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Department of Pediatrics, Division of Endocrinology (Y.K.v.P., A.C.S.H.-K.), Sophia Children’s Hospital/Erasmus Medical Centre, 3015 GJ Rotterdam, The Netherlands; and Departments of Pediatric Psychiatry (F.S.M.S., H.M.K.) and Medical Psychology (H.J.D.), Erasmus Medical Centre, 3015 GJ Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. A. C. S. Hokken-Koelega, M.D., Sophia Children’s Hospital/Erasmus MC, Department of Pediatrics, Division of Endocrinology, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: a.hokken{at}erasmusmc.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Patients were assigned to one of two treatment groups (1 or 2 mg GH/m2 body surface·d, or 
0.035 or 0.07 mg/kg·d). Intelligence and psychosocial functioning were evaluated at start of GH treatment (n = 74), after 2 yr of GH treatment (n = 76), and in 2001 (n = 53). IQ was assessed by a short-form Wechsler Intelligence Scale for Children-Revised or Wechsler Adult Intelligence Scale (Block-design and Vocabulary subtests). Behavioral problems were measured by the Achenbach Child Behavior Checklist or Young Adult Behavior Checklist, and self-perception was measured by the Harter Self-Perception Profile.
Mean (SEM) birth length SD score was –3.6 (0.2), mean age and height at start was 7.4 (0.2) yr and –3.0 (0.1) SD score, respectively, mean duration of GH treatment was 8.0 (0.2) yr, and mean age in 2001 was 16.5 (0.3) yr. After 2 yr of GH treatment, 96% of both GH groups showed a height gain SD score of 1 SD from the start of treatment or more, resulting in a normal height (i.e. height 
–2.0 SD for age and sex) in 70% of the children. In 2001, 48 (91%) of the 53 children participating in this study had reached a normal height. Block-design s-score and the estimated total IQ significantly increased (P < 0.001 and P < 0.001, respectively) from scores significantly lower than Dutch peers at start (P < 0.001 and P < 0.001, respectively) to comparable scores in 2001. The increase over time for the Vocabulary s-score was not significant. Internalizing Behavior SD scores remained comparable to Dutch peers, whereas Externalizing Behavior SD scores and Total Problem Behavior SD scores improved significantly during GH therapy (P < 0.01 and P < 0.05, respectively) to scores comparable to Dutch peers. Self-perception SD scores improved from start of GH treatment until 2001 (P < 0.001) to scores significantly higher than Dutch peers (P < 0.05). No significant differences between the two GH dosage groups were found. Improvement in Externalizing and Total Problem Behavior SD scores over time was significantly related to change in height SD score (P < 0.05 and P < 0.01, respectively), whereas scores over time for Vocabulary, Block-design, Internalizing, or total Harter Self-Perception score were not related to change in height SD scores.
In conclusion, parallel to a GH-induced catch-up growth in adolescents born SGA, IQ, behavior, and self-perception showed a significant improvement over time from scores below average to scores comparable to Dutch peers. In addition, children whose height over time became closer to that of their peers showed less problem behavior.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Seventy-nine short children born SGA participated in a multicenter double-blind randomized dose-response GH trial (Table 1
). Of these 79 children, six children dropped out and were lost to follow-up. Fifty-three children agreed to participate in the evaluation of IQ and psychosocial functioning in 2001 (T3), during a mean of 8 yr of GH treatment, whereas 20 children were not motivated to participate (T3 response rate, 73%). In the previous evaluations at start (T1) and after 2 yr of GH treatment (T2), a small part of the GH groups had not been able to participate due to the age minimum of the questionnaires. The response rates for the previous evaluations at T1 and T2 were 100% (74 of 74 subjects) and 97% (76 of 78 subjects), respectively. Sixty-three percent (50 of 79 subjects) was evaluated three times, and 94% (74 of 79 subjects) participated at least twice in the evaluation of IQ and psychosocial functioning.
