The multidimensional value of natriuretic peptides in heart failure, integrating laboratory and clinical aspects.

Natriuretic peptides (NP) play an essential role in heart failure (HF) regulation, and their measurement has improved diagnostic and prognostic accuracy. Clinical symptoms and objective measurements, such as NP levels, should be included in the HF definition to render it more reliable and consistent among observers, hospitals, and healthcare systems. BNP and NT-proBNP are reasonable surrogates for cardiac disease, and their measurement is critical to early diagnosis and risk stratification of HF patients. NPs should be measured in all patients presenting with dyspnea or other symptoms suggestive of HF to facilitate early diagnosis and risk stratification. Both BNP and NT-proBNP are currently used for guided HF management and display comparable diagnostic and prognostic accuracy. Standardized cutoffs for each NP assay are essential for data comparison. The value of NP testing is recognized at various levels, including patient empowerment and education, analytical and operational issues, clinical HF management, and cost-effectiveness.

How Well Do Laboratories Adhere to Recommended Guidelines for Cardiac Biomarkers Management in Europe? The CArdiac MARker Guideline Uptake in Europe (CAMARGUE) Study of the European Federation of Laboratory Medicine Task Group on Cardiac Markers.

BACKGROUND: The CARdiac MARker Guideline Uptake in Europe (CAMARGUE) program is a multi-country audit of the use of cardiac biomarkers in routine clinical practice. METHODS: An email link to a web-based questionnaire of 30 multiple-choice questions was distributed via the professional societies in Europe. RESULTS: 374 questionnaires were returned from 39 countries, the majority of which were in northern Europe with a response rate of 8.2%-42.0%. The majority of the respondents were from hospitals with proportionately more responses from central hospitals than district hospitals. Cardiac troponin was the preferred cardiac biomarker, evenly split between cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Aspartate transaminase and lactate dehydrogenase are no longer offered as cardiac biomarkers. Creatine kinase, creatine kinase MB isoenzyme, and myoglobin continue to be offered as part of the cardiac biomarker profile in approximately on 50% of respondents. There is widespread utilization of high sensitivity (hs) troponin assays. The majority of cTnT users measure hs-cTnT. 29.5% of laboratories measure cTnI by a non-hs method but there has been substantial conversion to hs-cTnI. The majority of respondents used ng/L and use the 99th percentile as the upper reference limit (71.9% of respondents). A range of diagnostic protocols are in use. CONCLUSIONS: There is widespread utilization of hs troponin methods. A significant minority do not use the 99th percentile as recommended and there is, as yet, little uptake of very rapid diagnostic strategies. Education of laboratory professionals and clinicians remains a priority.

Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.

How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE).

BACKGROUND: We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS: In 2013-2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS: In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS: There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA).

First-trimester maternal serum ADAM12-s and PAPP-A levels are altered in pregnancies conceived after assisted reproduction techniques (ART).

OBJECTIVE: The objective of this article is to estimate whether the maternal serum levels of A disintegrin and metalloprotease domain 12 (ADAM12-s), pregnancy-associated plasma protein-A (PAPP-A), and free beta human chorionic gonadotrophin (fß-hCG) are altered in assisted reproduction techniques (ART) pregnancies. METHOD: A retrospective cohort study with a control group was performed. Two hundred eighty-three ART pregnancies and 1008 controls were studied. The patients were divided into groups according to the type of conception: (1) controls, (2) fresh embryo transfer (ET) following controlled ovarian stimulation (COH) and in vitro fertilization (IVF), (3) fresh ET following COH and intracytoplasmic sperm injection (ICSI), (4) frozen ET during natural menstrual cycle (NC-FET), and (5) frozen ET using hormone replacement therapy. The cases and controls were matched for gestational and maternal age and for the storage time of the samples. RESULTS: The ADAM12-s levels were statistically significantly higher in the entire ART group, IVF and ICSI groups, and NC-FET group when compared with those in the controls. The PAPP-A levels were decreased only in the ICSI group compared with those in the controls. fß-hCG levels were not altered in assisted pregnancies. The ADAM12-s levels tended to increase with advanced gestational age. ADAM12-s levels were correlated with PAPP-A and fß-hCG levels in several subgroups of ART pregnancies. CONCLUSION: ADAM12-s and PAPP-A levels are altered in several subgroups of ART pregnancies. Larger studies are required to confirm these findings.

