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Neonatal detection of hypothyroidism
EDITOR'S COLUMN
Neonatal detection of hypothyroidism
T H E IMPORTANCE of thyroid hormones to pqstnatal
growth and development of the human infant is well recognized; early diagnosis and treatment of congenital hypothyroidism are therefore crucial if normal growth and development, particularly of the central nervous system, is to be preserved. 13 In the past we have depended on physician acumen for early postnatal diagnosis, having assumed that the placenta was permeable to thyroid hormones and that the athyroid fetus was adequately supplied with maternal hormone in utero. This assumption seemed to account for the observations that the athyroid newborn infant appeared eutbyroid, without growth retardation at birth, and implied that hypothyroidism gradually developed as maternal thyroid hormones disappeared from the infant's circulation during the early days and weeks of intrauterine life.4 In addition, this assumption and inherent limitations in the protein-bound iodine and butanol extractable iodine procedures largely precluded attempts at screening of newborn infants for hypothyroidism. Recent data in a number of species, including man, have clearly indicated that placental transfer of thyroid hormones is exceptionally limited. 5-t2 With this information, and the very recent development of highly sensitive and specific radioimmunoassay systems for measurement o f thyroid hormones and thyrotropin in small volumes of blood, screening of newborn infants for congenital hypothyroidism has become feasible. Dr. Jean Dussault, who contributed in a major way to the background information which made this possible, reports in .this issue of THE JOURNALhow he and his colleagues have applied their adaptation of radioimmunoassay of thyroxine in dried blood on filter paper 13 to mass screening of newborn infants for congenital hypothyroidism. Utilizing the Quebec Provincial Network of Genetic Medicine, with its centralized laboratories, and a special program for automated data analysis, TM these investigators have screened some 50,000 newborn infants at a cost of about fifty cents per test: The screening program has detected one hypothyroid infant per 7,000 births so that the cost of detection approxi-
822
TheJournalof PEDIATRICS. Vol. 86, No. 5, pp. 822-824
mates $4,000 (United States currency) per affected infant. This is much less than the annual cost for institutional care of a mentally retarded child. Moreover, in none of the infants in the study was hypothyroidism suspected clinically in less than six to eight weeks after the laboratory diagnosis was made, Quebec provided an ideal laboratory in which to test screening for hypothyroidism because of the Provincial Network already existed to guarantee sampling of all newborn infants for other congenital disorders. More importantly, the routine follow-up and recall systems within the network could guarantee verification and treatment within three to four weeks, and with minor modifications treatment can be started within two weeks. Thus, the "network" provides a model for the optimal approach to screening of neonates in the United States. Presently, in Quebec, screening is routine for phenylketonuria, tyrosinemia, galactosemia, and hypothyroidism by using one series of seven spots of blood on filter paper collected from each infant. Optional testing is available for a number of other inborn defects. Abbreviation used TSH: thyroid-stimulating hormone The incidence of one hypothyroid infant per 7,000 newborn infants in Quebec is in good agreement with earlier epidemiologic estimates (one in 5,000 to one in 10,000). We have believed, however, that 60-80% of infants with congenital hypothyroidism have residual functioning thyroid tissue which might delay diagnosisJ 5The results of Dussault and, his associates suggest that this is not true because most of the expected hypothyroid infants (one in 7,000) seem to be detected in the neonatal period by their screening program. Almost surely, some affected infants will be missed, but the nuinber is not yet clear. Only further evaluation and follow-up will answer this and other questions regarding the spectrum of congenital hypothyroidism in the neonate.
