- Email: [email protected]
Neuropsychological development during the first two years in children with congenital hypothyroidism screened at birth: the Cuban experience
Screening, 1(1992) 167-173 0 1992 Elsevier Science Publishers B.V. All rights reserved 0925-6164/92/$5.00
SCREEN 00022
Neuropsychological development during the first two years in children with congenital hypothyroidism screened at birth: the Cuban experience M.A. Alvarez,a R. Guell,” J. Gonzalez,a A. Seuqa H. Perez,b R. Robaina” and J.L. Fernandez-Yero” “National Institute of Endocrinology, bInstitute of Pedagogical Sciences and “Immunoassay Center, Havana City, Cuba (Accepted 23 March 1992)
Sixty children with congenital hypothyroidism (CH) screened at birth and early treated were developmentally assessed three times during their first 2 years (average ages 200, 313 and 447 days) by the Brunet-Lezine Maturity Scale. These children also received psychomotor stimulation by their parents according to instructions given to them. For each child with CH there was a pair of healthy matched controls (CTR) whose data were averaged and used as single ones. For each subject the mean of these as well as the slope were calculated in order to know the general pattern of the development quotients (DQ). The data show that although the DQ of the CH were with normal ranges, they had significantly lower scores on the psychomotor scales (postural control and eye-hand coordination) than CTR. As related to language there were no significant differences in the mean DQ; however, the significant differences in the slope indicate that the trend in CH is toward a decrease in these values as time progresses. Analysis of covariance shows that the strongest predictor of development in CH is the age at which treatment begins. Key wordy: Development; Congenital hypothyroidism; Screening
Introduction Thyroid screening in newborns is a well-established method for prevention of the mental retardation (MR) caused by congenital hypothyroidism (CH) in developed Correspondence to: M.A. Alvarez, Department of Psychology, National Institute of Endocrinology, Zapata & D, Vedado, Havana 10400, Cuba.
168
countries [2,10]. In spite of this achievement (the elimination of MR) there is a general agreement that many early treated children with CH bear neurocognitive deficits. These impairments affect areas such as psychomotor development, language and behavior. These deficits are associated with thyroid-related factors as well as with environmental influences [3,7-91. However, much of the data on development in CH children have been gathered post hoc the actual programs, leading to methodological and practical problems that limit generalization of the results [5]. ‘Overall’ quality control in programs such as these requires precise assessment of target variables of development of the children, which should be identified and defined operationally throughout the entire program. This goal can only be reached by a multidisciplinary approach, which integrates endocrinologists, biochemists and psychologists as well as technichians and auxiliary personnel. The Cuban Program has made efforts to complement all the specialities [4]. The organizational structure of the Program begins with newborn screening. In this phase umbilical cord serum is obtained at birth and sent to the screening center for TSH determination by an Ultramicro ELISA method adapted to an ultramicro-analytic system [l]. When the TSH value in this sample is over 25 mU/l on duplicate analysis, the result is considered positive and a report submitted to the Care and Control Center. This leads to collection of a blood sample from the heel of the newborn infant for the determination of TSH. Until this newborn’s result is known, therapy with L-thyroxine is begun. If the second (newborn) test is also positive, the infant is continued on this treatment by a team that includes an endocrinologist, a psychologist and a technician specialized in psychological testing. The psychologist is responsible for coordinating the periodic assessments and for providing feedback of these results to the endocrinologist so that the clinical picture is complete. He also teaches the family how to carry out stimulation subprograms aimed at improving impaired areas. This paper is a preliminary report of the first data obtained on the follow-up of children with CH in the Cuban Program.
