Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program

We examined the results of the Northwest Regional Screening Program (NWRSP) over its first 10 years to determine whether the detection of hypopituitary hypothyroidism is a justified advantage of the primary thyroxine (T4)-supplemental thyroid-stimulating hormone (TSH) screening strategy, and to determine whether all such infants will be detected by this screening approach. Between May 1975 and May 1985, the NWRSP screened 850,431 infants, detecting 192 infants with primary hypothyroidism (1:4429) and eight with hypopituitary hypothyroidism (1:106,304). In 11 additional infants, TSH deficiency, not detected by the screening program, was diagnosed on recognition of clinical features over the same period. Thyroid hormone treatment was begun in seven of the 11 infants prior to obtaining the screening sample results because of clinical symptoms of hypopituitarism, including hypoglycemia, persistent jaundice, microgenitalia, diabetes insipidus, midface hypoplasia, cleft lip or palate, or abnormalities of vision. The other four infants were not detected despite clinical features of hypopituitarism (in retrospect) and low serum T4 with TSH concentration below assay sensitivity on at least one screening sample. The most accurate assessment of total cases comes from Oregon, where all cases of congenital hypopituitarism are referred to our center; we estimate a frequency of 1:29,000. In our experience, a combination of newborn T4-supplemental TSH screening measurements and recognition of clinical features of hypopituitarism is the optimal strategy for detecting infants with congenital hypopituitary hypothyroidism.     

Resetting the detection level of cord blood thyroid stimulating hormone (TSH) for the diagnosis of congenital hypothyroidism

An appraisal of a 17-year primary thyroid stimulating hormone (TSH) screening programme for the detection of congenital hypothyroidism was carried out to establish the reference interval of cord blood TSH in unaffected infants; the mean cord blood TSH concentration of affected infants and the incidence of congenital hypothyroidism in the Najran province of Saudi Arabia. Our findings show a reference interval of cord blood TSH of 2.0-16.8 mU/l in unaffected infants; a mean cord blood TSH concentration of 399 mU/l in affected infants; a false positive rate for the diagnosis of at-risk infants of 1.02% and a congenital hypothyroidism incidence rate of 34/100 000 (1 : 2931) live births. These findings suggest that there is a need to reset the cord blood TSH concentration for the detection of at-risk infants. We suggest that the detection level of cord blood TSH for the recognition of at-risk infants can be set at 90 mU/l rather than the recommended level of 30 mU/l. This should reduce the false positive rate for detection of infants at risk of congenital hypothyroidism.     

Permanent and transient congenital hypothyroidism in preterm infants

Aim: Transient fluctuations in thyroid function are well recognized in preterm infants. We wanted to assess TSH variation in babies with transient and permanent congenital hypothyroidism (CHT). Methods: Whole bloodspot TSH data in preterm infants (<35 weeks; 2005–2010) were assessed, and infants with bloodspot TSH values >6 mU/L identified. Permanent CHT was defined as a requirement for thyroxine beyond 3 years of age. Results: A first TSH sample was obtained from 5518 infants (median gestational age, 32 w; range, 22–35), with a second sample obtained from 5134 infants (median gestational age, 32 w; range, 22–35). Five infants had raised TSH concentrations on both occasions. Three of the five infants had a serum TSH >80 mU/L on second screen but two came off thyroxine beyond 3 years of age. All preterm babies with permanent or transient hypothyroidism were detected by the first TSH cut‐off of 6 mU/L. Only one infant with a birth weight <1500 g remains on thyroxine treatment beyond 2 years of age. Conclusions: The incidence of permanent CHT in preterm infants is similar to term infants. Profound abnormalities of thyroid function can occur in preterm babies with transient hypothyroidism but both categories of hypothyroidism can be detected by a ‘once‐only’ TSH screening strategy with a relatively low cut‐off.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.     

Subclinical hypothyroidism in in vitro fertilization babies

Aim: Assisted reproduction technology is used widely all over the world. There is a great concern about the morbidity of in vitro fertilization (IVF) babies, but investigations are mostly related to mechanical conditions that are attributed to multiparity. This paper aimed to investigate the effect of IVF on thyroid functions in newborns. Methods: A total of 98 healthy, term IVF newborns were evaluated between postnatal 2–4 weeks of age by screening of thyroid functions between July 2006 and April 2008. Ten subjects were assessed as a study group whose thyroid‐stimulating hormone (TSH) levels were higher than 6.5 mU/L. Control group consisted of randomly selected 10 naturally conceived infants with hyperthyrotropinemia (whose TSH levels were higher than 6.5 mU/L but under 15 mU/L) with the same age. All children were thoroughly examined, and serum fT4, TSH, anti‐thyroid peroxidase and anti‐thyroglobulin antibodies were measured, and a thyrotropin‐releasing hormone (TRH) test was performed in all subjects in both groups. Results: Euthyroid hyperthyrotropinemia was diagnosed in approximately 10% of IVF babies. Exaggerated TSH levels to TRH were obtained in all IVF babies (subclinical hypothyroidism) but in none of the controls. A significant difference was noted in the concentration of TSH at the 20th min between the two groups (p < 0.001). Besides, sustained and delayed TSH responses were observed in IVF babies. Neonatal screening tests were negative in both of the groups. Conclusion: In IVF babies, despite normal neonatal screening tests, subclinical hypothyroidism might be observed that suggests the need for screening in this respect.     

