Cost-effectiveness of newborn screening for cystic fibrosis determined with real-life data.

BACKGROUND: Previous cost-effectiveness studies using data from the literature showed that newborn screening for cystic fibrosis (NBSCF) is a good economic option with positive health effects and longer survival. METHODS: We used primary data to compare cost-effectiveness of four screening strategies for NBSCF, i.e. immunoreactive trypsinogen-testing followed by pancreatitis-associated protein-testing (IRT-PAP), IRT-DNA, IRT-DNA-sequencing, and IRT-PAP-DNA-sequencing, each compared to no-screening. A previously developed decision analysis model for NBSCF was fed with model parameters mainly based on a study evaluating two novel screening strategies among 145,499 newborns in The Netherlands. RESULTS: The four screening strategies had cost-effectiveness ratios varying from €23,600 to €29,200 per life-year gained. IRT-PAP had the most favourable cost-effectiveness ratio. Additional life-years can be gained by IRT-DNA but against higher costs. When treatment costs reduce with 5% due to early diagnosis, screening will lead to financial savings. CONCLUSION: NBSCF is as an economically justifiable public health initiative. Of the four strategies tested IRT-PAP is the most economic and this finding should be included in any decision making model, when considering implementation of newborn screening for CF.

[Neonatal screening for congenital hypothyroidism: more than 30 years of experience in the Netherlands]. / Neonatale screening op congenitale hypothyreoïdie: ruim 30 jaar ervaring in Nederland.

OBJECTIVE: To describe the Dutch neonatal screening programme for congenital hypothyroidism (CH). DESIGN: Descriptive study. METHOD: Data on neonatal screening for CH in the period 1 January 1981 through 31 December 2011 were obtained from the Department for Vaccine Supply and Prevention Programmes of the Dutch National Institute for Public Health and the Environment (RIVM), laboratories and paediatricians to whom babies with abnormal screening results were referred. The screening procedure has been amended several times. In the period 1981-1994, only T4 and TSH were measured in heel prick blood, for example. From 1995, thyroxine-binding globulin (TBG) was added to the screening protocol. RESULTS: The participation rate was 99.7%. Before 1995 the sensitivity, specificity and positive predictive value were 94%, 99.51% and 6%, respectively. From 1995 these percentages were 98%, 99.85% and 21%, respectively. The total prevalence of CH was 1:2670 (prevalence of CH of thyroidal origin was 1:3100 and CH of central origin was 1:21,600). The percentages of patients with severe CH treated before day 15 in the periods 1981-1990, 1991-2000 and 2001-2011 were 24% (63/263), 63% (170/269) and 96% (176/184), respectively. CONCLUSION: The sensitivity and specificity of the screening procedure has considerably increased since 1995 compared with the period before 1995. In recent years patients with severe CH were treated considerably earlier than in the first years of the screening. Neonatal screening for CH may be considered as an important success for public health care.

Evolution of an influenza pandemic in 13 countries from 5 continents monitored by protein microarray from neonatal screening bloodspots.

BACKGROUND: Because of lack of worldwide standardization of influenza virus surveillance, comparison between countries of impact of a pandemic is challenging. For that, other approaches to allow internationally comparative serosurveys are welcome. OBJECTIVES: Here we explore the use of neonatal screening dried blood spots to monitor the trends of the 2009 influenza A (H1N1) pdm virus by the use of a protein microarray. STUDY DESIGN: We contacted colleagues from neonatal screening laboratories and asked for their willingness to participate in a study by testing anonymized neonatal screening bloodspots collected during the course of the pandemic. In total, 7749 dried blood spots from 13 countries in 5 continents where analyzed by using a protein microarray containing HA1 recombinant proteins derived from pandemic influenza A (H1N1) 2009 as well as seasonal influenza viruses. RESULTS: Results confirm the early start of the pandemic with extensive circulation in the US and Canada, when circulation of the new virus was limited in other parts of the world. The data collected from sites in Mexico suggested limited circulation of the virus during the early pandemic phase in this country. In contrast and to our surprise, an increase in seroprevalence early in 2009 was noted in the dataset from Argentina, suggestive of much more widespread circulation of the novel virus in this country than in Mexico. CONCLUSIONS: We conclude that this uniform serological testing of samples from a highly standardized screening system offers an interesting opportunity for monitoring population level attack rates of widespread diseases outbreaks and pandemics.