Volume 86 Number 5
Also, we need further study of other approaches to mass screening, such as measurements of thyroxine and/or TSH in cord blood, measurements of TSH at two to four days, and studies of dried blood on filter paper vs. venous or capillary sampling. Klein and asssociates ~6 in a pilot program measured TSH .by radioimmunoassay in the cord b l o o d of a b o u t 4,000 n e o n a t e s ; they detected one hypothyroid infant. Since the measurem e n t of seum TSH is the most sensitive test for primary hypothyroidism, this approach has theoretic advantages and several groups are attempting to adapt the TSH radioimmunoassay to filter paper spots. Measurements of TSH in cord blood would seem applicable at present for small-scale hospital screening programs, b u t if commercial laboratories are used for the assays, at a cost ap: proximating $15 per test, the cost for detection would exceed $100,000 per affected infant. The detection of TSH deficiency in~ the immediate postnatal period now makes it possible to study the effects of early therapy of congenital hypothyroidism on central nervous system development. The fact that the placenta is essentially i m p e r m e a b l e to thyroid hormones and that the newborn hypothyroid infant appears euthyroid implies that fetal growth and developm e n t are not dependent on thyroid hormone. That this is so for somatic growth and for linear bone growth is now conceded; the hypothyroid n e o n a t e is longer and heavier than his normal counterpart, even though bone maturation may be somewhat delayedS The extent to which brain growth and development are dependent on thyroid hormone in utero, however, is not clear. Without doubt there is a critical period in which normal central nervous system development is dependent on thyroid hormone. 1-3,5: 18, 19This period occurs postnatally in the rat s, 18, 19and presumably extends into the intrauterine period in man and other species in which the central nervous system is more mature at birth. The extent of this dependency and its reversibility, however, remains to be resolved. Recent observations in fetal sheep suggest that intrauterine hypothyroidism does not impair brain growth and o n l y minimally delays myelination.2~ Moreover, thyroid therapy in the rat, when begun at seven to ten days seems to reverse completely the effects of hypothyroidism induced at birth, s, 18These studies and the fact that therapy prior to three months of age will minimize the mental retardation of hypothyroidism in the h u m a n infant 1,2suggest that any intrauterine damage to the central nervous system occurs late enough to be largely reversible. Only careful study, however, of infants in whom hypothyroidism is detected and treated early will answer this important
Editor's column
823
question. In the. meantime, study of possible approaches to intrauterine diagnosis and therapy, already underway,12, 2~-23should continue, particularly in highrisk populations. It is apparent that we are entering a new era of understanding and management of congenital hypothyroid, ism. Severe mental retardation due to thyroid hormone deficiency at birth can promptly be eliminated where mass screening programs can be established, and the benefit to the patient and the anguished parents will be m a t c h e d by the economic b e n e f i t to society. Dr. Dussault and his colleagues as well asothers involved in e x p e r i m e n t a l s c r e e n i n g programs for c o n g e n i t a l hypothyroidism are to be heartily congratulated. Delbert A. Fisher, M.D. Department o f Pedia trics UCLA School o f Medicine Harbor General Hospital 1000 West Carson St. Torrance, Calif. 90509
REFERENCES
1. Smith DW, Blizzard RM, and Wilkins L: The mental prognosis in hypothyroidism of infancy and childhood: A review of 128 cases, Pediatrics 18:1011, 1957. 2. Raiti S, and Newns GH: Cretinism: Early diagnosis and its relation to mental prognosis, Arch Dis Child 46:692, 1971. 3. Klein A, Meltzer S, and Kenny F: Improved prognosis in congenital hypothyroidism treated before age three months, J PEDIATR81:912, 1972. 4. Childs B, and Gardner LI: Etiologic factors in sporadic cretinism, an analysis of ninety cases, Ann Hum Genet 19:90, 1954. 5. Geloso JP, Hemon P, Legrand J, Legrand C, and Jost A: Some aspects of thyroid physiology during theperinatal period, Endocrinology 10:191, 1968. 6. Hopkins PS, and Thorburn GD: Placental permeability to maternal thyroxine in sheep, J Endocrinol 49:549, 1971. 7. Dussault JH, Hobel CJ, and Fisher DA: Maternal and fetal thyroxine secretion during pregnancy in the sheep, Endocrinology 88:47, 1971. 8..Dussault JH, Hobel CJ, DiStefano JJ III, Erenberg A, and Fisher DA: Triiodothyronine turnover in maternal and fetal sheep, Endocrinology 90:1301, 1972. 9. Fisher DA, Dussault JH, Erenberg A, and Lain RW: Thyroxine and tri-iodothyronine metabolism in maternal and fetal sheep, Pediatr Res 6:894, 1972. 10. Erenberg A, Omori K, Oh W, and Fisher DA: The effect of fetal thyroidectomy on thyroid hormone metabolism in maternal and fetal sheep, Pediatr Res 7:807, 1973. 11. Fisher DA, Dussault JH, Hobel CJ, and Lam RW: Serum and thyroid gland triiodothyronine in the human fetus, J Clin Endocrinol Metab 36:397, 1973. 12. Van Herle AJ, Young RT, Fisher DA, Uller RP, Brickman CH: Intrauterine treatment of a hypothyroid fetus, J Clin Endocrinol Metab 40:474, 1975.
