British Joiirnnl of 0bsieiric.s and Gynaecnlogy November 19Y0, Vol. 97, pp. 1003-1008
Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder SYLVAINE CLAVEL. ANNE-MARIE MADEC, HUBERT BORNET, PHILIPPE DEVILLER, ANNE STEFANUTTI, J . ORGIAZZI
Summary. The study was designed to test further the usefulness of the radioreceptor assay of thyroid stimulating hormone (TSH) binding inhibitory immunoglobulins (‘1’BIT) and the bioassay of thyroid stimulating antibodies (TSAb) or TSH stimulated CAMPresponse inhibitory antibodies (TBkAb) in the prediction of neonatal thyroid dysfunction. Of 63 pregnant wonicn with a current or past history of autoimmune thyroid disorder, 11 (one with active and six with a past history of Graves’ disease and four with autoimmune thyroiditis) gave birth to a baby with transient hyper or hypo-thyroidism. Only high maternal titres (which could persist after partial thyroidectomy) of anti ‘1SH-receptor antibodies (TRAb) led to neonatal hyperthyroidism. Both types of assay were able to detect the antibodies responsible for transitory neonatal autoimmune thyroid disease. TBTT values reflected TSAb titrcs so that there was a significant correlation between the results of both assays in women with Graves’ disease and in neonatal sera. Positive TBll and ‘T’Rk Ab activities were present in 5 of the 28 women with autoimmune thyroiditis. Therefore, when TBII is positive, the functional characterization of the antibodies warrants the use of the bioassay.
Maternal autoimmunc thyroid disordcrs may affect fctal and neonatal thyroid function
Inserm U. 197, Faculte de Medecine Alexis Carrel
J. ORGIAZZI A.-M. MADEC S. CLAVEL A. STEFANUTTI Laboratoirc de Binphysique, Faculte de Medecine Rockefcllcr
H. BORNET Laboratnire de Chimie Binlogique el Medicale, Faculte de Medecine Alexis Carrel Ph. L>EVILLEK
Corrcspondcncc: Pr J . Orgiazzi, lnserm U. 197, Faculte dc Mcdccine A. Carrel, 69372 Lyon Cedex 08. France
through placental transfcr of anti TSH-rcceptor antibodies (TRAb) (Blizzard ef al. 1960: Burman & Raker 1985). ‘lhese antibodies, mainly of thc IgG class, usually elicit thyroid stimulating activity but in rare cases may inhibit thyroid stimulation. Thyroid stimulating antibodies (TSAb) are usually encountered in Graves‘ disease, in which they are held responsible for thyruid hyperfunction (Zakarija et 111. 1980). Although more relevant to Hashitnoto’s thyroiditis and autoimmune hypothyroidism (Endo et al. 1978; Takasu et al. 1987), thyroid blocking antibodies (TBkAb) have been detected in some patients with Graves‘ disease (Volpe et uL. 1984). Children born to women with high titres of TRAb are therefore at risk of developing passive thyroid autoimmunc hypcrthyroidisrn (Hoffman et al. 1982; Zakarija & McKenzie 1983) o r 1003
1004
S. Clavel et al.
hypothyroidism (Matsuura ct al. 1980; Iseki etal. 1983; Takasu et al. 19x4). In order to devise a pcrinatal screening for potential fetal and neonatal autoimmune thyroid disorder in pregnancies with maternal autoimmune thyroid disorder. we havc mcasurcd T R A b in two ways. as stimulating or blocking antibody with a thyroid cell culture CAMPassay system, and as TSH-binding inhibitor immunoglobulins (TBII) with a radioreceptor assay of TSH. Subjects and methods Patients with autoimmune thyroid disease and their offspring were tested for anti TSH-receptor antibody as part ol' their regular investigations. Thirty-five pregnant women with Graves' disease and 28 with autoimmune thyroidilis and their offsprings were studied. Blood samplcs were obtained from the women during the third trimester of prcgnancy and from the newborn either at birth as cord blood or during the first days o l life by venepuncture. Of the 35 women with Graves' disease (Table 1)29 had active Graves' disease and were receiving carbimazole treatment (group 1). 5-30 mg per day, at time of blood sampling. Of thesc 29 patients. 25 were euthyroid and four were hyperthyroid according to free T4 estimatedwith cornniercially available kits. The othcr six had a past history of Graves' disease for which thcy had undergone partial thyroidectomy (group 2). A t the time of study, four of them were clinically and biochemically euthyroid without trcatmcnt
Table 1. Clinical data of 35 pregnant women ~ i t h Gravcs' disease Neondial thyroid status Maternal thyroid status Active Graves' disease Duthyrvid Hypcrthyroid Past history of Graves'
17
Euthyroid
Hyperthyroid
25 1
25 3
0 1
ti'
0
6
discasc
(thyroidectom y) Euthyroid
"Two of them had to bc treated with antithyroid drugs
bccausc of ovcrt recurrence of hyperthyroidism during pregnancy.