Extension of dynamic range of sensitive nanoparticle-based immunoassays.

Nanoparticles have successfully been employed in immunometric assays that require high sensitivity. Certain analytes, however, require dynamic ranges (DRs) around a predetermined cut-off value. Here, we have studied the effects that antibody orientation and addition of free solid-phase and detection antibodies have on assay sensitivity and DR in traditional sandwich-type immunoassays. D-dimer and cardiac troponin I (cTnI), both routinely used in critical care testing, were applied as model analytes. The assays were performed in microtitration wells with preimmobilized solid-phase antibody. Inherently fluorescent nanoparticles coated with second antibody were used to detect the analyte. The selection of antibody orientation and addition of free solid-phase or detection antibody, with nanoparticles and calibrator, desensitized the assays and extended the DR. With D-dimer the upper limit of the DR was improved from 50 to 10,000 ng/ml, and with cTnI from 25 to 1000 ng/ml. Regression analysis with the Stago STA Liatest D-dimer assay yielded a slope (95% confidence interval) of 0.09 (0.07-0.11) and a y-intercept of -7.79 (-17.87-2.29)ng/L (n=65, r=0.906). Thus it is concluded that Europium(III)-chelate-doped nanoparticles can also be employed in immunoassays that require wide DRs around a certain cut-off limit.

Novel sensitive cardiac troponin I immunoassay free from troponin I-specific autoantibody interference.

BACKGROUND: Cardiac troponins (cTnI and cTnT) are the recommended biomarkers of myocardial infarction. As cTn-specific autoantibodies (cTnAAb) can interfere with the cTn detection by state-of-the-art cTnI assays, our objective was to develop a sensitive cTnI immunoassay free from this analytical interference. METHODS: The assay used antibody-coated spots containing three capture Mabs/Fabs directed against the N-terminus, midfragment and C-terminus of cTnI and a europium chelate-labeled tracer Mab against the C-terminus. Following a 3-h sample incubation and washing, cTnI was quantified by time-resolved fluorometry. RESULTS: The limit of detection (LoD) was 2.9 ng/L and the assay was linear up to 50,000 ng/L. The total precision of 10% CV was not reached, but 20% CV was reached at 10 ng/L. Mean cTnI (10-50,000 ng/L) recoveries were 100% and 119% in three cTnAAb-positive and two cTnAAb-negative individuals, respectively, verifying the interference resistance of the antibody design used. On average, Architect hs-cTnI assay gave seven-fold higher cTnI concentrations than the new assay but the correlation between the assays was good (r=0.958). Of apparently healthy individuals (n=159), 18% had measurable cTnI values (>LoD) and 10% were cTnAAb-positive. The proportion of measurable cTnI values, however, was significantly higher in cTnAAb-positive individuals (13/16, median cTnI 8.5 ng/L) than in cTnAAb-negative individuals (15/143, median cTnI

Implementation of high sensitivity troponin into routine clinical practice - results of the extended CARdiac MArkers guideline uptake in Europe group (CARMAGUE) survey.

BACKGROUND: Measurement of cardiac troponin (cTn) by a high sensitivity method is now the recommended strategy for the detection of myocardial injury. An international survey was undertaken to assess how this has been implemented. METHODS: A questionnaire based around 14 domains on cardiac biomarkers was distributed electronically with the aid of professional societies accessed by a web link within the invitation. Results were returned electronically then extracted into a relational database for analysis. RESULTS: Responses were obtained from 663 laboratories across 76 countries ranging from 1 to 69 largest country. The majority of responses (79.6%) came from the European area. Responses were grouped into broad geographic areas for analysis. Most responses came from hospitals providing a local and regional service of which the majority provided angioplasty. cTn measurement was the dominant biomarker. The majority of laboratories include creatine kinase (CK) in their cardiac profile and approximately 50% also offer the MB isoenzyme of CK. The majority of laboratories (91.9%) measure cTn by a high sensitivity method. Sex specific reference ranges were typically implemented for cardiac troponin I but not for cardiac troponin T. The preferred unit of measurement was nanograms/L. A structured decision-making pathway utilising high sensitivity cTn measurement was used by 83.3% of laboratories who responded. Single sample rule out is common but the majority used serial sampling strategy based on measurement on admission and three hours. CONCLUSIONS: Measurement of cTn by a high sensitivity method is now well established internationally, the use of rapid diagnostic protocols lags behind.