Decline of IgG pertussis toxin measured in umbilical cord blood, and neonatal and early infant serum.

Maternal pertussis-specific antibodies are passively acquired by infants during pregnancy. An IgG pertussis toxin (IgG-PT) concentration of >20 U/ml is considered to protect neonates against pertussis. To evaluate the IgG concentration at birth and during the first two months of life, we examined the IgG-PT concentration in the umbilical cord blood and three times during the neonatal and early infant period. IgG-PT was measured by validated IgG-specific enzyme-linked immunosorbent assays (ELISA) in umbilical cord blood and in Guthrie card blood samples of umbilical cord blood in 2,790 children, born between 1 August 2006 and 1 December 2008. These measurements were comparable. All children with concentrations of IgG-PT >30 U/ml were included. IgG-PT was also measured in Guthrie card blood samples, when the neonates or early infants were 5 days, 1 month and 2 months old. The mean concentrations of IgG-PT were calculated. The mean concentration of IgG-PT in umbilical cord blood was 60.1 U/ml (LN 4.1; 0.6 SD; n = 103). At the age of 5 days, 1 month and 2 months, the mean concentration of IgG-PT was 40.6 U/ml (LN 3.7; 0.5 SD; n = 103), 20.7 U/ml (LN 3.0; 0.7 SD; n = 62) and 16.7 U/ml (LN 2.8; 0.9 SD; n = 61), respectively. Four percent of the neonates had a concentration of IgG-PT >30 U/ml in umbilical cord blood, which declined to levels around the concentration needed for protection against pertussis (>20 U/ml) in the first two months of life. Hence, it is of great importance to further investigate the safety of maternal immunisation during pregnancy to prevent life-threatening pertussis in newborns.

Newborn screening for hunter disease: a small-scale feasibility study.

Hunter disease (Mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS). Two main therapies have been reported for MPS II patients: enzyme-replacement therapy (ERT) and hematopoietic stem-cell transplantation (HSCT). Both treatment modalities have been shown to improve some symptoms, but the results with regard to cognitive functioning have been poor. Early initiation of therapy, i.e., before neurological symptoms have manifested, may alter cognitive outcome. The need for early identification makes Hunter disease a candidate for newborn screening (NBS). Our objective was to explore the use of a fluorometric assay that could be applicable for high-throughput analysis of IDS activity in dried blood spots (DBS). The median IDS activity in DBS samples from 1,426 newborns was 377 pmol/punch/17 h (range 78-1111). The IDS activity in one sample was repeatedly under the cutoff value (set at 20% of the median value), which would imply a recall rate of 0.07%. A sample from a clinically diagnosed MPS II individual, included in each 96-well test plate, had IDS activities well below the 20% cutoff value. Coefficients of variation in quality control samples with low, medium, and high IDS activities (190, 304, and 430 pmol/punch/17 h, respectively) were 12% to 16%. This small-scale pilot study shows that newborn screening for Hunter disease using a fluorometric assay in DBS is technically feasible with a fairly low recall rate. NBS may allow for identification of infants with Hunter disease before clinical symptoms become evident enabling early intervention.

Antibody levels against B. pertussis in neonates measured in dried blood spots.

