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Transient hypothyroidism in the newborn infant
974
June 1978 The Journal of P E D I A T R I C S
Transient hypothyroidism in the newborn infant Francois Delange,* Jos~e Dodion, Ren6e Wolter, Pierre Bourdoux, Anne Dalhem, Daniel Glinoer, and Andre-Marie Ermans, Brussels, Belgium
NEONATAL SCREENING for congenital hypothyroidism is important because of the possibility that mental retardation may be avoided if treatment is started early.' The diagnosis rests on the detection of a high serum level of TSH and low T, during the first few days of life. Whether the presence of these biochemical signs soon after birth necessarily indicates permanent thyroid insufficiency is unknown. Recent data suggest that, in some circumstances, thyroid insufficiency may be transient. Premature infants with respiratory distress have low T4 and T~ levels associated with high TSH levels in cord blood, 2 but these abnormalities revert progressively.:* Furthermore, preliminary data' show a temporary drop in serum T4 values in some premature infants admitted to an intensive care unit. Herein we discuss six infants in whom thyroid insufficiency was detected in the early days of life and disappeared spontaneously after a few weeks. PATIENTS The six infants, five of them premature, were admitted to the neonatal intensive care unit for different serious conditions (Table I). In Patients 2 to 6 abnormal thyroid function was suspected on the basis of high serum TSH values on the fifth day of life) and in Patient 1 because of thyroid hyperplasia detected on the forty-fifth day. From the Departments of Pediatrics, Radioisotopes and Internal Medicine, Saint-Pierre Hospital, University of Brussels'. Supported in part by "Fonds de la Recherche Scientifique Mbdicale (Belgium) and by a contract with the Ministbre de la Politique Scientifique (Belgium) within the framework of the Association Euratom- University of Brussels- University of Pisa. *Reprint address: Department of Radioisotopes, H6t~ital Saint-Pierre, 322, rue Haute, 1000 Brussels, Belgium.
Vol. 92, No. 6, pp. 974-976
METHODS Serum levels of T , T:, TSH, TBG, and thyroglobulin antibodies were measured by radioimmunoassay: TSH, T4, and T3 by methods described previously~; TBG by the method of Gershengorn and associates~'; and thyroglobulin antibodies by the method of Delespesse and associates. 7 Urinary iodine was measured by the method of Riley and Gochman, using a Technicon AutoAnalyzer? The values obtained for these measures in 16 normal 5 to 30-day-old infants were as follows (means • SD): TSH 2.2 + 1.3 /zU/ml; T4 10.6 _+ 2.0/~g/dl; T:, 224 _+ 48 ng/ dl; TBG 1.83 • 0.34 mg/dl; thyroglobulin antibodies, undetectable (less than 10 /~U/ml); urinary iodine 6.4 • 4.3/~g/dl.
See related articles, pp. 963, 968, and 1035 Abbreviations used T4: thyroxine T~: tri-iodothyronine TSH: thyrotropin TBG: thyroxine-binding globulin Thyroid scintigrams and estimation of the degree of bone maturation were performed according to previously described methods? In Patients 1 and 2, treatment with L-thyroxine (50/~g/ day) was given concurrently with 10 t~g of tri-iodo-Lthyronine (administered in four divided doses) during the first few days of life. Patients 3 and 4 received T3 only and Patients 5 and 6 received no treatment. RESULTS The evolution of the biochemical measures of thyroid function in the six patients, from the time of screening until the last day of the follow-up period, is shown in Table II.
0022-3476/78/0692-0974500.30/0 9 1978 The C. V. Mosby Co.