Early detection of neonatal hypothyroidism by serial TSH determination in dried blood. Six months experience with a reliable, efficient and inexpensive method

Mass newborn screening for primary hypothyroidism was introduced in Switzerland on January 1st, 1977, using a radioimmunoassay of TSH in dried blood spotted on filter paper. After incubation for 38 h at 20 degrees C, bound and free TSH is separated by double antibody precipitation. The filter paper discs of 6.5 mm diameter remain in the test tubes. At present, one TSH determination costs approx. SFr. 4.40. All reagents used are commercially available and their costs amount to not more than 15% of the total expenses. During the first 8 months of 1977, of 21862 newborns tested routinely on day 5 (together with the Guthrie-test), 7 infants with primary hypothyroidism were discovered owing to blood TSH values of greater than 100 muU/ml. Diagnosis was not recognized clinically although all of the infants showed some symptoms. Thyroxin therapy was started within the second week of life. The incidence of about 1 in 3000 newborns is higher than reported so far. It has to be shown whether this is due to genetic or geographic factors, to the occurrence of transitory forms, or to a higher efficiency of screening by the TSH (versus T4) assay.     

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.     

Hypothyroidism in Children with Filter Paper TSH of 30 to 50 μU/ml at Initial Screening Implication of the TSH Cut-off Point for Recalling of Infants at Risk

ABSTRACT. In a systematic screening of newborns in France daring the period from 1979 to 1983, 959 infants with hypothyroidism were detected. In 16 cases of confirmed hypothyroidism the initial filter paper TSH (FP-TSH) was between 30 and 50 μU/ml. These cases emphasize the necessity of keeping a Y"security zone" for FP-TSH value between 30 and 50 (μU/ml and of recalling these patients for a second test filter paper TSH.     

Hypothyroidism in children with filter paper TSH of 30 to 50 microU/ml at initial screening. Implication of the TSH cut-off point for recalling of infants at risk

In a systematic screening of newborns in France during the period from 1979 to 1983, 959 infants with hypothyroidism were detected. In 16 cases of confirmed hypothyroidism the initial filter paper TSH (FP-TSH) was between 30 and 50 microU/ml. These cases emphasize the necessity of keeping a "security zone" for FP-TSH value between 30 and 50 microU/ml and of recalling these patients for a second test filter paper TSH.     

TSH AND THYROXINE IN STORED NEONATAL FILTER-PAPER BLOOD SAMPLES FROM PATIENTS WITH CONGENITAL HYPOTHYROIDISM

ABSTRACT. Filter paper blood samples collected neonatally from infants with congenital hypothyroidism were analysed retrospectively for TSH ( n = 41) and thyroxine ( n = 16). The patients were detected by clinical signs and symptoms and treatment was started during the first two years of life. Similar blood samples from control infants were analysed for comparison. All CH patients would have been detected neonatally if screening had been based on TSH analyses with a cut-off limit corresponding to 50 mU of TSH/I of plasma. A screening programme involving analyses of thyroxine would require considerably higher recall frequency to yield 100% sensitivity. These results support a nationwide CH screening program based on TSH analyses of PKU filter paper blood samples using 50 mU/I of plasma as the cut-off limit.     

Usefulness of serum thyrotropin-binding inhibitory index measurements in infantile hypothyroidism. Relationship to serum thyrotropin concentrations

Transplacental passage of thyrotropin (TSH)-binding inhibitory immunoglobulins may result in transient congenital hypothyroidism. We measured serum TSH-binding inhibitory index (TBII) in 11 infants with abnormal screening findings using a commercially available kit. Two of the infants, who were siblings, had markedly elevated TBII values (90% and 100%, respectively), as did their mother (89%, 100%), and had a clinical course consistent with transient antibody-mediated hypothyroidism. Four other infants had a borderline or mildly elevated TBII that was not present in maternal serum, suggesting that endogenous TSH was being measured in this assay. The TBII was measured in the sera of 18 additional children with primary hypothyroidism and in human TSH standards from 25 to 2000 mU/L. Increasing concentrations of TSH were associated with a linear increase in TBII. Measurement of TBII by this method may identify infants with transient antibody-mediated hypothyroidism, although simultaneous assessment of maternal serum is necessary.     