824
13.
Editor's column
Dussault JH, and Laberge C: Thyroxine (T4) determination in dried blood by radioimmunoassay: A screening method for neonatal hypothyroidism? Union Med Can 102:2062, 1973. 14. Nadeau A, Morisette J, and Dussault JH: A computer approach in radioimmunoassay data processing, Union Med Can 102:15 !1, 1973. 15. Little G, Clifton KM, Cunningham R, and Pittman JA: 9" C r y p t 0 t h y r o i d i s m , " the major source of sporadic ',athyreotic" cretinism, J Clin Endocrinol Metab 25:1529, 1965. 16. Klein AH, Agustin AV, and Foley TP: Successful laboratory screening for congenital hypothyroidism, Lancet 2:77, 1974. 17. Andersen HJ: Nongoitrous hypothyroidism, in Gardner Ll,editor: Endocrine and genetic diseases of chiidhood,
The Journal of Pediatrics May 1975
Philadelphia, 1969, WB Saunders Company, pp 216-234. 18. Legrand J: Influence de l'hypothyroidism sur la maturation du cortex cerebelleaux, C R Acad Sci (Paris) 261:544, 1965. 19. Balazs R: l~ffects of hormones and nutrition on brain development, Adv E x p Med Biol 30:385, 1972. 20. Erenberg A, Omori K, Menkes JH, Oh W, and Fisher DA: Growth and development of the thyroidectomized ovine fetus, Pediatr Res 8:783, 1974. 21. Kaufman S: Protein bound iodine (PBI)in human amnibtic fluid, J PEDIATR68:990,-1966. 22. Hollingsworth DR, and Austin E: Thyroxine derivatives in amniotic fluid, J PEDIATR79:923, 1971. 23. Sack J, Hobel C, and Fisher DA: Immunoreactive T4 and free T4 in human arnniotic fluid, Clin Res 22:215A, 1974.
Erratum. In the January, !975, issue of THE JOURNALon page 3 of the article "Total parenteral nutrition" by William C. Heird, M.D., and Robert W. Winters, M.D., the recommended allowance for vitamin B12 given in Table I should have been 5-10/xg/day.
Neonatal detection of hypothyroidism
T H E IMPORTANCE of thyroid hormones to pqstnatal
growth and development of the human infant is well recognized; early diagnosis and treatment of congenital hypothyroidism are therefore crucial if normal growth and development, particularly of the central nervous system, is to be preserved. 13 In the past we have depended on physician acumen for early postnatal diagnosis, having assumed that the placenta was permeable to thyroid hormones and that the athyroid fetus was adequately supplied with maternal hormone in utero. This assumption seemed to account for the observations that the athyroid newborn infant appeared eutbyroid, without growth retardation at birth, and implied that hypothyroidism gradually developed as maternal thyroid hormones disappeared from the infant's circulation during the early days and weeks of intrauterine life.4 In addition, this assumption and inherent limitations in the protein-bound iodine and butanol extractable iodine procedures largely precluded attempts at screening of newborn infants for hypothyroidism. Recent data in a number of species, including man, have clearly indicated that placental transfer of thyroid hormones is exceptionally limited. 5-t2 With this information, and the very recent development of highly sensitive and specific radioimmunoassay systems for measurement o f thyroid hormones and thyrotropin in small volumes of blood, screening of newborn infants for congenital hypothyroidism has become feasible. Dr. Jean Dussault, who contributed in a major way to the background information which made this possible, reports in .this issue of THE JOURNALhow he and his colleagues have applied their adaptation of radioimmunoassay of thyroxine in dried blood on filter paper 13 to mass screening of newborn infants for congenital hypothyroidism. Utilizing the Quebec Provincial Network of Genetic Medicine, with its centralized laboratories, and a special program for automated data analysis, TM these investigators have screened some 50,000 newborn infants at a cost of about fifty cents per test: The screening program has detected one hypothyroid infant per 7,000 births so that the cost of detection approxi-
822
TheJournalof PEDIATRICS. Vol. 86, No. 5, pp. 822-824
mates $4,000 (United States currency) per affected infant. This is much less than the annual cost for institutional care of a mentally retarded child. Moreover, in none of the infants in the study was hypothyroidism suspected clinically in less than six to eight weeks after the laboratory diagnosis was made, Quebec provided an ideal laboratory in which to test screening for hypothyroidism because of the Provincial Network already existed to guarantee sampling of all newborn infants for other congenital disorders. More importantly, the routine follow-up and recall systems within the network could guarantee verification and treatment within three to four weeks, and with minor modifications treatment can be started within two weeks. Thus, the "network" provides a model for the optimal approach to screening of neonates in the United States. Presently, in Quebec, screening is routine for phenylketonuria, tyrosinemia, galactosemia, and hypothyroidism by using one series of seven spots of blood on filter paper collected from each infant. Optional testing is available for a number of other inborn defects. Abbreviation used TSH: thyroid-stimulating hormone The incidence of one hypothyroid infant per 7,000 newborn infants in Quebec is in good agreement with earlier epidemiologic estimates (one in 5,000 to one in 10,000). We have believed, however, that 60-80% of infants with congenital hypothyroidism have residual functioning thyroid tissue which might delay diagnosisJ 5The results of Dussault and, his associates suggest that this is not true because most of the expected hypothyroid infants (one in 7,000) seem to be detected in the neonatal period by their screening program. Almost surely, some affected infants will be missed, but the nuinber is not yet clear. Only further evaluation and follow-up will answer this and other questions regarding the spectrum of congenital hypothyroidism in the neonate.