Do laboratories follow heart failure recommendations and guidelines and did we improve? The CARdiac MArker Guideline Uptake in Europe (CARMAGUE).

BACKGROUND: Natriuretic peptides (NP) are well-established markers of heart failure (HF). During the past 5 years, analytical and clinical recommendations for measurement of these biomarkers have been published in guidelines. The aim of this follow-up survey was to investigate how well these guidelines for measurement of NP have been implemented in laboratory practice in Europe. METHODS: Member societies of the European Federation of Clinical Chemistry and Laboratory Medicine were invited in 2009 to participate in a web-based audit questionnaire. The questionnaire requested information on type of tests performed, decision limits for HF, turn-around time and frequency of testing. RESULTS: There was a moderate increase (12%) of laboratories measuring NP compared to the initial survey in 2006. The most frequently used HF decision limits for B-type NP (BNP) and N-terminal BNP (NT-proBNP) were, respectively, 100 ng/L and 125 ng/L, derived from the package inserts in 55%. Fifty laboratories used a second decision limit. Age or gender dependent decision limits were applied in 10% (8.5% in 2006). The vast majority of laboratories (80%) did not have any criteria regarding frequency of testing, compared to 33% in 2006. CONCLUSIONS: The implementation of NP measurement for HF management was a slow process between 2006 and 2009 at a time when guidelines had just been established. The decision limits were derived from package insert information and literature. There was great uncertainty concerning frequency of testing which may reflect the debate about the biological variability which was not published for most of the assays in 2009.

Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation.

BACKGROUND: Correct information provided by guidelines may reduce laboratory test related errors during the pre-analytical, analytical and post-analytical phase and increase the quality of laboratory results. METHODS: Twelve clinical practice guidelines were reviewed regarding inclusion of important laboratory investigations. Based on the results and the authors' experience, two checklists were developed: one comprehensive list including topics that authors of guidelines may consider and one consisting of minimal standards that should be covered for all laboratory tests recommended in clinical practice guidelines. The number of topics addressed by the guidelines was related to involvement of laboratory medicine specialists in the guideline development process. RESULTS: The comprehensive list suggests 33 pre- analytical, 37 analytical and 10 post-analytical items. The mean percentage of topics dealt with by the guidelines was 33% (median 30%, range 17%-55%) and inclusion of a laboratory medicine specialist in the guideline committee significantly increased the number of topics addressed. Information about patient status, biological and analytical interferences and sample handling were scarce in most guidelines even if the inclusion of a laboratory medicine specialist in the development process seemingly led to increased focus on, e.g., sample type, sample handling and analytical variation. Examples underlining the importance of including laboratory items are given. CONCLUSIONS: Inclusion of laboratory medicine specialist in the guideline development process may increase the focus on important laboratory related items even if this information is usually limited. Two checklists are suggested to help guideline developers to cover all important topics related to laboratory testing.

Four automated 25-OH total vitamin D immunoassays and commercial liquid chromatography tandem-mass spectrometry in Finnish population.

BACKGROUND: Comparing four fully automated 25-OH-D immunoassays to a commercially available liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with human serum samples from Finnish population. METHODS: 400 samples were analyzed with the Liaison Total Vitamin D, the IDS-iSYS 25-Hydroxy Vitamin D, the ARCHITECT 25-OH Vitamin D, the ADVIA Centaur Vitamin D Total, and a commercially available LC-MS/MS 25-OH D (PerkinElmer) method. RESULTS: The Liaison method mean value (95% confidence intervals) was 65.6 nmol/L (62.6 - 68.6); the IDS-iSYS mean was 70.3 nmol/L (67.4 - 73.1); the ARCHITECT mean was 69.0 nmol/L (65.5 - 72.5); ADVIA Centaur mean was 71.6 nmol/L (68.9 - 74.3), and the LC-MS/MS mean was 82.8 nmol/L (79.4 - 86.2). The regression coefficients (r) between the LC-MS/MS and immunoassays were 0.650 for Liaison, 0.757 for IDS-iSYS, 0.721 for ARCHITECT and 0.684 for ADVIA Centaur. With the Passing-Bablok analysis, none of the immunoassays gave results equivalent to LC-MS/MS. Two of the four automated 25-OH-vitamin D assays (IDS-iSYS, ADVIA Centaur) were overall in good clinical agreement with LC-MS/MS, even though the results obtained with all compared methods were not equivalent. CONCLUSIONS: In conclusion, in routine clinical laboratory both immunoassays and LC-MS/MS are useful for measuring 25-OH-vitamin D provided that these methods are correctly standardized and especially sample pretreatment is carefully performed.

