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.     

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.     

Congenital hypothyroidism: causes for delayed initiation of treatment]

The aim of neonatal screening programs for congenital hypothyroidism is to ensure early treatment in order to prevent brain dysfunction. There are several reasons why infants are missed in the screening program. We report on three patients with congenital hypothyroidism, who had a pathological screening result and initiation of therapy was delayed. The first patient had an increased TSH level, but she was missed because of mistakes in the confirmatory serum test. During the follow-up the patient showed typical symptoms of hypothyroidism and got a thyroxine supplementation not before the age of three years. The second patient did not get a therapy before the age of six months because of the noncompliance of the parents and physicians. The third patient had a central hypothyroidism. The neonatal screening-program revealed no measurable TSH activity. Although the child had clinical signs of a severe hypothyroidism diagnosis was not made before the age of 5.5 months. Although different reasons are known for screening errors, all these 3 patients were missed because of failures in the follow-up of a pathological screening result, indicating a poor quality in the follow-up procedure.     

Three-year follow-up of borderline congenital hypothyroidism

The purpose of this study was to determine whether children with borderline hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years of levothyroxine replacement therapy. Fourteen term infants with slightly abnormal newborn screening results (thyroxine <10th percentile, thyroid stimulating hormone ?TSH <40 microU/mL) were identified. The subsequent serum confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8 microU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory TSH (4.6 and 4.7 microU/mL) had abnormal TSH responses to thyrotropin releasing hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13 patients, and repeat thyroid function tests were obtained 1 month later. Levothyroxine was not discontinued in one patient because he had an elevated random TSH (10 microU/mL) while receiving therapy. At 3 years of age, 13 patients had persistently abnormal thyroid function tests (TSH >4.6 microU/mL or a thyroid releasing hormone test result consistent with primary hypothyroidism), and levothyroxine was reinitiated. Only one patient had normal thyroid function studies. Although prospective studies are still lacking, we recommend levothyroxine replacement in newborns with borderline hypothyroidism.     

Recovery Period of Hypersecretion of Thyroid-Stimulating Hormone in Patients with Congenital Hypothyroidism Treated with Thyroid Hormone

The recovery periods of serum thyroid stimulating hormone (TSH) were studied in patients with congenital hypothyroidism found on neonatal screening. L-T4 was administered at 37.8 ± 15.1 days of age (M ± SD), and serum T4, T3, and TSH concentrations were measured. After L-T4 therapy with 10 µg/kg, the serum TSH levels decreased to below 10 µU/ml in five patients within a week, and in another two patients, within two weeks, and in the total number of 12 patients out of 15 (80%), by one month. These results suggest that the recovery of serum TSH occurs rapidly in hypothyroid infants. Thus, the serum TSH concentration may be a good measurement for assessing the adequacy of thyroid hormone therapy from early infancy in patients with congenital hypothyroidism.     

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.     

Dopamine infusion: a possible cause of undiagnosed congenital hypothyroidism in preterm infants.

OBJECTIVE: To describe the possibility that dopamine infusion can prevent early diagnosis of congenital hypothyroidism. DESIGN: Case report. SETTING: Medical neonatal intensive care unit of a tertiary academic medical center. PATIENTS: We report four preterm newborns affected by transient primary congenital hypothyroidism who showed low serum thyroxine and normal thyroid-stimulating hormone concentrations on primary screening performed during treatment with dopamine. INTERVENTIONS: Thyroid reevaluation screening after dopamine discontinuation. MEASUREMENTS AND MAIN RESULTS: Thyroid reevaluation showed elevated thyroid-stimulating hormone levels. CONCLUSION: We emphasize that dopamine capacity to suppress thyroid-stimulating hormone could prevent early diagnosis of congenital hypothyroidism. We suggest all newborns to be tested simultaneously for thyroid-stimulating hormone and thyroxine values at primary screening. A reevaluation of thyroid hormones after dopamine discontinuation is advisable in patients treated with dopamine.     

Borderline congenital hypothyroidism in the neonatal period

One of the most important etiological factors causing prolonged jaundice in the neonatal period is congenital hypothyroidism. Some infants may have abnormal thyroid function test results rather than overt congenital hypothyroidism. Although serum TSH levels are accepted as diagnostic when >20 microIU/l, TSH values higher than 7 microIU/ml cause a hypometabolic condition. In this study, we evaluated infants who had prolonged jaundice for hypothyroidism. A hundred and ten infants suffering from prolonged jaundice were admitted to our clinic during the study period. Among them, 61 infants had normal thyroid function results. Six patients had overt primary hypothyroidism. TRH stimulation test was administered to the 43 patients with mildly elevated TSH levels of between 5 and 20 microIU/ml. Peak TSH values were above 35 microIU/ml in seven patients, and these were considered as having an exaggerated response (borderline hypothyroidism). During the neonatal period, prolonged jaundice is a valuable diagnostic clue for hypothyroidism. In addition, the TRH stimulation test can be a diagnostic tool in evaluating infants with mildly abnormal thyroid function test results.     

