Maternal TSH-Receptor Antibodies and TSH Antibodies in Screening for Congenital Hypothyroidism

ABSTRACT. Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyper-thyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

Circulating Thyroid Antibodies in Congenital Hypothyroidism

ABSTRACT. The role of maternal thyroid antibodies in congenital hypotyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated CAMP production in a rat thyroid cell line, FRTLS. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.     

Maternal TSH-receptor antibodies and TSH antibodies in screening for congenital hypothyroidism

Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyperthyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

Circulating thyroid antibodies in congenital hypothyroidism.

The role of maternal thyroid antibodies in congenital hypothyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated cAMP production in a rat thyroid cell line, FRTL5. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.     

Study of antibody-dependent cell mediated cytotoxicity and thyroid growth blocking antibodies in congenital hypothyroidism

Antibody-dependent cell mediated cytotoxicity (ADCC) and thyroid growth immunoglobulin blocking (TGI block) which have been found in autoimmune thyroiditis in adults, as well as TSH receptors binding inhibitory antibodies (TBI ab) and antimicrosomal (Mc ab) and antithyroglobulin (Tg ab) antibodies were search in 42 mothers-infants pairs called at hospital after a positive screening for congenital hypothyroidism. The etiologic diagnoses were: 12 athyreosis, 12 ectopies, 7 anatomically normal glands and 11 transients. Tg ab and Mc ab were measured by commercial hemagglutination tests, TBI ab were determined using a radio ligand assay. ADCC in a 51Cr release assay by human thyroid cells in culture and TGI block by incorporation of 3H-thymidine using the same cells. Results were 38% for TBI ab in infants mainly in patients with dysgenesis without any concordance between mothers and infants. ADCC were found in 24% and TGI block in 24% with respectively mothers-infants concordance of 90% and 84%. Five mothers had autoimmune diseases (2 thyroiditis, 2 Graves' diseases and 1 insulin-dependent diabetes). Beside these rare cases of maternal diseases, the significantly high number of antibodies without any expression in the mothers suggests that autoimmunity plays a role in the etiology of congenital hypothyroidism.     

Increased recall rate at screening for congenital hypothyroidism in breast fed infants born to iodine overloaded mothers.

Skin disinfection with povidine-iodine (PVP-I) is widely used in obstetrics. We evaluated the influence of PVP-I in mothers at delivery on the serum thyroid stimulating hormone concentrations of their infants at the time of screening for congenital hypothyroidism. The study covered 4745 infants who were either breast fed (3659, 77%) or bottle fed (1086, 23%); 3086 (65%) of them were born to mothers with no iodine overload (controls) and 1659 (35%) to mothers with iodine overload. Compared with the control group, the breast and bottle fed infants born to mothers with iodide overload had a shift of neonatal thyroid stimulating hormone concentration towards high values. The shift was maximal in the breast fed infants with a 25 to 30 fold increase in the recall rate at screening for congenital hypothyroidism (serum thyroid stimulating hormone greater than 50 mU/l) while in the bottle fed infants, the recall rate was barely modified. In conclusion, the use of PVP-I in mothers at delivery induces a transient impairment of thyroid function in their infants, especially if breast fed. This situation is detrimental to screening for congenital hypothyroidism. Consequently PVP-I is not recommended in obstetrics.     

Contributions of bone maturation measurements to the differential diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism

AIM: To a) evaluate the contribution of bone maturation in the diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism in full-term newborns, and b) use bone maturation to test the hypothesis that neonatal transient hypothyroidism is perinatal in onset. MATERIALS AND METHODS: The study included 20 patients with dyshormonogenetic and 43 with transient hypothyroidism. Thyroid function and measurements of the distal femoral epiphysis area, obtained at the time of first confirmatory diagnosis, were compared between the two groups. The epiphysis area in two control groups with normal thyroid function was also measured and compared with that in patients with transient hypothyroidism, at age 1-3 d (control A), or at the age when normal thyroid function was confirmed (control B). RESULTS: Mean epiphysis area was 0.04 cm2 in patients with dyshormonogenetic versus 0.22 cm2 in patients with transient hypothyroidism (p < 0.0001). An area <0.05 cm2 was limited to patients with dyshormonogenetic hypothyroidism. Conversely, a normal area (>0.2 cm2) was only observed in patients with transient hypothyroidism. Mean epiphysis areas in control A (0.20 cm2) and in patients with transient hypothyroidism were similar (p = 0.37), consistent with perinatal onset of transient hypothyroidism. Mean epiphysis area in control B (0.31 cm2) was significantly greater than in patients with transient hypothyroidism (p < 0.01). CONCLUSIONS: A short duration of hypothyroidism can significantly delay bone maturation. Examination of bone maturation at initial confirmatory evaluation yields important information pertaining to congenital hypothyroidism, not only to predict intellectual development, but also to evaluate the risk of dyshormonogenetic hypothyroidism.     

