Published online November 1, 2007
PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1237-e1244 (doi:10.1542/peds.2006-3277)
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ARTICLE

Size at Birth and Motor Activity During Stress in Children Aged 7 to 9 Years

Wolff Schlotz, PhDa,b, Alexander Jones, PhDa, Naomi M.M. Phillipsc, Keith M. Godfrey, PhDa and David I.W. Phillips, PhDa

a Medical Research Council Epidemiology Resource Centre
b School of Psychology, University of Southampton, Southampton, United Kingdom
c School of Psychology, University of Cardiff, Cardiff, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Small size at birth is linked with metabolic and cardiovascular disease. There is increasing evidence that it is also linked with physiologic stress responses and abnormal behavior, in particular, symptoms of hyperactivity. Therefore, we investigated associations between size at birth and motor activity during psychosocial stress.

METHODS. In 123 children aged 7 to 9 years, we examined the relations of birth weight, head circumference, length, and ponderal index at birth with motor activity on exposure to both stress and nonstress situations. Videos were recorded while the children performed a story and a math task in front of an audience (stress) and watched a movie (nonstress); motor activity was defined as lifting or tilting of a foot.

RESULTS. Children who had had a smaller head circumference at birth demonstrated greater motor activity during the stress test. There were marked gender differences in the results. In boys, lower birth weight, head circumference, and ponderal index were associated with greater motor activity during the stress test but not associated with motor activity during the nonstress situation. The findings remained significant when potential confounding variables were controlled for. There were no associations in girls.

CONCLUSIONS. The findings suggest long-term effects of an adverse fetal environment on the behavioral stress response in boys and parallel similar gender-specific effects on different stress response systems in humans and animals. The results could reflect permanent alterations of dopaminergic neurotransmission and have implications for the etiology of clinical hyperactivity.

Key Words: birth weight • birth head circumference • stress • hyperactivity • child behavior

Abbreviations: ADHD—attention-deficit/hyperactivity disorder • TSST-C—Trier Social Stress Test for children • PI—ponderal index • IQR—interquartile range

Small size at birth is linked with metabolic and cardiovascular disease.1 There is increasing evidence that it is also linked with abnormal behavior, in particular, hyperactivity. In children, birth weight has been shown to be inversely related to symptoms of attention-deficit/hyperactivity disorder (ADHD),2–4 as well as various other behavioral problems.2,5,6

However, only a few studies have tested associations of size at birth with biobehavioral stress responses in humans. In these studies, low birth weight has been associated with enhanced blood pressure and heart rate responses to psychological stressors in women but not men,7 whereas associations with enhanced hypothalamic-pituitary-adrenal axis responses to psychosocial stress have been observed in young men8 and boys9 but not in girls. In a cohort of 18-year-old boys who underwent a standardized interview to diagnose suitability for military combat duty in Sweden, it has been shown that psychological stress susceptibility as assessed by the interviewer was inversely associated with birth weight and head circumference.10,11 These studies suggest that an adverse fetal environment may influence biobehavioral stress responses.12 However, no human study has investigated associations of size at birth with motor activity in response to a psychosocial stressor.

We observed motor activity during a psychosocial stress situation and during a nonstress situation in children aged 7 to 9 years whose mothers had been recruited in early pregnancy for a previous research study. On the background of associations of anthropometric birth outcome measures with hyperactivity and physiologic stress responses in children, we examined for associations between size at birth and motor activity during these situations.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
The mothers of the children in this study had taken part in an earlier study of fetal growth in white women with singleton pregnancies and known menstrual dates who registered in early pregnancy with participating obstetricians at the Princess Anne Maternity Hospital (Southampton, United Kingdom).13 Families whose addresses were traceable were contacted for participation in a follow-up study of the impact of fetal growth on physiologic responses to psychosocial stress.9 The local research ethics committee approved the study, and both parents and children gave written informed consent. A total of 123 children (61 boys and 62 girls with an age range of 7.6–9.8 years) were recorded by a video camera during the whole stress test, and digitized video files were analyzed by 2 observers.