AIM: We designed this study to investigate if immunoglobuline G-Pertussis toxin (IgG-PT) against Bordetella pertussis in umbilical cord blood can reliably be determined in dried blood spots on filter paper (Guthrie) cards. PATIENTS AND METHODS: We prospectively included 129 mothers and their newborns born in a general hospital in the Netherlands. The relation between IgG-PT against B. pertussis from the umbilical cord measured in dried blood spots (Guthrie card) and in serum samples was studied by means of a Bland-Altman graph, using regression analysis to evaluate the level of agreement of both measurement methods. RESULTS: IgG-PT in Guthrie cards show a high coefficient of correlation with IgG-PT in serum samples from the umbilical cord when calibrated against blood spot calibrators (p<0.05). CONCLUSION: Maternal IgG-PT against B. pertussis measured in cord blood applied to Guthrie cards and calibrated against blood spot calibrators show good agreement with measurement of IgG-PT in cord serum. This offers new perspectives for future studies concerning B. pertussis antibodies.

Relationship between neonatal screening results by HPLC and the number of α-thalassaemia gene mutations; consequences for the cut-off value.

OBJECTIVES: To evaluate the relationship between FAST peak percentage by adapted Bio-Rad Vnbs analysis using the valley-to-valley integration and genotypes with the aim to improve differentiation between severe α-thalassaemia forms (HbH disease) and the milder disease types. METHOD: DNA analysis for α-thalassaemia was performed on 91 dried blood spot samples presenting normal and elevated FAST peak levels, selected during three years of Dutch national newborn screening. RESULTS: Significant differences were found between samples with and without α-thalassaemia mutations, regardless of the genetic profiles. No significant difference was demonstrated between HPLC in -α/αα and -α/-α, between -α/-α and - -/αα and between - -/αα and - -/-α genotypes. CONCLUSION: This study confirms that the percentage HbBart's, as depicted by the FAST peak, is only a relative indication for the number of α genes affected in α-thalassaemia. Based on the data obtained using the modified Bio-Rad Vnbs software, we adopted a cut-off value of 22.5% to discriminate between possible severe α-thalassaemia or HbH disease and other α-thalassaemia phenotypes. Retrospectively, if this cut-off value was utilized during this initial three-year period of neonatal screening, the positive predictive value would have been 0.030 instead of 0.014.

Pertussis disease burden in the household: how to protect young infants.

BACKGROUND: We conducted a population-based, nation-wide, prospective study to identify who introduced pertussis into the household of infants aged 6 months admitted to the hospital for pertussis in the Netherlands. METHODS: During the period 2006-2008, a total of 560 household contacts of 164 hospitalized infants were tested by polymerase chain reaction, culture, and serological examination to establish Bordetella pertussis infection. Clinical symptoms and vaccination history were obtained by a questionnaire submitted during sample collection and 4-6 weeks afterwards. RESULTS: Overall, 299 household contacts (53%) had laboratory-confired pertussis; 159 (53%) had symptoms compatible with typical pertussis infection, and 42 (14%) had no symptoms. Among children vaccinated with a whole-cell vaccine, 17 (46%) of 37 had typical pertussis 1-3 years after completion of the primary series, compared with 9 (29%) of 31 children who had been completely vaccinated with an acellular vaccine. For 96 households (60%), the most likely source of infection of the infant was established, being a sibling (41%), mother (38%), or father (17%). CONCLUSIONS: If immunity to pertussis in parents is maintained or boosted, 35%-55% of infant cases could be prevented. Furthermore, we found that, 1-3 years after vaccination with whole-cell or acellular vaccine, a significant percentage of children are again susceptible for typical pertussis. In the long term, pertussis vaccines and vaccination strategies should be improved to provide longer protection and prevent transmission.

Quality of nuchal translucency measurements in The Netherlands: a quantitative analysis.