Thyroid function in young children with Down syndrome

A retrospective review of thyroid function tests (TFTs) was performed on 49 young children (aged 4 months to 3 years) with Down syndrome compared with age-matched controls screened for hypothyroidism because of developmental delay or failure to thrive. Three of the 49 children with Down syndrome had congenital hypothyroidism; of the three, one had Hirschsprung's disease and two had duodenal atresia. Thyroiditis was uncommon, with only two children having thyroid antibodies present: one had acquired hypothyroidism and the other acquired hyperthyroidism. Twenty-seven percent of the Down syndrome cohort had mildly increased thyrotropin (TSH) and normal thyroxine levels. When compared with children with Down syndrome who had normal TFTs, no significant differences in sex, growth rate, maternal age, associated anomalies, developmental or specific thyroid symptoms were present. Transient elevations of TSH level were common in children with Down syndrome whether or not TSH values were initially normal or elevated. Routine neonatal and sequential thyroid screening in young children with Down syndrome is warranted.     

TRANSITORY CONGENITAL HYPOTHYROIDISM AND MATERNAL THYROIDITIS

ABSTRACT. Ritzén, E. M., Mahler, H. and Alveryd. A. (Department of Paediatrics, Karolinska Hospital, Stockholm and Department of Surgery, Huddinge Hospital, Huddinge, Sweden). Transitory congenital hypothyroidism and maternal thyroiditis. Acta Paediatr Scand 70:765,.–The case histories of two sisters with congenital hypothyroidism are described. Their mother had had high titers of circulating thyroid antibodies during each pregnancy. In the older sister, antibodies were detected at 4 weeks but not a 6 months of age. This girl showed a partial hypothyroidism, that required replacement therapy. However, in the younger sister, the hypothyroidism was reversible and replacement therapy was discontinued after 2 years.     

Congenital familial transient hypothyroidism secondary to transplacental thyrotropin-blocking autoantibodies

Three patients demonstrated transient neonatal hypothyroidism, presumably secondary to maternally derived thyrotropin (TSH)-blocking antibodies. Although transient, this disorder might not have been benign in the first child, who exhibited significant developmental delay. A thyroid scan was not helpful in making this diagnosis. Although uncommon, this disorder should be suspected in infants with a maternal history of autoimmune thyroid disease, multiple siblings with congenital hypothyroidism, or a clinical course characterized by continually suppressed TSH levels, despite low doses of levothyroxine sodium replacement. Measurement of TSH-blocking antibodies may be used in the diagnosis of transient neonatal hypothyroidism at birth and is becoming more readily available from reference laboratories. Once diagnosed, the patient may then be prepared for monitored withdrawal of levothyroxine replacement therapy at 2 to 3 years of age and will not be committed to lifelong replacement therapy.     

Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibiting immunoglobulin

Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibitor immunoglobulin (TBII), a thyroid-stimulating hormone (TSH)-receptor blocking antibody, is described in three male siblings born to a mother with autoimmune thyroiditis. These cases are believed to be the first described in Australia. The first child was found to have a serum TSH of 565 mU/L and had a negative thyroid scan when presented for neonatal screening. He was treated with thyroxine but became thyrotoxic at 3 months of age when he was on a dosage of 85 μg/m² of body surface area. He was euthyroid 6 months after discontinuation of therapy. Nine years later a second hypothyroid sibling was born, with a serum TSH of 709 mU/L on day 4. Both mother and child were demonstrated to be strongly positive for TBIl. Again this child was able to cease therapy by the age of 9 months. A third sibling, also TBIl positive, was born 12 months after the second. His TSH was 90 mU/L and his serum thyroxine (T₄) was 169 nmol/L. On this occasion, thyroid stimulation-blocking antibody was found to be present in the serum of both mother and child. Thyroxine therapy was ceased at 1 month. The family present a picture of varying degrees of transient neonatal hypothyroidism due to the transplacental passage of a maternal receptor blocking antibody. The condition is self-limiting, resolving when the immunoglobuiin is cleared from the infant's circulation.     