Material and Methods Subjects Group 1: Congenital hypothyroidism (CH): We have studied 60 children with CH. This paper presents the results of the first three evaluations on the follow-ups of these children. Their mean ages at the time of these evaluations were 200, 313 and 447 days. A full clinical history was obtained for each patient. In this paper we will analyze the age in days when treatment began, the weight and length at birth, the Apgar scores at 1 and 5 minutes, two determinations of blood TSH (in umbilical cord serum and newborn blood), gestational age, and the age of the parents. The hormonal substitutive treatment consisted of L-thyroxine 5 pg/kg. Group 2: Healthy controls (CTR): For each CH patient we evaluated two healthy
169
controls matched for sex, age (within 15 days) and place of residence. The values of these two controls were averaged and used as the control data for each case. The children were selected from kindergarten, so they spent each day in a stimulating environment. Due to the need for matching, the control group was recruited after the CH group. For this reason the number of matched controls drops from 60 in the first, to 48 in the second and 26 in the third. Assessm
170
Results Analysis of the 25 cases in which each had two matched controls for all three evaluations indicates that the means of all the areas of DQ were within normal ranges. However, the psychomotor areas (postural control and eye-hand coordination) had significantly lower scores than the controls, indicating subtle impairments in this area, more evident in eye-hand control (Table 1). These subscales account for the lower total scores in the hypothyroid group. All slopes are negative including those of the controls, suggesting that the higher values during the first months are due to the fact that some of the data acquired were supported by the mother with the resulting overstimulation of ability. The assessment at later ages is more precise, thus allowing more reliable results. Two slopes, eye-hand coordination and language, differ significantly between the CH and control children. For eye-hand coordination the slope in the CH is flat and remains so, probably because the initial values are low, whereas the slope for the controls is negative. By contrast, in language the CH group has a bigger negative slope than the controls. This suggests that despite there being no significant differences in language between the groups during the first 2 years, the trend is toward a reduction in the scores of the CH children, indicating a risk for impairment in this area. The comparison according to sex (Table 2) shows that females had significant lower scores in the postural control and eye-hand coordination areas than males. Among females the slope for eye-hand coordination was similar to that of the general group with a higher value in the control group, indicating initial lower scores in CH children. Males with CH did not differ from controls in any of the variables measured. Predictor variables
A correlation was calculated among the variables to exclude the possibility that the high correlations between variables could interfere with the general analysis. The variables included the day of age when treatment began, the Apgar score at 5 minutes, TABLE 1 Mean DQ scores and slopes in congenital hypothyroidism compared to matched averaged controls (n = 25)
DQ (Mean & SD)
Slope
CH
Controls
P
CH
Controls
P
Postural Eye-hand Language Sociability
113+17 99k18 120+24 117&17
125* 10 114+ 6 112*12 119+29
0.012 0.005 n.s. n.s.
-0.003 -0.018 -0.22 -0.61
-0.02 -0.05 0.038 -0.113
n.s. 0.049 0.013 n.s.
Total
108+ 18
116+ 7
0.04
-0.05
-0.04
n.s
CH, congenital hypothyroidism; n.s., not significant.
171
TABLE 2 Wilcoxon matched-pairs signed rank test Males (n= 13)
Females (n= 12)
Mean
Slope
Slope
Mean
Z
P
Z
P
z
P
z
P
Postural Eye-hand Language Sociability
-0.84 -2.07 -1.47 -1.77
n.s. 0.03 n.s. n.s.
-2.7 -2.7 -1.7 -1.6
ns. ns. n.s. n.s.
-0.35 -0.71 -0.71 -1.77
ns. ns. n.s. n.s.
-0.71 -2.10 -0.88 -1.59
ns. n.s. n.s. n.s.
Total
-0.08
n.s.
-1.6
n.s.
-0.78
n.s.
-1.49
n.s.
n.s., not significant.
TABLE 3 Analysis o,T covariance results Dependent variable Slope
Average
Source
P
P
Covariates Beginning of treatment (days) Apgar 5 min TSH in cord Weight Maternal age
0.968 n.s. ns. n.s. n.s. n.s.
