Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

Effectiveness of a sensory integrative therapy program for children with perceptual-motor deficits.

This study was an evaluation of the sensory integrative therapy (SIT) program (Ayres, 1972a) for children at the Christchurch Hospital. Fifty-five children were randomly assigned to the SIT program, a parallel physical education program, or to a no-treatment condition. The children were assessed before and after treatment on measures of perceptual-motor development, language and reading development, self-concept, and handwriting skills. Covariance analysis, with age and pretest scores as covariates, found no significant differences between groups on any of the measures except reading progress among those children who could already read at the beginning of the program. Children who made the least progress during therapy were those who (a) had epilepsy, (b) were from a low-income, single-parent family, or (c) had behavioral problems.

Antenatal maternal serum screening for Down's syndrome: results of a demonstration project.

OBJECTIVES: To assess the implementation of antenatal screening for Down's syndrome in practice, using individual risk estimates based on maternal age and the three serum markers: alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin. DESIGN: Demonstration project of Down's syndrome screening; women with a risk estimate at term of 1 in 250 or greater were classified as "screen positive" and offered diagnostic amniocentesis. SETTING: Hospital and community antenatal clinics in four health districts in London. SUBJECTS: 12,603 women of all ages with singleton pregnancies seen between February 1989 and the end of May 1991, with follow up of the outcome of pregnancy completed to the end of 1991. MAIN OUTCOME MEASURES: Uptake of screening, detection rate for Down's syndrome, false positive rate, odds of being affected given a positive result, and uptake of amniocentesis in women with positive screening results, together with the costs of the screening programme. RESULTS: The uptake of screening was 74%. The detection rate was 48% (12/25), and the false positive rate was 4.1%, consistent with results expected from previous work based on observational studies. There was a loss of detection due to the selective use of ultrasound scans among women with positive screening results. One affected pregnancy occurred among 205 reclassified as negative; this illustrated the danger of false negatives occurring in this group and lends weight to the view that if an ultrasound estimate of gestational age is used it should be carried out routinely on all women rather than selectively among those with positive results. The estimated cost of avoiding the birth of a baby with Down's syndrome was about 38,000 pounds, substantially less than the lifetime costs of care. CONCLUSION: Antenatal maternal serum screening for Down's syndrome is effective in practice and can be readily integrated into routine antenatal care. It is cost effective and performs better than selection for amniocentesis on the basis of maternal age alone.

Maternal serum screening for Down's syndrome in early pregnancy.

The possibility of improving the effectiveness of antenatal screening for Down's syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Down's syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Down's syndrome in the United Kingdom from about 900 a year to about 350 a year.

Repeat maternal serum testing in multiple marker Down's syndrome screening programmes.

The effect of repeat testing in maternal serum multiple marker screening for Down's syndrome was estimated using samples stored in an antenatal serum bank. Human chorionic gonadotropin (hCG) and unconjugated oestriol (uE3) levels were determined in 142 pairs of routinely collected samples which had already been tested for alpha-fetoprotein (AFP). For each marker, about two-thirds of the pairs of values were within 20 per cent of each other and most were within 40 per cent. A multivariate Gaussian model was used to estimate the detection and false-positive rates for different repeat testing policies. A policy of repeat testing those with a high risk of a Down's syndrome term pregnancy given age and marker levels would reduce the false-positive rate but there would also be a reduction in the detection rate. For example, using all three markers and a 1 in 250 cut-off risk, the estimated false-positive rate would fall from 5.3 to 3.8 per cent but the detection rate would decrease from 58 to 55 per cent. A policy of repeating those with either high or borderline risks would produce a modest improvement in screening efficiency. Repeating the 11 per cent with a risk exceeding 1 in 500 yields an estimated false-positive rate of 5.0 per cent and a detection rate of 60 per cent. A policy of selective repeat testing is not recommended as it would not substantially improve screening efficiency. Nonetheless, if a repeat test has been performed, the parameters given in this paper will enable an unbiased estimate of the Down's syndrome risk to be calculated for individual women.

Maternal serum free alpha-human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down's syndrome.

Maternal serum free alpha-human chorionic gonadotrophin (free alpha-hCG) levels were determined in twin and singleton pregnancies at 15-22 weeks of gestation using a set of stored serum samples relating to 200 twin pregnancies and 600 singleton control pregnancies matched for gestational age and duration of storage. Free alpha-hCG values are, on average, 1.66 times greater in twin pregnancies than in singleton pregnancies (95 per cent confidence interval 1.56-1.76). If maternal serum free alpha-hCG is used in screening for Down's syndrome, values in twin pregnancies can be adjusted using this result so that screening can be performed in twin pregnancies as well as in singleton pregnancies.

Maternal serum free beta-human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down's syndrome.