Volume 92 Number 6
Transient hypothyroidism
975
Table 1. Clinical data in the six p a t i e n t s
Patients
Sex
Gestational age (wk)
Birth weight (gm)
1
M
29
1,200
2
M
37
3,600
3 4 5 6
F M F M
31.5 35 33 36
1,730 1,780 2,000 2,450
Clinical findings Twin birth, recurring apnea, delayed closure of ductus arteriosus, goiter day 45 Cesarean birth, severe respiratory distress, persistent hypotonia, goiter, day 16 Recurring apnea, functional ileus, goiter, day 12 Cesarean birth, dysmaturity, severe hypoglycemia Neonatal asphyxia, icterus Transient respiratory distress
Table 1I. E v o l u t i o n o f t h e b i o c h e m i c a l m e a s u r e s o f t h y r o i d f u n c t i o n f r o m the time o f s c r e e n i n g u p to the last d a y o f the f o l l o w - u p p e r i o d
Treatment Patients 1
2
3
4
5
6
Clinical steps Screening Diagnosis Start of therapy Normal values obtained End of therapy Last day of follow-up Screening Diagnosis Start of therapy Normal values obtained and therapy stopped Last day of follow-up Birth (cord blood) Screening Diagnosis Start of therapy Normal values obtained and therapy stopped Last day o f follow-up Screening Diagnosis Start of therapy End of therapy Normal values obtained Last day of follow-up Screening Diagnosis Normal values obtained Last day o f follow-up Screening Diagnosis Normal values obtained Last day of follow-up
5 45 50 127 169 218 5 12 17 77
6.4 > 51 > 51 1.1 1.3 2.8 37.4 > 51 > 51 3.5
1.5" 2.7 3.3 10.0 4.1 9.5 Undet. Undet. 7.2
-47 80 186 307 286 92 129 350
151 0 5 11 17 43
1.9 14.7 39.1 49.3 58.0 4.2
11.4 7.3 4.1 Undet. 1.0 7.0
251 29 51 37 55 257
136 5 17 22 43 49 255 5 12 19 133 5 13 25 254
1,2 > 51 > 51 > 51 2.7 2.8 2.2 20.3 > 51 4.1 1.1 34.0 23.5 4.4 3.5
11.0 Undet. Undet. 4.2 4.8 10.8 -0.8 11,3 10,8 -2,7 6.7 6.9
206
Under. = Undetectable. *Kindly determined by J.H. Dussault from dried blood collected on paper on day 5.
116 225 245 115 142 223 247 142 65 243 218
Drugs (l~g/day)
Time after birth (days)
T,~(50)+Td5) T.~(50) T~(5)
50-57 58-127 128-169
T,(50) +T~(5) T~(5)
17-63 64-67
T~(10)
17-43
Tall0 )
22-43
976
Delange et al.
The diagnosis of primary hypothyroidism was established on the basis of high TSH levels and low or undetectable T~ levels. T3 was low in four infants (less than 100 ng/dl). In all six patients bone maturation was normal and the thyroid gland was in the normal position, as indicated by the presence of goiter or by a normal scintigram. The concentration of urinary iodine, measured in four patients, ranged from 3.4 to 20.0 /~g/dl. Thyroglobulin antibodies were undetectable in all cases. Serum levels of TBG, measured when the other values reverted to normal or during the follow-up period, range d from 1.99 to 2.92 mg/dl,~ the mean value was 2.32 _+ 0.30 (SD) mg/dl. Patients 1 and 2 were treated with a combination of T~ and T3. Their levels ofT4, T3, and TSH reverted to normal by the fifth day of treatment. The levels remained normal throughout the period of treatment and after withdrawal of T~ and T:~. Patients 3 and 4 were treated with T~ only; T~ increased substantially and TSH reverted to normal. Of great interest was the steady rise of serum T4; normal T.~ values were reached by 43 and 49 days, respectively. All the values remained within the normal range for more than three months after cessation of T~ treatment. Patients 5 and 6 received no treatment. The levels of TSH, T4, and T~ reverted spontaneously to normal by the nineteenth and twenty-fifth days, respectively, and remained so throughout the 8Vz-month follow-up period. The physical and psychomotor development of the six infants was normal throughout the follow-up period. DISCUSSION These six infants had biochemical features typical of primary thyroid insufficiency soon after birth. The main interest of our findings is the indication that thyroid failure was transient in these patients. In all of them normal thyroid function was restored and maintained for periods ranging from 11 to 33 weeks after treatment was stopped. Furthermore, the progressive return to normal T4 levels in Patients 3 to 6, who received no T4 supplementation, indicates that the observed hypothyroidism was not only transient but also spontaneously reversible. This temporary state of hypothyroidism seems particularly frequent in premature infants with associated severe disorders. In this study, five of the six infants were premature. Four of them were born in our Maternity Department among a total number of 4,610 births. In infants with low serum concentrations of T~, elevated serum concentrations of TSH and normal TB G concentrations (ruling out a congenital defect of the binding protein) replacement therapy appears to be necessary, as proposed by Klein and associates.:' t~owever, treatment is
The Journal of Pediatrics June 1978
