Risk factors of persistent adolescent thinness: findings from the UK Millennium Cohort Study.

BACKGROUND: Thinness during adolescence can increase the risk of adverse health outcomes across the life-course and impede development. There is limited research examining the prevalence and determinants of persistent adolescent thinness in the United Kingdom (UK). We used longitudinal cohort data to investigate determinants of persistent adolescent thinness. METHODS: We analyzed data from 7,740 participants in the UK Millennium Cohort Study at ages 9 months, 7, 11, 14 and 17 years. Persistent thinness was defined as thinness at ages 11, 14 and 17; thinness was defined as an age- and sex-adjusted Body Mass Index (BMI) of less than 18.5 kg/m2. In total, 4,036 participants, classified either as persistently thin or at a persistent healthy weight, were included in the analyses. Logistic regression analyses were conducted to examine associations between 16 risk factors and persistent adolescent thinness by sex. RESULTS: The prevalence of persistent thinness among adolescents was 3.1% (n = 231). Among males (n = 115), persistent adolescent thinness was significantly associated with non-white ethnicity, low parental BMI, low birthweight, low breastfeeding duration, unintended pregnancy, and low maternal education. Among females (n = 116), persistent adolescent thinness was significantly associated with non-white ethnicity, low birthweight, low self-esteem, and low physical activity. However, after adjusting for all risk factors, only low maternal BMI (OR: 3.44; 95% CI:1.13, 10.5), low paternal BMI (OR: 22.2; 95% CI: 2.35, 209.6), unintended pregnancy (OR: 2.49; 95% CI: 1.11, 5.57) and low self-esteem (OR: 6.57; 95% CI: 1.46,29.7) remained significantly associated with persistent adolescent thinness among males. After adjustment for all risk factors, not reaching the recommended physical activity levels (OR: 4.22; 95% CI: 1.82, 9.75) remained significantly associated with persistent adolescent thinness among females. No appreciable associations were found between persistent adolescent thinness and sex, premature birth, smoking during pregnancy, income, maternal postnatal depression, mother-infant attachment or socio-emotional difficulties (p > 0.05). CONCLUSION: Persistent adolescent thinness is not rare and appears to be associated with both physical and mental health factors, with some sex specific differences. Healthy weight initiatives should consider the full weight spectrum. Further research is required to understand thinness at a population level, including among those whose BMI changes during child and adolescent development.

Life-course socio-economic position, area deprivation and Type 2 diabetes: findings from the British Women's Heart and Health Study.

OBJECTIVES: We examined whether area deprivation influenced risk of Type 2 diabetes, fasting blood glucose and insulin resistance over and above the effect of individual socio-economic position (SEP) measured across the life course. METHODS: A cross-sectional analysis of 4286 women aged 60 to 79 years from 457 British electoral wards in 23 towns. RESULTS: Area deprivation was positively associated with diagnosed [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.13, 1.53, per quintile of area deprivation, n = 2895], but not undiagnosed Type 2 diabetes after adjustment for individual life-course SEP. This association was robust to adjustment for adult health behaviours and physiological risk factors. Insulin resistance [homeostasis model assessment (HOMA) score] increased by 1.90% (95% CI 0.01, 3.82, n = 2526) per quintile of area deprivation after adjustment for individual SEP, while fasting blood glucose increased by 0.69% (95% CI 0.16, 1.22, n = 2875) after adjustment for individual SEP. CONCLUSIONS: Area level deprivation independently influences diagnosed Type 2 diabetes, insulin resistance and fasting blood glucose. Examination of more specific characteristics of places is needed to understand the mechanisms by which these effects arise.

Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention.