Free beta-human chorionic gonadotrophin values are, on average, 1.90 times greater in twin pregnancies than in singleton pregnancies [95 per cent confidence interval (CI) 1.69-2.13]. This information can be used in screening for Down's syndrome, so that twin pregnancies can be interpreted in addition to singleton pregnancies.

Method for estimating rate of fat loss during treatment of obesity by calorie restriction.

Rates of weight and fat loss in sixteen female and nine male obese patients during calorie restriction (655-789 kcal/day) for up to 120 days were studied by a method for estimating daily changes in body composition. Fat mass is calculated by subtracting daily fluid (calculated from sodium and potassium balances) and protein mass changes from daily weight changes. After the natriuresis of the first 4 days, there was a slower rate of weight loss between days 5 and 28 due largely to a decreasing contribution from fluid and protein losses. No significant change in the rate of weight loss could be shown after the first 28 days. The rate of fat loss did not change significantly from day 5 onwards suggesting no significant change in total energy expenditure during the study period. After 68 days, 93.4% of the weight loss was fat.

A comparison of some classification methods used to determine benthic macro-invertebrate species associations in river survey work based on data obtained from the River Ely, South Wales.

The results of a survey of the macro-invertebrates of the polluted River Ely, South Wales, are used as a basis for comparing several classification methods which have been used previously in river survey work to determine species groupings. The methods compared are product-moment correlation (clustered by the nearest neighbour technique), Kendall's tau coefficient (clustered by the nearest neighbour and average linkage techniques), and Squared Euclidean-Distance coefficient (clustered by nearest neighbour and Ward's techniques). The species groupings determined by these methods were influenced both by the association coefficient and the technique used to cluster it. Some species were grouped together by all or most of the methods. The ecological validity of these robust groups is examined. A clear recommendation regarding the most appropriate method is frustrated by incomplete knowledge of the ecological requirements of most of the aquatic macro-invertebrates used in the data-set. However, Kendall's tau coefficient clustered by the average linkage technique appeared to produce ecologically meaningful species groups. Product-moment correlation was also reasonably successful and since it is based on absolute abundance data whereas Kendall's tau coefficient is based on relative abundance data, the use of the two together is recommended for determining robust groups.

Detection of hydatidiform mole in maternal serum screening programmes for Down's syndrome.

OBJECTIVE: To determine how frequently hydatidiform mole will be detected in a maternal serum Down's syndrome screening programme. DESIGN: Affected pregnancies were identified using a national register. Unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) were measured in stored serum samples and alphafetoprotein (AFP) levels were available from previous neural tube defect screening at 15-20 weeks gestation. SUBJECTS: Ten pregnancies with a complete mole (i.e., hydropic placenta without a fetus), nine with stored serum samples and one with an AFP level only. RESULTS: The median values were 0.08, 0.13 and 1.83 multiples of the normal median for AFP, uE3 and hCG respectively. Six out of nine (67%) tested for all three markers had a high risk of Down's syndrome given maternal age and the marker levels. CONCLUSION: Many molar pregnancies that have not presented clinically before 15 weeks will be detected through Down's syndrome screening.

Repeat maternal serum testing for Down's syndrome screening using multiple markers with special reference to free alpha and free beta-hCG.

To determine the effect of routine repeat testing in serum screening for Down's syndrome, we compared estimates of the detection and false-positive rates. Five serum markers were measured--alpha-fetoprotein (AFP), unconjugated oestriol (uE3), human chorionic gonadotrophin (hCG), and its two subunits, free alpha and free beta-hCG. First and repeat test marker levels were available from 142 women whose samples had been routinely collected and stored in an antenatal serum bank. Different repeat testing policies were compared for various combinations of the markers. If all women had repeat tests using the four markers AFP, uE3, and free alpha and free beta-hCG, the detection rate for a 5 per cent false-positive rate was 69 per cent compared with 65 per cent if no women were repeated. Policies of repeating selected women gave similar results. The small gain in screening performance with repeat testing performed routinely is not worthwhile. If a woman does happen to have a repeat test, her risk estimate should, however, be based on both results, not just the second.

Serum alpha-fetoprotein and neural tube defects in the first trimester of pregnancy. MRC Vitamin Study Research Group.

As part of the Medical Research Council randomized trial of vitamin supplementation in the prevention of neural tube defects (NTDs), maternal serum alpha-fetoprotein (AFP) was available for 19 NTD pregnancies. Each of these was matched with four unaffected controls, by maternal age, participating centre, and duration of sample storage. The samples came from women whose gestational age ranged from 6 to 14 completed weeks. The median AFP level in the affected pregnancies was 1.2 multiples of the median value in unaffected pregnancies of the same gestational age (95 per cent confidence interval (CI) 0.83-1.59). This confirmed the view that serum AFP measurement is of no practical value in the detection of NTDs in the first trimester of pregnancy. The study also showed that folic acid supplementation, used as a method of preventing NTDs, had no effect on the concentrations of maternal serum AFP up to 14 weeks of pregnancy.