probably not required when hypothyroidism resolves spontaneously and rapidly, as in Patients 5 and 6. The data suggest that treatment with T3 may be suitable for distinguishing between transient and permanent hypothyroidism without interruption of replacement therapy. The cause of the thyroid insufficiency in these patients remains unknown. The data rule out the classical causes of congenital hypothyroidism. Two factors might explain the transient inability of the thyroid to maintain Sufficient hormonal secretion in premature infants during serious illness, when peripheral utilization of hormones is increased? The first is the low thyroidal content of iodine reported in newborn infants, especially if premature~; this situation could be aggravated in Belgium by the relatively low iodine supply. The second is a delay in the maturation of the enzymatic mechanisms involved in intrathyroidal hormonogenesis. These hypotheses call for further research. The authors thank Drs. J. H. Dussault, C. Delespesse, and H. L. Loeb for their help. REFERENCES
1. Fisher DA, Burrow GN, Dussault JH, Hollingsworth DR, Larsen PR, Man EB, and Walfish PG: Recommendations for screening programs for congenital hypothyroidism. Report of a Committee of The American Thyroid Association, J PEDIATR89:692, 1976. 2. Cuestas RA, Lindall A, and Engel RR: Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood, N Engl J Med 295:297, 1976. 3. Klein AH, Stinson D, Foley B, Larsen PR, and Foley TP Jr: Thyroid function studies in preterm infants recovering from the respiratory distress syndrome, J P~t)IATR91:261, 1977. 4. Uhrmann S, Marks KH, Maisels MJ, Friedman Z, Murray F, Fulin H, Kaplan M, and Utiger R: Thyroid function in infants admitted to a neonatal intensive unit (NICU): A longitudinal assessment, Pediatr Res 11:432, 1977. 5. Delange F, Camus M, Winkler M, Dodion J, and Ermans AM: Serum thyrotropin determination on day 5 of life as screening procedure for congenital hypothyroidism, Arch Dis Child 52:89, 1977. 6. Gershengorn MC, Larsen PR, and Robbins J: Radioimmunoassay for serum thyroxine-binding globulin: results in normal subjects and in patients with hepato cellular carcinoma, J Clin Endocrinol 42:907, 1976. 7. Delespesse G, Hubert C, Gausset Ph, and Govaerts A: Radioimmunoassay for human antithyroglobulin antibodies of different immunoglobulin classes, Horm Metab Res 8:50, 1976. 8. Gregerman RI, and Solomon N: Acceleration of thyroxine and triiodothyronine turnover during bacterial pulmonary infections and fever: implications for the functional state of the thyroid during stress and in senescence, J Clin Endocrinol 27:93, 1967. 9. Etling N: Concentration of thyroglobulin, iodine contents of thyroglobulin and of iodoaminoacids in human neonates thyroid glands, Acta Paediatr Scand 66:97, 1977.
June 1978 The Journal of P E D I A T R I C S
Transient hypothyroidism in the newborn infant Francois Delange,* Jos~e Dodion, Ren6e Wolter, Pierre Bourdoux, Anne Dalhem, Daniel Glinoer, and Andre-Marie Ermans, Brussels, Belgium
NEONATAL SCREENING for congenital hypothyroidism is important because of the possibility that mental retardation may be avoided if treatment is started early.' The diagnosis rests on the detection of a high serum level of TSH and low T, during the first few days of life. Whether the presence of these biochemical signs soon after birth necessarily indicates permanent thyroid insufficiency is unknown. Recent data suggest that, in some circumstances, thyroid insufficiency may be transient. Premature infants with respiratory distress have low T4 and T~ levels associated with high TSH levels in cord blood, 2 but these abnormalities revert progressively.:* Furthermore, preliminary data' show a temporary drop in serum T4 values in some premature infants admitted to an intensive care unit. Herein we discuss six infants in whom thyroid insufficiency was detected in the early days of life and disappeared spontaneously after a few weeks. PATIENTS The six infants, five of them premature, were admitted to the neonatal intensive care unit for different serious conditions (Table I). In Patients 2 to 6 abnormal thyroid function was suspected on the basis of high serum TSH values on the fifth day of life) and in Patient 1 because of thyroid hyperplasia detected on the forty-fifth day. From the Departments of Pediatrics, Radioisotopes and Internal Medicine, Saint-Pierre Hospital, University of Brussels'. Supported in part by "Fonds de la Recherche Scientifique Mbdicale (Belgium) and by a contract with the Ministbre de la Politique Scientifique (Belgium) within the framework of the Association Euratom- University of Brussels- University of Pisa. *Reprint address: Department of Radioisotopes, H6t~ital Saint-Pierre, 322, rue Haute, 1000 Brussels, Belgium.
