Neonatal thyroid function: influence of perinatal factors.

Indices of thyroid function were measured in 229 healthy term neonates at birth and at 5, 10, and 15 days of age. Results were analysed to assess whether maternal diabetes mellitus, toxaemia of pregnancy, intrapartum fetal distress, duration of labour, method of delivery, asphyxia at birth, race, sex, birthweight, birth length, head circumference, or method of feeding influenced any index. Thyroxine, the free thyroxine index, and free thyroxine concentrations at birth correlated with birthweight. Method of delivery influenced mean thyroxine and free thyroxine index values at birth and at age 5 days. Mean values of triiodothyronine, reverse triiodothyronine, thyroxine binding globulin, and thyroid stimulating hormone were not affected by any of the perinatal factors studied. Birthweight and perhaps method of delivery should be taken into account when interpreting neonatal thyroxine parameters but determination of thyroid stimulating hormone as a screen for congenital hypothyroidism in healthy term neonates circumvents these considerations.     

Ectopic Thyroid: Residual Function after Withdrawal of Treatment in Infancy and Later Childhood

ABSTRACT. Plasma thyroxine (T4) and thyrotrophin (TSH) were estimated in 34 children identified by neonatal hypothyroid screening and subsequently found to have ectopic thyroid tissue on isotope scan. Before treatment plasma T4 ranged from 8–143 nmol/1 and TSH from 39–1230 mU/l. After one week off treatment during their second year, repeat T4 in 26 of these cases showed a significant correlation with the pre-treatment values ( r = 0.57). However, only 3 of the 5 children with pre-treatment T4 levels over 100 nmol/1 at diagnosis had normal T4 values when retested. Similarly, when 10 children with pre-treatment T4 values over 65 nmol/1 were retested off treatment at the ages of 5.8–8.2 years, only 4 had plasma T4 levels in the normal range. These results illustrate the wide range of thyroid function which can occur in children with ectopic thyroid tissue and indicate that some continue to have near-normal thyroid function for considerable periods. However, pre-treatment T4 results do not allow accurate identification of these latter cases.     

Thyroid function during exchange transfusion.

The changes in plasma thyroid hormone concentration were studied during exchange transfusion performed for haemolytic disease. 24 transfusions were performed using blood preserved with acid-citrate and dextrose and in 11 cases 10 or 50 mug glucagon was added to the donor blood. Plasma tri-iodothyronine (T3), thyroxine (T4), thyrotropin (TSH), thyroid hormone binding capacity, and free thyroxine index were measured in the donor blood and in the infant at the start and at intervals during the transfusion. Before transfusion the plasma TSH levels of the infants fell as postnatal age indreased and plasma T3 and T4 were correlated with one another. In 20 transfusions the mean infant/donor ratio of TSH was approximately 10, of T4 3, and of T3 2. During these transfusions there was a progressive fall in the infant's plasms TSH, T4, and T3 concentration. In 3 transfusions in which the donor plasma TSH was greater than that of the infant, plasma TSH levels rose during the transfusion and in 2 cases this was associated with a late rise in plasma T3 levels. The addition of glucagon to donor blood had no effect on thyroid hormone levels. It is concluded that erythroblastotic infants have normal thyroid function and that they became biochemically hypothyroid during transfusion. Acute changes in plasma thyroid hormone and glucagon concentration do not induce TSH responses by the neonatal pituitary during the period of the exchange transfusion.     

Serum Levels of Thyroid Hormones, Thyroxine-Binding Globulin and Thyrotropin in Arterial and Venous Cord Blood in Newborn Infants Are Identical

Thyroxine, tri-iodothyronine, reverse tri-iodothyronine, free tri-iodothyronine, free thyroxine, tri-iodothyronine resin uptake, thyrotropin, thyroxine-binding globulin and free thyroxine index in both arterial and venous cord blood of 20 normal full-term newborn infants were investigated. There was little difference in the values in arterial and venous cord blood in all examinations. The results suggest that venous cord blood, which is more easily obtainable in sufficient quantity than arterial cord blood, and arterial cord blood are equally useful in the determination of thyroid function in the newborn infant.     

Update of newborn screening and therapy for congenital hypothyroidism

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine.

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

Thyroid status in the newborn infant: Effective thyroxine ratio and free thyroxine index

The effective thyroxine ratio (ETR) was determined in 28 term and 17 premature infants at birth and in 17 infants aged 0 to 6 weeks. The mean values found were significantly higher than those in 20 adult euthyroid controls. Serum thyroxine (T₄), T₃ resin uptake ratio (T₃ RUR), free thyroxine index (FTI), and ETR were determined in 14 term infants at birth. It was concluded that the raised T₄ was partly due to an increase in thyroxine binding globulin but that there was also a degree of true thyroid hyperactivity. Serum thyroxine alone was not considered a suitable index of thyroid function in infants and the free thyroxine index or the effective thyroxine ratio was preferred instead.     

