Cardiovascular diseases in grandparents and the risk of congenital heart diseases in grandchildren.

Hyperglycemia, dyslipidemia and hyperhomocysteinemia are associated with both adult cardiovascular disease (CVD) and having a child with a congenital heart disease (CHD). We investigated associations between CVD in grandparents and the risk of CHD in grandchildren. In a case-control family study, we obtained detailed questionnaire information on CVD and CHD in 247 families with a CHD child and 203 families without a CHD child. Grandparents with CVD or intermittent claudication (IC) were significantly associated with an increased risk for CHD in grandchildren [OR 1.39 (95% CI 1.03-1.89) and OR 2.77 (95% CI 1.02-7.56), respectively]. The risk of CHD grandchildren was particularly increased in paternal grandfathers with CVD [OR 1.85 (95% CI 1.01-3.37)]. Overall, having a grandparent with CVD increased the risk for CHD in the grandchild by 1.65 (95% CI 1.12-2.41). After adjustment for potential maternal confounders, this risk was 1.44 (95% CI 0.94-2.21). Having two or more grandparents with CVD was associated with an approximately threefold risk for CHD grandchildren [OR adjusted 2.72 (95% CI 1.08-6.89)]. Our data suggest that CVD and IC in grandparents are associated with an increased risk of having a CHD grandchild. These first findings may be explained by shared causality of derangements in metabolic pathways and are in line with the fetal origins of health and disease.

A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring.

OBJECTIVE: To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. DESIGN: Case-control study. SETTING: Western part of the Netherlands, 2003-08. POPULATION: One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. METHODS: Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. MAIN OUTCOME MEASURES: Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. RESULTS: The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (ß = 0.92, P < 0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (ß = 0.44, P < 0.001) and inversely with SAH (ß =-0.08, P < 0.001). Strong adherence to this dietary pattern resulted in higher serum (P <0.05) and red blood cell (P < 0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2-0.6). CONCLUSIONS: The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial.

Sperm DNA integrity in cancer patients before and after cytotoxic treatment.

BACKGROUND: We assessed sperm DNA fragmentation index (DFI) in cancer patients before and after treatment to evaluate if sperm DNA integrity is compromised by cancer itself or its treatment. METHODS: In a prospective study, DFI was assessed in 127 patients diagnosed with testicular germ cell tumours (TGCT), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL) and various malignancies. The severity of cancer and tumour markers at diagnosis was recorded. Follow-up DFI after treatment was available in 52 patients who were mostly less severely affected. RESULTS: In patients diagnosed with TGCT, HL and various malignancies, pretreatment DFI levels were not significantly different from that of proven fertile controls, but in patients with NHL an increased DFI was found. An overall significant decrease in post-treatment DFI (13.2% range 5.0-70.5) compared with pretreatment values (17.1% range 5.1-66.6) was found (P = 0.040). In TGCT patients, post-treatment DFI was significantly higher in patients who were treated with radiotherapy (16.9% range 11.5-39.9) compared with that in patients treated with chemotherapy (CT) alone (10.9% range 5.5-39.9) (P = 0.037). In HL patients, the type of treatment or number of CT cycles was not associated with DFI. Overall, post-treatment DFI in cancer patients was not significantly different from that of proven fertile controls. CONCLUSIONS: In this study, the presence of cancer does not seem to negatively affect the sperm DNA integrity in TGCT and HL patients; only NHL patients showed increased DFI at the time of diagnosis compared with healthy controls. Our results confirm previous reports that DFI decreases significantly following various anti-cancer treatments. In contrast, radiotherapy in TGCT patients is associated with an increase in DFI compared with CT treatment alone.

The predictive value of testicular ultrasound abnormalities for carcinoma in situ of the testis in men at risk for testicular cancer.

