Neugeborenenscreening in Deutschland, Österreich und der Schweiz

Since the end of the 1960s newborn screening has been established in Germany, Austria and Switzerland to prevent congenital disease. After initially only detecting phenylketonuria, all screening programs were expanded to include hypothyroidism, congenital adrenal hyperplasia, biotinidase deficiency as well as classical galactosemia. The introduction of tandem mass spectrometry (TMS) has enabled simultaneous screening of various amino- and organoacidopathies as well as fatty acid oxidation disorders. Subsequently, in 2005 neonatal screening was regulated in Germany by the introduction of a mandatory children’s guideline which most importantly included a catalogue of specific target disorders. In Germany and Austria the number of screened disorders, with the exception of cystic fibrosis, is similar, while in Switzerland only phenylketonuria and medium chain acyl CoA dehydrogenase (MCAD) deficiency are analyzed using TMS. In comparison to the recommendations of the American College of Medical Genetics, all of these screening programmes are more restrictive. However, it has to be borne in mind that an ever changing ethical, legal and technological environment requires regular re-evaluation of the respective programmes.     

Expanding screening for rare metabolic disease in the newborn: an analysis of costs, effect and ethical consequences for decision-making in Finland

Aim: Currently, the only metabolic disorder that newborns are screened for in Finland is congenital hypothyroidism. A proposal to start a pilot study on screening for other rare metabolic diseases using tandem mass spectrometry prompted a health technology assessment project on the effect and costs of expanded newborn screening programme options. Method: A modelling study using data from current published studies, healthcare registers and expert opinion. Results: The annual running cost of screening 56 000 newborns for the chosen five disorders (congenital adrenal hyperplasia, medium-chain acyl-CoA dehydrogenase deficiency [MCADD], long chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD], phenylketonuria [PKU] and glutaric aciduria type 1 [GA 1]) was estimated to be €2.5 million or €45 per newborn when starting costs were included. The costs per quality-adjusted life year (QALY) gained are a maximum of €25 500. Prevention of severe handicap in one newborn would reduce the costs to a maximum of €18 000 per QALY gained.
Conclusions: Expanding the Finnish neonatal screening programme would require a new organization. The cost-effectiveness, resources, ethics and equity need to be considered when deciding in favour of or against starting a new screening programme.     

Descriptive epidemiology of missed cases of phenylketonuria and congenital hypothyroidism

We conducted a structured telephone survey of state public health laboratory directors of neonatal screening programs to determine the extent of the problem of missed cases of phenylketonuria (PKU) and congenital hypothyroidism. A total of 76 missed cases were reported--43 PKU and 33 congenital hypothyroidism. We looked at the following characteristics of the missed cases: the stage at which the miss occurred, which included specimen collection, laboratory procedures, or follow-up; the size of the program; the type of screening program; the age of the infant at the time of screening; and any legal action that resulted from the miss. The 76 missed cases probably represent an underascertainment of the true number, yet we believe that our data provide an overview of some of the problems associated with mass neonatal screening. There was one missed case of PKU for every 70 cases detected, and one missed case of congenital hypothyroidism for every 120 cases detected; in other words, two congenital hypothyroidism cases were missed for every 1 million infants screened. Regarding the stage of screening in which the miss occurred, 14% occurred during specimen collection, 45% during the laboratory procedures stage, 16% during follow-up, 11% were the result of biologic variation, and in 14% the stage could not be identified. We conclude that neonatal screening programs have been highly successful but that there may be additional safeguards to be developed, tested, and implemented when practical.     

Growth in early treated congenital hypothyroidism.

The growth of 361 children with congenital hypothyroidism diagnosed by screening was assessed by estimating mean values for height, weight, body mass index (BMI), and head circumference on each birthday up to the age of 4 years. In the group of children with severe congenital hypothyroidism (pretreatment plasma thyroxine < or = 30 nmol/l), the mean heights at 1 and 2 years were less than standards for healthy children, but this may be due to technical factors related to difficulties in measuring young infants and the method used to estimate height on each birthday. By the age of 3-4 years the values for mean height in the children with either severe or less severe congenital hypothyroidism were equal to or greater than those for healthy children. At all ages mean head circumference in boys and girls with severe congenital hypothyroidism was greater than standards for healthy children, but this only reached statistical significance in girls at 1 year. With the exception of the results for boys at 1 year, mean values for BMI were slightly greater in the children with severe congenital hypothyroidism. The mean BMI results for children with either severe or less severe congenital hypothyroidism were significantly greater than those for healthy French children at all ages, but they showed the same trends with increasing age. It is concluded that by the age of 3-4 years stature is essentially normal in children with early treated congenital hypothyroidism but that the increased head size reported before screening may still be evident in early infancy.     

