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Recommendations for screening programs for congenital hypothyroidism
Recommendations for Screening Programs for Congenital Hypothyroidism Report of a Committee of the American Thyroid Association
D. A. FISHER, M.D. Torrance, California G. N. BURROW, M.D. iVe w /-/aven, Connecticut J. H. DUSSAULT,
M.D.
Quebec, Canada D. R. HOLLINGSWORTH,
M.D
Lexington, Kentucky P. R. LARSEN, M.D. Boston, Massachusetts E. B. MAN, Ph.D. North Stonington, Connecticut P. G. WALFISH,
M.D.
Ontario, Canada
Requests for reprints should be addressed to Dr. D. A. Fisher, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509.
932
December
1976
The American
Journal
The importance of early treatment of congenital hypothyroidism has been emphasized by many investigators. Currently, however, we usually rely on physician acumen for early diagnosis. Since the majority of cases are sporadic with subtle and nonspecific manifestations appearing early in the course, the diagnosis often is not suspected before six to eight weeks of age and may be delayed until three to six months of age. In the past, the placenta has been considered to be permeable to thyroid hormones so that the hypothyroid fetus was expected to have normal circulating levels of thyroxine (T4). This assumption, coupled with inherent limitations in the protein-bound iodine and butanol extractable iodine procedures, largely precluded attempts at screening newborns for hypothyroidism. Recent evidence that the placental transfer of thyrotropin (TSH) and thyroid hormones is markedly limited, as well as the recent availability of highly sensitive and specific radioimmunoassay systems for measuring thyroid hormones and TSH in biologic fluids, have made screening of newborns for congenital hypothyroidism feasible. During the past three years, pilot screening programs have been established in Quebec, Pittsburgh and Toronto; and The American Thyroid Association appointed a Committee on Newborn Screening for Hypothyroidism to monitor these programs and to make recommendations regarding screening based on the accumulated results of these pilot programs. The committee and the Association believe that enough evidence has accumulated to make preliminary recommendations which are included in this report. This report was approved for publication by the members of The American Thyroid Association at the business meeting on June 12, 1975. Dr. Dussault and colleagues [ 1,2] in Quebec adapted the T4 radioimmunoassay system to eluates of filter paper blood spots already in use for phenylketonuria screening. Dr. Larsen [3] has further simplified the filter paper spot T4 method. Dr. Foley and colleagues [l-4] in Pittsburgh have screened cord blood using a conventional TSH radioimmunoassay system. Dr. Walfish and collaborators [ 1,5] in Toronto have screened newborns using the filter paper spot T4 method at three to five days of age and utilizing T4 and TSH radioimmunoassay of cord blood samples. In the Quebec program approximately 100,000 infants had been screened by June 1975, and 15 hypothyroid newborns
of Medicine
Volume 61
SCREENING PROGRAMS FOR HYPOTHYROIDISM-FISHER
and six infants with low thyroxine-binding globulin (TBG) levels were detected. In Pittsburgh, 15,000 infants had been screened; four hypothyroid newborns and one infant with a low TBG level were detected. In the Toronto program 6,000 infants had been screened and two hypothyroid newborns and six infants with low TBG levels were detected. The total number of newborn infants screened approximated 121,000, and 21 infants with congenital hypothyroidism had been detected (Table I), an incidence of one in 5,760 newborns. Analysis of the test results from the 2 1 infants with proved congenital hypothyroidism (Table II) detected by the screening programs revealed the following: (1) Measured or estimated cord serum T4 values in all were <7 pg/lOO ml. Estimates were based on the measured filter paper spot result at two to four days. This method may overestimate somewhat. (2) In five of six infants with cord blood TSH measurements TSH levels were > 100 pU/ml. In seven of the 10 infants in the Quebec study with serum TSH measurements conducted on recall between two and four weeks, levels were in excess of 50 &l/ml. One other had a modestly elevated level (32 pU/ml). One of the remaining two infants was hypopituitary with a low serum TSH, and one was euthyroid with a normal serum TSH concentration and a high serum triiodothyronine (T3) level. (3) Five of six infants had low serum T3 values (<50 ng/lOO ml). One other infant with dyshormonogenesis had a high serum T3 level at three weeks. Logistical difficulties in recall for retesting can be significant. From 0.7 to 1.O per cent of samples require retesting in the filter paper T4 screening programs, and from 2.0 to 2.5 per cent of samples require retesting in cord blood T4 screening programs. Very’preliminary evidence suggests that cord blood TSH screening may miss a few infants with hypothyroidism secondary to TSH deficiency. Filter paper spot T4 screening may miss a few infants with compensated or partial thyroid
TABLE
II
T4, T3 and TSH Preliminary
Measurement
Screening Cord
Results of Preliminary for Congenital
Screening
Programs
Hypothyroidism No. of Abnormal Infants Detected
No. of Infants Hypo- Low Screened thyroid TBG Dussault et al. Quebec
100,000
6
Filter paper spot, 2 to 4 days
15,000
4
1
Cord blood TSH
6,000
2
6
Cord blood T4 and TSH; filter paper blood spot at 3 to 5 days
121,000
21
13
Walfish et al. Toronto
Totals NOTE:
Type of Screening
15
Foley et al. Pittsburgh
TBG = thyroxine-binding
globulin.