the other two were euthyroid on carbimazole thcrapy aftcr rclapsc during pregnancy. The 28 pregnant women with autoimmune thyroiditis and their offsprings were also investigated. Maternal diagnosis was made on the basis of clevatcd antithyroglobulin and antimicrosomal antibody titrcs andlor hypothyroidism or primary myxoedema. All the patients were euthyroid at the time of blood sampling, with or without T3 replacement therapy. Of these 28 women. three gave birth to a hypothyroid child and one gave birth to two hypothyroid children in two succcssive pregnancies. Two o f thesc four women had had a normal child before the onset of their thyroid disease; another had had two hypothyroid children whose disease was also recognized as transient at the time of the third infant's investigations. TSAb was assayed as described previously by Madec et a1. (1984) using human thyroid cells in monolayer culture with some modifications. The cells (10' cells per well) were exposed for 2 h to 40 pi of the sera to be tested or control scra in 160 pl of modificd Kahagi et al. (19x2) medium supplemented with 20 mM Hepes. 1-OmM3-isobutyl-1-niethylxanthine (IBMx) and 0.3% BSA, p H 7 4 . After incubation, cAMP released from the cells was determined by a solid phase radioitnmunoassay. All samples were assayed in triplicate wells. Stimulation was assessed by comparison with control wells. TSAb activity was expressed as a percentage of basal values. TBkAb was determined as described previously (Madec et al. 1988). Sera to be tested were co-incubated with either 0.03mU of b-TSH or 2 ul of an in-house-standard TSAb per well in the conditions of thc stimulating assay. Sera wcre also tested alone. Presence of blocking antibodies was detected by comparison with control cells incubated in thc prcscncc of normal serum and either stimulator. Activity of THkAh was expressed as percent inhibition as comparcd to cAMP conccntrations obtained in the presence ol'the stimulators alone. Antibodies with the capacity of inhibiting thc binding of 125 I-labelled TSH to it5 receptors (TSH binding inhibitory immunoglobu1ins:'I'BlI) were detected by radioreceptor assay (Smith Pr Hall 1981) using a commercial kit (TRAK-Hehring). Kesults were expressed as Uil as recommended by the manufacturer.
Results P a t i o m with Graves' disease Seven women gave birth to clinically and bio-
Anti TSH-receptor antibodies in prrgnoricy chemically hyperthyroid children (F1’3 range 26-4-50 pniolil at day 0-2 of life; normal: 3.5-Y). Their sera had a strongly positivc TSAb activity of >350% of basal values (Fig. 1); TSAb was also detected in the hyperthyroid babies. Six ol these women wcrc euthyroid and had a past history of Graves’ disease (group 2); the seventh was hyperthyroid (group 1) despite carbimazole treatment (Table 1). Neonatal disease was characterized by spontaneous regression, delayed for bctwccn 4 and 24 weeks. Four infants received supportive therapy, carbimaTole or propylthiouracil for 8 to 20 weeks; in none was a goitre detected by clinical examination. The remaining 28 women in group 1(25 cuthyroid and three hyperthyroid) gave birth to clinically and biochemically euthyroid children (TSH range 7-X-48-0mU/l at day 0-3 of life). TSAb was undetectable in 19 womcn and in thc other ninc TSAb was present but was etween maternal and neonatal thyroid status was seen. but all the women who gave birth to hypothyroid infants had no goitre and two of them had an atrophic thyroid. One of the aims of this study was to investigate the usefulness of the commercial kit (TRAKBehring) in this setting in comparison with the more demanding method hased on CAMP production by thyroid cells. Multiple attempts have been made to correlate TBII and TSAb activities in patients with Graves’ disease. Several studies failed to find any association between these activitics (Sugenoya et (11. 1979: Macchia et al. 1981). 111contrast, Borges c t n l . (1982) and Biro ef a/. (1982) were able to demonstrate a good concordance between TBII and TSAb activities. Tn our patients. the correlation between the results of the two assays was largely satisfactory. Only some of the weakly pocitive sera in either assay appeared discordant. It is not yet clear whether discordances between TBII and TSAb arc due to antibody hctcrogeneity or to mcthodological inadequacy. Of great theoretical importance is the correlation between TBII and TBkAb. Matsuura et al. (1988) reported a lack of concordance between these two activilies, a result not confirmed by Takasu et a / . (1987). Our five patients with TBkAh were also positive with the TKAK assay and none of the patients negative by this assay had TBkAb in their serum. T R A b activity levels during pregnancy are
