PII: S0022-3476(95)70377-2

Abstract

Reply To the EditorDrs. Mitchell and Klein contend that early and adequate treatment will ensure optimal outcome in all children with hypothyroidism. Our observation that some patients with congenital hypothyroidism (CH) detected by neonatal screening have a less favorable cognitive and motor outcome is interpreted as disheartening news for physicians. Drs. Mitchell and Klein seem to have just one explanation: it cannot be the patient, so it must be the doctor, and they demand proof that our patients with CH were treated adequately.We consider it a blessing that in the 1970s a group of North American investigators, among them Drs. Mitchell and Klein, showed that the devastating effects of CH are preventable by introducing neonatal mass screening. In those days it was thought that fetal hypothyroidism had little or no impact on cerebral development, because early-treated patients had such favorable outcomes. Moreover, it was thought that there was no significant maternal-fetal transfer of thyroid hormone, and it was argued that a fetus could develop properly even in the absence of any thyroid hormone. Now we know that thyroxine (T4) passes the placenta, and we are aware of the devastating effects of maternal hypothyroidism on the developing central nervous system. The fetal brain needs thyroid hormone, although the questions of when and how much remain to be answered. It is hard to believe that the limited maternal supply of T4 is sufficient in all cases of severe CH; we have demonstrated that T4 levels in cord blood from infants with a complete inability to produce T4 show considerable variation,1Vulsma T Gons MH de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (603) Google Scholar and that especially in severe CH, plasma T4 concentrations decrease during the first few weeks after birth. In our opinion, one can hardly expect all children with CH to have completely normal motor skills and intelligence even when they are treated early and adequately.In the Netherlands the neonatal thyroid screening was set up according to the American methods. Treatment criteria also fit well with the guidelines published by the New England Congenital Hypothyroidism Collaborative.2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The Dutch health care system guarantees that every patient has access to the same quality of treatment and follow-up. There is no reason to believe that Dutch pediatricians provide less adequate care than their colleagues abroad.The criteria that we used for scoring treatment compliance are provided in our article.3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar Hormone levels were measured frequently, with the interval increasing gradually from at least once a week to about once every 3 months after 1 year of age. On the basis of the hormone level readings, almost all patients received adequate long-term treatment. Some irregularities in the administration of T4 may have occurred, but it is highly unlikely that such irregularities coincided preferentially with cases of severe CH.The only way to determine the cerebral damage caused by fetal and neonatal hypothyroidism is to correlate the individual cognitive and motor outcome with data concerning severity and duration of the hypothyroid phase, and with other complicating factors. This requires etiologic classification of the study population. Many studies, in particular those of the New England Congenital Hypothyroidism Collaborative,2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 4New England Congenital Hypothyroidism Collaborative Neonatal hypothyroidism screening: status of patients at 6 years of age.J PEDIATR. 1985; 107: 915-919Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar, 6New England Congenital Hypothyroidism Collaborative Elementary school performance of children with congenital hypothyroidism.J PEDIATR. 1990; 116: 27-32Abstract Full Text PDF PubMed Scopus (82) Google Scholar have presented data only on the CH population as a whole. By including milder cases, such studies risk “diluting” the effects of the severe cases. Mitchell and Klein refer to three smaller studies to illustrate their contention that “early and adequate treatment, including frequent monitoring, will ensure optimal outcome in all children with hypothyroidism, regardless of type.” One of these studies reports that at 6 years of age, 13 children with athyrosis had a mean IQ of 84, whereas 22 children with ectopic or hypoplastic glands had a mean IQ of 100.7Heyerdahl S. Intellectual development of children with congenital hypothyroidism in Norway.in: Research in congenital hypothyroidism. Plenum Press, New York1989: 298-299Google ScholarTwo recent publications from the United Kingdom support our (unfortunate) results.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar, 9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar Simons et al.