SCREENING FOR CONGENITAL HYPOTHYROIDISM

ABSTRACT. Larsson, A., Ljunggren, J. G., Ekman, K., Nilsson, A. and Olin, P. (Departments of Paediatrics and Child Psychiatry, Karolinska Institute, St. Goran's Children's Hospital; the Department of Medicine, St. Göran's Hospital; and the PKU Section of the Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Sweden). Screening for congenital hypothyroidism. I. Laboratory results of a pilot study based on dried blood samples collected for PKU screening. Acta Paediatr Scand, 70:141, 1981. – A pilot study was performed to establish optimal conditions for nation-wide screening for congenital hypothyroidism in Sweden. The levels of T₄ and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 1979, 2 infants born in the Stockholm area during a 14-month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or–if they were not preterm–the T₄ concentration was less than -2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine-binding globulin. The results of the follow-up analyses from recalled infants showed that determination of the reverse-T₃ level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation-wide screening for congenital hypothyroidism is proposed.     

Efficacy of congenital hypothyroidism neonatal screening in preterms less than 32 weeks of gestational age: more evidence

OBJECTIVE: To evaluate the double screening performed for congenital hypothyroidism (CH) to preterm infants <32 weeks of gestational age (GA) between 1994 and 2003. INFANTS AND METHODS: TSH was assessed by IFMA. Infants were classified as: term (T) (>37 weeks GA); preterm (PT) (33-37 weeks GA); and very preterm (VPT) (< or =32 weeks GA). RESULTS: In 585,221 screened infants, CH was confirmed in 228 T, 23 PT and seven VPT. An increasing incidence of CH was found with decreasing GA, affecting 1:1,603 PT and 1:585 VPT. PT infants had 1.5 times more risk than full-term infants of suffering CH, and VPT 4 times more. Only 4/7 affected VPT had an adequate double screening as requested. Three had elevated TSH values in the first sample and in one a normal TSH (10.3 mIU/l) at 3 days rose to 240 mIU/l after day 15. In the remaining three VPT, TSH in the unique filter paper sample (21 to 34 days) was markedly elevated. CONCLUSIONS: Our findings reinforce the need for awareness in neonatal settings for adequate screening of VPT infants. Screening in the first week of life was effective in detection of most but not all affected VPT. Larger studies are needed in order to establish accurate screening recommendations for VPT newborns. Until this step is reached, repeated screening is advised in these infants.     

Tc]-99m thyroid scintigraphy in congenital hypothyroidism screening program

The aetiology of congenital hypothyroidism (CH) may be important in determining disease severity, outcome and treatment schedules because athyroid patients need higher treatment doses and close monitoring particularly early in life. The aim of this study was to evaluate thyroid scintigraphy (TS) findings in infants with CH and to determine the relationship of serum TSH and T4 values with thyroid agenesia, in an attempt to identify factors that may detect thyroid agenesia before treatment. Since August 2002 to April 2005, screening program for CH was carried out in the Isfahan University of Medical Sciences and Health Services, Isfahan, Iran. Screening was performed by measuring both the serums T4 and TSH concentration at day 3-7 of birth. Full-term newborns were recalled based on a serum TSH >20 mIU/l or serum T4 < 6.5 microg/dl and premature newborns based on T4 level by weight and TSH level by age. After repeating the laboratory test and clinical evaluation, Tc-99m TS was recommended for all infants with suspected CH before thyroxin replacement therapy. On the basis of Tc-99m TS, the thyroid gland was classified as normal scan, ectopic, goiter and athyrosis. TS results were compared with serum T4 and TSH levels. Of 93 381 newborns screened over a period of nearly 3 years, 262 neonates were found to have CH. The overall incidence of CH was 1 : 357 live births with a female/male ratio (F/M) of 1.4/1. Thyroid scan was performed on 116 (54%) of the infants with CH; of them, 33 cases (28.4%) were athyrotic (F/M = 0.8/1) while seven infants (6%) had ectopic thyroid (F/M = 1.3/1) and 76 cases (65.6%) had a normal thyroid scan (F/M = 1.5/1). Infants with the absence of thyroid in TS had significantly higher TSH value in comparison with those with ectopic or normal TS (116.3 +/- 109.64 vs. 108.10 +/- 62.92 or 55.35 +/- 48.26 mIU/l, respectively, P < 0.0001). Although not statistically different, the mean T4 level was higher in normal TS group than in ectopic and athyrotic groups (8.03 +/- 3.48 vs. 6.36 +/- 5.57 or 5.04 +/- 3 microg/dl, respectively, P = 0.09). We conclude that Tc-99m TS is a useful diagnostic tool for the initial investigation of suspected CH and considering the correlation of TS results with blood TSH levels, proper management and close monitoring of hypothyroid infants with severe hormonal alterations is necessary for the detection of thyroid agenesia.     

