87.2 (3.1) 87.1 (3.6) .92 Height in SD units, mean (SD)d 0.3 (1.1) 0.3 (1.2) .95

Head circumference, mean (SD), cm 49.2 (1.4) 49.3 (1.5) .71 Head circumference in SD units,

mean (SD)d

1.1 (1.0) 1.1 (1.0) .99

No. of hospitalizations, mean (SD) 0.9 (1.7) 0.8 (1.3) .09

Continuous medication, % 25.8 21.3 .33

Asthma, % 9.8 6.4 .46

PVL indicates periventricular leukomalacia; IVH, intraventricular hemorrhage; BPD, bronchopul-monary dysplasia.

aRange is 24.6 to 35.0 weeks. bRange is 620 to 2660 g.

cData are according to Finnish growth charts.

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children exposed to repeat betamethasone for ⱕ24 hours; duration of exposure did not affect temperament outcome in the placebo group (P⫽.01 for interaction; Fig 1). The effect was similar when the duration of exposure was analyzed as a continuous variable (P⫽.07 for interaction; for every 6-hour increase in exposure, impulsivity increased by 0.10 SD [95% confidence in-terval: 0.04 – 0.20] [P⫽.003]; in the placebo group, the

increase in exposure had no effect on impulsivity [P

.89]). Additional adjustments for number of hospitaliza-tions, need for continuous medication, and asthma, and after excluding children with hemiplegic cerebral palsy or dysmorphic features and developmental delay, strengthened the effect when using the binary variable of duration of exposure (P⫽ .008 for interaction, P

.001 for difference in impulsivity in repeat betametha-sone group, andP⬎.44 in the placebo group), as well as when using the continuous measure of duration expo-sure in hours (P ⫽ .07 for interaction, P ⫽ .001 for association between duration of exposure and impulsiv-ity in repeat betamethasone group, andP⫽.72 in pla-cebo group).

Fetal Growth

Table 5 shows that every 1.00-SD increase in birth weight was associated with an increase of 0.18 SD in inhibitory control, a decrease of 0.16 SD in activity level and motor activity, and a decrease of 0.15 SD in shyness. In summary scales, this was reflected as a decrease of 0.19 SD in negative affectivity and an increase of 0.14 SD in effortful control (Pfor allⱕ.05).

For every 1.00-SD increase in length, attentional fo-cusing increased by 0.17 SD, cuddliness by 0.12 SD, inhibitory control by 0.16 SD, and soothability by 0.11 SD, whereas activity level decreased by 0.13 SD, motor activity by 0.17 SD, and frustration by 0.12 SD. In rela-tion to summary scales, this was reflected as a decrease of 0.17 SD in negative affectivity and an increase of 0.16 SD in effortful control (Pvaluesⱕ.05; Table 5).

TABLE 3 Descriptions of the Early Childhood Behavior Questionnaire Temperament Scales

Scale Description

Subscale

Activity Level of gross motor activity, including rate and extent of locomotion

Attentional focusing Sustained duration of orienting on an object of attention; resisting distraction

Attentional shifting The ability to transfer attentional focus from 1 activity/ task to another

Cuddliness Child’s expression of enjoyment in and moulding of the body to being held by a caregiver

Discomfort Amount of negative affect related to sensory qualities of stimulation, including intensity, rate, or complexity of light, sound, or texture Fear Negative affect, including unease, worry, or

nervousness related to anticipated pain or distress and/or potentially threatening situations; startle to sudden events

Frustration Negative affect related to interruption of ongoing tasks or goal blocking

High-intensity pleasure

Pleasure or enjoyment related to situations involving high stimulus intensity, rate, complexity, novelty, and incongruity

Impulsivity Speed of response initiation

Inhibitory control The capacity to stop, moderate, or refrain from a behavior under instruction

Low-intensity pleasure

Pleasure or enjoyment related to situations involving low stimulus intensity, rate, complexity, novelty, and incongruity