BACKGROUND: Results from prospective studies of serum homocysteine levels and ischemic heart disease (IHD) are inconclusive. We carried out a further prospective study to help clarify the position. METHODS: In the British United Provident Association (BUPA) prospective study of 21,520 men aged 35 to 64 years, we measured homocysteine levels in stored serum samples and analyzed data from 229 men without a history of IHD at study entry who subsequently died of IHD and 1126 age-matched control subjects (nested case-control design). RESULTS: Serum homocysteine levels were significantly higher in men who died of IHD than in men who did not (mean, 13.1 vs 11.8 micromol/L; P<.001). The risk of IHD among men in the highest quartile of serum homocysteine levels was 3.7 times (or 2.9 times after adjusting for other risk factors) the risk among men in the lowest quartile (95% confidence interval [CI], 1.8-4.7). There was a continuous dose-response relationship, with risk increasing by 41% (95% CI, 20%-65%) for each 5-micromol/L increase in the serum homocysteine level. After adjustment for apolipoprotein B levels and blood pressure, this estimate was 33% (95% CI, 22%-59%). In a meta-analysis of the retrospective studies of homocysteine level and myocardial infarction, the age-adjusted association was stronger: an 84% (95% CI, 52%-123%) increase in risk for a 5-micromol/L increase in the homocysteine level, possibly because the participants were younger; the relationship between serum homocysteine level and IHD seems to be stronger in younger persons than in older persons. CONCLUSIONS: Our positive results help resolve the uncertainty that resulted from previous prospective studies. The epidemiological, genetic, and animal evidence together indicate that the association between serum homocysteine level and IHD is likely to be causal. A general increase in consumption of the vitamin folic acid (which reduces serum homocysteine levels) would, therefore, be expected to reduce mortality from IHD.

Serum triglyceride: a possible risk factor for ruptured abdominal aortic aneurysm.

BACKGROUND: We aimed to determine the relationship between ruptured abdominal aortic aneurysm (AAA) and serum concentrations of lipids and apolipoproteins. METHODS: A cohort of 21 520 men, aged 35-64 years, was recruited from men attending the British United Provident Association (BUPA) clinic in London for a routine medical examination in 1975-1982. Smoking habits, weight, height and blood pressure were recorded at entry. Lipids and apolipoproteins were measured in stored serum samples from the 30 men who subsequently died of ruptured AAA and 150 matched controls. RESULTS: Triglyceride was strongly related to risk of ruptured AAA. In univariate analyses the risk in men on the 90th centile of the distribution relative to the risk in men on the 10th (RO10-90) was 12 (95% confidence interval [CI] : 3.8-37) for triglyceride, 5.5 (95% CI: 1.8-17) for apolipoprotein B (apoB) (the protein component of low density lipoprotein [LDL]), 0.15 (95% CI : 0.04-0.56) for apo A1 (the protein component of high density lipoprotein [HDL]), 3.7 (95% CI: 1.4-9.4) for body mass index and 3.0 (95% CI: 1.1-8.5) for systolic blood pressure. Lipoprotein (a) (Lp(a)) was not a significant risk factor (RO10-90 = 1.6, 95% CI: 0.6-3.0). In multivariate analysis triglyceride retained its strong association. CONCLUSION: Triglyceride appears to be a strong risk factor for ruptured AAA, although further studies are required to clarify this. If this and other associations are cause and effect, then changing the distribution of risk factors in the population (by many people stopping smoking and adopting a lower saturated fat diet and by lowering blood pressure) could achieve an important reduction in mortality from ruptured AAA.

The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study.

BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.

Cerebrospinal fluid S100B correlates with brain atrophy in Alzheimer's disease.

S100B is a predominantly astrocytic protein with dose-dependent cytotoxic and neurotrophic properties encoded on chromosome 21q22.3. Concentrations of S100B were measured in the cerebrospinal fluid (CSF) of 31 patients with Alzheimer's disease (AD), 36 patients with frontotemporal lobe dementia (FTLD) and 49 patients with other non-inflammatory neurological diseases. Additional CSF S100B concentrations were correlated with normalised brain volume measurements in AD and FTLD. CSF S100B was significantly higher in AD (Mean+/-standard deviation=0.4+/-0.2 ng/ml) and FTLD (0.42+/-0.19 ng/ml) patients when compared with control subjects (0.25+/-0.08, P<0.001). In patients with AD, S100B correlated negatively with normalised brain volume (R(S)=-0.53, P<0.001). No such correlation was found for FTLD patients. This study supports the concept that S100B is of pathological relevance for degeneration of the central nervous system in AD.

Normalization of cerebral volumes by use of intracranial volume: implications for longitudinal quantitative MR imaging.