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0.035 or 0.07 mg/kg·d). GH treatment was discontinued after reaching adult height (height velocity < 0.5 cm in 6 months) or on patient’s decision after reaching a satisfactory height (near adult height). Of the participants in the evaluation of IQ and psychosocial functioning in 2001, 37 (70%) of the 53 adolescents had discontinued GH treatment. The evaluation of IQ and psychosocial functioning, being part of the GH trial, started in 1991 and was approved by the ethics committees of the participating centers in The Netherlands. Due to ethical considerations, the ethics committees did not allow for a control group until adult height as part of the GH trial. Written informed consent was obtained from the parents or custodians of each child.
Clinical evaluation
Height was measured using a Harpenden stadiometer (20). Four measurements per visit were taken, and the mean was used for analysis. Target height was adapted from Dutch reference data with the addition of 3 cm for secular trend and calculated using the following formula: 1/2 x (Heightfather + Heightmother + 12) + 3 for boys and 1/2 x (Heightfather + Heightmother – 12) + 3 for girls (21). Height, target height, and head circumference were expressed as SD score for CA and gender (21, 22).
Evaluation of IQ and psychosocial functioning
The evaluation of IQ and psychosocial functioning was performed at T1, T2, and T3 by an experienced psychologist. At start, all parents returned the questionnaires. In the evaluation at 2 yr of GH treatment, two parents did not return the questionnaires, and in 2001, eight parents did not return the questionnaires. Data on occupational levels were provided by both parents and adolescents. Parental occupational level [or socioeconomic status (SES)] ranged from 1 (lower occupation) to 3 (higher occupation). When both parents were employed, the highest of the two SES levels was used. For unemployment, the lowest SES was used (23).
Intelligence. To assess intelligence, a short form of two subtests (Block-design, a performance IQ subtest, and Vocabulary, a verbal IQ subtest) of the Wechsler Intelligence Scale for Children-Revised, Dutch version (WISC-R) (24), was used for children aged between 6 and 16 yr, and a short form (also Block-design and Vocabulary subtests) of the Wechsler Adult Intelligence Scale, Dutch version (WAIS) (25) was used for adolescents aged 17 yr and older (only used in 2001). Good correlations have been found between the short-form IQ and the full-scale IQ both for the WISC-R (26) and the WAIS (27). The subtest scores for Block-design and Vocabulary were expressed as normalized standard scores (s-scores) with a mean of 10, ranging from 1 (–3 SD) to 19 (+3 SD), based on Dutch population sample data for the same age (24, 25). S-scores for the WAIS and WISC-R were combined to enable time trend analysis of the subtests. In the time trend analysis, a dummy variable (WAIS, yes or no) was added, when significant, to correct for type of IQ test used in 2001. A higher s-score indicated a better result in the subtest. Total IQ score was calculated according to an equation based on the outpatient population reference data of the Child Psychiatry Department of the Sophia Children’s Hospital (total IQ = 45.3 + 2.91 x Vocabulary s-score + 2.50 x Block-design s-score).
Behavior. Behavioral problems were measured by 3-point scale standardized questionnaires, which were designed by Achenbach and translated and validated in the Dutch language (28, 29, 30, 31, 32). For children aged between 4 and 18 yr, the 120-item Child Behavior Checklist (CBCL; filled in by parents) was used, and for adolescents aged 19 yr and older, the 115-item Young Adult Behavior Checklist (YABCL; filled in by parents) was used. Because all questionnaires were constructed in a similar way, SD scores of three scales (Internalizing, Externalizing, and Total Problem scores) were combined (CBCL/YABCL). A higher SD score indicated more problem behavior.
Self-perception. The inventory, called in Dutch the Hoe ben ik and in English the Harter Self-Perception Profile (HSPP), was designed by Harter to describe sense of self-worth and capability in several areas, using 4-point scales (33, 34). At the T1 and T2 evaluations, the 36-item child version of HSPP for children aged 8–12 yr (HSPP-c) was used; at the T3 evaluation, the 45-item adolescent version was used (HSPP-a). Because both versions were constructed in a similar way, SD scores of one scale (Total HSPP score) could be combined to enable analysis of time trend.