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.     

Brain TRH levels during development of the rat, in neonatal hypothyroidism and after caloric deprivation

The effect of neonatal hypothyroidism and neonatal caloric deprivation on brain TRH levels and serum and pituitary TSH levels has been determined in rats on the following postnatal days: 1, 5, 10, 15, 25, 40 and 60. After neonatal hypothyroidism, there was a slight reduction in brain TRH content although TRH concentration in the brain increased. Serum TSH was elevated at birth, suggesting that the feedback of thyroid hormones on the pituitary gland acts in rat fetuses. After neonatal caloric deprivation, a decrease in brain TRH content was observed along with a decrease in circulating TSH levels, however, there was no change in brain TRH concentration.     

Analysis of Thyrotropin-Thyroxine Secretory Dynamics in Infantile Hyperthyrotropinemia: An Aid for Early Differential Diagnosis

For the purpose of differentiating neonatal hyperthyrotropinemia, the interrelation between serum thyrotropin (TSH) and thyroxine (T4) was examined in 10 infants with primary hypothyroidism during 12 months of T4 replacement therapy. A significant inverse correlation was obtained between elevated TSH (Y) (above 12 μU/ml) and T4 (X) levels; Y = 324 - 22 X (r = -0.801, p < 0.001). One patient had an abnormally high threshold of TSH-inhibition by T4. Based on this regression line, a scattergram of TSH-T4 correlation and changes in the time course was analyzed in 13 infants with neonatal hyperthyrotropinemia, including eight with transient hyperthyrotropinemia (t-TSH), three with compensated hypothyroidism (c-Hypo) and two with transient hypothyroidism (t-Hypo). All plots from t-TSH were distributed under the regression line and shifted downward with concomitant rise in T4 and free T4 levels. In contrast, plots from c-Hypo and t-Hypo showed a vertical upward shift above the line during 3–4 months of observation without treatment. These results indicate that (1) using the TSH-T4 regression line, differentiation of c-Hypo from t-TSH is possible by 3 months of age, (2) the cause of t-TSH is not an elevated threshold for TSH release, but rather the maturational delay in responsiveness of the thyroid to TSH, and (3) suppression of TSH alone should not be used as the index of adequate T4 dose in infantile hypothyroidism, because of the existence of patients with a high threshold of TSH-inhibition by T4.     

Results of a regional cord blood screening programme for detecting neonatal hypothyroidism.

Our regional cord blood screening programme for detecting neonatal hypothyroidism using initial cord blood thyroxine (T4) determinations, with supplemental thyrotropin (TSH), and triiodothyronine resin uptake (T3U) measurements, gave an incidence of thyroid abnormalities of 1/3000 births, with 1/5000 infants having severe primary hypothyroidism. No hypothyroid infant detected in the programme had been suspected clinically before the screening and, in retrospect, only a few babies had any signs of hypothyroidism. Supplemental TSH and T3U determinations were required on 8-12% of the population screened initially with a T4 test to avoid missing affected cases. With an initial T4 and supplementary TSH and T3U testing on cord blood serum, recalls to exclude primary hypothyroidism were reduced to 0.16% of the screened population. The incidence of abnormalities detected in this cord blood screening programme was comparable with that reported by others using neonatal dried blood screening methods, indicating that cord blood screening can be effective provided the appropriate recall criteria and transport conditions are used. Nevertheless, for several practical reasons, neonatal dried blood methods are recommended as the screening test of choice for surveying large populations over extensive geographical areas.     

Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene.

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the betaTSH gene that was diagnosed in the early neonatal period. Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started. Because there was no indication for other pituitary hormone deficiencies, sequence analysis of the betaTSH gene was initiated. A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. This altered betaTSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result.     

A Case with Hyperthyroidism Who Had Been Treated with Thyroid Hormone Because of Congenital Hypothyroidism

We encountered a case with hyperthyroidism at the age of 14 who had been diagnosed with congenital hypothyroidism (CH) and had received thyroid hormone replacement therapy. At the age of 16 d, the patient was referred to our hospital because of positive results at neonatal screening for CH. Serum level of TSH was 91.0 μU/ml and serum level of T4 was 6.9 μg/dl. The patient was diagnosed as having hypothyroidism, and hormone replacement therapy was started. Thereafter the dosage of thyroid hormone was adjusted and increased gradually as he grew to a maximum dose of 110 μg/day at the age of 11. Until the age of 13, the patient’s serum levels of TSH were within the normal range; then, at the age of 13 yr and 4 mo, his serum level of TSH dropped to a level below the detectable range. The dosage of administered thyroid hormone was tapered off and eventually eliminated at the age of 14. A thyroid scan and a radioactive iodine uptake test demonstrated a diffuse goiter with homogeneous uptake of radioactive iodine; the uptake rate was 60% at 24 h, and the serum level of TSH receptor antibody (TRAb) was 62.5% at that time. Administration of an antithyroid drug was started after confirmation that our patient had developed hyperthyroidism. There have been no case reports similar to our case.     