Volume 86 Number 5
Also, we need further study of other approaches to mass screening, such as measurements of thyroxine and/or TSH in cord blood, measurements of TSH at two to four days, and studies of dried blood on filter paper vs. venous or capillary sampling. Klein and asssociates ~6 in a pilot program measured TSH .by radioimmunoassay in the cord b l o o d of a b o u t 4,000 n e o n a t e s ; they detected one hypothyroid infant. Since the measurem e n t of seum TSH is the most sensitive test for primary hypothyroidism, this approach has theoretic advantages and several groups are attempting to adapt the TSH radioimmunoassay to filter paper spots. Measurements of TSH in cord blood would seem applicable at present for small-scale hospital screening programs, b u t if commercial laboratories are used for the assays, at a cost ap: proximating $15 per test, the cost for detection would exceed $100,000 per affected infant. The detection of TSH deficiency in~ the immediate postnatal period now makes it possible to study the effects of early therapy of congenital hypothyroidism on central nervous system development. The fact that the placenta is essentially i m p e r m e a b l e to thyroid hormones and that the newborn hypothyroid infant appears euthyroid implies that fetal growth and developm e n t are not dependent on thyroid hormone. That this is so for somatic growth and for linear bone growth is now conceded; the hypothyroid n e o n a t e is longer and heavier than his normal counterpart, even though bone maturation may be somewhat delayedS The extent to which brain growth and development are dependent on thyroid hormone in utero, however, is not clear. Without doubt there is a critical period in which normal central nervous system development is dependent on thyroid hormone. 1-3,5: 18, 19This period occurs postnatally in the rat s, 18, 19and presumably extends into the intrauterine period in man and other species in which the central nervous system is more mature at birth. The extent of this dependency and its reversibility, however, remains to be resolved. Recent observations in fetal sheep suggest that intrauterine hypothyroidism does not impair brain growth and o n l y minimally delays myelination.2~ Moreover, thyroid therapy in the rat, when begun at seven to ten days seems to reverse completely the effects of hypothyroidism induced at birth, s, 18These studies and the fact that therapy prior to three months of age will minimize the mental retardation of hypothyroidism in the h u m a n infant 1,2suggest that any intrauterine damage to the central nervous system occurs late enough to be largely reversible. Only careful study, however, of infants in whom hypothyroidism is detected and treated early will answer this important
Editor's column
823
question. In the. meantime, study of possible approaches to intrauterine diagnosis and therapy, already underway,12, 2~-23should continue, particularly in highrisk populations. It is apparent that we are entering a new era of understanding and management of congenital hypothyroid, ism. Severe mental retardation due to thyroid hormone deficiency at birth can promptly be eliminated where mass screening programs can be established, and the benefit to the patient and the anguished parents will be m a t c h e d by the economic b e n e f i t to society. Dr. Dussault and his colleagues as well asothers involved in e x p e r i m e n t a l s c r e e n i n g programs for c o n g e n i t a l hypothyroidism are to be heartily congratulated. Delbert A. Fisher, M.D. Department o f Pedia trics UCLA School o f Medicine Harbor General Hospital 1000 West Carson St. Torrance, Calif. 90509