BACKGROUND AND PURPOSE: MR-based volumetric measures of cerebral structures are increasingly used for diagnostic purposes and to measure progression of atrophy. Variations in individual head size may be corrected by normalization with use of a total intracranial volume (TIV) measurement. The TIV also may be used to correct for voxel size fluctuations in serial studies. The TIV should be measured from the same images used for structural volumetry, usually T1-weighted imaging. The objectives were to show that normalization with TIV reduces interindividual variation, to develop and validate a simple protocol for measuring TIV from T1-weighted MR images, and to apply TIV normalization to serial brain measures in controls and subjects with Alzheimer disease (AD). METHODS: We measured TIV with a semiautomated segmentation technique on T1- and T2-weighted MR images in 55 controls, 10 AD patients, and two persons at risk of familial AD. Whole-brain volumes also were measured and normalized with TIVs. RESULTS: The TIV normalization of cross-sectional brain volumes significantly reduced interindividual variation; the coefficient of variation (CV) was reduced from 10.0% to 6.0% in controls (P <.001). The TIVs measured on T1-weighted images had low variability (CV, 0.16%) and did not differ significantly from those measured on T2-weighted images (P =.16). The TIV normalization of serial brain-volume measurements reduced interimage differences caused by voxel-scaling variations (CV reduced from 1.3% to 0.5%, P =.002) in 10 controls and five AD patients. CONCLUSION: Structural volumes should be normalized with a TIV, measured cross-sectionally, to reduce interindividual variation, and longitudinally with a concurrent measurement, to reduce subtle interimage differences. This may have important implications in progression studies.

The target plot: a new way of displaying the performance of a screening test.

OBJECTIVES: To produce a graphical method to represent the performance of a screening test that illustrates the prevalence of the disorder being screened for, as well as its discriminatory potential. CONCEPT: A target plot was constructed in which the risk of the disorder is represented by a series of concentric circles of constant risk (isorisks) equivalent to specified false positive rates, with the highest risk in the centre and lower risks spreading outwards towards the circumference. Dots were drawn to represent cases of the disorder; these were of a size such that their total area as a proportion of the area of the whole target plot equalled the prevalence of the disorder in the screened population. The discriminatory power of the test was seen as the clustering of dots around the centre or bull's eye of the target. The detection rate could be estimated as the proportion of dots which fell within the isorisk corresponding to a specified false positive rate. APPLICATION: The target plot was applied to second trimester antenatal screening for Down's syndrome using different combinations of screening markers, and also to screening for ischaemic heart disease using protein components of cholesterol (apolipoproteins A I and B and Lp(a) lipoprotein), systolic blood pressure, and smoking status. DISCUSSION: The efficacy of the different methods of screening for Down's syndrome is readily apparent using the target plot, as is the poorer performance of screening for ischaemic heart disease. CONCLUSIONS: The target plot is a simple and quantitative way of displaying the performance of a screening test that may be useful in teaching and educational material.

Reliability of statistics on Down's syndrome notifications.

OBJECTIVES: To evaluate the completeness of notifications of Down's syndrome live births and terminations to the Office for National Statistics (ONS) using data from the National Down Syndrome Cytogenetic Register (NDSCR). To examine the agreement of observed birth prevalence of Down's syndrome with the expected birth prevalence derived from published maternal age specific rates. METHODS: The number of live births (adjusted to allow for the estimated underascertainment) and the number of terminations due to fetal Down's syndrome from NDSCR were compared with those figures reported to the ONS. Subsequently, using the NDSCR figures, the live birth prevalence of Down's syndrome that would have occurred in the absence of antenatal diagnosis and selective termination was calculated in England and Wales in the years 1990-1993. These figures were compared with those derived by applying published age specific prevalences to the maternal age distribution in England and Wales. RESULTS: It is estimated that only 48% and 46% respectively of Down's syndrome live births and terminations of pregnancy were notified to ONS between 1990 and 1993. The annual expected birth prevalences of Down's syndrome obtained by applying maternal age specific prevalences to the maternal age distribution were in close agreement with observed rates from NDSCR. CONCLUSIONS: There is considerable underreporting of Down's syndrome births and terminations to ONS. The NDSCR data are more complete and therefore the effects of screening should be monitored using data from this source, or using estimates derived from the age specific rates of Down's syndrome.

Prospective study of effect of switching from cigarettes to pipes or cigars on mortality from three smoking related diseases.