Motor activity Repetitive small-motor movements; fidgeting Perceptual

sensitivity

Detection of slight, low-intensity stimuli from the external environment

Positive anticipation Excitement about expected pleasurable activities Sadness Tearfulness or lowered mood related to exposure to

personal suffering, disappointment, object loss, loss of approval, or response to other’s suffering Shyness Slow or inhibited approach and/or discomfort in social

situations involving novelty or uncertainty Soothability Rate of recovery from peak distress, excitement, or

general arousal

Sociability Seeking and taking pleasure in interactions with others

Summary scales

Extraversion Rapid response initiation, high activity level, preference for situations characterized by high-intensity stimuli, relative lack of unease in new situations

Negative affectivity Tendency to experience frequent and intensive negative emotions, such as anger, fear, or sadness with a slow rate of recovery

Effortful control Regulation of attention and behavior; ability to inhibit dominant response and to perform a subdominant response

TABLE 4 Child Temperament in Repeated Betamethasone and Placebo Groups

Variable Repeated

Betamethasone, Mean (SD)

Placebo, Mean (SD)

Pa

Activity 4.5 (0.7) 4.7 (0.9) .69

Attentional focusing 4.4 (0.8) 4.4 (0.9) .64 Attentional shifting 5.0 (0.7) 5.0 (0.7) .60

Cuddliness 5.3 (0.8) 5.6 (0.7) .35

Discomfort 2.3 (0.8) 2.3 (0.9) .80

Fear 1.8 (0.6) 2.0 (0.8) .74

Frustration 2.9 (0.7) 3.0 (0.7) .71

High-intensity pleasure 4.4 (0.9) 4.5 (1.0) .52

Impulsivity 4.6 (0.4) 4.7 (0.4) .27

Inhibition 4.1 (1.0) 4.0 (1.0) .74

Low-intensity pleasure 5.2 (0.9) 5.0 (0.7) .22

Motor activity 2.0 (0.8) 2.0 (0.8) .71

Perceptual sensitivity 4.5 (1.1) 4.6 (1.2) .75 Positive anticipation 5.2 (0.8) 5.5 (0.8) .07

Sadness 2.5 (0.7) 2.8 (0.7) .22

Shyness 3.3 (0.9) 3.4 (1.0) .57

Soothability 5.9 (0.8) 5.7 (0.8) .44

Sociability 6.1 (0.8) 6.0 (0.9) .57

Extraversion 5.0 (0.4) 5.0 (0.7) .40

Negative affectivity 2.7 (0.5) 2.8 (0.5) .50

Effortful control 4.8 (0.5) 4.8 (0.5) .74

aModel is adjusted for maternal age and education, child gender, gestational age, birth weight

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With regard to head circumference at birth, 1.00-SD increase in the circumference was associated with in-creases of 0.20 SD in attentional focusing and 0.14 SD in inhibitory control and with a decrease of 0.19 SD in activity level. In relation to summary scales, this was reflected as a decrease of 0.14 SD in negative affectivity and an increase of 0.18 SD in effortful control (Pvalues ⱕ.05; Table 5).

The associations remained significant after additional adjusting for number of hospitalizations, need for con-tinuous medication, and asthma and with the exclusion of children with hemiplegic cerebral palsy or dysmorphic features and developmental delay (Pvalues ⬍.05; data

not shown), except for the association between birth weight SD and effortful control, which was rendered nonsignificant (P⬍.06).

DISCUSSION

In this follow-up study of children of mothers at risk for preterm delivery who were randomly assigned to a sin-gle repeat dose of betamethasone or placebo, exposure to repeat antenatal betamethasone had no significant main effects on temperamental traits of the offspring at 2 years of corrected age. By temperament, we referred to biologically based, individual differences in children’s emotional reactivity and self-regulation, which manifest Dose given ≤24 h before birth

Dose given >24 h before birth

Repeated

betamethasone 3.50

4.00 4.50 5.00

Im

p

ul

s

ivi

ty

P = .001 P = .72

Placebo

FIGURE 1

Interaction between duration of exposure and study group (P⫽.01 for interaction).