Comparison of combined, biochemical and nuchal translucency screening for Down syndrome in first trimester in Northern Finland.

OBJECTIVE: To compare the efficacy of fetal nuchal translucency screening, maternal serum screening and combined screening for Down syndrome. DESIGN: A prospective study. SETTING: University hospital and its public health care district in Northern Finland. POPULATION: A total of 35,314 women participated in the first-trimester screening for Down syndrome within the public healthcare system in 2002-08. There were 95 pregnancies involving Down syndrome. Serum samples were obtained from 35,314 women, nuchal translucency was measured in 27,144 pregnancies and full combined screening was performed in those pregnancies, including 76 involving Down syndrome. METHODS: The adjusted estimated risk for Down syndrome was calculated using the Perkin Elmer AutoDELFIA® time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free ß-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel in a university or district hospital. Risk cut-off figures 1:250 and 1:300 at term were used. MAIN OUTCOME MEASURES: Differences in detection rate, false-positive rate, positive and negative predictive values between nuchal translucency screening, serum screening and combined screening. RESULTS: Using the risk cut-off figure 1:250, the detection rates for serum screening, nuchal translucency screening and combined screening were 64.2, 64.5 and 72.4%, respectively and the false-positive rates were 7.8, 4.4 and 4.0%, respectively. CONCLUSIONS: Combined screening is the method of choice for Down syndrome screening in Finland.

Effect of parity and fetal sex on placental and luteal hormones during early first trimester.

OBJECTIVE: Earlier studies have shown that maternal hormone secretion during late first or second trimester may be affected by gravidity. We examined the luteoplacental hormone secretion during 5-11 weeks of gestation in relation to gravidity. METHOD: Forty-one naturally conceived pregnancies underwent weekly assessment of serum human chorionic gonadotrophin, progesterone and 17-OH progesterone, estradiol, testosterone, and pregnancy-associated plasma protein A levels. In addition, the volume and the vasculature of the dominant ovary with corpus luteum were assessed with the use of a 3-dimensional power Doppler ultrasonography. Areas under the curve for hormonal and ultrasonographic parameters were calculated. RESULTS: Twenty-two out of the 41 women were pregnant for the first time. All the pregnancies were uncomplicated and resulted in term deliveries of appropriately grown newborns. During pregnancy weeks 5-11, the secretion (area under the curve) of human chorionic gonadotrophin (6.54 ± 0.03 vs 6.39 ± 0.05, p = 0.010), progesterone (3.49 ± 0.02 vs 3.36 ± 0.03, p = 0.003), and 17-OH progesterone (2.73 ± 0.03 vs 2.62 ± 0.03, p = 0.013) were higher in primigravid than in multigravid women. No other differences were detected between primigravid and multigravid women. CONCLUSION: The placental function already differs between primigravid and multigravid women during the first weeks of pregnancy, which reflects the corpus luteal function.

Comparison of automated 25-OH vitamin D immunoassays with liquid chromatography isotope dilution tandem mass spectrometry.