Procedure
The children attended a clinical research facility to participate in a version of the Trier Social Stress Test that has been adapted for use in children (TSST-C).14 For a baseline measure of physiologic parameters, the children were asked to stand in front of a video camera and watch a nonemotional film (Tales of the River Bank) on a screen next to the camera for 5 minutes (nonstress situation). For the TSST-C, the children were asked to stand in front of a microphone and perform an exciting story of their own invention followed by a serial subtraction task for an audience of 3 adult strangers. In both situations, the children were instructed to stand still and to look at the screen where the film was presented (nonstress situation) or at the member of the audience who gave the instructions during the TSST-C. They had 5 minutes to prepare before the stress test, which lasted ~10 minutes. The original TSST-C protocol14 was modified to reduce task difficulty appropriately for our younger age group, and motivation was increased by offering toys as potential rewards for high performance. At 7 time points during the visit, saliva samples were taken (compare with ref 9), and momentary distress was assessed.

Measurements
Pregnancy Outcomes and Related Measures
At birth, the infant's weight was measured using digital scales, and 2 trained field workers recorded neonatal head circumference and crown-heel length using standard techniques; the infant's gestational age at birth was calculated from the date of the last menstrual period and confirmed by ultrasound.13 Maternal alcohol or tobacco use during pregnancy was obtained at different occasions by questionnaires. Tobacco use was assessed at the last menstrual period, early pregnancy, and late pregnancy. Alcohol use was assessed at early and late pregnancy. Mother's socioeconomic class was recorded during the follow-up visit and classified using the United Kingdom National Statistics socioeconomic classification.

Cortisol and Momentary Distress
Cortisol concentrations were measured from saliva samples as described in Jones et al.9 Momentary distress was measured using a visual scale with 5 faces representing variation in affective valence: very positive, rather positive, neutral, rather negative, and very negative. The ends of the scale were explained to the child using examples drawn from their own experience, such as a school or music examination. Scale scores ranged from 0 (very positive) to 4 (very negative).

Motor Activity
Both sessions were recorded on videotape, displaying the full body during the complete stress test and the nonstress situation. The tapes were digitized, and the children's motor activity was quantified using the software program The Observer 5.0 (Noldus Information Technology, Wageningen, Netherlands), applying a 1–0 sampling15 with 15-second sample intervals. Because the children's arms and trunk were restricted because they were wearing instruments to measure cardiovascular responses (not reported here), the records were confined to motor activity of the feet. The operational definition of motor activity was given as, "at least one foot is lifted or tilted so that at least a part of it looses its contact to the ground." The motor activity sum score was computed as the sum of the sample intervals during which motor activity occurred. The motor activity rate score was computed as the proportion of all of the sample intervals during which motor activity occurred; this was the principal outcome variable. Each video from the TSST-C was analyzed independently by 2 observers. Because of the very high reliability of the measure, motor activity in the nonstress situation was coded by 1 observer.