Testicular microlithiasis (TM) is sometimes observed during scrotal ultrasound examinations in men. It has been suggested that TM is more prevalent in testes of men at risk for testicular carcinoma in situ (CIS), the precursor cells of all testicular germ cell tumours (TGCT). We have performed a retrospective analysis of ultrasound images and additional clinical data of a selected cohort of men and have determined the risk factor of TM and other ultrasound abnormalities for testicular CIS. Between 2002 and 2007, 176 testicular biopsies were performed in men with abnormalities found on the scrotal ultrasound. TM was found in 76/176 men (43.2%) and CIS was diagnosed in 20 of these men (26.3%). Here, we focused on the group of 76 men with TM to determine additional risk factors, besides TM, for CIS. In both groups, those with and without CIS, reproductive hormones, scrotal ultrasound images and patient history were compared. Predictive ultrasound findings for CIS were TM (sensitivity 100%, 95% CI: 0.8-1.0; specificity 64.1%, 95% CI: 0.6-0.7; PPV 26.3%, 95% CI: 0.2-0.4) and within this group an inhomogeneous testicular parenchyma (OR 16.1, 95% CI 2.4-106.8; sensitivity 75.0%, 95% CI: 0.5-0.9; specificity 79.0%, 95% CI: 0.7-0.9; PPV 50.0%, 95% CI: 0.3-0.7). Other significantly ultrasound characteristics for CIS in this population with TM were clusters of TM (p = 0.02) and intra-testicular lesions (p = 0.01). Men with CIS were found to have significantly lower values of inhibin-B (p = 0.02). Clusters of TM, intra-testicular lesions and lower values of inhibin-B were not significantly different in logistic regression analysis. TM on scrotal ultrasound of men with risk factors for TGCT and men with clinical signs of testicular maldevelopment has a high predictive value for CIS. However, the predictive value of an inhomogeneous testicular parenchyma, besides TM, for CIS is much higher.

High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring.

OBJECTIVE: To study associations between maternal dietary and supplement intake of antioxidants vitamin E, retinol and congenital heart defects (CHDs). DESIGN: Case-control study. SETTING: Erasmus MC, University Medical Center Rotterdam, the Netherlands. POPULATION: Participants were 276 case mothers of a child with CHD and 324 control mothers with their children. METHODS: Food frequency questionnaires covering the intake of the previous 4 weeks were filled out at 16 months after the index pregnancy. Data were compared between cases and controls using the Mann-Whitney U test. Risk estimates for the association between CHD and dietary intake of vitamin E and retinol were estimated in a multivariable logistic regression model. MAIN OUTCOME MEASURES: Medians (5-95th percentile) and odds ratios with 95% CI. RESULTS: Dietary vitamin E intake was higher in case mothers than in controls, 13.3 (8.1-20.4) and 12.6 (8.5-19.8) mg/day (P= 0.05). CHD risk increased with rising dietary vitamin E intakes (P-trend = 0.01). Periconception use of vitamin E supplements in addition to a high dietary vitamin E intake above 14.9 mg/day up to nine-fold increased CHD risk. Retinol intakes were not significantly different between the groups and not associated with CHD risk. CONCLUSIONS: High maternal vitamin E by diet and supplements is associated with an increased risk of CHD offspring.

Clinical correlates of the biological variation of sperm DNA fragmentation in infertile men attending an andrology outpatient clinic.

Determination of sperm DNA fragmentation, as assessed by the sperm chromatin structure assay (SCSA), has become an important tool for the evaluation of semen quality. The aim of the present study was to describe the biological variation of sperm DNA fragmentation in men attending an andrology clinic and to identify clinical correlates of the biological variation of sperm DNA fragmentation. For this study, two consecutive semen samples from 100 patients attending our andrology outpatient clinic were subjected to semen analysis, performed in parallel according to WHO guidelines and by SCSA. A good agreement between pairs of samples was found for SCSA-derived variables, as indicated by a significantly lower median coefficient of variation (CV) of the DNA Fragmentation Index (DFI) and the high DNA stainability (HDS) compared with WHO semen parameters. In half of the men attending our andrology clinic, however, the individual biological variation of DFI and HDS, expressed as CV of two samples, exceeded 10%. Dysregulation of spermatogenesis, as seen as testicular insufficiency or varicocele, was not associated with increased variability of DFI or HDS. A backward multiple linear regression analysis, however, indicated that the biological variation of DFI may be more profound in men with characteristics of normal spermatogenesis. In conclusion, we confirm previous reports that sperm DNA fragmentation has a lower biological variability than classical semen parameters. We hypothesize that the sperm chromatin structure may be more influenced in patients with normal spermatogenesis, whereas in men with disturbed spermatogenesis, the chromatin structure may be already so impaired that the effect of unidentified factors leading to variability of sperm DNA fragmentation in time may not be as profound.

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval.

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels. To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area. At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer. Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores. Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.

The value of (-7, -5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer.