1007
useful in the prediction of neonatal thyroid clysfunction. especially in women with active, or a history of Graves’ disease, o r who have had a thyroidcctomy lor Graves’ disease, o r who have autoimmune thyroiditis. Neonatal transient hyper- and hypo-thyroidism should bc treated with appropriate drugs, but the detection of T R A b is useful to monitor the time of drug withdrawal. In those clinical situations, only high titres o f T R A b are deleterious. TBII assays are suitable for the detection of both TSAb and TBkAb. Therefore, when the TBII assay is positive and regardless of clinical, historical or biological considerations, the more complex bioassay for TSAb or TBkAb is mandatory to identify the functional activity of thc antibody. In conclusion, this work illustrates the uscfulncss of the assay of T R A b in pregnant women with a current o r a past history of autoimmune thyroid disorder. It also demonstrates the appropriateness of the readily available TBII assays. However, in selected cases, TBII assay must be reinforced by the functional bioassay. The dctcction of high titres of either TSAb o r TBkAb in a pregnant woman is indicative of late fetal or neonatal transferred autoimmune thyroid disease. Acknowledgments
We wish to thank Prs and Drs P. Beauvais. J. Berthet, G . Danion, X . Ducottet, L. A. Gratccos, M. Guibout, J. Leclere, J . Lefebvre, M. Lestradet, M. Malinsky, A . Martin. J . L. Mesnil. R . Mornex, D. Pallo, M. Pugeat, A . Raffi,P. Rambaud, 11. Kousset, P. Rubin, A. Salle, L. Sann, G. Teyssier, J . Tourniairc. for providing us with the mothers’ and newborns’ blood samples. References Biro J . (1982) Thyroid stimulating antibodies in Graves’ disease and the effect of thyrotrophinbinding globulins on their dctcrniination. J Entlocrinol92, 175.184. Blizzard R. B.. Chandlcr K . W., Landing B. H . cf 01. (1960) Maternal autoimin~ii~izatio~i to thyroid as a probable cause of athyrotic cretinism. N Ens/ J Mt’d 263, 327-336. BorgesM., Ingbar J . C., Endo K., Arnir S.. Uchimura 11.; Nagataki S. & Ingbar S. 11. (1982) .4 new method for assessing the thyrotropin binding inhibitory activity in thc imn~unuglobulins and uholc serum of patients with GI-avcs’ disease. J Clin Endocrinol Mctah 54, 552-558. Burman K. D. Rr Bakcr J . K. (1985) Immunc mcch-
1008
S. Clavel et al.
anisms in Graves’ disease. Endocritze Rev 6, 183-232. Dirmikis S. M. & Munro D. S. (1975) Placental transmission o f thyroid stimulating imniunoglohulins. Br Med J 2, 665-666. Endo K., Kasagi K . ; Ikekuho K., Okuno T., Takcday C.. Mori T. & Torizuka K . (1978) Detection and properties of TSH binding inhibition immunoglobulins in patients with Graves’ disease and Hashinloto’s thyroiditis. .I Cliu Endocrinol M r t h 46, 734-739. Fisher 0. A . (1986) Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. 7hyroid 70day Y, 1-10. Hoffman W. H., Sahasranaiiaii P., Fei-andos S. S . , Burek C. L . , & Kose N . R. (1982) Transient thyrotoxicosis in an infant delivered to a long-acting thyroid stimulator (LATS) and LAI‘S protcctornegative thyroid-stimulating antibody-positivc woman with Hashimoto’s thyroiditis. J Clin Endocrinol Metah 53, 354-356. Iscki M.; Shimizu Y. M., Oikawa T.. Hojo 11.. Arikawa K., Ichikawa, Momotani N. & Ito K. (1983) Sequential serum measurements of thyi-otropin binding inhibition immunoglobulin G in transient familial neonatal hypothyroidism. J Cliri Eridocrin01 h’fPfUb 57, 384-387. Kasagi. K., Konishi J . , lida Y., Ikekubo K . , Mori T.. Kuma K. 6r Torizuha K. (1982) A new in vitro assay for human thyroid stimulator using cultured thyroid cells: effect of
Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder SYLVAINE CLAVEL. ANNE-MARIE MADEC, HUBERT BORNET, PHILIPPE DEVILLER, ANNE STEFANUTTI, J . ORGIAZZI