BACKGROUND: Comparing two fully automated 25-OH-D immunoassays with a validated liquid chromatography isotope dilution tandem mass spectrometry (LC-IDMS/MS) method in human serum samples. METHODS: 180 samples were analyzed with the Liaison TOTAL Vitamin D, the IDS-iSYS 25-Hydroxy Vitamin D, and a validated LC-IDMS/MS 25-OH D method. RESULTS: The Liaison method mean +/- standard deviation (SD) was 64.3 +/- 23.5 nmol/L; the IDS-iSYS 70.1 +/- 27.0 nmol/L, and the LC-IDMS/MS 68.9 +/- 24.6 nmol/L. The correlation coefficient (r) between the Liaison and LC-IDMS/MS was 0.723, and the r between the IDS-iSYS and LC-IDMS/MS was 0.799. When the samples were grouped by females and males, the r between the Liaison and LC-IDMS/MS was 0.680 and 0.846, being 0.781 and 0.863 between the IDS-iSYS and LC-IDMS/MS, respectively. With the Passing-Bablok analysis, only the IDS-iSYS gave equivalent results to LC-IDMS/MS. CONCLUSIONS: The automated 25-OH-D immunoassays were in clinically good overall agreement with the LC-IDMS/MS method.

Evaluation of IDS-iSYS intact parathyroid hormone (iPTH) and comparison to Siemens Advia Centaur iPTH assay in chronic renal failure patients and in controls.

BACKGROUND: IDS-iSYS intact parathyroid hormone (iPTH) assay was evaluated. Two automated second generation assays for measuring iPTH were also compared to each other. The compared assays detected PTH fragments 1-84 and 5-84. METHODS: The iPTH was analyzed from controls (n = 88) and samples of patients with chronic kidney disease (CKD) (n = 100) on the IDS-iSYS (iSYS) and Siemens ADVIA Centaur (Centaur) immunoanalyzers. RESULTS: In controls, the iSYS method mean value (95% CI ranges) was 37.1 pg/mL (34.3 to 39.9) and the Centaur was 39.3 pg/mL (36.3 to 42.3). The regression coefficient (r) between the iSYS and the Centaur was 0.850 in controls. Correspondingly, in CKD patients the iSYS method mean value (95% CI ranges) was 183.3 pg/mL (154.3 to 212.4) and the Centaur was 199.7 pg/mL (170.4 to 229.0). In CKD patients the regression coefficient (r) between the iSYS and the Centaur was 0.964. With Passing-Bablok analysis, the automated iPTH methods gave clinically similar results in controls and in CKD patients. However, in the difference blots, the iSYS gave lower concentrations when the mean concentration increased. CONCLUSIONS: The IDS-iSYS iPTH assay is precise. The iSYS concentrations of iPTH were clinically similar with those determined by Centaur.

False-negative results in routine combined first-trimester screening for down syndrome in Finland.

We analyzed the frequency and possible causes of false-negative (Fn) screening results in first-trimester combined Down syndrome screening in Finland. During the study period (May 1, 2002, to December 31, 2008), 76,949 voluntary women with singleton pregnancies participated in screening. Maternal age at screening, week of gestation, levels of pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (fß-hCG), and nuchal translucency (NT) measurement were compared and statistically analyzed between true-positive (Tp) and Fn cases. There were a total of 188 Down syndrome cases (1:409) in the screened population; 154 confirmed Tp and 34 Fn cases. Most Fn cases (n = 25) occurred at 12 + 0 to 13 + 6 weeks' gestation and only nine Fn cases presented between 10 and 11 weeks' gestation. According to the logistic regression analysis, the NT measurement was the most powerful discriminating factor in Fn screening results and accounted for 37.2% of Fn results. The second most important factor was fß-hCG, adding 14.0% to R(2), followed by PAPP-A, which contributed a further 14.3%. The chosen parameters explain 83.9% of Fn results, but 16.1% remain due to unknown factor(s). All investigated parameters contributed to Fn screening results, but fetal NT was the most discriminating factor leading to an Fn screening result.

Focusing on the clinical impact of standardization of creatinine measurements: a report by the EFCC Working Group on Creatinine Standardization.

The recent campaign for standardization of creatinine measurements has been promoted to allow the widespread use of formulas for estimating the glomerular filtration rate (GFR). However, studies on trueness verification and measurement interferences still show disappointing interassay variation of serum creatinine results. Creatinine recalibration has major clinical consequences. In particular, in pediatrics where reference ranges for serum and plasma creatinine are low, calculation of the GFR is problematic when based on alkaline picrate methods because of method non-specificity and the lack of appropriate GFR estimating formulas. Therefore, enzymatic creatinine assays are preferred. In the near future, cystatin C might offer an interesting alternative for GFR estimation. For the calculation of drug doses, the Modification of Diet in Renal Disease study formula generally offers reliable data. However, attention has to be paid to the elderly. Also, the calculation of the Model for End-Stage Liver Disease score, which is used to prioritize patients for liver transplantation, may significantly be influenced by recalibration of creatinine assays. Creatinine restandardization may also affect the current guidelines for referral of chronic kidney disease patients to nephrologists.