OBJECTIVE: To assess the value of the precursor form (-7,5pro) of prostate-specific antigen (PSA) and human kallikrein-2 (hK2) for detecting and grading prostate cancer, as better serum markers with improved specificity are needed in men with lower ranges of total (t)PSA. PATIENTS AND METHODS: tPSA, free PSA (fPSA), the precursor (-7,5)proPSA and hK2 were measured in a subset of participants of the European Randomised Study of Screening of Prostate Cancer. In a pilot study, sera from 143 men biopsied but with no prostate cancer, 142 with BPH, and 146 with prostate cancer were analysed to determine the relative value of serum markers for differentiating between the groups. Then, in 141 men with prostate cancer who had a radical prostatectomy, these serum markers were related to the pathological grading to analyse their value as prognostic variables. RESULTS: Levels of (-7,5)proPSA, hK2 and fPSA could be used to distinguish between BPH and cancer, but proPSA and hK2, alone or combined, did not improve the specificity of fPSA for discriminating BPH and cancer. There was also no correlation between these serum markers and pathological tumour grade. CONCLUSION: The clinical effect of using (-7,5)proPSA or hK2 for detecting and grading prostate cancer remains limited.

Consistency of prostate cancer grading results in screened populations across Europe.

OBJECTIVE: To assess the consistency of grading outcome among seven of eight participating centres of the European Randomised Screening Program of Prostate Cancer (ERSPC), a multicentre randomized trial intended to detect a difference in prostate cancer-related mortality between screened participants and a control group. Currently, tumour stage and grade in prostatectomy specimens represent the most predictive variables for biological behaviour. In prostate needle biopsies the tumour grade is a strong factor for deciding therapy. PATIENTS AND METHODS: Within the ERSPC all prostate cancers detected in needle biopsies were graded according to the Gleason score system. Gleason scores were compressed in three categories of < or = 6, 7 and 8-10. Data for grading outcome were obtained from the databases from seven individual centres; in one centre the slide sets with cancer were separately reviewed. RESULTS: Combining the data of seven ERSPC centres 66% of cancers detected in the screening arm were Gleason score < or = 6 and 92% were < or = 7. Gleason score 8-10 cancers varied from 2 to 11%. This variation in Gleason scores may be attributed to differences in the population characteristics and biopsy indications. CONCLUSIONS: These data indicate that in the seven ERSPC centres most screen-detected cancers have favourable characteristics on biopsy. Men with these cancers are amenable for treatment with curative intent. The observed differences in Gleason score distribution in different centres may partly be attributed to geographical differences and differences in the age range of the screened populations.

Different PSA assays lead to detection of prostate cancers with identical histological features.

OBJECTIVE: Because different PSA assays still show a wide inter-assay variation, we wondered what influence these discrepancies could have on the individual tumour characteristics of the cancers that each of these assays detect in a critical low PSA range. We analysed five different PSA assays in a biopsy simulation with PSA cut-offs of 3.0 and 4.0 ng/ml. MATERIALS AND METHODS: Randomly taken samples of 360 men with prostate cancer and 96 with benign prostatic disease from a screened population with PSA range of 1.0-6.0 ng/ml (Tandem-E) were investigated. In all cases the diagnosis was confirmed by sextant biopsies. One hundred and thirty-seven men (38%) underwent radical prostatectomy. Variability amongst assays was illustrated in terms of missed cancers and unnecessary biopsies, and in terms of pathologic features of detected cancers at both PSA cut-offs. RESULTS: Compared to Tandem-E, all assays, except Access, showed significant differences in PSA measurements. Furthermore, none of the assays discriminated significantly between benign and malignant prostatic disease (p>0.05). Tandem-E and Elecsys lead significantly more frequently to the detection of cancers at the cost of more unnecessary biopsies compared to the other assays. Yet, at both PSA cut-offs the proportion of cancers with a certain pathologic grade or stage that were detected by each assay were approximately the same. CONCLUSIONS: Our study shows that the use of different PSA assays only have consequences for the number, and not for the tumour characteristics of the prostate cancers that are detected. Thus, different PSA assays detect prostate cancers with the same tumour features.

Discordant performance of assays for free and total prostate-specific antigen in relation to the early detection of prostate cancer.