insufficiency, although the proportion of such cases is not yet clear. Finally, the effects of early thyroid hormone treatment (begun before one month) have yet to be defined. It is anticipated, however, that results will be at least as good as those obtained with therapy begun before three months of age; 85 per cent of such infants have IQ values >85 [S]. The cost of T4 screening using filter paper spots or cord blood samples approximates 60 cerits a test whereas the cost of cord blood or filter paper TSH screening is approximately $1.50 a test. The cost of detecting each congenitally hypothyroid newborn by T4 screening approximates $4,000 and by TSH screening $12,000. Assuming, conservatively, that 30 per cent of the infants in whom the diagnosis is delayed will require institutional care at $10,000 yearly for 30 years and that only IO per cent of the infants in whom the diagnosis is made at birth will require such care, a
Results in Infants
with Hypothyroidism
Detected
by Several
SerumConcentration* Cord
T3 (ng/dl)
5.0-7.0
<50
50-100
>lOO
11/15*
4115
213
__,
1/3+
214
214
313
212
.
<5.0
I
Programs
T4 Lug/d11
Dussault et al. Quebec Foley etal. Pittsburgh Walfish et al. Toronto
TABLE
ET AL.
TSH (JJ/ml)
50-100
..,
... .
.
>lOO
1 I2
Later TSH (JJ/ml)t <20
20-50
>50
>lOO
2110
l/IO
2/l 0
5110
II2
II2
414
...
l/2
.
.
Measured directly or estimated from 2 to 4 day filter paper spot sample. + Measurements conducted between two and four weeks. * Eleven of 15 samples tested. l
December 1976
The American Journal of Medicine
Volume 61
933
SCREENING PROGRAMS FOR HYPOTHYROIDISM-FISHER
ET AL.
screening program can save $600,000 for each 10 infants detected. Thus, there now is good evidence for an incidence of congenital hypothyroidism of at least one in 6,000 births in North America, and evidence that screening newborns for this disorder can be effective and cost accounted. The American Thyroid Association recommends: (1) The establishment and. expansion of preliminary screening programs for congenital hypothyroidism. (2) Combining testing for hypothyroidism with existing newborn screening programs to improve cost effectiveness and to help guarantee quality control and efficient follow-up. The advantages of a regional approach to screening have been demonstrated in Quebec, and this experience can serve as a model for other areas. (3) Screening for congenital hypothyroidism using a filter paper T4 method with filter paper TSH testing
of suspicious samples. This approach is particularly applicable when samples must be mailed to a central laboratory, or (4) Screening for congenital hypothyroidism using cord blood T4 testing when samples can be processed locally. Suspicious samples should be retested using a TSH radioimmunoassay. (5) Further development of TSH measurement methods for screening newborns for hypothyroidism, particularly for filter paper samples. Recent studies have shown that such measurements are feasible [7,8]. (6) Study of screening for hypothyroidism using reverse T3 measurements [9]. This method may be applicable to in utero screening of high risk mothers as well as screening of newborns. (7) Development of adequate pools of T4 and TSH antiserums to support widespread public screening programs for congenital hypothyroidism.