OBJECTIVE: To estimate the extent to which cigarette smokers who switch to cigars or pipes alter their risk of dying of three-smoking related diseases-lung cancer, ischaemic heart disease, and chronic obstructive lung disease. DESIGN: A prospective study of 21520 men aged 35-64 years when recruited in 1975-82 with detailed history of smoking and measurement of carboxyhaemoglobin. MAIN OUTCOME MEASURES: Notification of deaths (to 1993) classified by cause. RESULTS: Pipe and cigar smokers who had switched from cigarettes over 20 years before entry to the study smoked less tobacco than cigarette smokers (8.1 g/day v 20 g/day), but they had the same consumption as pipe and cigar smokers who had never smoked cigarettes (8.1 g) and had higher carboxyhaemoglobin saturations (1.2% v 1.0%, P < 0.001), indicating that they inhaled tobacco smoke to a greater extent. They had a 51% higher risk of dying of the three smoking related diseases than pipe or cigar smokers who had never smoked cigarettes (relative risk 1.51; 95% confidence interval 0.96 to 2.38), a 68% higher risk than lifelong non-smokers (1.68; 1.16 to 2.45), a 57% higher risk than former cigarette smokers who gave up smoking over 20 years before entry (1.57; 1.04 to 2.38), and a 46% lower risk than continuing cigarette smokers (0.54; 0.38 to 0.77). CONCLUSION: Cigarette smokers who have difficulty in giving up smoking altogether are better off changing to cigars or pipes than continuing to smoke cigarettes. Much of the effect is due to the reduction in the quantity of tobacco smoked, and some is due to inhaling less. Men who switch do not, however, achieve the lower risk of pipe and cigar smokers who have never smoked cigarettes. All pipe and cigar smokers have a greater risk of lung cancer than lifelong non-smokers or former smokers.

Prospective observational study to assess value of prostate specific antigen as screening test for prostate cancer.

OBJECTIVE: To evaluate measurement of serum prostate specific antigen as a potential screening test for future clinical prostate cancer among healthy men. DESIGN: Nested case-control study with stored serum samples collected from 49,261 men with follow up using national death and cancer registration systems. SUBJECTS: 265 asymptomatic men who subsequently developed clinical prostate cancer and 1055 controls matched for age, study centre, and duration of storage of samples. MAIN OUTCOME MEASURES: Distribution of concentrations of the antigen in men who developed prostate cancer and in controls. RESULTS: Prostate specific antigen concentrations were significantly higher in men who subsequently developed prostate cancer than in controls. In the first three years after blood collection the median concentration was 23 times greater in cases than in controls of the same age at the same centre (that is, 23 multiples of the median). A smaller difference persisted thereafter; 4.0 multiples of the median 3-6 years after blood collection, 3.6 6-10 years, and 1.8 after 10 years. In the first three years the proportion of men who developed prostate cancer and had raised levels of the antigen (> or = 12 multiples of the median) (detection rate or sensitivity) was 81% (95% confidence interval 54% to 96%). The proportion of men who did not develop prostate cancer but had levels this high (false positive rate) was only 0.5%. CONCLUSION: Prostate specific antigen measurement is a highly discriminatory screening test for prostate cancer among healthy men. In the general population, 60-74 year old men who had > or = 12 times the normal median level would have about a 50% chance of developing clinical prostate cancer in the next three years. Measurement of this antigen is a good enough screening test to justify a randomised controlled trial to determine any reduction in mortality from prostate cancer.

Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study.

BACKGROUND: Falls and fractures contribute to morbidity and mortality in bradykinetic rigid syndromes. METHODS: The authors performed a retrospective case notes review at the Queen Square Brain Bank for Neurological Disorders and systematically explored the relation between clinical features and falls and fractures in 782 pathologically diagnosed cases (474 with Parkinson's disease (PD); 127 progressive supranuclear palsy (PSP); 91 multiple system atrophy (MSA); 46 dementia with Lewy bodies (DLB); 27 vascular parkinsonism; nine Alzheimer's disease; eight corticobasal degeneration). RESULTS: Falls were recorded in 606 (77.5%) and fractures in 134 (17.1%). In PD, female gender, symmetrical onset, postural instability, and autonomic instability all independently predicted time to first fall. In PD, PSP, and MSA latency to first fall was shortest in those with older age of onset of disease. Median latency from disease onset to first fall was shortest in Richardson's syndrome (12 months), MSA (42), and PSP-parkinsonism (47), and longest in PD (108). In all patients fractures of the hip were more than twice as common as wrist and forearm fractures. Fractures of the skull, ribs, and vertebrae occurred more frequently in PSP than in other diseases. CONCLUSION: Measures to prevent the morbidity associated with falls and fractures in bradykinetic rigid syndromes may be best directed at patients with the risk factors identified in this study.