OBJECTIVE: To assess the value of applying rigid threshold values in interpreting prostate specific antigen (PSA) results, by selecting and comparing five current methods for measuring free and total PSA. MATERIALS AND METHODS: Samples taken from an ongoing screening study for prostate cancer (total PSA by Tandem-E assay, 17 334 participants; biopsy criterion a PSA of 3.0 microg/L, 4 464 men) from men with a total PSA of 1.0-6.0 microg/L were measured for free and total PSA using the Access, Immulite, Elecsys and Prostatus analysis kits, in two patient groups, i.e. with prostate cancer or no evidence of disease. RESULTS: Both patient groups had equal means for total PSA but not for free PSA. In all, 360 samples from men with cancer and 96 from men with no evidence of disease were analysed. All methods applied to both groups deviated statistically significantly from the Tandem-E result for total PSA, except for the Access kit. There was a close correlation among all the methods (correlation coefficients of 0.89-0.97). There were very discordant results for the combination of the Tandem-E vs Prostatus (8% difference), representing 315 participants at a threshold of 3.0 microg/L. For free PSA (free/total PSA) the situation was worse, with extreme differences of 32% and 36% for both patient groups (Elecsys vs Access). CONCLUSIONS: Depending on the threshold value applied as an indication for biopsy, when using the total PSA alone or combined with the free/total PSA, care is needed in interpreting patient groups because of the discordance among PSA assays.

Molecular cytogenetic analysis of prostatic adenocarcinomas from screening studies : early cancers may contain aggressive genetic features.

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Prognostic value of cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer.

PURPOSE: Molecular tissue markers may give the clinician additional information about patients with prostate cancer at risk for treatment failure after retropubic radical prostatectomy. We substantiate the prognostic value of 3 tissue markers, the cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s, in addition to more conventional pathological prognosticators in an historical (before prostate specific antigen) cohort of patients with prostate cancer. MATERIALS AND METHODS: Representative tumor sections from 92 patients who underwent retropubic radical prostatectomy were immunohistochemically stained with antibodies against p27(kip1), MIB-1 (Ki-67) and CD44s, and assessed in a semiquantitative manner. Gleason score and pathological tumor stage were recorded. All variables were correlated with clinical progression and disease specific survival on univariate and multivariate analyses. RESULTS: On univariate analysis low (less than 50%) p27(kip1), high (10% or greater) MIB-1 and loss of CD44s expression were significantly associated with clinical outcome parameters, although MIB-1 did not reach statistical significance for disease specific survival. All 3 molecules were highly correlated with Gleason score and pathological tumor stage. Multivariate analysis showed that low p27kip1 was independent of grade and stage in predicting clinical recurrence (p <0.001) and disease specific survival (p = 0.045), while loss of CD44s was an additional independent prognostic factor for clinical recurrence (p = 0.02). CONCLUSIONS: Reduced p27(kip1) expression is an independent predictor of poor outcome in prostate cancer, while MIB-1 is not. Decreased expression of CD44s yields additional information in predicting clinical recurrence. These tissue markers may identify patients at risk for disease recurrence after retropubic radical prostatectomy who may benefit from adjuvant therapy.

Efficacy of cascade testing for fragile X syndrome.

OBJECTIVE: Fragile X syndrome is the most common cause of mental retardation from a single gene defect, transmitted in an X-linked semidominant fashion. Cloning of the gene responsible for fragile X syndrome has made it possible to identify carriers who are at risk of giving birth to a child with fragile X syndrome. One of the proposed strategies for identifying carriers is cascade testing, in which relatives of a patient with fragile X syndrome (the index case) are tested. Because the effectiveness of this type of testing is unknown, the objective of this study was to develop a simulation model for studying the consequences of cascade testing for fragile X syndrome. METHODS: With this model, 100,000 five-generation pedigrees were simulated to assess the maximum number of carriers that would be detected for three scenarios: (a) only first degree relatives of the index case are tested; (b) relatives up to the third degree are tested; (c) relatives up to the fifth degree are tested. RESULTS: In the start-up phase of the testing programme, 18% of couples who will have a fragile X syndrome child are detected. After this phase the (stabilised) cascade testing programme detects 7% of undetected couples who would have a fragile X syndrome child if only first degree relatives were tested, 12% if first to third degree relatives were tested, and 15% if first to fifth degree relatives were tested. To detect 90% of all premutation and full mutation carriers at least eight consecutive generations need to be tested. CONCLUSIONS: The results of our analysis show that cascade testing is not very effective in detecting carriers.

Preconceptional screening of couples for carriers of cystic fibrosis: a prospective evaluation of effects, costs and savings for different mutation detection methods.