Summary. The study was designed to test further the usefulness of the radioreceptor assay of thyroid stimulating hormone (TSH) binding inhibitory immunoglobulins (‘1’BIT) and the bioassay of thyroid stimulating antibodies (TSAb) or TSH stimulated CAMPresponse inhibitory antibodies (TBkAb) in the prediction of neonatal thyroid dysfunction. Of 63 pregnant wonicn with a current or past history of autoimmune thyroid disorder, 11 (one with active and six with a past history of Graves’ disease and four with autoimmune thyroiditis) gave birth to a baby with transient hyper or hypo-thyroidism. Only high maternal titres (which could persist after partial thyroidectomy) of anti ‘1SH-receptor antibodies (TRAb) led to neonatal hyperthyroidism. Both types of assay were able to detect the antibodies responsible for transitory neonatal autoimmune thyroid disease. TBTT values reflected TSAb titrcs so that there was a significant correlation between the results of both assays in women with Graves’ disease and in neonatal sera. Positive TBll and ‘T’Rk Ab activities were present in 5 of the 28 women with autoimmune thyroiditis. Therefore, when TBII is positive, the functional characterization of the antibodies warrants the use of the bioassay.
Maternal autoimmunc thyroid disordcrs may affect fctal and neonatal thyroid function
Inserm U. 197, Faculte de Medecine Alexis Carrel
J. ORGIAZZI A.-M. MADEC S. CLAVEL A. STEFANUTTI Laboratoirc de Binphysique, Faculte de Medecine Rockefcllcr
H. BORNET Laboratnire de Chimie Binlogique el Medicale, Faculte de Medecine Alexis Carrel Ph. L>EVILLEK
Corrcspondcncc: Pr J . Orgiazzi, lnserm U. 197, Faculte dc Mcdccine A. Carrel, 69372 Lyon Cedex 08. France
through placental transfcr of anti TSH-rcceptor antibodies (TRAb) (Blizzard ef al. 1960: Burman & Raker 1985). ‘lhese antibodies, mainly of thc IgG class, usually elicit thyroid stimulating activity but in rare cases may inhibit thyroid stimulation. Thyroid stimulating antibodies (TSAb) are usually encountered in Graves‘ disease, in which they are held responsible for thyruid hyperfunction (Zakarija et 111. 1980). Although more relevant to Hashitnoto’s thyroiditis and autoimmune hypothyroidism (Endo et al. 1978; Takasu et al. 1987), thyroid blocking antibodies (TBkAb) have been detected in some patients with Graves‘ disease (Volpe et uL. 1984). Children born to women with high titres of TRAb are therefore at risk of developing passive thyroid autoimmunc hypcrthyroidisrn (Hoffman et al. 1982; Zakarija & McKenzie 1983) o r 1003
1004
S. Clavel et al.
hypothyroidism (Matsuura ct al. 1980; Iseki etal. 1983; Takasu et al. 19x4). In order to devise a pcrinatal screening for potential fetal and neonatal autoimmune thyroid disorder in pregnancies with maternal autoimmune thyroid disorder. we havc mcasurcd T R A b in two ways. as stimulating or blocking antibody with a thyroid cell culture CAMPassay system, and as TSH-binding inhibitor immunoglobulins (TBII) with a radioreceptor assay of TSH. Subjects and methods Patients with autoimmune thyroid disease and their offspring were tested for anti TSH-receptor antibody as part ol' their regular investigations. Thirty-five pregnant women with Graves' disease and 28 with autoimmune thyroidilis and their offsprings were studied. Blood samplcs were obtained from the women during the third trimester of prcgnancy and from the newborn either at birth as cord blood or during the first days o l life by venepuncture. Of the 35 women with Graves' disease (Table 1)29 had active Graves' disease and were receiving carbimazole treatment (group 1). 5-30 mg per day, at time of blood sampling. Of thesc 29 patients. 25 were euthyroid and four were hyperthyroid according to free T4 estimatedwith cornniercially available kits. The othcr six had a past history of Graves' disease for which thcy had undergone partial thyroidectomy (group 2). A t the time of study, four of them were clinically and biochemically euthyroid without trcatmcnt
Table 1. Clinical data of 35 pregnant women ~ i t h Gravcs' disease Neondial thyroid status Maternal thyroid status Active Graves' disease Duthyrvid Hypcrthyroid Past history of Graves'
17
Euthyroid
Hyperthyroid
25 1
25 3
0 1
ti'
0
6
discasc
(thyroidectom y) Euthyroid
"Two of them had to bc treated with antithyroid drugs
bccausc of ovcrt recurrence of hyperthyroidism during pregnancy.