SD scores
To allow combining outcome variables over time (CBCL/YABCL and HSPP-c/HSPP-a), the psychosocial test scores were transformed into SD scores. For the CBCL, YABCL, and HSPP-a, a Dutch general population sample aged between 12 and 22 yr was used to calculate SD scores (n = 600, SES 1/2/3: 30/36/34%; male, 40%; mean age ± SEM, 16.4 ± 0.13 yr) (32). Comparison between the GH groups at T3 and the population sample by logistic regression (group as dependent variable and SES, gender, and age as independent variables) showed no significant differences in SES and age between the normative group and the GH groups but did show a difference for gender (more males in GH group, P < 0.01). For the HSPP-c, used at T1 and T2, Dutch normative data of the same age range (8–12 yr) as the GH groups at start were used (n = 300; male, 48%; mean age ± SEM, 9.7 ± 0.06 yr) (35). Comparison between the GH groups who filled in the HSPP-c at T1 and the population sample showed a significant difference for gender (more males in GH groups, P < 0.05) when logistic regression was applied (group as dependent variable and gender and age as independent variables).
To correct for the skewed distribution in gender of the population sample, the mean and SD of the female and male outcome was averaged and used to calculate SD scores.
Statistical analysis
To maintain the double-blind design until all participants reached adult height, an independent statistician (H.J.D.) performed the statistical analyses. All data were expressed as mean (SEM) unless otherwise specified. To compare mean outcome scores with the normative means, one-sample t tests were performed, using test value 10 for the s-scores and test value 0 for the SD scores. To estimate the time trend of the IQ and psychosocial test scores, the effect of height SD score at time of evaluation, and the effect of GH dosage on the IQ and psychosocial test scores, random regression models (RRMs) were used for continuous data. The effect on IQ and psychosocial test scores was expressed as an unstandardized estimate (b). To find the optimal model fit, the following strategy was used: 1) fixed linear time trend with and without random linear time effect; 2) fixed linear and quadratic time trend; and 3) model 1 or 2 with covariables of age and gender (1/2: male/female) and GH dosage (1 or 2 mg/m2·d). To limit the effect of collinearity, the variables height SD score and age were centered (individual value minus mean value), and the variable time was divided by 2 (0, 1, and 4.65 yr). To correct for skewed distributions, the square roots of the CBCL/YABCL scores plus 1.5 were used for analysis. The effect of GH dosage was estimated by the addition of the interaction term GH dosage x time to the optimal model. The effect of change in height was estimated by the addition of height SD score at time of evaluation to the optimal model. The advantage of using RRM, instead of a multivariate analysis of variance for repeated measurements, is that RRM copes better with missing data because it estimates missing data based on nonmissing data for that individual, assuming that missing data are missing at random (36, 37). In addition, in RRM using an unstructured error structure, variance and covariance are not assumed to be the same between time points. All calculations were done by SPSS 9.0 (SPSS, Inc., Chicago, IL), except for RRMs (SAS 6.12; SAS Institute, Cary, NC). A two-tailed P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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shows characteristics at start of GH treatment for all short children born SGA who were included in the GH trial and for those who participated in the IQ and psychosocial evaluation in 2001. No significant differences in baseline characteristics were found between the 53 GH-treated children who participated in the IQ and psychosocial evaluation in 2001 and the 26 who did not participate. Table 2 shows the clinical characteristics at time of evaluation for the children who participated in the IQ and psychosocial evaluation at T1, T2, T3. After 2 yr of GH treatment, 96% of both GH groups (73 of 76 subjects) showed a gain in height SD score of 1 SD or more, as measured from the start of treatment. This already resulted in a normal height (i.e. height –2.0 SD for age and sex) after 2 yr of GH treatment in 70% of the children (53 of 76 children). In 2001, 48 (91%) of the 53 children who participated in the IQ and psychosocial evaluation had reached a normal height. Mean (SEM) duration of GH treatment was 8.0 (0.2) yr. In 2001, 24% of the parents had a lower occupation, 35% had an intermediate occupation, and 41% had a higher occupation.