The use of free beta-hCG in antenatal screening for Down's syndrome.

OBJECTIVE: To investigate the value of the measurement of free beta human chorionic gonadotrophin (hCG) as a serum marker of Down's syndrome in the second trimester of pregnancy. DESIGN: A prospective observational study using stored antenatal serum samples. SETTING: Serum samples collected from women receiving routine antenatal care in Oxford. SUBJECTS: Seventy-five singleton pregnancies with fetal Down's syndrome and 367 unaffected singleton pregnancies. Each affected pregnancy was matched with five control pregnancies for maternal age, gestational age, and duration of storage of the serum sample. None of the pregnancies were associated with neural tube defects. MAIN STUDY MEASURES: Maternal serum free beta-hCG levels. These were compared with total hCG levels in the same pregnancies. The performance of screening using free beta-hCG was compared with that using the principal markers, namely alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and total hCG together with maternal age. RESULTS: The median free beta-hCG level in the affected pregnancies was 2.22 multiples of the normal median (MoM), significantly higher than in the unaffected pregnancies (95% confidence interval, 1.84-2.68 MoM). The discriminatory performances of free beta-hCG and total hCG, each considered separately, were similar; with a cut-off level of 2.5 MoM the detection rate was 43% and 5.7 of unaffected pregnancies had raised free beta-hCG levels (likelihood ratio of 7.5 (43/5.7)), somewhat better discrimination than the 32% and 4.6% respectively using total hCG (likelihood ratio of 7.0 (32/4.6)). With a higher cut-off level of 3.5 MoM, the rates were 19% and 2.7% respectively (likelihood ratio of 7.0), using free beta-hCG, worse than the 19% and 1.4% using total hCG (likelihood ratio of 13.6). Screening using maternal age, AFP, uE3 and free beta-hCG (instead of total hCG) yielded a detection rate of 62% (instead of 58%) at a screening risk cut-off level corresponding to a 5% false-positive rated). CONCLUSION: The main advantage in using free beta-hCG instead of total hCG is that there is a small increase in the detection rate (4%) for a given false-positive rate when used with maternal age, AFP and uE3. The main disadvantage is that there is less practical experience with free beta-hCG measurement and insufficient data to screen in certain categories of pregnancy (e.g. twins). The best practical advice is to use total hCG for the present but consider changing to free beta-hCG either (i) after further data are available that will permit the interpretation of screening results in the same way as is currently available with total hCG, or (ii) if its use with another marker confers a worthwhile increase in the detection rate for a given false-positive rate.

The effects of triiodothyronine on energy expenditure, nitrogen balance and rates of weight and fat loss in obese patients during prolonged caloric restriction.

We studied ten obese patients on prolonged caloric restriction by metabolic balance techniques two weeks before and two weeks after the start of treatment with triiodothyronine (T3) (0.36-1.01 micrograms/kg/d). The rate of weight, nitrogen and fat loss calculated from metabolic balance increased during T3 therapy and these effects were maximal in the second week of treatment. In seven patients studied continuously for four weeks on T3 therapy, the rates of weight and fat loss during the fourth week of treatment were not significantly different from pretreatment values while nitrogen loss was still significantly greater. The increase in nitrogen loss, studied after the period of adaptation to caloric restriction, implies that prolonged treatment with T3 can result in significant losses of lean tissue in addition to that resulting from caloric restriction alone. Mean weight loss increased by 92 g/d during T3 therapy. T3 significantly increased the metabolic rate as measured by two other independent measures: the resting energy expenditure (REE), measured by indirect calorimetry (fourteen patients), and the sleeping heart rate (six patients).

Serum vitamin E and subsequent risk of cancer.

In a prospective study of about 22,000 men attending a screening centre, serum samples were collected and stored. The concentration of vitamin E (alpha-tocopherol) was measured in the stored serum samples from 271 men subsequently notified as having cancer and from 533 unaffected controls, matched for age, smoking history and duration of storage of the serum samples. The mean vitamin E level of the cancer subjects was not significantly different from that of their matched controls. The mean level in the cancer subjects who were diagnosed as having cancer before the elapse of one year from the date of blood collection was, however, significantly lower than the mean concentration of their matched controls (10.0 and 11.5 mgl-1 respectively, P = 0.003). For subjects whose cancers were diagnosed one or more years after blood collection the difference was not statistically significant either for all cancers or for cancers of six sites considered separately, viz. lung, colon and rectum, stomach, bladder, central nervous system and skin. The most likely explanation for these results is that the low vitamin E levels observed in these subjects were a metabolic consequence, rather than a precursor, of the cancer. This would explain, at least in part, the overall inverse association between serum vitamin E and risk of cancer observed in the published epidemiological studies on serum vitamin E and cancer.