Growth in early treated congenital hypothyroidism

The growth of 361 children with congenital hypothyroidism diagnosed by screening was assessed by estimating mean values for height, weight, body mass index (BMI), and head circumference on each birthday up to the age of 4 years. In the group of children with severe congenital hypothyroidism (pretreatment plasma thyroxine < or = 30 nmol/l), the mean heights at 1 and 2 years were less than standards for healthy children, but this may be due to technical factors related to difficulties in measuring young infants and the method used to estimate height on each birthday. By the age of 3-4 years the values for mean height in the children with either severe or less severe congenital hypothyroidism were equal to or greater than those for healthy children. At all ages mean head circumference in boys and girls with severe congenital hypothyroidism was greater than standards for healthy children, but this only reached statistical significance in girls at 1 year. With the exception of the results for boys at 1 year, mean values for BMI were slightly greater in the children with severe congenital hypothyroidism. The mean BMI results for children with either severe or less severe congenital hypothyroidism were significantly greater than those for healthy French children at all ages, but they showed the same trends with increasing age. It is concluded that by the age of 3-4 years stature is essentially normal in children with early treated congenital hypothyroidism but that the increased head size reported before screening may still be evident in early infancy.     

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.     

Screening for congenital hypothyroidism: results of screening one million North American infants.

Pilot programs for screening of newborn infants for congenital hypothyroidism began in North America in 1972. To date, the five oldest programs (Quebec, Pittsburgh, Toronto, Oregon Regional, and New England Regional) have screened 1,046,362 infants. A total of 277 infants with congenital hypothyroidism have been detected and seven have been missed, resulting in a total of 284 affected infants in the screened population and an overall incidence of one in 3,684 live births. Of the affected infants, 246 were determined to have primary hypothyroidism, an incidence of one in 4,254 births. Ten infants with secondary-tertiary hypothyroidism were detected in Quebec, Oregon, and Toronto, an incidence of one in 68,200 births. Of all the infants with primary hypothyroidism who were adequately studied, 63% were determined to have aplastic or hypoplastic glands, 14% normal or enlarged glands, and 23% ectopic thyroid tissue. The estimated minimum incidence of infants with TBG deficiency is one in 8,913 births. Only 8 of the 277 detected infants were suspected clinically to have congenital hypothyroidism prior to the time of confirmation of the diagnosis at 4 to 8 weeks of age. The cost of screening varied from $0.70 to $1.60 per infant, depending on which costs were included in the estimate. Preliminary evidence from Quebec suggests that infants treated in the program have normal developmental testing scores at 18 months of age.     

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.     

Neonatal Mass Screening of Hereditary Metabolic Diseases in S. Paulo-Brasil

The authors report their experience in neonatal mass screening of hereditary metabolic disease in S. Paulo regarding hyperphenylalaninemia (by own programmation), others aminoacidophaties, congenital hypothyroidism, carbohydrates, mucopolysaccharides and heterozygotes for GM2-gangliosidosis type I (Tay-Sachs disease). The importance of the performing of such populational screening tests, even in developing countries is stressed.     

Quality evaluation of newborn screening programs

In the last four decades in many countries and regions all over the world newborn screening programs have been developed. Traditionally, most programs focus on phenylketonuria and congenital hypothyroidism. However, with development of new technologies, screening for a large variety of other disorders has become available. The decision-making process on what to screen or not to screen for is usually driven by personal interest of the professionals involved, by local legislation and access to funding, resulting in large differences among countries. In general, quality evaluation is only applied to the pure laboratory analytical phase. Less attention is given to the pre-analytical phase (e.g. timely sampling, maximum coverage) and the post-analytical phase (follow-up and treatment, evaluation of long-term effects, cost-effectiveness, etc.). In order to gain more insight into the current situation worldwide we developed a questionnaire which was sent to leading screening centers in more than 30 countries. As expected, the results show large differences in degree of organization, turnover times, completeness of coverage and follow-up. There appears to be no relationship between screening procedures and the degree of legislation or the system of funding. In presenting the more detailed results we hope to be of service to program organizers.     