TABLE 5 Temperament Characteristics in Relation to Fetal Growth

Variable Birth Weight SD Length at Birth SD Head Circumference at Birth SD

Ba(95% CI) P Ba(95% CI) P Ba(95% CI) P

Activity level ⫺0.16 (⫺0.30 to⫺0.02) .03 ⫺0.13 (⫺0.24 to⫺0.02) .03 ⫺0.19 (⫺0.33 to⫺0.06) .005 Attentional focusing 0.13 (⫺0.01 to 0.27) .06 0.17 (0.06 to 0.29) .004 0.20 (0.07 to 0.34) .003 Attentional shifting 0.00 (⫺0.15 to 0.14) .99 0.03 (⫺0.09 to 0.15) .57 0.13 (⫺0.02 to 0.27) .08

Cuddliness 0.11 (0.00 to 0.20) .21 0.12 (0.00 to 0.23) .05 0.09 (⫺0.05 to 0.23) .19

Discomfort ⫺0.08 (⫺0.22 to 0.06) .24 ⫺0.11 (⫺0.22 to 0.01) .07 ⫺0.10 (⫺0.24 to 0.04) .15 Fear ⫺0.03 (⫺0.16 to 0.11) .68 ⫺0.09 (⫺0.20 to 0.01) .09 ⫺0.10 (⫺0.23 to 0.03) .13 Frustration ⫺0.07 (⫺0.21 to 0.07) .34 ⫺0.12 (⫺0.23 to⫺0.00) .05 ⫺0.05 (⫺0.19 to 0.10) .52 High-intensity pleasure ⫺0.06 (⫺0.20 to 0.09) .45 0.01 (⫺0.12 to 0.12) .99 ⫺0.04 (⫺0.18 to 0.10) .57 Impulsivity ⫺0.04 (⫺0.18 to 0.10) .58 0.00 (⫺0.11 to 0.11) .99 ⫺0.08 (⫺0.22 to 0.05) .22 Inhibitory control 0.18 (0.04 to 0.32) .01 0.16 (0.05 to 0.28) .005 0.14 (⫺0.00 to 0.28) .05 Low-intensity pleasure 0.02 (⫺0.12 to 0.16) .82 0.03 (⫺0.09 to 0.14) .65 0.09 (⫺0.05 to 0.23) .23 Motor activity ⫺0.16 (⫺0.29 to⫺0.02) .03 ⫺0.17 (⫺0.28 to⫺0.06) .003 ⫺0.10 (⫺0.24 to 0.03) .13 Perceptual sensitivity ⫺0.11 (⫺0.25 to 0.03) .11 ⫺0.06 (⫺0.18 to 0.05) .28 ⫺0.10 (⫺0.24 to 0.05) .18 Positive anticipation 0.01 (⫺0.13 to 0.15) .92 ⫺0.02 (⫺0.14 to 0.10) .74 0.02 (⫺0.12 to 0.16) .76 Sadness ⫺0.08 (⫺0.22 to 0.05) .23 ⫺0.04 (⫺0.15 to 0.08) .50 ⫺0.02 (⫺0.15 to 0.12) .81 Shyness ⫺0.15 (⫺0.28 to⫺0.01) .04 ⫺0.08 (⫺0.19 to 0.03) .16 ⫺0.07 (⫺0.22 to 0.06) .30 Soothability 0.13 (⫺0.01 to 0.27) .06 0.11 (0.00 to 0.22) .05 0.11 (⫺0.03 to 0.25) .11 Sociability 0.04 (⫺0.10 to 0.17) .62 0.03 (⫺0.09 to 0.14) .63 0.00 (⫺0.14 to 0.14) .99 Extraversion ⫺0.02 (⫺0.16 to 0.13) .81 0.00 (⫺0.12 to 0.12) .99 ⫺0.03 (⫺0.17 to 0.12) .70 Negative affectivity ⫺0.19 (⫺0.32 to⫺0.05) .008 ⫺0.17 (⫺0.28 to⫺0.06) .003 ⫺0.14 (⫺0.28 to⫺0.07) .04 Effortful control 0.14 (0.00 to 0.29) .05 0.16 (0.04 to 0.27) .007 0.18 (0.04 to 0.31) .01