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Intelligence.
Block-design s-score, corrected for gender, age at start, and GH dosage, showed a significant linear increase of 2.2 s-score from start to 2001 (b = 0.48, P < 0.001; Fig. 1). Compared with the Dutch population sample, mean Block-design s-scores for the GH groups at start and after 2 yr of GH treatment were significantly lower (P < 0.001 at both times). In 2001, mean Block-design s-score was comparable to the Dutch population sample mean. The increase over time for Vocabulary s-score was not significant. Compared with the Dutch population sample, mean Vocabulary s-scores for the GH groups at start, after 2 yr of GH treatment, and in 2001 were significantly lower (P < 0.01, P < 0.001, and P < 0.05, respectively; Fig. 2). To analyze whether the type of IQ test used in 2001 could explain the change in IQ s-scores, a dummy variable was added (1 = WAIS at 2001 and 0 = WISC-R at 2001). The dummy variable, however, had no significant explanatory effect on both the changes in Block-design and Vocabulary s-scores. The estimate of the total IQ, corrected for gender, age at start, GH dosage, and type of IQ test used in 2001, increased significantly by 7.0 s-score over time (b = 1.51, P < 0.001; Fig. 3). Compared with the mean of the Dutch population sample (total IQ = 100), mean total IQ scores for the GH groups at start and after 2 yr of GH treatment were significantly lower (P < 0.001 and P < 0.001, respectively). In 2001, mean total IQ score was comparable to the Dutch population sample mean. No significant difference between the two GH dosage groups was found in change over time for both subtests and total IQ.
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). Externalizing SD scores and Total Problem Behavior SD scores, however, decreased linearly and significantly by 0.7 and 0.5 SD score, respectively, during GH therapy (b = –0.05, P < 0.01; and b = –0.04, P < 0.05, respectively; Figs. 5 and 6). When comparing Externalizing SD scores and Total Problem Behavior SD scores for the GH groups with the Dutch population sample mean at start and after 2 yr of GH treatment, the GH groups had higher scores (Externalizing: P < 0.001 and P < 0.01, respectively; Total Problem: P < 0.001 and P < 0.01, respectively), indicating more problem behavior. In 2001, however, the GH groups had Externalizing and Total Problem Behavior SD scores comparable to the population sample mean. No significant difference between the two GH groups was found in change over time for Internalizing, Externalizing, and Total Problem Behavior SD-scores.
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). Compared with the Dutch population sample mean, the GH groups had significantly lower scores at start (P < 0.001). After 2 yr of GH treatment, mean total HSPP SD score had increased to a mean SD score comparable to the normative mean, whereas in 2001, mean total HSPP SD score was significantly higher than the population sample mean (P < 0.05). No significant differences were found in change over time between the two GH groups.
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Externalizing and Total Problem Behavior SD scores over time were inversely related to change in height SD score (b = –0.05, P < 0.05; and b = –0.06, P < 0.01, respectively). To demonstrate the size of the effect of height SD score on behavioral problems, suppose a short SGA child commenced GH treatment with a height of –3 SD score, gained 1 SD score after 2 yr of GH treatment, and attained an adult height of –1 SD score in 2001. The child’s Externalizing Problem Behavior would have decreased by 0.8 SD score from start of GH treatment until 2001, whereas a short SGA child with no increase in height SD score would have an Externalizing Problem Behavior decrease of 0.5 SD score. When using the same height increase as in the previous example, the child’s Total Problem Behavior would have decreased by 0.5 SD score from the start of GH treatment until 2001, whereas a short SGA child with no increase in height SD score would have a Total Problem Behavior decrease of 0.1 SD score. The scores over time for Vocabulary, Block-design, Internalizing, or Total HSP were not related to change in height SD score. In 2001, scores for Vocabulary, Block-design, Internalizing, Externalizing, Total Problem Behavior, or total HSP were not related to height SD score in 2001, with or without correction for age, gender, or GH dosage.