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar tested the IQs of patients with CH at about the same age as we did. Their subgroup of patients with very low pretreatment plasma T4 concentrations (defined as ≤40 nmol/L) had a mean full-scale IQ 10 points below that of matched control subjects, and their subgroup of patients with moderately decreased pretreatment plasma T4 levels (>40 nmol/L) had a mean full-scale IQ similar to that of the control group. Timing of the T4 replacement therapy (23 ± 9 days [mean ± SD] for the Dutch patients with low neonatal T4 levels,3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar 26 days [range, 10 to 40 days] for the British patients with low neonatal T4 levels,8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar and 25 ± 15 days [mean ± SD] for the whole group of patients from New England [presumably slightly earlier for patients with severe CH])5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar cannot explain the differences in cognitive outcome. Although the Finnish screening program may be unique, enabling treatment to start at a median age of only 6 days, Virtanen et al.10Virtanen M Santavuori P Hirvonen E Perheentupa J. Multivariate analysis of psychomotor development in congenital hypothyroidism.Acta Paediatr Scand. 1989; 78: 405-411Crossref PubMed Scopus (24) Google Scholar concluded that some damage is inevitable and that its degree correlates with the severity of the [intrauterine] CH. Tillotson et al.9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar concluded that the severity of CH has a threshold effect on brain development, probably determined prenatally.Physicians must accept the fact that some patients with CH already have some cerebral damage at the time of referral, because of exposure to very low T4 levels prenatally or during the short interval between birth and referral. It is misleading to promise all parents beforehand a completely normal cognitive and motor development for their children. On the other hand, screening organizations should never rest in their attempts to reduce the time interval between birth and administration of the first dose of T4 as much as possible.9/35/62074 Reply To the EditorDrs. Mitchell and Klein contend that early and adequate treatment will ensure optimal outcome in all children with hypothyroidism. Our observation that some patients with congenital hypothyroidism (CH) detected by neonatal screening have a less favorable cognitive and motor outcome is interpreted as disheartening news for physicians. Drs. Mitchell and Klein seem to have just one explanation: it cannot be the patient, so it must be the doctor, and they demand proof that our patients with CH were treated adequately.We consider it a blessing that in the 1970s a group of North American investigators, among them Drs. Mitchell and Klein, showed that the devastating effects of CH are preventable by introducing neonatal mass screening. In those days it was thought that fetal hypothyroidism had little or no impact on cerebral development, because early-treated patients had such favorable outcomes. Moreover, it was thought that there was no significant maternal-fetal transfer of thyroid hormone, and it was argued that a fetus could develop properly even in the absence of any thyroid hormone. Now we know that thyroxine (T4) passes the placenta, and we are aware of the devastating effects of maternal hypothyroidism on the developing central nervous system. The fetal brain needs thyroid hormone, although the questions of when and how much remain to be answered. It is hard to believe that the limited maternal supply of T4 is sufficient in all cases of severe CH; we have demonstrated that T4 levels in cord blood from infants with a complete inability to produce T4 show considerable variation,1Vulsma T Gons MH de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (603) Google Scholar and that especially in severe CH, plasma T4 concentrations decrease during the first few weeks after birth. In our opinion, one can hardly expect all children with CH to have completely normal motor skills and intelligence even when they are treated early and adequately.In the Netherlands the neonatal thyroid screening was set up according to the American methods. Treatment criteria also fit well with the guidelines published by the New England Congenital Hypothyroidism Collaborative.2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The Dutch health care system guarantees that every patient has access to the same quality of treatment and follow-up. There is no reason to believe that Dutch pediatricians provide less adequate care than their colleagues abroad.The criteria that we used for scoring treatment compliance are provided in our article.3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar Hormone levels were measured frequently, with the interval increasing gradually from at least once a week to about once every 3 months after 1 year of age. On the basis of the hormone level readings, almost all patients received adequate long-term treatment. Some irregularities in the administration of T4 may have occurred, but it is highly unlikely that such irregularities coincided preferentially with cases of severe CH.The only way to determine the cerebral damage caused by fetal and neonatal hypothyroidism is to correlate the individual cognitive and motor outcome with data concerning severity and duration of the hypothyroid phase, and with other complicating factors. This requires etiologic classification of the study population. Many studies, in particular those of the New England Congenital Hypothyroidism Collaborative,2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 4New England Congenital Hypothyroidism Collaborative Neonatal hypothyroidism screening: status of patients at 6 years of age.J PEDIATR. 1985; 107: 915-919Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar, 6New England Congenital Hypothyroidism Collaborative Elementary school performance of children with congenital hypothyroidism.J PEDIATR. 