REFERENCES
1. Smith DW, Blizzard RM, and Wilkins L: The mental prognosis in hypothyroidism of infancy and childhood: A review of 128 cases, Pediatrics 18:1011, 1957. 2. Raiti S, and Newns GH: Cretinism: Early diagnosis and its relation to mental prognosis, Arch Dis Child 46:692, 1971. 3. Klein A, Meltzer S, and Kenny F: Improved prognosis in congenital hypothyroidism treated before age three months, J PEDIATR81:912, 1972. 4. Childs B, and Gardner LI: Etiologic factors in sporadic cretinism, an analysis of ninety cases, Ann Hum Genet 19:90, 1954. 5. Geloso JP, Hemon P, Legrand J, Legrand C, and Jost A: Some aspects of thyroid physiology during theperinatal period, Endocrinology 10:191, 1968. 6. Hopkins PS, and Thorburn GD: Placental permeability to maternal thyroxine in sheep, J Endocrinol 49:549, 1971. 7. Dussault JH, Hobel CJ, and Fisher DA: Maternal and fetal thyroxine secretion during pregnancy in the sheep, Endocrinology 88:47, 1971. 8..Dussault JH, Hobel CJ, DiStefano JJ III, Erenberg A, and Fisher DA: Triiodothyronine turnover in maternal and fetal sheep, Endocrinology 90:1301, 1972. 9. Fisher DA, Dussault JH, Erenberg A, and Lain RW: Thyroxine and tri-iodothyronine metabolism in maternal and fetal sheep, Pediatr Res 6:894, 1972. 10. Erenberg A, Omori K, Oh W, and Fisher DA: The effect of fetal thyroidectomy on thyroid hormone metabolism in maternal and fetal sheep, Pediatr Res 7:807, 1973. 11. Fisher DA, Dussault JH, Hobel CJ, and Lam RW: Serum and thyroid gland triiodothyronine in the human fetus, J Clin Endocrinol Metab 36:397, 1973. 12. Van Herle AJ, Young RT, Fisher DA, Uller RP, Brickman CH: Intrauterine treatment of a hypothyroid fetus, J Clin Endocrinol Metab 40:474, 1975.
824
13.
Editor's column
Dussault JH, and Laberge C: Thyroxine (T4) determination in dried blood by radioimmunoassay: A screening method for neonatal hypothyroidism? Union Med Can 102:2062, 1973. 14. Nadeau A, Morisette J, and Dussault JH: A computer approach in radioimmunoassay data processing, Union Med Can 102:15 !1, 1973. 15. Little G, Clifton KM, Cunningham R, and Pittman JA: 9" C r y p t 0 t h y r o i d i s m , " the major source of sporadic ',athyreotic" cretinism, J Clin Endocrinol Metab 25:1529, 1965. 16. Klein AH, Agustin AV, and Foley TP: Successful laboratory screening for congenital hypothyroidism, Lancet 2:77, 1974. 17. Andersen HJ: Nongoitrous hypothyroidism, in Gardner Ll,editor: Endocrine and genetic diseases of chiidhood,
The Journal of Pediatrics May 1975
Philadelphia, 1969, WB Saunders Company, pp 216-234. 18. Legrand J: Influence de l'hypothyroidism sur la maturation du cortex cerebelleaux, C R Acad Sci (Paris) 261:544, 1965. 19. Balazs R: l~ffects of hormones and nutrition on brain development, Adv E x p Med Biol 30:385, 1972. 20. Erenberg A, Omori K, Menkes JH, Oh W, and Fisher DA: Growth and development of the thyroidectomized ovine fetus, Pediatr Res 8:783, 1974. 21. Kaufman S: Protein bound iodine (PBI)in human amnibtic fluid, J PEDIATR68:990,-1966. 22. Hollingsworth DR, and Austin E: Thyroxine derivatives in amniotic fluid, J PEDIATR79:923, 1971. 23. Sack J, Hobel C, and Fisher DA: Immunoreactive T4 and free T4 in human arnniotic fluid, Clin Res 22:215A, 1974.
Erratum. In the January, !975, issue of THE JOURNALon page 3 of the article "Total parenteral nutrition" by William C. Heird, M.D., and Robert W. Winters, M.D., the recommended allowance for vitamin B12 given in Table I should have been 5-10/xg/day.