the other two were euthyroid on carbimazole thcrapy aftcr rclapsc during pregnancy. The 28 pregnant women with autoimmune thyroiditis and their offsprings were also investigated. Maternal diagnosis was made on the basis of clevatcd antithyroglobulin and antimicrosomal antibody titrcs andlor hypothyroidism or primary myxoedema. All the patients were euthyroid at the time of blood sampling, with or without T3 replacement therapy. Of these 28 women. three gave birth to a hypothyroid child and one gave birth to two hypothyroid children in two succcssive pregnancies. Two o f thesc four women had had a normal child before the onset of their thyroid disease; another had had two hypothyroid children whose disease was also recognized as transient at the time of the third infant's investigations. TSAb was assayed as described previously by Madec et a1. (1984) using human thyroid cells in monolayer culture with some modifications. The cells (10' cells per well) were exposed for 2 h to 40 pi of the sera to be tested or control scra in 160 pl of modificd Kahagi et al. (19x2) medium supplemented with 20 mM Hepes. 1-OmM3-isobutyl-1-niethylxanthine (IBMx) and 0.3% BSA, p H 7 4 . After incubation, cAMP released from the cells was determined by a solid phase radioitnmunoassay. All samples were assayed in triplicate wells. Stimulation was assessed by comparison with control wells. TSAb activity was expressed as a percentage of basal values. TBkAb was determined as described previously (Madec et al. 1988). Sera to be tested were co-incubated with either 0.03mU of b-TSH or 2 ul of an in-house-standard TSAb per well in the conditions of thc stimulating assay. Sera wcre also tested alone. Presence of blocking antibodies was detected by comparison with control cells incubated in thc prcscncc of normal serum and either stimulator. Activity of THkAh was expressed as percent inhibition as comparcd to cAMP conccntrations obtained in the presence ol'the stimulators alone. Antibodies with the capacity of inhibiting thc binding of 125 I-labelled TSH to it5 receptors (TSH binding inhibitory immunoglobu1ins:'I'BlI) were detected by radioreceptor assay (Smith Pr Hall 1981) using a commercial kit (TRAK-Hehring). Kesults were expressed as Uil as recommended by the manufacturer.
Results P a t i o m with Graves' disease Seven women gave birth to clinically and bio-
Anti TSH-receptor antibodies in prrgnoricy chemically hyperthyroid children (F1’3 range 26-4-50 pniolil at day 0-2 of life; normal: 3.5-Y). Their sera had a strongly positivc TSAb activity of >350% of basal values (Fig. 1); TSAb was also detected in the hyperthyroid babies. Six ol these women wcrc euthyroid and had a past history of Graves’ disease (group 2); the seventh was hyperthyroid (group 1) despite carbimazole treatment (Table 1). Neonatal disease was characterized by spontaneous regression, delayed for bctwccn 4 and 24 weeks. Four infants received supportive therapy, carbimaTole or propylthiouracil for 8 to 20 weeks; in none was a goitre detected by clinical examination. The remaining 28 women in group 1(25 cuthyroid and three hyperthyroid) gave birth to clinically and biochemically euthyroid children (TSH range 7-X-48-0mU/l at day 0-3 of life). TSAb was undetectable in 19 womcn and in thc other ninc TSAb was present but was etween maternal and neonatal thyroid status was seen. but all the women who gave birth to hypothyroid infants had no goitre and two of them had an atrophic thyroid. One of the aims of this study was to investigate the usefulness of the commercial kit (TRAKBehring) in this setting in comparison with the more demanding method hased on CAMP production by thyroid cells. Multiple attempts have been made to correlate TBII and TSAb activities in patients with Graves’ disease. Several studies failed to find any association between these activitics (Sugenoya et (11. 1979: Macchia et al. 1981). 111contrast, Borges c t n l . (1982) and Biro ef a/. (1982) were able to demonstrate a good concordance between TBII and TSAb activities. Tn our patients. the correlation between the results of the two assays was largely satisfactory. Only some of the weakly pocitive sera in either assay appeared discordant. It is not yet clear whether discordances between TBII and TSAb arc due to antibody hctcrogeneity or to mcthodological inadequacy. Of great theoretical importance is the correlation between TBII and TBkAb. Matsuura et al. (1988) reported a lack of concordance between these two activilies, a result not confirmed by Takasu et a / . (1987). Our five patients with TBkAh were also positive with the TKAK assay and none of the patients negative by this assay had TBkAb in their serum. T R A b activity levels during pregnancy are