1990; 116: 27-32Abstract Full Text PDF PubMed Scopus (82) Google Scholar have presented data only on the CH population as a whole. By including milder cases, such studies risk “diluting” the effects of the severe cases. Mitchell and Klein refer to three smaller studies to illustrate their contention that “early and adequate treatment, including frequent monitoring, will ensure optimal outcome in all children with hypothyroidism, regardless of type.” One of these studies reports that at 6 years of age, 13 children with athyrosis had a mean IQ of 84, whereas 22 children with ectopic or hypoplastic glands had a mean IQ of 100.7Heyerdahl S. Intellectual development of children with congenital hypothyroidism in Norway.in: Research in congenital hypothyroidism. Plenum Press, New York1989: 298-299Google ScholarTwo recent publications from the United Kingdom support our (unfortunate) results.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar, 9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar Simons et al.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar tested the IQs of patients with CH at about the same age as we did. Their subgroup of patients with very low pretreatment plasma T4 concentrations (defined as ≤40 nmol/L) had a mean full-scale IQ 10 points below that of matched control subjects, and their subgroup of patients with moderately decreased pretreatment plasma T4 levels (>40 nmol/L) had a mean full-scale IQ similar to that of the control group. Timing of the T4 replacement therapy (23 ± 9 days [mean ± SD] for the Dutch patients with low neonatal T4 levels,3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar 26 days [range, 10 to 40 days] for the British patients with low neonatal T4 levels,8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar and 25 ± 15 days [mean ± SD] for the whole group of patients from New England [presumably slightly earlier for patients with severe CH])5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar cannot explain the differences in cognitive outcome. Although the Finnish screening program may be unique, enabling treatment to start at a median age of only 6 days, Virtanen et al.10Virtanen M Santavuori P Hirvonen E Perheentupa J. Multivariate analysis of psychomotor development in congenital hypothyroidism.Acta Paediatr Scand. 1989; 78: 405-411Crossref PubMed Scopus (24) Google Scholar concluded that some damage is inevitable and that its degree correlates with the severity of the [intrauterine] CH. Tillotson et al.9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar concluded that the severity of CH has a threshold effect on brain development, probably determined prenatally.Physicians must accept the fact that some patients with CH already have some cerebral damage at the time of referral, because of exposure to very low T4 levels prenatally or during the short interval between birth and referral. It is misleading to promise all parents beforehand a completely normal cognitive and motor development for their children. On the other hand, screening organizations should never rest in their attempts to reduce the time interval between birth and administration of the first dose of T4 as much as possible. Drs. Mitchell and Klein contend that early and adequate treatment will ensure optimal outcome in all children with hypothyroidism. Our observation that some patients with congenital hypothyroidism (CH) detected by neonatal screening have a less favorable cognitive and motor outcome is interpreted as disheartening news for physicians. Drs. Mitchell and Klein seem to have just one explanation: it cannot be the patient, so it must be the doctor, and they demand proof that our patients with CH were treated adequately. We consider it a blessing that in the 1970s a group of North American investigators, among them Drs. Mitchell and Klein, showed that the devastating effects of CH are preventable by introducing neonatal mass screening. In those days it was thought that fetal hypothyroidism had little or no impact on cerebral development, because early-treated patients had such favorable outcomes. Moreover, it was thought that there was no significant maternal-fetal transfer of thyroid hormone, and it was argued that a fetus could develop properly even in the absence of any thyroid hormone. Now we know that thyroxine (T4) passes the placenta, and we are aware of the devastating effects of maternal hypothyroidism on the developing central nervous system. The fetal brain needs thyroid hormone, although the questions of when and how much remain to be answered. It is hard to believe that the limited maternal supply of T4 is sufficient in all cases of severe CH; we have demonstrated that T4 levels in cord blood from infants with a complete inability to produce T4 show considerable variation,1Vulsma T Gons MH de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (603) Google Scholar and that especially in severe CH, plasma T4 concentrations decrease during the first few weeks after birth. In our opinion, one can hardly expect all children with CH to have completely normal motor skills and intelligence even when they are treated early and adequately. In the Netherlands the neonatal thyroid screening was set up according to the American methods. Treatment criteria also fit well with the guidelines published by the New England