Vol. 92, No. 6, pp. 974-976
METHODS Serum levels of T , T:, TSH, TBG, and thyroglobulin antibodies were measured by radioimmunoassay: TSH, T4, and T3 by methods described previously~; TBG by the method of Gershengorn and associates~'; and thyroglobulin antibodies by the method of Delespesse and associates. 7 Urinary iodine was measured by the method of Riley and Gochman, using a Technicon AutoAnalyzer? The values obtained for these measures in 16 normal 5 to 30-day-old infants were as follows (means • SD): TSH 2.2 + 1.3 /zU/ml; T4 10.6 _+ 2.0/~g/dl; T:, 224 _+ 48 ng/ dl; TBG 1.83 • 0.34 mg/dl; thyroglobulin antibodies, undetectable (less than 10 /~U/ml); urinary iodine 6.4 • 4.3/~g/dl.
See related articles, pp. 963, 968, and 1035 Abbreviations used T4: thyroxine T~: tri-iodothyronine TSH: thyrotropin TBG: thyroxine-binding globulin Thyroid scintigrams and estimation of the degree of bone maturation were performed according to previously described methods? In Patients 1 and 2, treatment with L-thyroxine (50/~g/ day) was given concurrently with 10 t~g of tri-iodo-Lthyronine (administered in four divided doses) during the first few days of life. Patients 3 and 4 received T3 only and Patients 5 and 6 received no treatment. RESULTS The evolution of the biochemical measures of thyroid function in the six patients, from the time of screening until the last day of the follow-up period, is shown in Table II.
0022-3476/78/0692-0974500.30/0 9 1978 The C. V. Mosby Co.
Volume 92 Number 6
Transient hypothyroidism
975
Table 1. Clinical data in the six p a t i e n t s
Patients
Sex
Gestational age (wk)
Birth weight (gm)
1
M
29
1,200
2
M
37
3,600
3 4 5 6
F M F M
31.5 35 33 36
1,730 1,780 2,000 2,450
Clinical findings Twin birth, recurring apnea, delayed closure of ductus arteriosus, goiter day 45 Cesarean birth, severe respiratory distress, persistent hypotonia, goiter, day 16 Recurring apnea, functional ileus, goiter, day 12 Cesarean birth, dysmaturity, severe hypoglycemia Neonatal asphyxia, icterus Transient respiratory distress
Table 1I. E v o l u t i o n o f t h e b i o c h e m i c a l m e a s u r e s o f t h y r o i d f u n c t i o n f r o m the time o f s c r e e n i n g u p to the last d a y o f the f o l l o w - u p p e r i o d
Treatment Patients 1
2
3
4
5
6
Clinical steps Screening Diagnosis Start of therapy Normal values obtained End of therapy Last day of follow-up Screening Diagnosis Start of therapy Normal values obtained and therapy stopped Last day of follow-up Birth (cord blood) Screening Diagnosis Start of therapy Normal values obtained and therapy stopped Last day o f follow-up Screening Diagnosis Start of therapy End of therapy Normal values obtained Last day of follow-up Screening Diagnosis Normal values obtained Last day o f follow-up Screening Diagnosis Normal values obtained Last day of follow-up
5 45 50 127 169 218 5 12 17 77
6.4 > 51 > 51 1.1 1.3 2.8 37.4 > 51 > 51 3.5
1.5" 2.7 3.3 10.0 4.1 9.5 Undet. Undet. 7.2
-47 80 186 307 286 92 129 350
151 0 5 11 17 43
1.9 14.7 39.1 49.3 58.0 4.2
11.4 7.3 4.1 Undet. 1.0 7.0
251 29 51 37 55 257
136 5 17 22 43 49 255 5 12 19 133 5 13 25 254
1,2 > 51 > 51 > 51 2.7 2.8 2.2 20.3 > 51 4.1 1.1 34.0 23.5 4.4 3.5
11.0 Undet. Undet. 4.2 4.8 10.8 -0.8 11,3 10,8 -2,7 6.7 6.9
206
Under. = Undetectable. *Kindly determined by J.H. Dussault from dried blood collected on paper on day 5.
116 225 245 115 142 223 247 142 65 243 218
Drugs (l~g/day)
Time after birth (days)
T,~(50)+Td5) T.~(50) T~(5)
50-57 58-127 128-169
T,(50) +T~(5) T~(5)
17-63 64-67
T~(10)
17-43
Tall0 )
22-43
976
Delange et al.