Statistical Analysis
Differences in the child's and mother's characteristics, as well as duration of the TSST-C, motor activity score, and motor activity rate between boys and girls, were tested using 2-tailed t tests for continuous variables and Fisher's exact tests for categorical variables. Changes in cortisol were tested using paired t tests; changes in momentary distress were tested using Wilcoxon matched-pair signed-rank tests. A random-effects analysis of variance model was used to compute the intraclass correlation coefficient of the motor activity observations as a measure of the interrater reliability. The distribution of the motor activity data was nonnormal, with a high number of 0 scores and a very long right tale of the distribution. Thus, motor activity rates were recoded into 8 equally sized categories with ~15 subjects per group, assuming that this ordinal variable is related to a continuous, latent variable that indicates motor activity. An ordered logit regression model16 was used to predict the ordinal motor activity rate variable during the TSST-C and the nonstress situation, respectively, by measures of size at birth, and quadratic terms were included where appropriate to test for nonlinear associations. In the case of significant associations, 5 additional models controlled for variables that may confound the associations of size at birth with the children's behavior. In a first model, the age of the child at the date of the study was included as a predictor. A second model included variables that may affect birth outcomes, namely, parity, mother's age, and prepregnant BMI, and an additional model included gestational age. A subsequent model included mother's socioeconomic class to control for adverse environmental influences that are persistent throughout prenatal and postnatal life. Finally, alcohol intake and smoking during pregnancy were added to the model to control for their influence on the associations of size at birth with motor behavior. Because gender differences are common in studies on effects of prenatal adverse factors, all of the models were analyzed for the complete sample and were followed by separate analyses for boys and girls, even if the interaction term with gender was not significant. Stata 9.2 (Stata Corp, College Station, TX) was used for the statistical analysis.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Table 1 shows the characteristics of the study sample. The mean gestational age was 280 days, and the mean birth weight was 3.5 kg. Whereas gestational age, birth weight, and age at the date of the stress test did not differ between genders, boys had a higher mean head circumference, length, and ponderal index (PI) at birth than girls. There were no differences between boys and girls concerning the mother's age at conception, prepregnant BMI, or parity. Twenty-four percent of the mothers smoked during pregnancy; 80% consumed some alcohol while pregnant. However, the median of self-reported number of alcohol units consumed was low, with 0.5 units per week (interquartile range [IQR]: 2.9) in both early and late gestation. There were no differences in mother's smoking or alcohol consumption between boys and girls.


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  		TABLE 1 Characteristics of Children Participating in the Study and of Their Mothers During Pregnancy

 
Cortisol and Psychological Responses to Stress
Figure 1 shows the course of mean salivary cortisol and momentary distress values during the children's visit to the clinical research facility. Both cortisol and distress increased somewhat between measurements 2 and 3 in anticipation of the TSST-C (difference between measurements 2 and 3: cortisol, P = .001; distress, P = .023) and more markedly immediately after the TSST-C stress situation (difference between measurements 3 and 4: cortisol, P = .001; distress, P = .001).


Figure 1
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  		FIGURE 1 Geometric mean (±SE) of salivary cortisol (dashed line) and mean (±SE) of momentary distress (solid line) during the visit of the children at the clinical research facility.

 
Motor Activity in Nonstress and Stress Situations
The interrater reliability of the motor activity sum score for the TSST-C was very high (intraclass correlation coefficient: 0.96). Thus, the mean of the motor activity sum scores recorded by the 2 observers was used in the analyses. The nonstress situation encompassed, on average, 19.6 (SD: 2.6) and the TSST-C, on average, 41.7 (SD: 6.5) sample intervals. The median motor activity sum score for the nonstress situation was 6 (IQR: 8), and for the TSST-C it was 7.5 (IQR: 16.5). The median motor activity rate score, that is, the proportion of all of the sample intervals during which motor activity occurred, was 0.33 (IQR: 0.38) for the nonstress situation and 0.18 (IQR: 0.40) for the TSST-C. The Spearman correlation between the categorized motor activity rate scores during the nonstress and stress situation was an r of 0.50 (P < .001). There were no differences between boys and girls in the mean duration of the situation, the number of sample intervals, the motor activity sum score, or the motor activity rate score for either the nonstress situation or the TSST-C.