Congenital Hypothyroidism Collaborative.2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The Dutch health care system guarantees that every patient has access to the same quality of treatment and follow-up. There is no reason to believe that Dutch pediatricians provide less adequate care than their colleagues abroad. The criteria that we used for scoring treatment compliance are provided in our article.3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar Hormone levels were measured frequently, with the interval increasing gradually from at least once a week to about once every 3 months after 1 year of age. On the basis of the hormone level readings, almost all patients received adequate long-term treatment. Some irregularities in the administration of T4 may have occurred, but it is highly unlikely that such irregularities coincided preferentially with cases of severe CH. The only way to determine the cerebral damage caused by fetal and neonatal hypothyroidism is to correlate the individual cognitive and motor outcome with data concerning severity and duration of the hypothyroid phase, and with other complicating factors. This requires etiologic classification of the study population. Many studies, in particular those of the New England Congenital Hypothyroidism Collaborative,2New England Congenital Hypothyroidism Collaborative Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism.J PEDIATR. 1994; 124: 383-387Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 4New England Congenital Hypothyroidism Collaborative Neonatal hypothyroidism screening: status of patients at 6 years of age.J PEDIATR. 1985; 107: 915-919Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar, 6New England Congenital Hypothyroidism Collaborative Elementary school performance of children with congenital hypothyroidism.J PEDIATR. 1990; 116: 27-32Abstract Full Text PDF PubMed Scopus (82) Google Scholar have presented data only on the CH population as a whole. By including milder cases, such studies risk “diluting” the effects of the severe cases. Mitchell and Klein refer to three smaller studies to illustrate their contention that “early and adequate treatment, including frequent monitoring, will ensure optimal outcome in all children with hypothyroidism, regardless of type.” One of these studies reports that at 6 years of age, 13 children with athyrosis had a mean IQ of 84, whereas 22 children with ectopic or hypoplastic glands had a mean IQ of 100.7Heyerdahl S. Intellectual development of children with congenital hypothyroidism in Norway.in: Research in congenital hypothyroidism. Plenum Press, New York1989: 298-299Google Scholar Two recent publications from the United Kingdom support our (unfortunate) results.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar, 9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar Simons et al.8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar tested the IQs of patients with CH at about the same age as we did. Their subgroup of patients with very low pretreatment plasma T4 concentrations (defined as ≤40 nmol/L) had a mean full-scale IQ 10 points below that of matched control subjects, and their subgroup of patients with moderately decreased pretreatment plasma T4 levels (>40 nmol/L) had a mean full-scale IQ similar to that of the control group. Timing of the T4 replacement therapy (23 ± 9 days [mean ± SD] for the Dutch patients with low neonatal T4 levels,3Kooistra L Laane C Vulsma T Schellekens JMH van der Meere JJ Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J PEDIATR. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar 26 days [range, 10 to 40 days] for the British patients with low neonatal T4 levels,8Simons WF Fuggle PW Grant DB Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism.Arch Dis Child. 1994; 71: 232-234Crossref PubMed Scopus (65) Google Scholar and 25 ± 15 days [mean ± SD] for the whole group of patients from New England [presumably slightly earlier for patients with severe CH])5New England Congenital Hypothyroidism Collaborative Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar cannot explain the differences in cognitive outcome. Although the Finnish screening program may be unique, enabling treatment to start at a median age of only 6 days, Virtanen et al.10Virtanen M Santavuori P Hirvonen E Perheentupa J. Multivariate analysis of psychomotor development in congenital hypothyroidism.Acta Paediatr Scand. 1989; 78: 405-411Crossref PubMed Scopus (24) Google Scholar concluded that some damage is inevitable and that its degree correlates with the severity of the [intrauterine] CH. Tillotson et al.9Tillotson SL Fuggle PW Smith I Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.Br Med J. 1994; 309: 440-445Crossref PubMed Scopus (166) Google Scholar concluded that the severity of CH has a threshold effect on brain development, probably determined prenatally. Physicians must accept the fact that some patients with CH already have some cerebral damage at the time of referral, because of exposure to very low T4 levels prenatally or during the short interval between birth and referral. It is misleading to promise all parents beforehand a completely normal cognitive and motor development for their children. On the other hand, screening organizations should never rest in their attempts to reduce the time interval between birth and administration of the first dose of T4 as much as possible. 9/35/62074