Effect of head circumference
Head circumference SD score at start was positively and significantly related to Block-design and Vocabulary s-scores over time (b = 0.65, P < 0.05; and b = 1.06, P < 0.01, respectively). Head circumference SD score at start, however, was not related to the change over time for both Block-design and Vocabulary s-scores (interaction term: head circumference SD score at start x time). In addition, change in head circumference SD score was positively and significantly related to Block-design and Vocabulary s-scores over time (b = 0.72, P < 0.01; and b = 0.75, P < 0.01, respectively). Correction of head circumference SD score for height SD score did not contribute to the models.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Before the start of GH treatment, all children had short stature; this was an inclusion criterion for the trial. After 2 yr of GH treatment, 96% of both GH groups showed a gain in height SD score of 1 SD or more, as measured from the start of treatment. GH treatment, therefore, already resulted in a normal height (i.e. height –2.0 SD for age and sex) after 2 yr of GH treatment in 70% of the children (53 of 76 children), whereas this percentage had increased to 91% in 2001. In the present study, as part of a randomized, double-blind, GH-dose response study, we evaluated the effect of long-term GH therapy on IQ and psychosocial functioning, as measured by standardized IQ subtests and standardized questionnaires on behavioral problems and self-perception.
From start of GH treatment until 2001, we found a significant linear improvement in mean Block-design s-score (a performance IQ subtest) and estimated total IQ. Both s-scores increased from values significantly lower than the mean of Dutch peers to values comparable to the mean of Dutch peers. Vocabulary s-score, which is a verbal IQ subtest, however, remained lower than the mean of their Dutch peers. Regarding behavioral problems reported by the parents, we found a significant linear decrease over time of Externalizing Behavior SD score, indicating a decrease in behavioral problems. Both Externalizing and Total Problem Behavior scores decreased from values above the mean of the reference population sample to values comparable to the reference mean. Also, self-perception (total HSPP SD score) improved quadratically over time during GH treatment, showing that the largest improvement occurred in the first 2 yr of GH treatment. Self-perception increased from a score below the mean of their Dutch peers to a score above the mean.
Although one study found little difference in quality of life between GH-deficient adults and same-sex siblings (38), several other studies in GH-deficient children and adults, some placebo controlled, have shown that GH treatment had a beneficial effect on cognition, energy, mood, and behavior (39, 40, 41, 42, 43, 44). Therefore, the increase in test scores might be a direct effect of GH itself on cerebral functioning. Only Block-design s-scores, a subtest for performance IQ, improved over time, without change in the verbal IQ subtest, Vocabulary s-scores, possibly indicating a GH effect on the right hemisphere of the brain (45). Hopefully, further studies (for instance, into processing speed) will show the mechanisms behind this improvement. Although we did not find any significant differences in IQ test results and psychosocial functioning between the two GH dosage groups, this might have been because 1 mg/m2·d was enough to achieve the optimal effect on IQ and psychosocial functioning. This is similar to our findings regarding the effect of GH dosage on adult height (19). Another possible explanation for the improvement in IQ and psychosocial functioning might be the extra medical attention. Unfortunately, due to ethical considerations, it was not possible for us to include a nontreated randomized control group as part of the GH trial to explore the effect of the extra medical attention. We did not, however, provide psychological counseling to treat the behavioral problems found at start of GH treatment.
Interestingly, no differences in Internalizing Problem Behavior scores were found compared with Dutch peers. A possible reason might be the way short children are treated, unintentionally, by adults. They tend to treat short children as younger and evade age-appropriate demands on their intellect and behavior. This may lead to feelings of frustration, which, in this study group, was acted out by childish (age-inappropriate) and/or aggressive externalizing behavior.