OBJECTIVE: The Dutch Centre for Population Research has specified quality demands for nuchal translucency (NT) measurement in The Netherlands. We performed an analysis of the quality of NT measurement in 2005-2006 and its influence on screening performance. METHODS: This was a retrospective study of records of NT measurements (n = 27,738) obtained between January 2005 and December 2006 retrieved from the Dutch National Institute for Public Health and the Environment (RIVM). The performance of each individual operator was analyzed with regard to the quality standards, which involved calculation of operator-specific median NT-multiples of the median (MoM) values. For the entire population of operators, a curve was determined describing the relationship between crown-rump length and NT. Detection rates (DR) and false-positive rates (FPR) for Down syndrome were modeled with this new curve and compared to those originally obtained using previously published reference data. RESULTS: Only 22% of all operators met the quality requirement of performing more than 150 NT measurements per year. However, no relationship was found between the number of measurements per operator and their median NT-MoM. The mean of all operator-specific median NT-MoM values was 0.94 (target value 1.0). Overall, operators with The Fetal Medicine Foundation certificate measured a significantly higher median NT-MoM (mean of operator-specific medians, 0.98) as compared to the non-certified operators (0.92). During the study period, the monthly median NT-MoM of all operators rose steadily, from 0.86 in January 2005 to 0.96 in December 2006. Recalculation of the risk for Down syndrome after adjusting the reference NT medians using our own data led to a modeled 4% increase in DR at a 5% FPR. CONCLUSION: Improved monitoring of NT measurement put into effect during the study period seems to have led to an improvement in the accuracy of measurements. Strict quality demands, continued monitoring and scrupulous evaluation of individual operators is likely to lead to an even better performance.

First-trimester Down syndrome screening performance in the Dutch population; how to achieve further improvement?

OBJECTIVE: To study the performance of the first-trimester combined test between 2004 and 2006 compared to a previous period to investigate changes in time and identify reasons for sub-optimal performance. METHODS: Serum samples were analysed for pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotrophin (f beta-hCG). Nuchal translucency (NT) was measured between 10 and 14 weeks. Tests were considered screen positive, if their calculated Down syndrome (DS) risk was at least 1 in 250 at term. RESULTS: A total of 20,293 singleton pregnancies were included in the analysis. The median maternal age fell from 35.7 to 34.3 years. The overall median weight-corrected multiple of the median (MoM) values of PAPP-A and f beta-hCG were 1.12 and 1.03, respectively. The median MoM value of NT was 0.89 and increased from 0.82 to 0.96. Sixty-six DS cases were detected by the screening test. The detection rate (DR) for DS was 75.9%, with a FPR of 3.3%. CONCLUSION: The performance of the first-trimester test has improved over the years. A better performance of the NT measurement was the main reason, although NT assessment should further be improved. In addition, a better setting of the medians for the biochemical parameters may contribute to a higher DR.

Lack of standardization in determining gestational age for prenatal screening.

OBJECTIVES: To determine whether estimation of gestational age (GA) in the context of first-trimester Down syndrome screening is standardized in the Netherlands. METHODS: This was a retrospective study, carried out between January 2005 and December 2006, of women who underwent first-trimester Down syndrome screening (n = 40,730) based on GA, maternal serum analysis and nuchal translucency (NT) measurement. Date of the last menstrual period (LMP), dating scan information including measurement of crown-rump length (CRL), NT thickness and name of the sonographer were recorded for all pregnancies. The accuracy of estimation of GA was evaluated by comparing the GA based on the LMP with that estimated from the CRL, using relevant subsets of the database. A survey of 104 sonographers was performed to further investigate the findings of the preceding analysis. RESULTS: In 44% of all first-trimester combined tests the estimation of GA was based on the dating scan; the method of determination of GA was unknown in 23%. In 15% of all cases a dating scan was recorded but was not used to provide the estimation of GA at blood sampling. Detailed analysis showed that a consistent methodology for the estimation of GA from CRL was not maintained within hospitals and obstetric practices. For a single CRL, the reported GA differed by up to 10 days. Finally, it was demonstrated that individual sonographers reported different GAs for a given CRL. CONCLUSIONS: Currently, estimation of GA in the first trimester in the Netherlands is not standardized. To improve the performance of prenatal screening for Down syndrome, estimation of GA should be based on ultrasound examination, with one nationally accepted CRL curve.