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as various behaviors in different daily situations9,10and

exert significant continuity throughout childhood.19

Our results complement previous findings that have found no differences between repeat betamethasone and placebo groups in child problem behaviors at the age of 2 years7 but contradict reports of more attention,5

hy-perkinetic,8and aggression8problems among those

ex-posed to repeat antenatal betamethasone. Rather large differences in repeat corticosteroid doses may, however, contribute to these discrepancies; some of the children in the previous studies were exposed to several (2– 4) re-peated doses of corticosteroids5,7,8 in contrast to only 1

repeat dose (betamethasone: 12 mg⫻1) in the current study. In addition, French et al8reported that the

signif-icant increase in aggression and hyperkinetic behavior was specific to children exposed toⱖ3 courses of corti-costeroids. However, it is noteworthy that we had a considerably smaller sample size than in previous stud-ies.5,8

We found an interesting effect related to duration of exposure to antenatal betamethasone; those children whose antenatal exposure to repeat betamethasone dose lasted longer than 24 hours were significantly more impulsive at the age of 2 years than children whose antenatal exposure lasted for 1 to 24 hours. This effect was also observed when we analyzed duration of expo-sure as a continuous meaexpo-sure, such that for every 6-hour increase in exposure there was a 0.10-SD in-crease in impulsivity, a characteristic known to be a vulnerability factor in the development of attention-deficit/hyperactivity disorder20 and externalizing

prob-lems.13,21 Duration of exposure did not result in

differ-ences in impulsivity in the placebo group. Although this finding clearly warrants additional investigation and replication before definite conclusions can be drawn, animal models showing greater fetal adrenal suppression in prolonged antenatal glucocorticoid exposure22,23and

human evidence pointing to blunted cortisol responses in individuals with impulsive behavior24,25 may offer

some insight into the findings. Importantly, children subjected to several (2– 4) repeated doses of corticoste-roids are not only exposed to larger amounts of cortico-steroids but also to a longer duration of exposure. Thus, our findings agree with previous studies and generate a hypothesis stressing the importance of duration of ex-posure, rather than exex-posure, per se.

To the best of our knowledge, none of the earlier studies have investigated whether temperament out-comes are associated with fetal growth within the pre-maturely born population. Interestingly and consistent with previous studies in samples born at term,26 we

found that fetal growth, assessed as SDs from the mean weight, length, and head circumference at birth, had robust associations with temperament characteristics. Low birth weight, length, and head circumference pre-dicted lower self-regulative capacities (effortful control) and higher levels of negative affectivity. These associa-tions were independent of the repeat betamethasone versus placebo exposure. In addition, slower fetal growth was associated with higher activity level of the child. Our findings suggest that even the variation in

body size within prematurely born children matters for developmental outcomes, indicating that more attention should be directed to supporting the optimal develop-ment of infants born at the lower end of the fetal growth distribution. Importantly, longitudinal data on the rela-tions of temperament and later adjustment and psycho-pathology show that effortful control is a major contrib-utor to successful social development27,28and is related

longitudinally to externalizing problems12,13 and

atten-tion-deficit/hyperactivity disorder,12 whereas negative

affectivity is associated with later internalizing prob-lems.14

Our findings are in general agreement with the de-velopmental origins of health and disease hypothesis, which states that a suboptimal prenatal environment, reflected in smaller body size at birth, may have lifelong consequences for organ structure and function of vari-ous physiologic feedback systems, including the hypo-thalamic-pituitary-adrenocortical axis.29,30The

hypotha-lamic-pituitary-adrenocortical axis plays an important role in human behavior regulation and, thus, may have a role in explaining the associations of longer duration of betamethasone exposure with impulsivity and slower fetal growth with lower effortful control and higher negative affectivity.

There are some limitations to our study. First, com-pared with other recent studies on the long-term cogni-tive and behavioral effects of repeat doses of antenatal corticosteroids,5,7 we had a rather small sample size.