0.004 0.022 n.s. n.s. n.s. ns.
n.s. n.s.
n.s. ns
Main effects Sex
Stimulation n.s., not significant.
the TSH- value in cord serum, the weight at birth, the maternal age, the sex of the child and the level of stimulation (analyzed on the basis of estimation of adherence to the instructions). The analysis of covariance (Table 3) reveals no significant association with regard to the slope but significance with regard to mean of the DQ, (P=O.O4) with early treatment by far having the greatest significance (P=O.O22). No significant interactions were found with qualitative variables such as sex and level of stimulation.
172
Discussion
The importance of this preliminary report is to emphasize the value of a monitoring system aimed at providing complementary data for the clinical management of the patients and continuous feedback to determine screening program efficacy and performance. This multidisciplinary approach provides a new broad spectrum of philosophy in the treatment of these patients. This integrated approach allows neuropsychological deficits to be detected in their early stages. We believe that monthly follow-ups beginning in the first month of life are desirable not only for the evaluation and estimulation of development but also for interventions in family functioning [lo]. Although must of the CH patients functioned within the normal ranges of DQ, this neuropsychological assessment identified subtle impairments in psychomotor areas and led to an emphasis on vigilance in the verbal area, which tends to decrease in competence as the child gets older. Further analysis is needed to confirm and clarify the differences according to sex that we observed in this study. The lack of detected influences from stimulation by the parents could be explained by two factors. First, during the first 2 years of life development as measured by this evaluation is more linked to biological maturity than environmental stimulation. Perhaps this relatively gross method of measuring maturity and function cannot detect subtle influences of environment. Second, only 11 of our cases were classified as having poor compliance with the instructions. Since the families all lived in similar socioeconomical status and had relatively few differences among them, overall stimulation by parents may be similar regardless of compliance with instructions for additional parental stimulation. This result could suggest that the manner in which stimulation is communicated to the parents could be improved. The covariates analyzed indicated that the single major influence in the DQ score was the early treatment of CH; this supports the concept that treatment for CH should begin within the first weeks after birth. The follow-up of these patients during the next years, and the inclusion of additional instruments to explore different areas of development, will provide information that could lead to new means for optimal intervention in these children.
Acknowledgement
This research was partially supported by a grant from PAHO/WHO.
References 1 Bialy H. Cuba to market an ultra-microELISA system. Biotechnology 1987; July. 2 Dussauh JH. History and impact of screening programs for congenital hypothyroidism. In: Dussauh JH, Walker P, eds. Congenital Hypothyroidism. New York: Marcel Dekker, 1983;163. 3 Farriaux JP, Dhont JL, Lebecq MF. Intellectual outcome in hypothyroid children screened at birth.
173 In: Schmidt BJ, Diamont AJ, Loghin-Gross0 NS, eds. Current Trends in Infant Screening. Amsterdam: Elsevier Science Publishing, 1989; I 13. 4 Guell IR, Alvarez MA, Robaina R, Fernandez-Yero JL. Neonatal Thyroid screening: the Cuban program. In: Schmidt BJ, Diamont A, Loghin-Gross0 NS, eds. Currents Trends in Infant Screening. Amsterdam: Elsevier Science Publishing 1989;109. 5 Illig R, Largo RH, Qin Q, Torresani T, Rochichioli D, Larsson A: Mental development in congenital hypothyroidism after neonatal screening. Arch Dis Child 1987;62:1050. 6 Manual for the Brunet Lezine Maturity Scale. Ed MEPSA, Frances Rodriguez 47 Madrid. 7 Rovet .I. Does newborn screening for congenital hypothyroidism increase the risk of the ‘the vuhterdbie child syndrome’. Infant Screen 1991;14:3. 8 Rovet J, Ehrlich R, Sorbara D. The intellectual and behavioral characteristics of children with congenital hypothyroidism identified by neonatal screening in Ontario. The Toronto prospective study. In: Carter TP, Witty AM, eds. Genetic Disease. Screening and Management. New York: A Liss Inc., 1986:2:3 1. 9 Rovet J, Ehrhch R, Sorbara D. Intellectual outcome in children with fetal hypothyroidism. J Pediatr 1987;110~700. 10 Working Group on congenital hypothyroidism of the European Society for Pediatric Endocrinology: Epiderniological Inquiry on Congenital Hypothyroidism in Europe (198551986). Horm Res 1990:34: I