1007
useful in the prediction of neonatal thyroid clysfunction. especially in women with active, or a history of Graves’ disease, o r who have had a thyroidcctomy lor Graves’ disease, o r who have autoimmune thyroiditis. Neonatal transient hyper- and hypo-thyroidism should bc treated with appropriate drugs, but the detection of T R A b is useful to monitor the time of drug withdrawal. In those clinical situations, only high titres o f T R A b are deleterious. TBII assays are suitable for the detection of both TSAb and TBkAb. Therefore, when the TBII assay is positive and regardless of clinical, historical or biological considerations, the more complex bioassay for TSAb or TBkAb is mandatory to identify the functional activity of thc antibody. In conclusion, this work illustrates the uscfulncss of the assay of T R A b in pregnant women with a current o r a past history of autoimmune thyroid disorder. It also demonstrates the appropriateness of the readily available TBII assays. However, in selected cases, TBII assay must be reinforced by the functional bioassay. The dctcction of high titres of either TSAb o r TBkAb in a pregnant woman is indicative of late fetal or neonatal transferred autoimmune thyroid disease. Acknowledgments
We wish to thank Prs and Drs P. Beauvais. J. Berthet, G . Danion, X . Ducottet, L. A. Gratccos, M. Guibout, J. Leclere, J . Lefebvre, M. Lestradet, M. Malinsky, A . Martin. J . L. Mesnil. R . Mornex, D. Pallo, M. Pugeat, A . Raffi,P. Rambaud, 11. Kousset, P. Rubin, A. Salle, L. Sann, G. Teyssier, J . Tourniairc. for providing us with the mothers’ and newborns’ blood samples. References Biro J . (1982) Thyroid stimulating antibodies in Graves’ disease and the effect of thyrotrophinbinding globulins on their dctcrniination. J Entlocrinol92, 175.184. Blizzard R. B.. Chandlcr K . W., Landing B. H . cf 01. (1960) Maternal autoimin~ii~izatio~i to thyroid as a probable cause of athyrotic cretinism. N Ens/ J Mt’d 263, 327-336. BorgesM., Ingbar J . C., Endo K., Arnir S.. Uchimura 11.; Nagataki S. & Ingbar S. 11. (1982) .4 new method for assessing the thyrotropin binding inhibitory activity in thc imn~unuglobulins and uholc serum of patients with GI-avcs’ disease. J Clin Endocrinol Mctah 54, 552-558. Burman K. D. Rr Bakcr J . K. (1985) Immunc mcch-
1008
S. Clavel et al.
anisms in Graves’ disease. Endocritze Rev 6, 183-232. Dirmikis S. M. & Munro D. S. (1975) Placental transmission o f thyroid stimulating imniunoglohulins. Br Med J 2, 665-666. Endo K., Kasagi K . ; Ikekuho K., Okuno T., Takcday C.. Mori T. & Torizuka K . (1978) Detection and properties of TSH binding inhibition immunoglobulins in patients with Graves’ disease and Hashinloto’s thyroiditis. .I Cliu Endocrinol M r t h 46, 734-739. Fisher 0. A . (1986) Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. 7hyroid 70day Y, 1-10. Hoffman W. H., Sahasranaiiaii P., Fei-andos S. S . , Burek C. L . , & Kose N . R. (1982) Transient thyrotoxicosis in an infant delivered to a long-acting thyroid stimulator (LATS) and LAI‘S protcctornegative thyroid-stimulating antibody-positivc woman with Hashimoto’s thyroiditis. J Clin Endocrinol Metah 53, 354-356. Iscki M.; Shimizu Y. M., Oikawa T.. Hojo 11.. Arikawa K., Ichikawa, Momotani N. & Ito K. (1983) Sequential serum measurements of thyi-otropin binding inhibition immunoglobulin G in transient familial neonatal hypothyroidism. J Cliri Eridocrin01 h’fPfUb 57, 384-387. Kasagi. K., Konishi J . , lida Y., Ikekubo K . , Mori T.. Kuma K. 6r Torizuha K. (1982) A new in vitro assay for human thyroid stimulator using cultured thyroid cells: effect of