Associations of Motor Activity With Birth Weight
The ordered regression analysis for the complete sample showed that the motor activity rates during the nonstress situation and the TSST-C were not associated with birth weight (nonstress: b = –0.015; SE = 0.295; P = .961; TSST-C: b = –0.366; SE = 0.294; P = .214). Testing for gender differences revealed a tendency for differences in the associations for the TSST-C (P for interaction term = .104) and no differences in the nonstress situation (P = .283). Because the failure to confirm a statistically significant gender difference may be because of limited statistical power and because gender differences are common in studies of the effects of prenatal development, separate analyses for boys and girls were conducted, and the results are shown in Table 2. Motor activity during the nonstress situation was unrelated to birth weight in boys and girls. In contrast, lower birth weight was associated with higher motor activity scores in boys (P = .048), whereas no association was observed in girls. When standardized for the latent variable, the significant regression coefficient indicates that for a 1-kg increase in birth weight, the motor activity rate during the stress test in boys is expected to decrease by 0.43 SDs. To illustrate this association, gender-specific quartiles of birth weight were computed, and each category's average motor activity rate during stress for boys is shown in Fig 2. The pattern of mean motor activity rate scores suggests the possibility of a threshold effect, with higher motor activity in children with below-average weight at birth. Formal testing for nonlinearity using a quadratic term was, however, nonsignificant.


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  		TABLE 2 Results of Ordered Regressions of Motor Activity Rate During a Psychosocial Stress Situation on Birth Weight According to Gender

 

Figure 2
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  		FIGURE 2 Average motor activity rate (proportion of all sample intervals during which motor activity occurred) during the TSST-C for quartiles of birth weight (mean + SE) in boys. An ordered regression analysis revealed a significant linear effect of birth weight (P = .048).

 
As shown in the adjusted models section of Table 2, the association was stable when the following variables were added to the model: child's age at the study date (adjusted P = .034); parity, mother's prepregnancy BMI, and her age at conception (adjusted P = .010); gestational age (adjusted P = .024); social status (adjusted P = .019); and maternal smoking and alcohol consumption during pregnancy (adjusted P = .046).

Associations of Motor Activity With Head Circumference at Birth
In boys and girls combined, head circumference at birth was inversely related to motor activity during the TSST-C (b = –0.238; SE = 0.115; P = .038) but not to motor activity during the nonstress situation (b = –.046; SE = 0.112; P = .681). The standardized regression coefficient indicates an expected decrease in the motor activity rate score of 0.13 SDs of the latent variable with a 1-cm increase in head circumference. Similar to the results with birth weight, there were no statistically significant differences between boys and girls in the associations, as indicated by the interaction terms in the nonstress situation (P = .470) or the TSST-C (P = .232). The results of separate analyses for boys and girls are shown in Table 3. There was no association of head circumference at birth with motor activity rate during the nonstress situation in boys, as well as in girls, but a smaller head circumference at birth was associated with higher motor activity rate scores during the TSST-C in boys (P = .018). The standardized regression coefficient indicates that for a 1-cm increase in head circumference, the motor activity rate during the stress test in boys is expected to decrease by 0.19 SDs of the latent variable. Figure 3 illustrates this association using gender-specific quartiles of head circumference at birth. The pattern of mean motor activity rate scores suggests the possibility of a threshold effect, with higher motor activity in children with a small head circumference at birth. Formal testing for nonlinearity using a quadratic term was, however, nonsignificant. The adjusted models section of Table 3 documents that this association was stable when potentially confounding variables were controlled: child's age at the study date (adjusted P = .012); parity, mother's prepregnancy BMI, and her age (adjusted P = .004); gestational age (adjusted P = .005); social status (adjusted P = .005); and maternal smoking and alcohol intake during pregnancy (adjusted P = .010).


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  		TABLE 3 Results of Ordered Regressions of Motor Activity Rate During a Psychosocial Stress Situation on Head Circumference at Birth According to Gender

 

Figure 3
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  		FIGURE 3 Average motor activity rate (proportion of all sample intervals during which motor activity occurred) during the TSST-C for quartiles of head circumference at birth (mean + SE) in boys. An ordered regression analysis revealed a significant linear effect of head circumference at birth (P = 0.018).