First ISNS Reference Preparation for Neonatal Screening for thyrotropin, phenylalanine and 17alpha-hydroxyprogesterone in blood spots.

BACKGROUND: Neonatal screening for congenital disorders like phenylketonuria (PKU), congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH) is generally performed in dried blood spots on filter paper. The analytes of interest for testing for PKU, CH and CAH are phenylalanine, thyrotropin (TSH) and 17alpha-hydroxyprogesterone (17OHP), respectively. The International Society for Neonatal Screening (ISNS) decided to prepare a combined reference preparation for the three analytes on filter paper Schleicher & Schuell #903, Whatman BFC180 and Toyo Roshi 545. This 'First ISNS Reference Preparation for Neonatal Screening for TSH, phenylalanine and 17OHP in blood spots' (1st ISNS-RPNS) has been prepared by the RIVM (Bilthoven). METHOD: The number of filter paper cards prepared, each with two sets of six blood spot calibrators, was 480, 42 and 69 for Schleicher & Schuell #903, Whatman BFC180 and Toyo Roshi 545, respectively. The volume of blood dispensed was 50 microl. The range of concentrations for TSH was 1-121 mIU/L blood, for phenylalanine 65-865 micromol/L blood and for 17OHP 2.2-302 nmol/L blood. RESULTS: The linearity of the blood spot calibrators and the homogeneity of the batch (only tested for Schleicher & Schuell) were good. The differences between the three filter papers were small: i.e. the potency of the ISNS-RPNS on Whatman and Toyo Roshi in terms of Schleicher & Schuell was between 0.98 and 1.09 for the three analytes. CONCLUSION: The 1st ISNS-RPNS for TSH, phenylalanine and 17OHP can be said to be suitable as formal reference preparation and as a source for (re)calibrating kit calibrators.

Multi-centre first-trimester screening for Down syndrome in the Netherlands in routine clinical practice.

OBJECTIVES: This is the first report on the results of a first-trimester combined-test screening programme in the Netherlands in a multi-centre routine clinical setting. METHODS: Between July 2002 and May 2004, blood samples were taken from subjects in 44 centres in the Netherlands and sent to our laboratory to assay for maternal serum concentrations of fbeta-hCG and PAPP-A. Fetal nuchal translucency (NT) was measured in the participating centres at a gestational age (GA) of 10-14 weeks. Results of those pregnancies for which a combined biochemical and NT risk was calculated were included in the epidemiological analysis of this study. RESULTS: A total of 4033 singleton pregnancies were included in the analysis. The median maternal age of the analysed group was 36.5 years. The distribution of GA was biphasic, with median GA of 10.3 and 12.1 weeks, respectively. The detection rate using the combined ultrasound and serum screening at a cut-off level of 1 in 250 was 71% (15/21), with a screen-positive rate of 4.7%. CONCLUSION: The results of this study show that the first-trimester combined test is suitable as a prenatal screening test in a multi-centre routine clinical setting in the Netherlands. Strict performance evaluation should identify weaknesses in the organisation that impair the performance of the test. Here, the performance of NT was especially identified as a candidate for improvement.

Subacute toxicity of alpha-ergocryptine in Sprague-Dawley rats. 2: metabolic and hormonal changes.