SCREEN 00022
Neuropsychological development during the first two years in children with congenital hypothyroidism screened at birth: the Cuban experience M.A. Alvarez,a R. Guell,” J. Gonzalez,a A. Seuqa H. Perez,b R. Robaina” and J.L. Fernandez-Yero” “National Institute of Endocrinology, bInstitute of Pedagogical Sciences and “Immunoassay Center, Havana City, Cuba (Accepted 23 March 1992)
Sixty children with congenital hypothyroidism (CH) screened at birth and early treated were developmentally assessed three times during their first 2 years (average ages 200, 313 and 447 days) by the Brunet-Lezine Maturity Scale. These children also received psychomotor stimulation by their parents according to instructions given to them. For each child with CH there was a pair of healthy matched controls (CTR) whose data were averaged and used as single ones. For each subject the mean of these as well as the slope were calculated in order to know the general pattern of the development quotients (DQ). The data show that although the DQ of the CH were with normal ranges, they had significantly lower scores on the psychomotor scales (postural control and eye-hand coordination) than CTR. As related to language there were no significant differences in the mean DQ; however, the significant differences in the slope indicate that the trend in CH is toward a decrease in these values as time progresses. Analysis of covariance shows that the strongest predictor of development in CH is the age at which treatment begins. Key wordy: Development; Congenital hypothyroidism; Screening
Introduction Thyroid screening in newborns is a well-established method for prevention of the mental retardation (MR) caused by congenital hypothyroidism (CH) in developed Correspondence to: M.A. Alvarez, Department of Psychology, National Institute of Endocrinology, Zapata & D, Vedado, Havana 10400, Cuba.
168
countries [2,10]. In spite of this achievement (the elimination of MR) there is a general agreement that many early treated children with CH bear neurocognitive deficits. These impairments affect areas such as psychomotor development, language and behavior. These deficits are associated with thyroid-related factors as well as with environmental influences [3,7-91. However, much of the data on development in CH children have been gathered post hoc the actual programs, leading to methodological and practical problems that limit generalization of the results [5]. ‘Overall’ quality control in programs such as these requires precise assessment of target variables of development of the children, which should be identified and defined operationally throughout the entire program. This goal can only be reached by a multidisciplinary approach, which integrates endocrinologists, biochemists and psychologists as well as technichians and auxiliary personnel. The Cuban Program has made efforts to complement all the specialities [4]. The organizational structure of the Program begins with newborn screening. In this phase umbilical cord serum is obtained at birth and sent to the screening center for TSH determination by an Ultramicro ELISA method adapted to an ultramicro-analytic system [l]. When the TSH value in this sample is over 25 mU/l on duplicate analysis, the result is considered positive and a report submitted to the Care and Control Center. This leads to collection of a blood sample from the heel of the newborn infant for the determination of TSH. Until this newborn’s result is known, therapy with L-thyroxine is begun. If the second (newborn) test is also positive, the infant is continued on this treatment by a team that includes an endocrinologist, a psychologist and a technician specialized in psychological testing. The psychologist is responsible for coordinating the periodic assessments and for providing feedback of these results to the endocrinologist so that the clinical picture is complete. He also teaches the family how to carry out stimulation subprograms aimed at improving impaired areas. This paper is a preliminary report of the first data obtained on the follow-up of children with CH in the Cuban Program.