Most children showed a considerable catch-up in height during 8 yr of GH treatment, which was paralleled by an improvement in scores for IQ, behavior, and self-perception. In previous studies in other patient groups, such as idiopathic short stature, childhood GH deficiency, and Turner syndrome, an effect of height gain during GH treatment on psychosocial functioning was found (46, 47, 48). To test whether the considerable increase in height SD score in our study group could explain the improvement of the scores, we added height SD score over time to the models. Interestingly, the addition of height SD score to the regression model for Externalizing Behavior SD score, corrected for age and gender, showed a significant negative correlation, indicating that, over time, children whose height became closer to that of their peer group had less problem behavior. This finding might suggest that the decrease in externalizing behavioral problems was caused by the increase in height. For IQ and self-perception, however, the addition of height SD score had no effect on the model, indicating that height SD score at time of evaluation was not related to IQ or self-perception test scores. Several reasons might explain why we did not find such a relationship. For IQ, the influence of other factors, such as genetic predisposition, might have masked the effect of increase in height. Because all children showed GH-induced catch-up growth after start of GH treatment, the GH groups might have been too homogenous regarding height and too heterogeneous regarding factors such as genetic predisposition to show a relationship between increase in height and IQ. Another possibility is that the effect of GH treatment was a result of its direct action on cerebral functioning, as mentioned earlier, and was thus not related to its effect on increase in height. For self-perception, factors such as physical appearance and coping strategy but also the nonlinear increase in self-perception might have masked the effect of increase in height.
One factor previously reported to be positively related to intelligence is head circumference (15). We show that this relationship between head circumference and IQ also exists in short children born SGA, both at start of the GH trial as well as during GH treatment. In addition, we show that the head circumference SD score was low-normal at start of treatment and remained so during GH treatment. Thus, head circumference SD score did not improve with IQ scores during GH treatment. Height SD score, however, increased during GH treatment, leading to a head circumference SD score more in proportion to height SD score. One of the suggested reasons for a decreased IQ in SGA children was that brain development was affected by intrauterine malnutrition (14). Because a deficit in brain development is often accompanied by a smaller head circumference, it would be interesting to see whether head circumference before GH treatment would predict IQ development during treatment. We show that head circumference SD score at the start of treatment did not predict the IQ increase during GH treatment. This indicates that IQ scores improved in short children born SGA during GH treatment, regardless of whether head circumference had been spared from previous growth retardation.
In conclusion, parallel to a considerable GH-induced catch-up growth, children born SGA showed a significant improvement in IQ scores, behavior, and self-perception over time. During 8 yr of GH treatment, IQ and psychosocial functioning had improved from scores significantly below average to scores comparable to Dutch peers. In addition, the taller the child became over time, the less problem behavior the child showed. Although, in general, a child with a smaller pretreatment head circumference had a lower IQ at start of GH treatment, the increase in its IQ score during GH treatment occurred regardless of whether its head circumference had been spared from growth retardation. Considering the positive effects on IQ and psychosocial functioning, in addition to the catch-up growth during GH treatment, we recommend GH treatment for short SGA children without signs of persistent catch-up growth. Further follow-up will show whether GH treatment also has an effect on their life achievements in the future.
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Footnotes |
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Current address for H.M.K.: Department of Developmental Psychology, Free University Medical Center, Amsterdam, The Netherlands.
Abbreviations: CA, Chronological age; CBCL, Child Behavior Checklist; HSP, combined scores of both HSPP versions; HSPP, Harter Self-Perception Profile; HSPP-a, HSPP adolescent version; HSPP-c, HSPP child version; IQ, intelligence quotient; RRM, random regression model; SES, socioeconomic status; SGA, small for gestational age; T1, start of trial in 1991; T2, after 2 yr of GH treatment; T3, in the year 2001; WAIS, Wechsler Adult Intelligence Scale; WISC-R, Wechsler Intelligence Scale for Children-Revised; YABCL, Young Adult Behavior Checklist.
Received July 9, 2003.
Accepted April 1, 2004.
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