REFERENCES 1.
2.
3.
4.
934
(a) Newborn screening for hypothyroidism. Perinatal Thyroid Physiology and Disease (Fisher DA, Burrow GN, eds), New York, Raven Press, 1975. (b) Fisher DA, Sack J: Idem, p 197. (c) Larsen PR, Abuid J: Idem, p 211. (d) Dussault JH, Coulombe P, Laberge C: Idem, p 221. (e) Foley TP Jr, Klein AH, Agustin AV, Hopwood N: Idem, p 255. (f) Walfish PG: Idem, pp 239, 249, 263. Dussault JH, Coulombe P, Laberge C, et al.: Preliminary report on a mass screening for neonatal hypothyroidism. J. Pediatr 86: 670, 1975. Larsen PR, Broskin K: Thyroxine immunoassay using filter paper blood samples for screening of neonates for hypothyroidism. Pediatr Res 9: 604, 1975. Klein AH, Agustin AV, Foley TP Jr: Successful laboratory screening for congenital hypothyroidism. Lancet 1: 77, 1974.
December 1979
The American Journal of Medicine
5.
6.
7. 8.
9.
Walfish PG, O’Donnell J, Ulbright T, et al.: Screening for neonatal hypothyroidism. Comparison of neonatal dried capillary blood thyroxine (T4) to cord serum T4 and thyrotropin (TSH). Proceedings of the VII International Congress, Boston, June 1975. Thyroid Research (Robbins J, Braverman LE, eds), Amsterdam, Excerpta Medica, International Congress Series, 1976, p 601. Klein A, Meltzer S, Kenny MD: Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 81: 912, 1972. lrie M, Enomoto K, Naruse H: Measurement of thyroid-stimulating hormone in dried blood spot. Lancet 2: 1233. 1975. Grajwer LA, Lam RW, Bruce VA, et al.: A sensitive TSH radioimmunoassay for newborn thyroid screening. Clin Res 24: 192A, 1976. Chopra IJ, Crandall BF: Thyroid hormones and thyrotropin in amniotic fluid. N Engl J Med 293: 740, 1975.
Volume 61
D. A. FISHER, M.D. Torrance, California G. N. BURROW, M.D. iVe w /-/aven, Connecticut J. H. DUSSAULT,
M.D.
Quebec, Canada D. R. HOLLINGSWORTH,
M.D
Lexington, Kentucky P. R. LARSEN, M.D. Boston, Massachusetts E. B. MAN, Ph.D. North Stonington, Connecticut P. G. WALFISH,
M.D.
Ontario, Canada
Requests for reprints should be addressed to Dr. D. A. Fisher, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509.
932
December
1976
The American
Journal
The importance of early treatment of congenital hypothyroidism has been emphasized by many investigators. Currently, however, we usually rely on physician acumen for early diagnosis. Since the majority of cases are sporadic with subtle and nonspecific manifestations appearing early in the course, the diagnosis often is not suspected before six to eight weeks of age and may be delayed until three to six months of age. In the past, the placenta has been considered to be permeable to thyroid hormones so that the hypothyroid fetus was expected to have normal circulating levels of thyroxine (T4). This assumption, coupled with inherent limitations in the protein-bound iodine and butanol extractable iodine procedures, largely precluded attempts at screening newborns for hypothyroidism. Recent evidence that the placental transfer of thyrotropin (TSH) and thyroid hormones is markedly limited, as well as the recent availability of highly sensitive and specific radioimmunoassay systems for measuring thyroid hormones and TSH in biologic fluids, have made screening of newborns for congenital hypothyroidism feasible. During the past three years, pilot screening programs have been established in Quebec, Pittsburgh and Toronto; and The American Thyroid Association appointed a Committee on Newborn Screening for Hypothyroidism to monitor these programs and to make recommendations regarding screening based on the accumulated results of these pilot programs. The committee and the Association believe that enough evidence has accumulated to make preliminary recommendations which are included in this report. This report was approved for publication by the members of The American Thyroid Association at the business meeting on June 12, 1975. Dr. Dussault and colleagues [ 1,2] in Quebec adapted the T4 radioimmunoassay system to eluates of filter paper blood spots already in use for phenylketonuria screening. Dr. Larsen [3] has further simplified the filter paper spot T4 method. Dr. Foley and colleagues [l-4] in Pittsburgh have screened cord blood using a conventional TSH radioimmunoassay system. Dr. Walfish and collaborators [ 1,5] in Toronto have screened newborns using the filter paper spot T4 method at three to five days of age and utilizing T4 and TSH radioimmunoassay of cord blood samples. In the Quebec program approximately 100,000 infants had been screened by June 1975, and 15 hypothyroid newborns