Finnish national screening for hypothyroidism

National cord blood screening for congenital hypothyroidism has operated in Finland with complete coverage since 1980. A low frequency of false positives, 0.08%, was achieved by supplementing the TSH screen with a T4 determination in borderline samples. Among 175188 infants the incidence of (unconfirmed) hypothyroidism was 1/2637. The median age at start of therapy was 6 days. The programme imposed a 2–3 week therapy on the false positive cases. This did not appear to cause any adverse effects. A mechanism for masking congenital hypothyroidism was observed: two athyroid infants were euthyroid at birth because of feto-fetal transfusion.Abbreviation T4 serum total thyroxine     

A high prevalence of consanguineous and severe congenital hypothyroidism in an Iranian population

To determine the incidence of permanent congenital hypothyroidism (CH) in Tehran and Damavand, cord blood spots were collected from February 1998-August 2002 and infants with TSH > or =20 mU/l were recalled. CH was confirmed in neonates (aged > or =7 days) with serum TSH >10 mU/l and T4 <84 nmol/l. Cases were followed up until September 2003. Dysgenesis was detected by thyroid imaging. In eutopic cases, serum TSH and T4 measurements following levothyroxine discontinuation (2-3 years of age) confirmed dyshormonogenesis and transient CH. Of 35,067 neonates, 373 (1.06%) were recalled and 25 (1:1,403 births) had permanent CH (six had transient CH and four remain unknown). Dysgenesis was detected in 18 (1:1,948 births) and dyshormonogenesis in seven (1:5,010 births) infants. Parental consanguinity was present in 10 (55.6%) dysgenetic, three (42.9%) dyshormonogenetic, and overall 6,648 (28.6%) of 23,227 screened infants. Odds ratio (95%CI(OR)) of consanguinity in permanent CH and dysgenesis was 2.75 (1.17-6.47) and 3.74 (1.33-10.52), respectively. The high prevalence of parental consanguinity in infants with permanent CH warrants genetic assessment.     

Central Congenital Hypothyroidism Detected by Neonatal Screening in Sapporo, Japan (2000–2004): It’s Prevalence and Clinical Characteristics

In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter-paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency.     

Neonatal screening for hypothyroidism in Greece

One year's experience in screening for congenital hypothyroidism in Greece is reported. Thyroidstimulating hormone (TSH) determination by a radioimmunoassay on dried blood spots was selected as the screening method. During the first year of screening 75,879 newborn infants were tested from Guthrie blood spots taken on the 5th day of life. Eighteen cases of primary congenital hypothyroidism with serum TSH levels over 100 IU/ml were detected, giving an incidence of 1:4200. One case had already been diagnosed clinically. Replacement treatment was started between the 22nd and the 50th days of life.     

Newborn Screening Guidelines for Congenital Hypothyroidism in India: Recommendations of the Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) – Part I: Screening and Confirmation of Diagnosis

The Indian Society for Pediatric and Adolescent Endocrinology has formulated locally relevant Clinical Practice Guidelines for newborn screening, diagnosis and management of primary congenital hypothyroidism (CH). Recommendations: Screening should be done for every newborn using cord blood, or postnatal blood, ideally at 48 to 72 h of age. On this screen sample, neonates with TSH?>?20 mIU/L serum units (or >34 mIU/L for samples taken between 24 to 48 h of age) should be recalled for confirmation. For screen TSH?>?40 mIU/L, immediate confirmatory venous T4/FT4 and TSH, and for milder elevation of screen TSH, a second screening TSH at 7 to 10 d of age, should be taken. Preterm and low birth weight infants should undergo screening at 48–72 h postnatal age. Sick babies should be screened at least by 7 d of age. Venous confirmatory TSH >20 mIU/L before age 2 wk and >10 mIU/L after age 2 wk, with low T4 (<10 μg/dL) or FT4 (<1.17 ng/dL) indicate primary CH and treatment initiation. Imaging is recommended by radionuclide scintigraphy and ultrasonography after CH is biochemically confirmed but treatment should not be delayed till scans are performed. Levothyroxine is commenced at 10 to 15 μg/kg in the neonatal period. Serum T4/FT4 is measured at 2 wk and TSH and T4/FT4 at 1 mo, then 2 monthly till 6 mo, 3 monthly from 6 mo-3 y and every 3–6 mo thereafter. Babies with the possibility of transient congenital hypothyroidism should be re-evaluated at age 3 y, to assess the need for lifelong therapy.     

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.