 
Associations of Motor Activity With Length and PI at Birth
Length at birth was unrelated to motor activity during nonstress (P = .691) and stress situations (P = .504) in boys and girls combined. Separate analyses for boys and girls also showed nonsignificant associations of length at birth with motor activity during the nonstress (boys: b = 0.028; P = .762; girls: b = 0.114; P = .312) and stress situations (boys: b = –1.121; P = .197; girls: b = 0.085; P = .442).

PI at birth showed no association with motor activity during the nonstress situation (P = .338) and a weak inverse association during stress (b = –0.107; P = .136) in boys and girls combined. Separate analyses for boys showed no associations with motor activity during the nonstress situation (P = .241) but a significant inverse association of PI at birth with motor activity during the stress situation (b = –0.214; P = .040; no effect of a quadratic term when added to the model); in girls there was no association either during nonstress (P = .748) or stress (P = .557). The standardized regression coefficient indicates that for a 1-unit increase in PI, the motor activity rate during the stress situation in boys is expected to decrease by 0.11 SDs of the latent variable. Controlling for confounding factors in the model for boys had little effect on these results (adjusted P values: model 1, P = .035; model 2, P = .043; model 3, P = .055; model 4, P = .055); adjustment for maternal smoking and drinking alcohol during pregnancy marginally weakened the effect (model 5, P = .099).

A comparison of fully standardized coefficients for the effects in boys showed that the effect of head circumference at birth was strongest (–0.30), the effects of birth weight (–0.24) and PI (–0.25) were similar and slightly smaller, and the (nonsignificant) effect of length at birth was the weakest effect (–0.16).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The major finding of this study was an inverse association between size at birth and motor activity stress responses in boys aged 7 to 9 years. Boys who were born with a smaller head circumference, a lower weight, and a lower PI showed higher motor activity during stress, but there was no association of birth size with motor activity during a nonstress situation. The association was stronger for head circumference than for birth weight and PI, and it remained significant after controlling for age of the child, parity, mother's prepregnant BMI, her age at conception, her social class, and gestational age. The results suggest that gestational age may contribute to the effects observed in our study but that fetal growth restriction rather than preterm birth is the principal factor underlying the associations of birth size with motor activity during stress in this study. This is in contrast with a study in infants that demonstrated a shorter duration of daytime rest in preterm infants compared with term infants.17 However, our study sample consisted of predominantly term-born children, and our results were confined to motor activity during stress. Therefore, our results are not comparable to these results on activity in preterm infants. Controlling for maternal smoking and drinking alcohol during pregnancy weakened the associations slightly, suggesting that these specific prenatal factors contribute to increased stress-related motor activity in children in our study. Our results suggest that prenatal adversity alters motor activity on exposure to stress.

The results are consistent with the associations of small size at birth, corrected for gestational age, with increased hypothalamic-pituitary-adrenal stress responses8,9 and with susceptibility to psychological stress10,11 in male subjects. Our results thus add to the evidence for the effects of prenatal growth restriction on the biobehavioral stress response later in life. The fully standardized regression coefficients are in the range of –0.24 to –0.30 and demonstrate relatively strong effects compared with coefficients for associations of size at birth with parental ratings of inattention and hyperactivity reported by Lahti et al,4 which ranged between –0.11 and –0.15. The observation that the associations were confined to boys is consistent with human and animal studies that found marked gender differences in effects of prenatal adverse events on stress reactivity and emotional behavior later in life.7,9,18

The observation that size at birth was associated with motor activity during stress, but not during the nonstress situation, suggests different mechanisms for motor activity in these situations. This is corroborated by the moderate correlation between the motor activity rate scores. The marked increase in distress and cortisol during the stress situation further suggests that motor behavior during stress may be related to neuronal circuits that are activated in stressful situations. Whereas dopaminergic innervations of the basal ganglia19 play a major role in normal motor activity, partly by modulating the influence of prefrontal cortical inputs to striatal neurons,20 stress triggers a release of dopamine in the striatum and the prefrontal cortex21,22 and may, thus, influence motor activity. However, our study does not provide conclusive evidence as to the significance of increased motor activity during stress. Increased motor activity may be associated with a number of different states, for example, restlessness, excitement, or a motivation to escape the situation. Because other studies have shown inverse associations of size at birth with stress responses in different domains, we think that increased motor activity during stress may represent a component of the biobehavioral stress response that could have had an adaptive value in an ancient environment (see ref 12). However, our results need to be replicated in future studies, which could use automated movement measurement and should avoid restriction of arm movements.