of Medicine
Volume 61
SCREENING PROGRAMS FOR HYPOTHYROIDISM-FISHER
and six infants with low thyroxine-binding globulin (TBG) levels were detected. In Pittsburgh, 15,000 infants had been screened; four hypothyroid newborns and one infant with a low TBG level were detected. In the Toronto program 6,000 infants had been screened and two hypothyroid newborns and six infants with low TBG levels were detected. The total number of newborn infants screened approximated 121,000, and 21 infants with congenital hypothyroidism had been detected (Table I), an incidence of one in 5,760 newborns. Analysis of the test results from the 2 1 infants with proved congenital hypothyroidism (Table II) detected by the screening programs revealed the following: (1) Measured or estimated cord serum T4 values in all were <7 pg/lOO ml. Estimates were based on the measured filter paper spot result at two to four days. This method may overestimate somewhat. (2) In five of six infants with cord blood TSH measurements TSH levels were > 100 pU/ml. In seven of the 10 infants in the Quebec study with serum TSH measurements conducted on recall between two and four weeks, levels were in excess of 50 &l/ml. One other had a modestly elevated level (32 pU/ml). One of the remaining two infants was hypopituitary with a low serum TSH, and one was euthyroid with a normal serum TSH concentration and a high serum triiodothyronine (T3) level. (3) Five of six infants had low serum T3 values (<50 ng/lOO ml). One other infant with dyshormonogenesis had a high serum T3 level at three weeks. Logistical difficulties in recall for retesting can be significant. From 0.7 to 1.O per cent of samples require retesting in the filter paper T4 screening programs, and from 2.0 to 2.5 per cent of samples require retesting in cord blood T4 screening programs. Very’preliminary evidence suggests that cord blood TSH screening may miss a few infants with hypothyroidism secondary to TSH deficiency. Filter paper spot T4 screening may miss a few infants with compensated or partial thyroid
TABLE
II
T4, T3 and TSH Preliminary
Measurement
Screening Cord
Results of Preliminary for Congenital
Screening
Programs
Hypothyroidism No. of Abnormal Infants Detected
No. of Infants Hypo- Low Screened thyroid TBG Dussault et al. Quebec
100,000
6
Filter paper spot, 2 to 4 days
15,000
4
1
Cord blood TSH
6,000
2
6
Cord blood T4 and TSH; filter paper blood spot at 3 to 5 days
121,000
21
13
Walfish et al. Toronto
Totals NOTE:
Type of Screening
15
Foley et al. Pittsburgh
TBG = thyroxine-binding
globulin.
insufficiency, although the proportion of such cases is not yet clear. Finally, the effects of early thyroid hormone treatment (begun before one month) have yet to be defined. It is anticipated, however, that results will be at least as good as those obtained with therapy begun before three months of age; 85 per cent of such infants have IQ values >85 [S]. The cost of T4 screening using filter paper spots or cord blood samples approximates 60 cerits a test whereas the cost of cord blood or filter paper TSH screening is approximately $1.50 a test. The cost of detecting each congenitally hypothyroid newborn by T4 screening approximates $4,000 and by TSH screening $12,000. Assuming, conservatively, that 30 per cent of the infants in whom the diagnosis is delayed will require institutional care at $10,000 yearly for 30 years and that only IO per cent of the infants in whom the diagnosis is made at birth will require such care, a
Results in Infants
with Hypothyroidism
Detected
by Several
SerumConcentration* Cord
T3 (ng/dl)
5.0-7.0
<50
50-100
>lOO
11/15*
4115
213
__,
1/3+
214
214
313
212
.