Neonatal thyroid function: prematurity,prenatal steroids,and respiratory distress syndrome.

Indices of thyroid function were measured in 97 preterm infants at birth and at 5, 10, and 15 days of age. Triiodothyronine uptake, free thyroxine index, thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, and thyroxine binding globulin values at birth correlated with gestational age, whereas thyroid stimulating hormone values did not. Treatment with steroids prenatally had no apparent effect on thyroid function at birth or postnatally. Infants developing respiratory distress syndrome had normal values for all indices at birth. These infants had significantly lower thyroxine, free thyroxine index, free thyroxine, and triiodothyronine values at 5 days of age, while thyroid stimulating hormone values remained normal. This alteration in thyroid function was interpreted as being secondary to respiratory distress syndrome. Gestational maturity and respiratory distress syndrome, if present, must be taken into account when evaluating thyroxine variables in preterm infants, whereas measurement of thyroid stimulating hormone as the screen for congenital hypothyroidism circumvents these considerations.     

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.     

Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features.

The relationships between biochemical severity of hypothyroidism (as judged by plasma thyroxine) and the clinical and radiographic findings at diagnosis were evaluated in 449 infants born in 1982-4 with congenital hypothyroidism identified by neonatal screening. Details of pregnancy, delivery, and the neonatal period were also examined and compared with the findings in a normal population of 36,727 infants born in 1988. Infants with plasma thyroxine values of 30 nmol/l or less had a significantly higher incidence of prolonged jaundice, feeding difficulties, lethargy, umbilical hernia and macroglossia, showed more severe delay of bone maturation on a knee radiograph, and had a higher proportion of thyroid agenesis on isotope scan. In contrast, an ectopic or hypoplastic gland was more common in infants with plasma thyroxine values above 30 nmol/l. Prevalence of illness in pregnancy and mode of delivery was not related to severity of hypothyroidism and were similar to figures for the normal population. Induction of labour, gestation over 40 weeks, and birth weight above 3500 g were significantly more common in the hypothyroid infants. Perinatal illness and congenital malformations were more common in the infants with low plasma thyroxine values at diagnosis.     

Effect of fetal thyroidectomy on newborn thermogenesis in lambs

We investigated the effect of the transient neonatal hyperthyroid state on thermogenesis at birth by measuring rectal temperature, plasma free fatty acids, plasma catecholamines, and in vitro brown adipose tissue respiration in thyroidectomized (n = 6) and sham operated (n = 5) fetal sheep. Surgery was performed at an average of 133 days of gestation followed by cesarean delivery at 146 days. Fetuses were delivered into a constant room temperature of 25 degrees C. Serial measurements were made in utero before delivery and at timed intervals after birth. Serum 3,3',5 triiodothyronine and thyroxine concentrations in the neonatal period were normal in sham operated and nondetectable in thyroidectomized fetuses. Rectal temperatures and serum free fatty acid levels were reduced in thyroidectomized newborns. Plasma epinephrine concentrations were increased and the hypothyroid neonates were acidotic when compared to control animals. In vitro basal and norepinephrine stimulated brown adipose tissue respiration were reduced in thyroidectomized compared to control animals. These results indicate that thyroid hormone deficiency impairs nonshivering thermogenesis in brown adipose tissue and leads to hypothermia despite augmented plasma epinephrine values.     

THYROXINE-BINDING GLOBULIN DEFICIENCY IN EARLY CHILDHOOD

ABSTRACT. Jacobsen, B. B., Hansted, L. C, Brandt, N. J., Haahr, J., Hummer, L., Munkner, T. and Sorensen, S. S. (Department of Paediatrics, Viborg Hospital, Children's Hospital Fuglebakken, Department of Paediatrics, Section of Clinical Genetics and Department of Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark). Thyroxine-binding globulin deficiency in early childhood. Postnatal changes in serum concentrations of thyroid hormones and thyroid hormone-binding proteins. Acta Paediatr Scand, 70:155, 1981. –Serial determinations of serum thyroxine (T4), triiodothyronine (T3), thyrotropin(TSH), thyroid hormone-binding globulin (TBG), prealbumin (TBPA) and albumin were performed in a euthyroid girl with TBG deficiency and in her mother for a period of 22 months after delivery. At 8 days old the child had a serum TBG concentration around 50% of normal level which remained essentially unchanged during infancy. Total serum T4 and T3 concentrations were low, the free serum T4, free serum T3 and serum TSH concentrations were normal. The mother had received thyroid hormone from the age of 15 years. Her serum TBG level at 6 weeks post partum was similar to that of non-pregnant adults but decreased to about 50% of normal level, indicating a TBG deficiency. She remained euthyroid after withdrawal of T4 therapy. Serum TBPA and albumin concentrations were normal in mother and child. An X-linked inheritance of the TBG deficiency was suggested from a study of the family.     