Maternal serum unconjugated oestriol and human chorionic gonadotrophin levels in pregnancies with insulin-dependent diabetes: implications for screening for Down's syndrome.

OBJECTIVE: To investigate maternal serum unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) levels in pregnant women with insulin-dependent diabetes mellitus and to consider the implications of the results for antenatal screening for Down's syndrome. DESIGN: Descriptive study using stored antenatal serum samples. SETTING: Stored serum samples collected from women receiving routine antenatal care in Oxford. SUBJECTS: 126 singleton pregnancies in 92 women with insulin-dependent diabetes mellitus and for each pregnancy, two pregnancies without diabetes matched for gestational age and duration of storage of the serum sample. None of the pregnancies was associated with fetal neural tube defect or Down's syndrome. MAIN STUDY MEASURES: Maternal serum uE3 and hCG levels at 15-22 weeks gestation. Alpha-fetoprotein (AFP) levels were also measured for comparison. RESULTS: The median uE3 level in the diabetic pregnancies was 0.92 multiples of the median (MoM) for pregnancies without diabetes at the same gestational age (P less than 0.05); and the hCG level was 0.95 MoM (P = 0.48). The median AFP level was also reduced to 0.77 MoM (P less than 0.001). CONCLUSION: The reduction in uE3 and AFP levels in insulin-dependent diabetic pregnancies is sufficiently great to be taken into account in maternal serum screening programmes for Down's syndrome. Dividing the uE3 and AFP levels in such pregnancies by the corresponding median for insulin-dependent diabetic pregnancies will yield a similar false-positive rate in pregnancies with and without insulin-dependent diabetes mellitus.

Maternal serum screening for Down's syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight.

OBJECTIVE: To investigate the effect of using a routine ultrasound estimate of gestational age and maternal weight adjustment on maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) levels in antenatal screening for Down's syndrome. DESIGN: Women with a singleton pregnancy without Down's syndrome were screened using the three serum markers and an estimate of gestational age based on 'dates' (time since first day of the last menstrual period) and one based on an ultrasound scan examination was recorded together with maternal weight. SETTING: Women attending the Homerton Hospital, Hackney, for their antenatal care between February 1989 and January 1990. SUBJECTS: 2113 women with a singleton pregnancy without Down's syndrome. RESULTS: The use of ultrasound to estimate gestational age (usually based on the biparietal diameter of the fetal skull) led to a significant reduction in the variance of each marker at a given week of pregnancy. The level of each marker was negatively associated with maternal weight, so that adjustment for weight also led to a reduction in variance. These data on gestational age and maternal weight, taken together with published data on pregnancies associated with Down's syndrome, indicate that the routine use of ultrasound to estimate gestational age will increase the detection rate from 58% to 67% while maintaining the false-positive rate at 5%, or reduce the false-positive rate from 5.7% to 3.1% while maintaining the detection rate at 60%. Routine maternal weight adjustment for the serum marker levels was much less useful, increasing the detection rate by about 0.5% for a given false-positive rate, or reducing the false-positive rate about 0.1% for a given detection rate. CONCLUSION: An ultrasound gestational age estimate available at the time of Down's syndrome screening confers a substantial advantage to screening performance with a further small benefit resulting from maternal weight adjustment, which is worth adopting if it can be done without difficulty or extra cost.

Second trimester amniotic fluid oestriol, dehydroepiandrosterone sulphate, and human chorionic gonadotrophin levels in Down's syndrome.

OBJECTIVE: To investigate the reason for low maternal serum unconjugated oestriol (uE3) and raised human chorionic gonadotrophin (hCG) levels in Down's syndrome pregnancies. DESIGN: Measurement of uE3, total oestriol (tE3), dehydroepiandrosterone sulphate (DHEAS), a precursor of oestriol, and hCG in 15-20 week amniotic fluid samples from pregnancies with and without Down's syndrome. SETTING: The retrieval and use of stored amniotic fluid samples collected from women who had had an amniocentesis for antenatal diagnosis. SUBJECTS: 45 women with a Down's syndrome pregnancy and 224 unaffected controls of the same gestational age. RESULTS: The median level of amniotic fluid in affected pregnancies was low for uE3, tE3 and DHEAS but high for hCG: 0.50, 0.46, 0.35 and 1.58 multiples of the normal median, respectively. CONCLUSION: These results suggest that the abnormal maternal serum levels of uE3 and hCG in affected pregnancies are due mainly to abnormal feto-placental synthesis, rather than feto-maternal transfer.