The present study describes the metabolic changes observed in a dietary subacute toxicity experiment with the ergot alkaloid alpha-ergocryptine in Sprague-Dawley rats. The observed effects on metabolic and hormonal parameters were described separately from the general toxicological effects, in view of the important role of dopamine agonists in metabolism (e.g. ergot alkaloids in fescue toxicosis). The rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28-32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). Total cholesterol and high-density lipoprotein (HDL)-cholesterol were decreased dose dependently in females but the ratio HDL-cholesterol/total cholesterol was only decreased at 20 mg/kg body weight. Triglycerides and glucose concentrations were decreased in the highest dose groups of both sexes. Serum urea concentrations were increased in the 20, 100 and 500 mg/kg dose groups. Insulin, glucagon and liver glycogen were increased in the highest dose group at the end of the study, when the animals were allowed to eat prior to blood sampling and necropsy. Prolactin, T4 and FT4 were decreased in the 20, 100 and 500 mg/kg dose groups of both sexes. Follicle-stimulating hormone (FSH) was decreased in the 20, 100 and 500 mg/kg female dose groups and luteinizing hormone (LH) was increased in the 20, 100 and 500 mg/kg male dose groups. It is postulated that the observed effects on food intake, metabolism (lipid and carbohydrate) and hormonal parameters are due to an interaction of ergocryptine with central dopaminergic activities, which comprise a major functional component of a central regulatory system for metabolism.

Specificity and sensitivity of high levels of immunoglobulin G antibodies against pertussis toxin in a single serum sample for diagnosis of infection with Bordetella pertussis.

Laboratory confirmation of pertussis by culture, PCR, or detection of antibody increase in paired sera is hampered by low sensitivity in the later stages of the disease. Therefore, we investigated whether, and at which level, concentrations of immunoglobulin G (IgG) antibodies against pertussis toxin (PT), IgG-PT, in a single serum sample are indicative of active or recent pertussis. IgG-PT, measured by enzyme-linked immunosorbent assay in units per milliliter, was analyzed in 7,756 sera collected in a population-based study in The Netherlands, in the sera of 3,491 patients with at least a fourfold increase of IgG-PT, in paired sera of 89 patients with positive cultures and/or PCR results, and in the sera of 57 patients with clinically documented pertussis with a median follow-up of 1.4 years. We conclude that, independently of age, IgG-PT levels of at least 100 U/ml are diagnostic of recent or active infection with Bordetella pertussis. Such levels are present in less than 1% of the population and are reached in most pertussis patients within 4 weeks after disease onset and persist only temporarily.

Preparation of the first European working standard for phenylalanine determination in dried blood spots.

OBJECTIVE: To develop a standard preparation for measurement of phenylalanine in blood spots in phenylketonuria against which manufacturers of kits for phenylalanine determination could calibrate their own blood spot calibrators. METHODS: As most of the variation of phenylalanine concentration in dried blood spots is due to the way the blood spot calibrators are prepared, a minimum set of prerequisites for the preparation of blood spot calibrators was established by a group of scientific experts and manufacturers. A "European working standard for phenylalanine in blood spots" (EWS-Phe-01) was prepared and distributed to manufacturers taking part in this project. RESULTS: The control of the homogeneity, linearity, and stability of the EWS-Phe-01 batch gave results within expected ranges. The preliminary results of the recalibration of calibrators for phenylalanine against EWS-Phe-01 by the participating manufacturers were promising; the differences between measurements were much decreased. CONCLUSION: Manufacturers have agreed to use EWS-Phe-01, and since November 1996 EWS-Phe calibrators have been routinely available from these companies. This pilot study may act as a model for minimising discrepancies found in other screening tests.

The need for standardized bloodspot TSH-calibrators in congenital hypothyroidism screening.

INTRODUCTION: The preparation of bloodspot calibrators and quality control samples for neonatal thyrotropin (TSH), as part of the national quality assessment scheme in The Netherlands, is sometimes problematic. Often, the recovery of the added TSH is well above 100% when measured in plasma. Results from other External Quality Assessment Schemes for neonatal TSH show similar problems. METHODS AND RESULTS: A questionnaire was sent to 17 kit manufacturers and organizers of EQAS concerning the preparation of bloodspot calibrators for TSH; 13 completed questionnaires were returned. There are large differences with respect to type of filterpaper, matrix, assessment of TSH-concentrations to the calibrators, size of the bloodspots, shelf life, etc. DISCUSSION: Attention is focused on several items to be considered when attempting standardization of the preparation of TSH bloodspot calibrators.