<5.0
I
Programs
T4 Lug/d11
Dussault et al. Quebec Foley etal. Pittsburgh Walfish et al. Toronto
TABLE
ET AL.
TSH (JJ/ml)
50-100
..,
... .
.
>lOO
1 I2
Later TSH (JJ/ml)t <20
20-50
>50
>lOO
2110
l/IO
2/l 0
5110
II2
II2
414
...
l/2
.
.
Measured directly or estimated from 2 to 4 day filter paper spot sample. + Measurements conducted between two and four weeks. * Eleven of 15 samples tested. l
December 1976
The American Journal of Medicine
Volume 61
933
SCREENING PROGRAMS FOR HYPOTHYROIDISM-FISHER
ET AL.
screening program can save $600,000 for each 10 infants detected. Thus, there now is good evidence for an incidence of congenital hypothyroidism of at least one in 6,000 births in North America, and evidence that screening newborns for this disorder can be effective and cost accounted. The American Thyroid Association recommends: (1) The establishment and. expansion of preliminary screening programs for congenital hypothyroidism. (2) Combining testing for hypothyroidism with existing newborn screening programs to improve cost effectiveness and to help guarantee quality control and efficient follow-up. The advantages of a regional approach to screening have been demonstrated in Quebec, and this experience can serve as a model for other areas. (3) Screening for congenital hypothyroidism using a filter paper T4 method with filter paper TSH testing
of suspicious samples. This approach is particularly applicable when samples must be mailed to a central laboratory, or (4) Screening for congenital hypothyroidism using cord blood T4 testing when samples can be processed locally. Suspicious samples should be retested using a TSH radioimmunoassay. (5) Further development of TSH measurement methods for screening newborns for hypothyroidism, particularly for filter paper samples. Recent studies have shown that such measurements are feasible [7,8]. (6) Study of screening for hypothyroidism using reverse T3 measurements [9]. This method may be applicable to in utero screening of high risk mothers as well as screening of newborns. (7) Development of adequate pools of T4 and TSH antiserums to support widespread public screening programs for congenital hypothyroidism.
REFERENCES 1.
2.
3.
4.
934
(a) Newborn screening for hypothyroidism. Perinatal Thyroid Physiology and Disease (Fisher DA, Burrow GN, eds), New York, Raven Press, 1975. (b) Fisher DA, Sack J: Idem, p 197. (c) Larsen PR, Abuid J: Idem, p 211. (d) Dussault JH, Coulombe P, Laberge C: Idem, p 221. (e) Foley TP Jr, Klein AH, Agustin AV, Hopwood N: Idem, p 255. (f) Walfish PG: Idem, pp 239, 249, 263. Dussault JH, Coulombe P, Laberge C, et al.: Preliminary report on a mass screening for neonatal hypothyroidism. J. Pediatr 86: 670, 1975. Larsen PR, Broskin K: Thyroxine immunoassay using filter paper blood samples for screening of neonates for hypothyroidism. Pediatr Res 9: 604, 1975. Klein AH, Agustin AV, Foley TP Jr: Successful laboratory screening for congenital hypothyroidism. Lancet 1: 77, 1974.
December 1979
The American Journal of Medicine
5.
6.
7. 8.
9.
Walfish PG, O’Donnell J, Ulbright T, et al.: Screening for neonatal hypothyroidism. Comparison of neonatal dried capillary blood thyroxine (T4) to cord serum T4 and thyrotropin (TSH). Proceedings of the VII International Congress, Boston, June 1975. Thyroid Research (Robbins J, Braverman LE, eds), Amsterdam, Excerpta Medica, International Congress Series, 1976, p 601. Klein A, Meltzer S, Kenny MD: Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 81: 912, 1972. lrie M, Enomoto K, Naruse H: Measurement of thyroid-stimulating hormone in dried blood spot. Lancet 2: 1233. 1975. Grajwer LA, Lam RW, Bruce VA, et al.: A sensitive TSH radioimmunoassay for newborn thyroid screening. Clin Res 24: 192A, 1976. Chopra IJ, Crandall BF: Thyroid hormones and thyrotropin in amniotic fluid. N Engl J Med 293: 740, 1975.
Volume 61