Value of the ultrasensitive assay of plasma TSH for the surveillance of replacement treatment in children with congenital hypothyroidism

This study proposes some improvements in monitoring congenital hypothyroidism (CH) using an ultrasensitive plasma TSH assay (usTSH). Patients were 42 CH treated with levo-thyroxine (L-T4) for at least 6 months. Controls were 25 age-matched children (C). Comparative determinations of plasma TSH with classical radioimmunoassay (RIA), on one hand, and usTSH on the other hand, revealed RIA values to be beneath the sensitivity threshold in 3 C and in 15 CH. With usTSH, all the TSH values were assayed over the sensitivity threshold. Therefore the CH could be placed into 3 subgroups according to whether their values were below (n = 17), equal to (n = 15) or above (n = 10) those determined for C. Mean plasma levels of thyroxine (T4) or free thyroxine (FT4) were higher in the CH group, considered as a whole, than in C (p less than .01). Furthermore these values did not appear to be correlated with those in the TSH subgroups, anymore than they were with those of therapeutic doses of L-T4 administered. These discrepancies may be explained in terms of metabolism of exogenous thyroid hormones. UsTSH plasma values would therefore reflect the action of thyroid hormones on thyreotropic cells. To this extent the assay constitutes a sensitive index in detecting both therapeutic insufficiencies and overtreatments.     

Epidermal growth factor in neonatal mouse urine: maturative effect of thyroxine

Using a specific and sensitive epidermal growth factor (EGF) radioimmunoassay, we have shown measurable quantities of EGF in mouse urine during the neonatal period. Sephadex G-50 column chromatography demonstrated the presence of a single immunoreactive component at the position defined by standard EGF (mol wt 6045). Comparison of urine urea nitrogen and urine EGF levels in neonatal and adult mice showed adult values to be 3- and 16-fold higher, respectively. Kidney weights relative to body weight were similar in newborn and adult animals while kidney EGF concentration per mg protein was 2.5-fold higher in the adult. The relative submandibular gland (SMG) weight was slightly higher in adult female mice than in the newborn, whereas SMG-EGF concentration was 15,000-fold higher in the adult than in the newborn. Thyroxine administration to neonatal mice from day 0 to day 6 increased urine EGF concentration 7-fold compared to control pups. Though the hormone treatment elicited a significant increase in relative SMG weight, its EGF concentration like that of the kidneys remained unchanged. The results suggest that urine EGF is subject to thyroid hormone modulation in newborn animals and that the changes in urine EGF concentration are independent of changes in SMG and renal EGF levels.     

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.     

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.     

Thyroid function in thalassaemia major.

Serum concentrations of T4, T3, rT3, and TSH were measured by radioimmunoassay in 45 patients suffering from beta-thalassaemia. A TRH stimulation test was performed and the binding capacity of TBG and TBPA for T3 and T4 measured by reverse flow zone electrophoresis in a group of these patients. Mean T4 serum concentration was lower in thalassaemic patients than controls; T3, rT3, TSH levels, and the pituitary response to TRH were normal. TBPA binding capacity for thyroxine was greatly decreased, probably due to iron overload impairing the liver function. The decreased circulating total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration total thyroxine might be explained by the reduced TBPA capacity, serum free thyroid hormone concentration values being normal. It is concluded that thalassaemic children are euthyroid, despite often having low-normal or subnormal thyroxine levels.     

TUBULAR PROTEINURIA AFTER PERINATAL HYPOXIA

ABSTRACT. Milt7eacute;nyi, M., Pohlandt, F., Bóka, G. and Kun, E. (2nd Department of Paediatrics, Semmelweis University, Medical School, Budapest, Hungary, and the Section of Neonatology, Centre of Paediatrics, University of Ulm, Federal Republic of Germany). Tubular proteinuria after perinatal hypoxia. Acta Paediatr Scand, 70:399, 1981.–Urinary total protein (UTP) and urinary protein pattern have been studied in 23 newborn infants with Apgar scores ±S3 at one minute or acidosis (pH ±7.15) on the first day. On the first and second day UTP excretion was increased in 13 out of 18 patients. At this time the excretion of low molecular weight microproteins (T-4 and T-5) was elevated in 12 patients without increased plasma urea concentration in any case. The increased excretion of the smallest microproteins T-4/T-5 is an early sign of an impaired tubular function.     

HYDROPS OF THE GALLBLADDER IN THE NEONATAL PERIOD

Abstract. Appleby, G. A. J., Forestier, E. and Starck, C. J. (Department of Paediatrics, Sundsvalls Hospital, Sundsvall, Sweden). Hydrops of the gallbladder in the neonatal period. Acta Paediatr Scand, 70:117, 1981.–A case of hydrops of the gallbladder in the neonatal period in which the diagnosis was made with the help of ultrasonography is described. To our knowledge this is the first case of gallbladder hydrops that has been described in the newborn period.