The diagnosis of primary hypothyroidism was established on the basis of high TSH levels and low or undetectable T~ levels. T3 was low in four infants (less than 100 ng/dl). In all six patients bone maturation was normal and the thyroid gland was in the normal position, as indicated by the presence of goiter or by a normal scintigram. The concentration of urinary iodine, measured in four patients, ranged from 3.4 to 20.0 /~g/dl. Thyroglobulin antibodies were undetectable in all cases. Serum levels of TBG, measured when the other values reverted to normal or during the follow-up period, range d from 1.99 to 2.92 mg/dl,~ the mean value was 2.32 _+ 0.30 (SD) mg/dl. Patients 1 and 2 were treated with a combination of T~ and T3. Their levels ofT4, T3, and TSH reverted to normal by the fifth day of treatment. The levels remained normal throughout the period of treatment and after withdrawal of T~ and T:~. Patients 3 and 4 were treated with T~ only; T~ increased substantially and TSH reverted to normal. Of great interest was the steady rise of serum T4; normal T.~ values were reached by 43 and 49 days, respectively. All the values remained within the normal range for more than three months after cessation of T~ treatment. Patients 5 and 6 received no treatment. The levels of TSH, T4, and T~ reverted spontaneously to normal by the nineteenth and twenty-fifth days, respectively, and remained so throughout the 8Vz-month follow-up period. The physical and psychomotor development of the six infants was normal throughout the follow-up period. DISCUSSION These six infants had biochemical features typical of primary thyroid insufficiency soon after birth. The main interest of our findings is the indication that thyroid failure was transient in these patients. In all of them normal thyroid function was restored and maintained for periods ranging from 11 to 33 weeks after treatment was stopped. Furthermore, the progressive return to normal T4 levels in Patients 3 to 6, who received no T4 supplementation, indicates that the observed hypothyroidism was not only transient but also spontaneously reversible. This temporary state of hypothyroidism seems particularly frequent in premature infants with associated severe disorders. In this study, five of the six infants were premature. Four of them were born in our Maternity Department among a total number of 4,610 births. In infants with low serum concentrations of T~, elevated serum concentrations of TSH and normal TB G concentrations (ruling out a congenital defect of the binding protein) replacement therapy appears to be necessary, as proposed by Klein and associates.:' t~owever, treatment is
The Journal of Pediatrics June 1978
probably not required when hypothyroidism resolves spontaneously and rapidly, as in Patients 5 and 6. The data suggest that treatment with T3 may be suitable for distinguishing between transient and permanent hypothyroidism without interruption of replacement therapy. The cause of the thyroid insufficiency in these patients remains unknown. The data rule out the classical causes of congenital hypothyroidism. Two factors might explain the transient inability of the thyroid to maintain Sufficient hormonal secretion in premature infants during serious illness, when peripheral utilization of hormones is increased? The first is the low thyroidal content of iodine reported in newborn infants, especially if premature~; this situation could be aggravated in Belgium by the relatively low iodine supply. The second is a delay in the maturation of the enzymatic mechanisms involved in intrathyroidal hormonogenesis. These hypotheses call for further research. The authors thank Drs. J. H. Dussault, C. Delespesse, and H. L. Loeb for their help. REFERENCES
1. Fisher DA, Burrow GN, Dussault JH, Hollingsworth DR, Larsen PR, Man EB, and Walfish PG: Recommendations for screening programs for congenital hypothyroidism. Report of a Committee of The American Thyroid Association, J PEDIATR89:692, 1976. 2. Cuestas RA, Lindall A, and Engel RR: Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood, N Engl J Med 295:297, 1976. 3. Klein AH, Stinson D, Foley B, Larsen PR, and Foley TP Jr: Thyroid function studies in preterm infants recovering from the respiratory distress syndrome, J P~t)IATR91:261, 1977. 4. Uhrmann S, Marks KH, Maisels MJ, Friedman Z, Murray F, Fulin H, Kaplan M, and Utiger R: Thyroid function in infants admitted to a neonatal intensive unit (NICU): A longitudinal assessment, Pediatr Res 11:432, 1977. 5. Delange F, Camus M, Winkler M, Dodion J, and Ermans AM: Serum thyrotropin determination on day 5 of life as screening procedure for congenital hypothyroidism, Arch Dis Child 52:89, 1977. 6. Gershengorn MC, Larsen PR, and Robbins J: Radioimmunoassay for serum thyroxine-binding globulin: results in normal subjects and in patients with hepato cellular carcinoma, J Clin Endocrinol 42:907, 1976. 7. Delespesse G, Hubert C, Gausset Ph, and Govaerts A: Radioimmunoassay for human antithyroglobulin antibodies of different immunoglobulin classes, Horm Metab Res 8:50, 1976. 8. Gregerman RI, and Solomon N: Acceleration of thyroxine and triiodothyronine turnover during bacterial pulmonary infections and fever: implications for the functional state of the thyroid during stress and in senescence, J Clin Endocrinol 27:93, 1967. 9. Etling N: Concentration of thyroglobulin, iodine contents of thyroglobulin and of iodoaminoacids in human neonates thyroid glands, Acta Paediatr Scand 66:97, 1977.