Second, premature birth is associated with heightened risk for neonatal morbidity. Although we have adjusted for multiple fetal and maternal conditions, the possibility remains that these, or some other factors, remain inter-twined with the repeat antenatal betamethasone effect on temperament in a way that could not be specified in this study. Finally, we did not determine the underlying mechanisms leading to intrauterine growth retardation. These may involve placental, acquired, or constitutional factors.

CONCLUSIONS

We found no effect of exposure to repeat antenatal betamethasone on temperamental behavior at the cor-rected age of 2 years. Yet, children who were exposed to repeat antenatal betamethasone for ⬎24 hours were more impulsive than were children exposed to repeat antenatal betamethasone for a shorter duration. Thus, our findings generate the hypothesis that duration of antenatal betamethasone exposure, rather than beta-methasone exposure per se, may induce alterations in impulsivity. Regardless of the antenatal betamethasone exposure, slower fetal growth predicted lower self-reg-ulative capacities, and higher levels of negative affectiv-ity, all being characteristics that contribute to the suc-cessful social development of the child.27,28

ACKNOWLEDGMENTS

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The Antenatal Betamethasone Study Group was as follows: T. Raudaskoski, J. Ra¨sa¨nen, P. Jouppila, O. M. Peltoniemi, T. Saarela, and M. Hallman (Oulu University Hospital, Oulu, Finland); E. Halmesma¨ki, V. Stefanovic, M. A. Kari, and S. Andersson (Helsinki University Cen-tral Hospital, Helsinki, Finland); S. Heinonen, K. Hei-nonen, and K. Nikolajev (Kuopio University Hospital, Kuopio, Finland); J. Uotila and O. Tammela (University Hospital of Tampere, Tampere, Finland); U. Ekblad and L. Lehtonen (University Hospital of Turku, Turku, Fin-land); T. Kiviniemi and R. Lounamaa (Central Hospital of Central Finland, Jyva¨skyla¨, Finland); M. Heikkila¨ and R. Marttila (Seina¨joki Central Hospital, Seina¨joki, Fin-land); and E. Koistinen and M. Dalla Valle (Central Hospital of Northern Karelia, Joensuu, Finland).

REFERENCES

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Cochrane Database Syst Rev.2006;(3):CD004454

2. Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.Lancet.

2006;367(9526):1913–1919

3. Peltoniemi OM, Kari MA, Tammela O, et al. Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.Pediatrics.2007;119(2):290 –298 4. Wapner RJ, Sorokin Y, Thom EA, et al. Single versus weekly

courses of antenatal corticosteroids: evaluation of safety and efficacy.Am J Obstet Gynecol.2006;195(3):633– 642

5. Crowther CA, Doyle LW, Haslam RR, et al. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.N Engl J Med.2007;357(12):1179 –1189

6. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development.Am J Obstet Gynecol.1999;180(1 pt 1):114 –121 7. Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after

repeat doses of antenatal corticosteroids.N Engl J Med.2007; 357(12):1190 –1198

8. French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Re-peated antenatal corticosteroids: effects on cerebral palsy and childhood behavior.Am J Obstet Gynecol.2004;190(3):588 –595 9. Rothbart MK, Ahadi SA, Evans DE. Temperament and personality: Origins and outcomes. J Pers Soc Psychol. 2000; 78(1):122–135

10. Rothbart MK, Ahadi SA. Temperament and the development of personality.J Abnorm Psychol.1994;103(1):55– 66

11. Muris P, Ollendick TH. The role of temperament in the etiology of child psychopathology.Clin Child Fam Psychol Rev.2005;8(4): 271–289

12. Nigg JT. Temperament and developmental psychopathology.

J Child Psychol Psychiatry.2006;47(3– 4):395– 422

13. Eisenberg N, Ma Y, Chang L, et al. Relations of effortful control,

reactive undercontrol, and anger to Chinese children’s adjust-ment.Dev Psychopathol.2007;19(2):385– 409

14. Oldehinkel AJ, Hartman CA, Ferdinand RF, Verhulst FC, Ormel J. Effortful control as modifier of the association be-tween negative emotionality and adolescents’ mental health problems.Dev Psychopathol.2007;19(2):523–539

15. Rettew DC, Althoff RR, Dumenci L, Ayer L, Hudziak JJ. Latent profiles of temperament and their relations to psychopathology and wellness.J Am Child Psychol Psychiatry.2008;47(3):273–281 16. Pihkala J, Hakala T, Voutilainen P, Raivio K. Characteristic of recent fetal growth curves in Finland [in Finnish].Duodecim.