Material and Methods Subjects Group 1: Congenital hypothyroidism (CH): We have studied 60 children with CH. This paper presents the results of the first three evaluations on the follow-ups of these children. Their mean ages at the time of these evaluations were 200, 313 and 447 days. A full clinical history was obtained for each patient. In this paper we will analyze the age in days when treatment began, the weight and length at birth, the Apgar scores at 1 and 5 minutes, two determinations of blood TSH (in umbilical cord serum and newborn blood), gestational age, and the age of the parents. The hormonal substitutive treatment consisted of L-thyroxine 5 pg/kg. Group 2: Healthy controls (CTR): For each CH patient we evaluated two healthy
169
controls matched for sex, age (within 15 days) and place of residence. The values of these two controls were averaged and used as the control data for each case. The children were selected from kindergarten, so they spent each day in a stimulating environment. Due to the need for matching, the control group was recruited after the CH group. For this reason the number of matched controls drops from 60 in the first, to 48 in the second and 26 in the third. Assessm
170
Results Analysis of the 25 cases in which each had two matched controls for all three evaluations indicates that the means of all the areas of DQ were within normal ranges. However, the psychomotor areas (postural control and eye-hand coordination) had significantly lower scores than the controls, indicating subtle impairments in this area, more evident in eye-hand control (Table 1). These subscales account for the lower total scores in the hypothyroid group. All slopes are negative including those of the controls, suggesting that the higher values during the first months are due to the fact that some of the data acquired were supported by the mother with the resulting overstimulation of ability. The assessment at later ages is more precise, thus allowing more reliable results. Two slopes, eye-hand coordination and language, differ significantly between the CH and control children. For eye-hand coordination the slope in the CH is flat and remains so, probably because the initial values are low, whereas the slope for the controls is negative. By contrast, in language the CH group has a bigger negative slope than the controls. This suggests that despite there being no significant differences in language between the groups during the first 2 years, the trend is toward a reduction in the scores of the CH children, indicating a risk for impairment in this area. The comparison according to sex (Table 2) shows that females had significant lower scores in the postural control and eye-hand coordination areas than males. Among females the slope for eye-hand coordination was similar to that of the general group with a higher value in the control group, indicating initial lower scores in CH children. Males with CH did not differ from controls in any of the variables measured. Predictor variables
A correlation was calculated among the variables to exclude the possibility that the high correlations between variables could interfere with the general analysis. The variables included the day of age when treatment began, the Apgar score at 5 minutes, TABLE 1 Mean DQ scores and slopes in congenital hypothyroidism compared to matched averaged controls (n = 25)
DQ (Mean & SD)
Slope
CH
Controls
P
CH
Controls
P
Postural Eye-hand Language Sociability
113+17 99k18 120+24 117&17
125* 10 114+ 6 112*12 119+29
0.012 0.005 n.s. n.s.
-0.003 -0.018 -0.22 -0.61
-0.02 -0.05 0.038 -0.113
n.s. 0.049 0.013 n.s.
Total
108+ 18
116+ 7
0.04
-0.05
-0.04
n.s
CH, congenital hypothyroidism; n.s., not significant.
171
TABLE 2 Wilcoxon matched-pairs signed rank test Males (n= 13)
Females (n= 12)
Mean
Slope
Slope
Mean
Z
P
Z
P
z
P
z
P
Postural Eye-hand Language Sociability
-0.84 -2.07 -1.47 -1.77
n.s. 0.03 n.s. n.s.
-2.7 -2.7 -1.7 -1.6
ns. ns. n.s. n.s.
-0.35 -0.71 -0.71 -1.77
ns. ns. n.s. n.s.
-0.71 -2.10 -0.88 -1.59
ns. n.s. n.s. n.s.
Total
-0.08
n.s.
-1.6
n.s.
-0.78
n.s.
-1.49
n.s.
n.s., not significant.
TABLE 3 Analysis o,T covariance results Dependent variable Slope
Average
Source
P
P
Covariates Beginning of treatment (days) Apgar 5 min TSH in cord Weight Maternal age
0.968 n.s. ns. n.s. n.s. n.s.
0.004 0.022 n.s. n.s. n.s. ns.
n.s. n.s.
n.s. ns
Main effects Sex
Stimulation n.s., not significant.
the TSH- value in cord serum, the weight at birth, the maternal age, the sex of the child and the level of stimulation (analyzed on the basis of estimation of adherence to the instructions). The analysis of covariance (Table 3) reveals no significant association with regard to the slope but significance with regard to mean of the DQ, (P=O.O4) with early treatment by far having the greatest significance (P=O.O22). No significant interactions were found with qualitative variables such as sex and level of stimulation.