A standardised method for measuring magnetisation transfer ratio on MR imagers from different manufacturers--the EuroMT sequence.

Magnetisation transfer ratio (MTR) is increasingly used to evaluate neurological disorders, especially those involving demyelination. It shows promise as a surrogate marker of disease progression in treatment trials in multiple sclerosis (MS) but the value measured is highly dependent on pulse sequence parameters, making it hard to include the technique in large multi-centre clinical trials. The variations can be reduced by a normalisation procedure based on the flip angle and timing of the presaturation pulse, but correction for parameters such as saturation pulse shape, amplitude, duration and offset frequency remains problematic. We have defined a standard pulse sequence, to include a standard presaturation pulse and set of parameters, which can be implemented on scanners from both General Electric and Siemens, and has also been used on Phillips scanners. To validate the sequence and parameters, six European centres measured MTR in the frontal white matter of normal volunteers. It was possible to measure MTR values in controls which were consistent to within approximately +/-2.5 percentage units across sites. This degree of precision may be adequate in many situations. The remaining differences between sites and manufacturers are probably caused by B1 errors.

Serum markers for Down's syndrome in relation to number of previous births and maternal age.

We conducted a study to investigate the effect of parity on the following six serum markers used in screening for Down's syndrome, after adjusting them for ethnic group and maternal weight: alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and dimeric inhibin A. We aimed to estimate the effect of adjusting for any differences found on the screening performance. AFP, uE3, and hCG concentrations were available from 16,666 women with singleton pregnancies without Down's syndrome or neural tube defects and without insulin-dependent diabetes mellitus, who were screened between 15 and 22 weeks' gestational age. Stored serum samples were available on a subset of 1347 women and these were used to measure free alpha-hCG, free beta-hCG, and inhibin A. Serum concentrations were expressed as multiples of the median (MOM) for women of the same gestational age, weight, and ethnic group. Of the six markers, only hCG levels were affected by parity; hCG levels decreased by 3.1 per cent per previous birth (95 per cent confidence interval 2.2-4.0 per cent); there was no significant relationship between the number of previous abortions and hCG level after adjustment for the number of previous births. The effect of previous births on hCG was not due to maternal age. Only AFP was affected by maternal age, but the effect was small; levels increased by 4.4 per cent per 10 years of age (3.2-5.7 per cent). It is not worthwhile adjusting serum markers for parity or for maternal age in prenatal screening for Down's syndrome because their effect on the performance of screening is negligible.

Alternative methods of maternal weight adjustment in maternal serum screening for Down syndrome and neural tube defects.

Serum markers used in screening for Down syndrome and neural tube defects are often adjusted to take account of the effect of maternal weight on the marker levels. The standard adjustment procedure is based on a linear relationship between the marker concentration, expressed as the log of the multiple of the median (MOM), and maternal weight on a linear scale. It has been proposed that maternal weight adjustment may be better performed using a linear relationship between marker concentration expressed in MOM and the reciprocal of maternal weight. In a dataset of 8905 singleton pregnancies in white women without Down syndrome or neural tube defects we compared the two methods of weight adjustment and found that both were satisfactory and neither had an obvious advantage over the other. In the analysis it was noticed that hCG levels in very heavy women (> 120 kg) were higher than expected from the decreasing linear trend with maternal weight--a result that was statistically highly significant (p < 0.01) but for which we have no explanation. In screening it will have virtually no effect because the finding was restricted to only the 0.3 per cent of the heaviest women.

Integrated screening for Down's syndrome based on tests performed during the first and second trimesters.