Quality evaluation of newborn screening programs

In the last four decades in many countries and regions all over the world newborn screening programs have been developed. Traditionally, most programs focus on phenylketonuria and congenital hypothyroidism. However, with development of new technologies, screening for a large variety of other disorders has become available. The decision-making process on what to screen or not to screen for is usually driven by personal interest of the professionals involved, by local legislation and access to funding, resulting in large differences among countries. In general, quality evaluation is only applied to the pure laboratory analytical phase. Less attention is given to the pre-analytical phase (e.g. timely sampling, maximum coverage) and the post-analytical phase (follow-up and treatment, evaluation of long-term effects, cost-effectiveness, etc.). In order to gain more insight into the current situation worldwide we developed a questionnaire which was sent to leading screening centers in more than 30 countries. As expected, the results show large differences in degree of organization, turnover times, completeness of coverage and follow-up. There appears to be no relationship between screening procedures and the degree of legislation or the system of funding. In presenting the more detailed results we hope to be of service to program organizers.     

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.     

Screening for congenital hypothyroidism in Hong Kong

A pilot cord blood TSH screening program for congenital hypothyroidism was commenced in Hong Kong in April 1982. By April 1984, 14 411 neonates born in two hospitals were screened for this disorder. Five cases of primary hypothyroidism and two cases of transient hypothyroidism were detected. The detection of cases of congenital hypothyroidism with only moderately elevated cord blood TSH values means that the recall rate will remain high.     

Screening for congenital hypothyroidism in Hong Kong

A pilot cord blood TSH screening program for congenital hypothyroidism was commenced in Hong Kong in April 1982. By April 1984, 14 411 neonates born in two hospitals were screened for this disorder. Five cases of primary hypothyroidism and two cases of transient hypothyroidism were detected. The detection of cases of congenital hypothyroidism with only moderately elevated cord blood TSH values means that the recall rate will remain high.     

CONGENITAL HYPOTHYROIDISM IN SWEDEN Incidence and Age at Diagnosis

ABSTRACT. A total number of 112 children with congenital hypothyroidism were diagnosed in all Children's Hospitals and Pediatric Wards in Sweden during the 7-year period 1969–1975. Since it may be assumed that all cases of congenital hypothyroidism, which were diagnosed during that period were seen in one of these hospitals, the incidence of congenital hypothyroidism in Sweden can be calculated to be 1:6900 live births. In spite of an efficient National Health Care Program for Infants the diagnosis was delayed until after an age of three months in 52% of the cases. This fact supports the view that mass screening of newborns for congenital hypothyroidism has to be introduced in Sweden. However, the beneficial effects of such a program cannot be fully elucidated until it has been considered whether earlier instituted treatment would have improved the outcome of children in whom a diagnosis was made after 3 months of age.     

Congenital hypothyroidism in Sweden. Incidence and age at diagnosis

A total number of 112 children with congenital hypothyroidism were diagnosed in all Children's Hospitals and Pediatric Wards in Sweden during the 7-year period 1969-1975. Since it may be assumed that all cases of congenital hypothyroidism, which were diagnosed during that period were seen in one of these hospitals, the incidence of congenital hypothyroidism in Sweden can be calculated to be 1:6900 live births. In spite of an efficient National Health Care Program for infants the diagnosis was delayed until after an age of three months in 52% of the cases. This fact supports the view that mass screening of newborns for congenital hypothyroidism has to be introduced in Sweden. However, the beneficial effects of such a program cannot be fully elucidated until it has been considered whether earlier instituted treatment would have improved the outcome of children in whom a diagnosis was made after 3 months of age.     

Common childhood thyroid disorders

This article presents current knowledge about common childhood thyroid gland disorders. Included are congenital and acquired hypothyroidism, hyperthyroidism, disorders due to iodine deficiency, tumors and miscellaneous conditions. The significance of early diagnosis by screening and institution of treatment of congenital hypothyroidism is emphasized. Etiology, pathogenesis, clinical signs and symptoms, diagnosis and treatment are discussed.     