Transient neonatal 'athyreosis' resulting from thyrotropin-binding inhibitory immunoglobulins

Recognition of transient forms of neonatal hypothyroidism is difficult because of the urgency of thyroxine treatment. In the present report the first child born to a mother with Graves' disease developed transient hyperthyroidism during the newborn period. The mother underwent radioactive iodine treatment and was maintained euthyroid on l-thyroxine. Two subsequent children were detected by newborn thyroid screen to have low thyroxine and markedly elevated serum thyrotropin (TSH) levels. Technetium 99 metastable and iodine 123 scans at 22 days of age showed the second child to be athyreotic. The third child was not scanned. All three children were nongoitrous at birth. Patients 2 and 3 had continuous TSH suppression with thyroxine therapy for 3 and 4 years. Thyroid function measurements after discontinuation of therapy for 8 weeks were normal, and both children had normal 123I thyroid scans. The mother was found to have potent TSH-binding inhibitory immunoglobulin (TBII) levels in her serum (85.5%). A fourth child with low thyroxine and elevated TSH was born to a mother on a regimen of l-thyroxine for hypothyroidism. 99mTc scan at 26 days of age showed no thyroid tissue and was normal at 3 months. TBII activity was 35% in the maternal serum and absent in the infant's serum. The above laboratory and clinical data are compatible with the blocking nature of TBII, resulting in transient newborn hypothyroidism and an athyreotic appearance on scan. The TBII measurement can be a useful predictor of neonatal hypothyroidism as well as confirm the transient nature of the disease in newborns.     

Genetic Analysis in Children with Transient Thyroid Dysfunction or Subclinical Hypothyroidism Detected on Neonatal Screening

About 30% of children with elevated TSH levels during neonatal screening have a transient form of disorder. On the other hand, it has been reported that subclinical hypothyroidism persists in late childhood in about 30% of children found to be false-positive during neonatal screening. The aim of this study was to determine whether transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening are influenced by genetic background. The TSH receptor (TSHR), thyroid peroxidase (TPO) and dual oxidase 2 (DUOX2) genes, for which it has been reported that heterozygous defects cause neonatal transient thyroid dysfunction, were analyzed. Nine children with transient thyroid dysfunction or subclinical hypothyroidism detected during neonatal screening were studied. One child was heterozygous for a TSHR gene mutation (R450H), and another child was heterozygous for a TPO gene mutation (P883S). No children with mutation of the DUOX2 gene were identified. Genetic background may contribute to development of transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening.     

Thyroid antibodies in children of mothers with auto-immune thyroid disease

In a cross-sectional study, 29 children aged between 1 month and 15.3 years (average age 6.8 years) born to mothers with Graves disease or Hashimoto thyroiditis were examined clinically, biochemically, and by sonography of the thyroid gland. At the time of examination all children were clinically euthyroid. Tests of thyroid peroxidase antibody, thyroglobulin antibody, TSH receptor antibody and free thyroxine (fT₄) gave normal results. In 3 children subclinical hypothyroidism with elevated TSH and normal fT₄ concentrations were found; one of these children had a minor decrease of total thyroxine. Three children with otherwise normal test results had marginally elevated tri-iodothyronine concentrations. Increased antibody titres were present in 8 out of 29 children. TSH function-blocking antibodies were elevated in 8 cases. In addition, cytotoxic antibodies were found in one of the children. The distribution pattern of antibodies was different in each child and unrelated to the type of maternal thyroid disease. Conclusion Children of mothers with auto-immune thyroid disease often have thyroid antibodies without signs of thyroid disease. Whether antibody-positive children have an increased risk of developing thyroid disorders later in life must be examined in a longitudinal study. Received: 15 December 1997 / Accepted in revised form: 16 February 1998     

先天性甲状腺功能减低症筛查及治疗效果分析

目的了解先天性甲状腺功能减低症(CH)的筛查及替代治疗结果。方法回顾性分析2003年7月—2015年7月采用时间分辨荧光免疫法测定新生儿促甲状腺激素(TSH)水平筛查CH的资料;阳性召回的可疑患儿采用化学免疫发光法测定血清甲状腺功能,确诊者予左旋甲状腺素钠替代治疗并定期随访。结果 12年来共筛查新生儿1 228 289例,确诊950例,CH发病率1/1 293。接受正规治疗、随访满2年及以上的635例CH患儿中,488例(76.85%)为永久性CH,147例(23.15%)为暂时性CH。CH患儿随访至1岁和3岁时,体格生长和发育商(DQ)无异常。结论新生儿筛查可早期诊断CH,早期实施替代治疗。     