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.     

Congenital hypothyroidism. The effect of stopping treatment at 3 years of age

Fifty-six children with congenital hypothyroidism diagnosed by neonatal screening were reviewed at 3 years of age or older. The presence or absence of the thyroid gland was determined by radionuclide scanning prior to treatment in the newborn period. Thyroxine therapy was discontinued in those children who did not have anatomic defects or a secondary rise in their thyrotropin (thyroid-stimulating hormone [TSH]) level once it was suppressed by thyroid hormones. Sixteen of 17 children developed a low thyroxine and an elevated TSH level within three to six weeks. One child was not receiving thyroxine for nine months and was clinically and biochemically euthyroid. We conclude that (1) newborn thyroid scans are useful to determine the cause of hypothyroidism, (2) a secondary rise in the TSH level indicates permanent hypothyroidism, (3) only about one third of infants whose condition is diagnosed by newborn screening will qualify for a trial off therapy at 3 years of age, (4) only 1% to 2% of infants whose condition is diagnosed by newborn screening have transient hypothyroidism, and (5) a three-week period of hormone withdrawal after the age of 3 years seems adequate and safe to confirm permanent hypothyroidism.     

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。     

Newborn screening for congenital hypothyroidism

Most neonates born with congenital hypothyroidism (CH) have normal appearance and no detectable physical signs. Hypothyroidism in the newborn period is almost always overlooked and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of neonatal screening. Blood spot T4 or TSH or both can be used in neonatal screening for CH. The latter, which is more sensitive, is not cost effective, so the first two are used in different programs in the world. TSH screening was shown to be more specific in the diagnosis of CH; T4 screening is more sensitive in detecting newborns especially with rare hypothalamic-pituitary hypothyroidism, but less specific with a high frequency of false positives mainly in low birth weight and premature infants. The time at which the sample is taken may vary between centers, with the majority taking blood from a heel prick after 24 hours of age to minimize the false positive high TSH due to the physiological neonatal TSH surge that elevates TSH levels and causes dynamic T4 and T3 changes in the first 1 or 2 days after birth. Early discharge of mothers postpartum has increased the ratio of false positive TSH elevations. Although transient hypothyroidism may occur frequently, all suspected infants should be treated as having CH for the first 3 years of life, taking into account the risks of mental retardation. A reevaluation after 3 years is needed in such patients. The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as reflected by T4 and TSH levels, as rapidly as possible. Iodine deficiency is the most important cause of CH worldwide. Iodine is essential for thyroid hormone synthesis and is present in soil, water and air. Prevention of iodine deficiency can be by iodized salt, iodized oil, iodized bread or iodine tablets.     

Dopamine infusion and anterior pituitary gland function in very low birth weight infants

BACKGROUND: Previous studies demonstrated that dopamine infusion reduces plasma concentration of thyroxine (T4), thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) in adults, children, and infants. OBJECTIVES: The purpose of this prospective observational study was to evaluate the relationship between dopamine infusion and the dynamics of T4, TSH, PRL, and GH in preterm newborns weighing less than 1,500 g (very low birth weight infants, VLBW) admitted in a neonatal intensive care unit of a university hospital over a one year period. METHODS: A total of 97 preterm newborns were enrolled and divided into two groups: group B included hypotensive infants treated with plasma expanders and dopamine infusion; group A was the control group including newborns who were never treated with dopamine. The newborns were studied dynamically through blood samples taken every day till 10 days. Newborns of group B were studied during dopamine infusion and after its withdrawal. RESULTS: Among the VLBW newborns who were given dopamine, the four pituitary hormones had different dynamics: a reduction of T4, TSH, and PRL levels was noticed since the first day of treatment, and a rebound of their levels was evident since the first day after its interruption. On the contrary, the postprandial GH levels were roughly constant: GH plasma concentrations were in fact a little lower in newborns treated with dopamine, and a slight increase was observed after its withdrawal. However, observed differences were not statistically significant. CONCLUSIONS: The results suggest that dopamine infusion reduces T4, TSH, and PRL plasma levels in preterm VLBW infants and have no effect on postprandial GH rate. This hormonal suppression reverses rapidly after dopamine withdrawal. This observation suggests that the iatrogenic pituitary suppression probably cannot produce long-term injuries.     

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.