BACKGROUND: Both first-trimester screening and second-trimester screening for Down's syndrome are effective means of selecting women for chorionic-villus sampling or amniocentesis, but there is uncertainty about which screening method should be used in practice. We propose a new screening method in which measurements obtained during both trimesters are integrated to provide a single estimate of a woman's risk of having a pregnancy affected by Down's syndrome. METHODS: We used data from published studies of various screening methods employed during the first and second trimesters. The first-trimester screening consisted of measurement of serum pregnancy-associated plasma protein A in 77 pregnancies affected by Down's syndrome and 383 unaffected pregnancies and measurements of nuchal translucency obtained by ultrasonography in 326 affected and 95,476 unaffected pregnancies. The second-trimester tests were various combinations of measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in 77 affected and 385 unaffected pregnancies. RESULTS: When we used a risk of 1 in 120 or greater as the cutoff to define a positive result on the integrated screening test, the rate of detection of Down's syndrome was 85 percent, with a false positive rate of 0.9 percent. To achieve the same rate of detection, current screening tests would have higher false positive rates (5 to 22 percent). If the integrated test were to replace the triple test (measurements of serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin), currently used with a 5 percent false positive rate, for screening during the second trimester, the detection rate would be higher 85 percent vs. 69 percent), with a reduction of four fifths in the number of invasive diagnostic procedures and consequent losses of normal fetuses. CONCLUSIONS: The integrated test detects more cases of Down's syndrome with a much lower false positive rate than the best currently available test.

The effect of differences in the distribution of maternal age in England and Wales on the performance of prenatal screening for Down's syndrome.

We aimed to determine how differences in the age at which women had their pregnancies influenced the expected detection and false-positive rates of serum screening for Down's syndrome (i) between 1970 and 1993 in England and Wales, and (ii) between regions and districts of England and Wales in 1991. We applied published estimates of Down's syndrome screening to regional and district data on the age distribution of maternities and changes in the age distribution over time in England and Wales obtained from the Office of Population Censuses and Surveys. From 1970 to 1993 women, on average, became pregnant at an older age; the percentage of maternities among women aged 35 or more increased from 7 to 9.2 per cent. This was not a great enough change to have had a material effect on the performance of Down's syndrome screening. In 1991, the percentage of maternities among women aged 35 or more varied from 5 to 20 per cent among Health Districts, a difference that would influence the performance of screening; for example, using the triple test and a risk cut-off of 1 in 250, the detection rates would have varied from about 55 to 70 per cent and the false-positive rates from 4.4 to 8.8 per cent across different districts. The tendency for women to have their pregnancies at an older age would have had a negligible impact on the performance of serum screening for Down's syndrome, but differences in the age when women had their pregnancies in different parts of the country would lead to twice as many women being referred for amniocentesis in some districts than in others when offered the same method of serum screening and at the same risk cut-off level. The results will have important implications for the local purchasers of Down's syndrome screening services.

Fetal loss in Down syndrome pregnancies.

It is recognized that pregnancies with Down syndrome are liable to end in spontaneous fetal loss. It is important to determine the magnitude of this effect so that it can be taken into account when assessing the results of antenatal screening programmes for Down syndrome. Failure to do so will tend to overestimate the detection rate in intervention studies in which the screening results are used to identify women for a diagnostic test and the offer of a termination of pregnancy if indicated. We present new data on the spontaneous fetal loss in Down syndrome pregnancies from the National Down Syndrome Cytogenetic Register (1989-1996). We compare our results with published results of other studies on the subject to obtain a summary estimate. We exclude one study from the meta analysis due to incorrect methodology resulting in an overestimate of fetal loss. Based on the combined data (i) between the time of chorionic villus sampling and term an estimated 43 per cent (95 per cent CI: 31-54 per cent) of pregnancies ended in a miscarriage or still birth, (ii) between the time of amniocentesis and term an estimated 23 per cent (95 per cent CI: 19 28 per cent) of pregnancies ended in a miscarriage or still birth, and (iii) 12 per cent (95 per cent CI: 2-23 per cent) of births were stillborn or resulted in a neonatal death.

Maternal serum inhibin-A in pregnancies with insulin-dependent diabetes mellitus: implications for screening for Down's syndrome.

A nested case-control study using stored serum samples collected as part of a prospective study of the outcome of pregnancy was performed to investigate concentrations of (dimeric) inhibin-A in maternal serum between 15 and 22 weeks of pregnancy in 126 pregnancies among 92 women with insulin-dependent diabetes mellitus (IDDM). Each IDDM pregnancy was matched with two control singleton pregnancies for gestational age (same completed week) and duration of sample storage (same calendar quarter). The median inhibin-A level in the IDDM pregnancies was 0.88 multiples of the median (MOM) for pregnancies without IDDM at the same gestational age (P = 0.05) (95 per cent confidence interval 0.78-1.00) or 0.91 MOM after adjustment for maternal weight. These results enable inhibin-A values to be adjusted so that prenatal screening for Down's syndrome can be performed using this marker in IDDM pregnancies as well as in non-diabetic pregnancies.