The finding that head circumference at birth, a good indicator of brain volume,23 was a stronger predictor of motor activity effects than birth weight and PI indicates that the observed functional changes may result from cerebral growth restriction. This is in accordance with recent studies that demonstrated a significantly reduced total brain volume in prenatally growth restricted 15-year-old children24 and a smaller total cerebral volume in patients with ADHD, as well as negative correlations of brain volumes with ADHD symptom severity.25

Because prenatal and postnatal development of the central nervous system is complex,26 and behavioral effects of insults depend on the timing of the event (eg, ref 27), there are a number of potential neurodevelopmental pathways that could mediate this effect. The dopaminergic system is particularly interesting here, because it is involved in motor activity,20 it is activated by stress,21,22 and the prenatal development of dopaminergic neurons seems to be sensitive to growth disruption.28 In addition, there are clear gender differences in dopaminergic neurotransmission,29–32 which could underlie the gender-specific effects observed in our study.

Although we controlled for a number of potential confounding factors, some uncertainty about the key factors remains. For example, although prenatal development may be influenced by parity, mother's age, and prepregnant BMI, these factors did not change the results when included as covariates. We cannot exclude postnatal environmental exposures as the cause of our findings. However, postnatal exposures tend to cluster in low socioeconomic status groups, and inclusion of socioeconomic status as a control variable did not change our results. Furthermore, the relative contribution of genetic and intrauterine environmental factors on fetal growth is unclear. Although birth weight has been shown to reflect the impact of environmental influences on prenatal development,33 it has also been demonstrated to be influenced by genetic factors (eg, refs 34 and 35). On the basis of our data, we cannot draw conclusions about the relative significance of genetic factors, prenatal environmental factors, or their interaction for the associations of size at birth with stress-related motor activity.

Our observations may have clinical implications in relation to hyperactivity and the etiology of ADHD. Our results are consistent with animal studies that demonstrated enhanced locomotor activity in a novel environment after prenatal stress36–38 and with human studies suggesting that prenatal adversity may particularly affect symptoms of ADHD.2–4,39–43 Moreover, motor activity during situations that require sustained attention or mental effort, similar to the TSST-C, has been demonstrated to be enhanced in children with ADHD,44–46 and early adverse events have a permanent impact on relevant neurotransmitter systems.47


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We found that small size at birth was associated with increased motor activity during stress but not during a nonstress situation. The associations were confined to boys and were stable after controlling for potential confounding factors. The anthropometric birth size measures used in this study are only crude measures of prenatal development, and they do not indicate specific factors. However, a permanent effect of the fetal environment on neurodevelopment is a plausible explanation of the effects found in this study, and future studies on potential neurobehavioral mechanisms could provide important insights into the developmental origins of stress-related motor behavior, with potential implications for ADHD.


   ACKNOWLEDGMENTS
 
The study was funded by National Institute of Child Health and Human Development grant 1 R01 HD41107-01. Subjects were drawn from a cohort study funded by WellBeing and the Medical Research Council. Behavioral observations, analysis, and preparation of the article were supported by German Research Foundation (Deutsche Forschungsgemeinschaft) fellowship grant DFG SCHL 1708/1-1 (to Dr Schlotz).


   FOOTNOTES
 
Accepted May 3, 2007.

Address correspondence to Wolff Schlotz, PhD, Medical Research Council Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, United Kingdom. E-mail: ws{at}mrc.soton.ac.uk

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


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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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