First trimester biochemistry at different maternal ages.

BACKGROUND: The performance of first trimester biochemical screening was compared at different pregnancy weeks and maternal ages during 2002-2008 in a screened population of 76,949 women. METHODS: The detection rates, as well as the median multiples of a median (MOMs) of free ß-human chorionic gonadotropin (free ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A), were compared between completed gestational weeks 8-13 and between different maternal ages separated into 5-year groupings. RESULTS: The number of singleton Down syndrome pregnancies was 221. The median age of the screened women was 30 years and the proportion of women aged ≥ 35 years 16.9%. The median age of the women with a Down syndrome pregnancy was 37 years. In women aged <35 years, the biochemical markers provided a detection rate of only 38.6%, whereas in women aged ≥ 35 years, the biochemical markers detected 82.7% of cases (p<0.01). CONCLUSIONS: Biochemical screening works best amongst women aged ≥ 35 years. For younger mothers aged <35 years, combined screening should be the method of choice.

Screening and outcome of chromosomal abnormalities other than trisomy 21 in Northern Finland.

OBJECTIVE: To examine the performance of first-trimester combined screening after adding the specific algorithms for trisomies 18 and 13 in the Down syndrome screening program for chromosomal abnormalities other than trisomy 21 and to determine the outcomes of such pregnancies. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. POPULATION: Pregnant women (n=56 076) participating voluntarily in first-trimester combined Down syndrome screening in Northern and Eastern Finland during the study period 1 June 2002 to 31 December 2008. METHODS: The data of all known cases of chromosomal abnormalities other than trisomy 21 were collected. MAIN OUTCOME MEASURES: Risk algorithms for trisomies 21, 18 and 13 were used for the calculation of patient-specific risks for certain chromosomal abnormalities. Algorithms were based on maternal age, crown-rump length, nuchal translucency, and measurement of free ß-human chorionic gonadotrophin and pregnancy-associated plasma protein-A. Detection rates and false-positive rates were calculated. RESULTS: A total of 27 cases of trisomy 18, 11 cases of trisomy 13 and 30 cases of other chromosomal abnormalities were analyzed. The algorithm for Down syndrome detected 55.6% of trisomy 18 cases, 36.4% of trisomy 13 cases and 60.0% of other chromosomal abnormalities. When specific risk algorithms were added, the detection rates improved for trisomy 18 (74.0%) and for trisomy 13 (54.5%), with only a slight increase of the false-positive rate of 0.2%. The detection rate for other chromosomal abnormalities did not improve. CONCLUSIONS: Adding the trisomy 18 algorithm to the Down screening program resulted in the detection of five additional trisomy 18 cases.

More invasive procedures are done to detect each case of Down's syndrome in younger women.

OBJECTIVE: To evaluate the performance of first-trimester combined screening in 5-year periods according to maternal age in a low-risk population. DESIGN: A prospective study. SETTING: Multicenter study in Finland. POPULATION: A total of 76949 voluntary women with singleton pregnancies participated in first-trimester combined screening in public healthcare between 1 May 2002 and 31 December 2008. METHODS: The serum samples were analyzed using the PerkinElmer AutoDELFIA® time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel (midwives or physicians) in a university or central hospital. MAIN OUTCOME MEASURES: Performance, detection rate, false positive rate and the number of invasive procedures needed to detect a single case of Down's syndrome were analyzed. RESULTS: There was a direct connection between maternal age and the prevalence of Down's syndrome with a low prevalence in young women being 1:1 193 in the 25-29 age group and 1:150 in the 35-39 age group. Consequently, for a fixed false positive rate of 5%, the number of invasive procedures needed to detect one case of Down's syndrome is higher in younger women to achieve the same detection rate. CONCLUSIONS: In combined first trimester screening the risk for Down's syndrome is individual, varying with maternal age. This should be taken into consideration when counseling women.