172
Discussion
The importance of this preliminary report is to emphasize the value of a monitoring system aimed at providing complementary data for the clinical management of the patients and continuous feedback to determine screening program efficacy and performance. This multidisciplinary approach provides a new broad spectrum of philosophy in the treatment of these patients. This integrated approach allows neuropsychological deficits to be detected in their early stages. We believe that monthly follow-ups beginning in the first month of life are desirable not only for the evaluation and estimulation of development but also for interventions in family functioning [lo]. Although must of the CH patients functioned within the normal ranges of DQ, this neuropsychological assessment identified subtle impairments in psychomotor areas and led to an emphasis on vigilance in the verbal area, which tends to decrease in competence as the child gets older. Further analysis is needed to confirm and clarify the differences according to sex that we observed in this study. The lack of detected influences from stimulation by the parents could be explained by two factors. First, during the first 2 years of life development as measured by this evaluation is more linked to biological maturity than environmental stimulation. Perhaps this relatively gross method of measuring maturity and function cannot detect subtle influences of environment. Second, only 11 of our cases were classified as having poor compliance with the instructions. Since the families all lived in similar socioeconomical status and had relatively few differences among them, overall stimulation by parents may be similar regardless of compliance with instructions for additional parental stimulation. This result could suggest that the manner in which stimulation is communicated to the parents could be improved. The covariates analyzed indicated that the single major influence in the DQ score was the early treatment of CH; this supports the concept that treatment for CH should begin within the first weeks after birth. The follow-up of these patients during the next years, and the inclusion of additional instruments to explore different areas of development, will provide information that could lead to new means for optimal intervention in these children.
Acknowledgement
This research was partially supported by a grant from PAHO/WHO.
References 1 Bialy H. Cuba to market an ultra-microELISA system. Biotechnology 1987; July. 2 Dussauh JH. History and impact of screening programs for congenital hypothyroidism. In: Dussauh JH, Walker P, eds. Congenital Hypothyroidism. New York: Marcel Dekker, 1983;163. 3 Farriaux JP, Dhont JL, Lebecq MF. Intellectual outcome in hypothyroid children screened at birth.
173 In: Schmidt BJ, Diamont AJ, Loghin-Gross0 NS, eds. Current Trends in Infant Screening. Amsterdam: Elsevier Science Publishing, 1989; I 13. 4 Guell IR, Alvarez MA, Robaina R, Fernandez-Yero JL. Neonatal Thyroid screening: the Cuban program. In: Schmidt BJ, Diamont A, Loghin-Gross0 NS, eds. Currents Trends in Infant Screening. Amsterdam: Elsevier Science Publishing 1989;109. 5 Illig R, Largo RH, Qin Q, Torresani T, Rochichioli D, Larsson A: Mental development in congenital hypothyroidism after neonatal screening. Arch Dis Child 1987;62:1050. 6 Manual for the Brunet Lezine Maturity Scale. Ed MEPSA, Frances Rodriguez 47 Madrid. 7 Rovet .I. Does newborn screening for congenital hypothyroidism increase the risk of the ‘the vuhterdbie child syndrome’. Infant Screen 1991;14:3. 8 Rovet J, Ehrlich R, Sorbara D. The intellectual and behavioral characteristics of children with congenital hypothyroidism identified by neonatal screening in Ontario. The Toronto prospective study. In: Carter TP, Witty AM, eds. Genetic Disease. Screening and Management. New York: A Liss Inc., 1986:2:3 1. 9 Rovet J, Ehrhch R, Sorbara D. Intellectual outcome in children with fetal hypothyroidism. J Pediatr 1987;110~700. 10 Working Group on congenital hypothyroidism of the European Society for Pediatric Endocrinology: Epiderniological Inquiry on Congenital Hypothyroidism in Europe (198551986). Horm Res 1990:34: I