OBJECTIVE: The aim of this study was to perform a prospective evaluation of the effects, costs and savings of a preconceptional screening programme of couples for carriers of cystic fibrosis (CF). METHODS: A decision model for both single-entry two-step (SETS) and double-entry two-step (DETS) couple screening was constructed. Two mutation detection methods were considered: allele-specific oligonucleotide (ASO) hybridisation screening of 32 mutations, with a sensitivity of 90%, and denaturing gradient gel electrophoresis (DGGE), with a sensitivity of 98%. In our model, the following combinations were used: (1) ASO for both steps; (2) DGGE for both steps, and (3) ASO for the first step and DGGE for the second step. The model is demonstrated using figures from the Netherlands, where there is a carrier frequency of 1:30. We estimated the value of different choices and probabilities in a decision tree and determined the costs of screening for CF and the costs of the illness itself. RESULTS: We found that with most of the combinations of mutation detection methods, SETS couple screening could offer positive net savings in the Netherlands. The ASO/DGGE combination resulted in the highest net savings. DETS couple screening for all combinations, including testing with DGGE in both steps, did not show a positive cost-savings balance at all, not even with an uptake rate of 100%. The maximum number of carrier couples identified when screening 100,000 couples with the ASO/DGGE combination was 98 (SETS). This could result in about 25 fewer children born with CF each year in the Netherlands, under the following assumptions: (1) each couple has two children and 10% of couples are unable to have children; (2) of detected carrier couples, 15% decide not to have children and 85% make use of prenatal diagnosis; (3) of those fetuses diagnosed with CF, 80% are aborted, and (4) prenatal diagnosis carries a 0.75% risk of iatrogenic abortion. CONCLUSIONS: The results of this evaluation show that there are no financial objections to the preconceptional screening of couples in the Netherlands when the above-mentioned assumptions apply; thus, further evaluation can concentrate on the balance of the non-economic consequences of screening for participants and for society.

Costs, effects, and savings of screening for cystic fibrosis gene carriers.

STUDY OBJECTIVE: Evaluating the costs, effects, and savings of several strategies for cystic fibrosis (CF) gene carrier screening. DESIGN: A general model for evaluating prenatal, preconceptional, school, and neonatal carrier screening was constructed. For prenatal and preconceptional screening, two strategies were evaluated: single entry and double entry two step couple screening. Firstly, the Dutch situation was evaluated prospectively; subsequently the results were generalised to other carrier frequencies. SETTING: Prospective simulation model. MAIN RESULTS: Of all screening strategies, neonatal carrier screening gives most carrier couples an informed choice concerning reproduction. If the parents of carrier newborns would not be tested however, prenatal screening detects most carrier couples. Prenatal and single entry preconceptional screening programmes have a favourable cost-savings balance in the Netherlands under a wide range of assumptions. For double entry preconceptional screening and neonatal screening, high enough values of uptake of screening, prenatal diagnosis, and induced abortion are necessary. School carrier screening does not have a favourable cost-savings balance. CONCLUSIONS: If a CF screening programme is judged to be useful on individual and social grounds, costs considerations are no obstacle for prenatal and single entry preconceptional screening.

[Preconception screening of parents and carrier state of cystic fibrosis in the Netherlands: expenses and savings]. / Preconceptionele screening van paren op dragerschap van cystische fibrose in Nederland: kosten en besparingen.

OBJECTIVE: To evaluate effects, costs and savings for a preconceptional couple screening programme for cystic fibrosis (CF) carriers. SETTING: State University Groningen, the Netherlands. DESIGN: Prospective theoretical evaluation. METHOD: A decision tree and an arithmetic model were constructed for two different strategies of preconceptional CF screening of couples: 'single entry two step' (SETS; start by testing one partner), and 'double entry two step' (DETS; test both partners). The difference between costs of screening and costs of CF illness prevented by screening was determined. RESULTS: DETS couple screening with the assumptions used for e.g. sensitivity and use of options can detect 81.5% of carrier couples in the Netherlands (against 70% for SETS), but results in twice as many positive/negative couples as SETS couple screening. The maximum number of carrier couples identified when screening 100,000 couples would be 88, resulting in a decrease of the number of children with CF of 25 each year. The costs of screening equal the savings if approximately 8,000 couples are screened yearly in the Netherlands. CONCLUSIONS: There are no financial objections to preconceptional couple screening in the Netherlands, even with an uptake ratio of around 10%. Whether screening for CF carriers should be offered or not should be decided on the basis of non-financial arguments.