北京市20年新生儿疾病筛查回顾性分析

目的分析北京市1989—2009年新生儿先天性甲状腺功能减退症（CH）和苯丙酮尿症（PKU）的筛查结果,为进一步提高新生儿疾病筛查的管理水平及干预措施提供依据。方法 采集出生72h后、正常哺乳的新生儿足跟血于特定滤纸上,进行CH及PKU筛查。PKU筛查检测指标为血苯丙氨酸（Phe）浓度,分别采用细菌抑制法（1989—2003年）和荧光法（2004—2009年）;CH筛查检测指标为血促甲状腺激素（TSH）水平,分别采用放免法（1989—2003年）及时间分辨荧光免疫分析法（DELFIA）（2003—2009年）。结果 1989—2009年,北京市共筛查新生儿1745998名,筛查率由1989年的14.01%提高到2009年98.16%,可疑患儿复诊率由1991年的65.85%提高到2009年的92.18%,共确诊CH482例,发病率1：3622;PKU192例,发病率1：9094。结论 新生儿疾病筛查是包括管理、筛查、随访、诊治、评估、教育等多个环节的系统服务工程,各部门的协调配合是提高筛查管理质量的有效措施,完善的新生儿疾病筛查工作可有效降低残疾儿的发生。     

The magnitude and challenge of false-positive newborn screening test results

OBJECTIVES: This study examined for the first time to our knowledge the national data available from newborn screening programs in the United States and determined the salient characteristics of various screening tests for 3 hereditary metabolic disorders and 2 congenital endocrinopathies with emphasis on positive predictive values (PPVs) to delineate the magnitude of false-positive results. METHODS: Reports published by the Council of Regional Networks for Genetic Services for 1990 through 1994 were examined carefully, paying particular attention to phenylketonuria, galactosemia, biotinidase deficiency, congenital hypothyroidism, and congenital adrenal hyperplasia (CAH). Because of recent improvements in data collecting, reporting, and tabulating, we used data from 1993 and 1994 to determine the apparent sensitivity, specificity, relative incidence rates, and PPVs for the 5 disorders. For biotinidase deficiency and CAH, we also calculated relative incidence rates and PPVs for 1991 and 1992. RESULTS: Our analyses revealed the following best estimates for the relative incidence rates of 5 disorders: phenylketonuria, 1:14,000; galactosemia, 1:59,000; biotinidase deficiency, 1:80,000; congenital hypothyroidism, 1:3,300; and CAH, 1:20,000. An apparent sensitivity of 100% has been reported by the various states for most of the disorders, and specificity levels are all above 99%. The PPVs, however, range from 0.5% to 6.0%. Consequently, on average, there are more than 50 false-positive results for every true-positive result identified through newborn screening in the United States. CONCLUSIONS: The magnitude of false-positive results generated in newborn screening programs, particularly for congenital endocrinopathies, presents a great challenge for future improvement of this important public health program. Attention must be given to improved laboratory tests, use of more specific markers, and better risk communication for families of patients with false-positive test results.     

A ten-year temporal analysis of primary congenital hypothyroidism in Israel.

It was previously shown that some congenital malformations present seasonal variations, suggesting a seasonal etiology such as viral infections. Some earlier studies have shown a certain degree of variation in the incidence rates of congenital hypothyroidism. As from April 1978 all infants born in Israel were screened for congenital hypothyroidism (CH) in one central laboratory at the Sheba Medical Center Tel-Hashomer. During the 10-year screening period (April 1978 to March 1988) 303 infants were found to have primary CH, which constitutes an overall incidence of 1/3192 live births. The annual and monthly birth incidence was calculated for the 120 months of the screening period. The annual CH incidence was significantly low in 1978 and 1979 and significantly high in 1985. There were wide and significant variations in the individual monthly incidences of CH. The average monthly incidence showed a low peak in August; however the autocorrelation analysis of the monthly incidences of CH showed no significant periodicity. This was supported by the Fourier analysis which showed no distinctive frequency peak. The last menstrual period was calculated for 138 of the infants' mothers and an autocorrelation analysis of these dates showed no significant periodicity. These results support a non-periodic etiology for sporadic primary CH in Israel.