PLACENTAL TRANSFER OF MATERNAL ANTI-RABBIT IgG CAUSING FALSELY ELEVATED TSH LEVELS IN NEONATES

Abstract. Larsson, A., Hedenborg, G. and Carlström, A. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, and the Department of Clinical Chemistry, Karolinska Institute, Danderyd's Hospital, Danderyd, Sweden). Placental transfer of maternal anti-rabbit IgG causing falsely elevated TSH levels in neonates. Acta Paediatr Scand, 70:699,.–Two infants were found to have markedly increased TSH levels, 104 and 154 mU/l of plasma, respectively, in a routine screening programme for congenital hypothyroidism. The recall limit used was 50 mU/l of plasma. On follow-up, both infants were clinically euthyroid and had normal serum T₄ and T₃. The elevated TSH levels were confirmed only with some commercial radioimmunoassay kits–but not with others. Similar results were obtained in TSH assays of samples from their mothers, who had no other biochemical or clinical evidence of thyroid dysfunction. Both mothers had intense contact with rabbits over long periods. The apparent TSH activity was found to be associated with the IgG fraction. It was neutralized by the addition of normal rabbit serum to the samples and was caused by antibodies to rabbit immunoglobulin. The activity was eliminated from the circulation of both infants with a half-life of approximately one month. Apparently, the heterophilic antibodies were of maternal origin and were transferred to the foetus via the placenta. Infants with so-called transient hyperthyrotropinaemia identified in screening programmes have to be reevaluated to exclude false TSH elevations of this type.     

TRANSIENT CONGENITAL HYPOTHYROIDISM IN AN INFANT WITH CONGENITAL NEPHROSIS OF FINNISH TYPE

ABSTRACT. Congenital hypothyroidism was detected on routine neonatal screening in an infant with congenital nephrosis of Finnish type and followed up for 3 years. The hypothyroidism was transient; clinical and biochemical signs and symptoms disappeared after a 20-month period of thyroid replacement therapy and partial improvement of nephrotic symptoms.     

Transient primary hypothyroidism in the newborn: Experience of the Victorian Neonatal Thyroid Screening Programme

Abstract Between May 1977 and December 1986, the Victorian Thyroid Screening Programme tested approximately 570 000 newborns for congenital hypothyroidism. One hundred and sixty-six cases of primary hypothyroidism, confirmed by formal thyroid function tests, were identified, of which 24 were later found to be transient. In addition, there were two patients with permanent dyshormonogenesis who passed through a stage of being biochemically euthyroid and so could have been diagnosed mistakenly as transient hypothyroidism. Fourteen of the transient cases were due to excessive intake of iodine. In two, this was due to maternal ingestion of iodide during pregnancy and in 12 the babies received large amounts of topical iodine antiseptic. Two cases were caused by maternal anti-thyroid antibodies and in eight instances the cause was unknown. The large number of cases due to the topical application of iodine antiseptic emphasizes the need for caution when using this substance in neonates.     

The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities

OBJECTIVE: To evaluate how intrauterine and neonatal thyroid hormone deficiencies affect infant cognitive abilities. METHOD: 26 infants with intrauterine or neonatal thyroid hormone deficiency and 20 full-term infants with normal thyroid economies were studied at 6 months of age or corrected age. Reasons for thyroid hormone deficiency were maternal hypothyroidism, maternal hyperthyroidism treated with antithyroid medication, congenital hypothyroidism, and low-risk prematurity. A computer-generated task during which infants' eye-movements were videotaped was used to assess attention, memory, and learning abilities RESULTS: Data from transcribed videotapes showed the study group was significantly less attentive and had longer reaction times than controls but did not differ on indices of sustaining attention or learning. Within thyroid-deficient groups, offspring of treated hyperthyroid mothers showed an atypical profile suggestive of hypervigilance. CONCLUSION: A decreased fetal or maternal thyroid hormone supply in pregnancy is associated with infants' poorer attention and altered rates of information processing.