1989;105(18):1540 –1546

17. World Health Organization. WHO child growth standards: methods and development. Available at: www.who.int/ childgrowth/standards/en. Accessed July 6, 2007

18. Putnam SP, Gartstein MA, Rothbart MK. Measurement of fine-grained aspects of toddler temperament: the early child-hood behavior questionnaire. Infant Behav Dev. 2006;29(3): 386 – 401

19. Komsi N, Raikkonen K, Pesonen A-K, et al. Continuity of temperament from infancy to middle childhood.Infant Behav Dev.2006;29(4):494 –508

20. Sagvolden T, Aase H, Johansen EB, Russell VA. A dynamic developmental theory of attention-deficit/hyperactivity disor-der (ADHD) predominantly hyperactive/impulsive and com-bined subtypes.Behav Brain Sci.2005;28(3):397– 468 21. Eisenberg N, Spinrad TL, Fabes RA, et al. The relations of

effortful control and impulsivity to children’s resiliency and adjustment.Child Dev.2004;75(1):25– 46

22. Ikegami M, Jobe AH, Newnham J, et al. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.Am J Respir Crit Care Med.1997;156(1):178 –184 23. Sloboda DM, Moss TJ, Li S, et al. Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007;292(1): E61–E70

24. King JA, Barkley RA, Barrett S. Attention-deficit hyperactivity disorder and the stress response.Biol Psychiatry. 1998;44(1): 72–74

25. Blomqvist M, Holmberg K, Lindblad F, et al. Salivary cortisol levels and dental anxiety in children with attention deficit hyperactivity disorder.Eur J Oral Sci.2007;115(1):1– 6 26. Pesonen AK, Raikkonen K, Kajantie E, et al. Fetal

program-ming of temperamental negative affectivity among children born healthy at term.Dev Psychobiol.2006;48(8):633– 643 27. Eisenberg N, Fabes RA, Guthrie IK, Reiser M. Dispositional

emotionality and regulation: Their role in predicting quality of social functioning.J Pers Soc Psychol.2000;78(1):136 –157 28. Kochanska G, Murray KT, Harlan ET. Effortful control in early

childhood: Continuity and change, antecedents, and implica-tions for social development.Dev Psychol.2000;36(2):220 –232 29. Seckl JR. Glucocorticoids, developmental programming and the risk of affective dysfunction. Prog Brain Res. 2008;167: 17–34

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DOI: 10.1542/peds.2008-1809 originally published online December 15, 2008;

2009;123;e31

Pediatrics

Hallman and M. Anneli Kari

Anu-Katriina Pesonen, Katri Räikkönen, Aulikki Lano, Outi Peltoniemi, Mikko

Implications for Temperament Traits at the Age of 2 Years

Antenatal Betamethasone and Fetal Growth in Prematurely Born Children:

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http://pediatrics.aappublications.org/content/123/1/e31#BIBL This article cites 28 articles, 1 of which you can access for free at:

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DOI: 10.1542/peds.2008-1809 originally published online December 15, 2008;

2009;123;e31

Pediatrics

Hallman and M. Anneli Kari

Anu-Katriina Pesonen, Katri Räikkönen, Aulikki Lano, Outi Peltoniemi, Mikko

Implications for Temperament Traits at the Age of 2 Years

Antenatal Betamethasone and Fetal Growth in Prematurely Born Children:

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Figure

TABLE 1Demographic Characteristics and Major Morbidity ofPregnant Women
TABLE 2Characteristics and Major Morbidity of Children
TABLE 4Child Temperament in Repeated Betamethasone andPlacebo Groups
FIGURE 1Interaction between duration of exposure and study group

References

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