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.

Effect of allowing for ethnic group in prenatal screening for Down's syndrome.

We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.

Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy. International Prenatal Screening Research Group.

OBJECTIVE: To determine the value of serum screening for Down's syndrome at 8-14 weeks of pregnancy using seven potential serum markers (alpha-fetoprotein, unconjugated oestriol, total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, pregnancy associated plasma protein A (PAPP-A), and dimeric inhibin A). DESIGN: Stored blood samples collected from women at about 10 weeks of pregnancy, prior to having chorionic villus sampling procedure on account of advanced maternal age, were retrieved from pregnancies associated with Down's syndrome and from matched unaffected pregnancies. SETTING: Twenty-one obstetric centres in nine countries. SUBJECTS: Seventy-seven pregnancies associated with Down's syndrome each matched with five controls (except in two cases that were matched with four controls) for maternal age (same five year age groups), duration of storage of the serum sample (same calendar year), and gestational age (usually same week of pregnancy). RESULTS: The levels of two potential markers differed between affected and unaffected pregnancies sufficiently to be of value in screening--free beta-hCG and PAPP-A. The median free beta-hCG level in affected pregnancies was 1.79 times the median level for unaffected pregnancies, and the median PAPP-A level was 0.43 times the normal median. These two markers were combined with maternal age to estimate a woman's risk of having a fetus with Down's syndrome. A screening programme that used a risk cutoff level of 1:300 would detect 63% of affected pregnancies and also classify 5.5% of unaffected pregnancies as screen positive. None of the other five markers added more than 2% detection for the same false-positive rate. CONCLUSION: The performance of screening using maternal age and serum-free beta-hCG and PAPP-A at 10 weeks of pregnancy was better than the double test (alpha-fetoprotein and hCG with maternal age) and similar to the triple test (alpha-fetoprotein, unconjugated oestriol and hCG with maternal age) at 15-22 weeks.

Prenatal screening for Down's syndrome using inhibin-A as a serum marker.

The value of measuring inhibin-A (a beta A dimer) with human chorionic gonadotrophin (total or the sub-units free a-hCG and free beta-hCG separately), alpha-fetoprotein (AFP), and unconjugated oestriol (uE3) was examined to determine the effect on the performance of serum screening for Down's syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples from 77 Down's syndrome singleton pregnancies and 385 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the sample, supplemented by data from 970 white women with unaffected pregnancies. Inhibin-A was elevated in the serum of women with Down's syndrome pregnancies with a median of 1.79 multiples of the median (MOM). Using the four serum markers AFP, uE3, total hCG, and inhibin-A, in addition to maternal age, 70 per cent of Down's syndrome pregnancies were detected for a 5 per cent false-positive rate compared with 59 per cent with the conventional triple test (AFP, uE3, and total hCG with maternal age). If the estimate of gestational age were based on an ultrasound scan examination, the detection rate would be 77 per cent [95 per cent confidence interval (CI) 69-85 per cent] using the four serum markers including inhibin-A, compared with 67 per cent with the triple test or 79 per cent (95 per cent CI 71-87 per cent) if marker values were adjusted for maternal weight. If the detection rate were kept at 70 per cent and the gestational age were estimated by an ultrasound scan examination, the four-marker test would reduce the false-positive rate from 6-1 per cent using the triple test to 2-9 per cent. The results were virtually the same if free beta-hCG was used instead of total hCG. The inhibin-A-based four-marker test is the most effective method of prenatal screening for Down's syndrome suitable for routine use. If the extra cost required to carry out the inhibin-A test were less than about [symbol: see text]3 per woman screened, the four-marker test including inhibin-A would be financially cost-effective.

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.

The tar reduction study: randomised trial of the effect of cigarette tar yield reduction on compensatory smoking.

BACKGROUND: Observational and short term intervention studies have reported that smokers of low tar cigarettes inhale more deeply (that is, compensate) than those who smoke high tar cigarettes. To quantify this effect a long term randomised trial was conducted on the effects of switching to low tar cigarettes. METHODS: The trial was carried out between April 1985 and March 1988 among cigarette smokers in the British Civil Service, measuring blood carboxyhaemoglobin (COHb) levels and serum cotinine levels as markers of tobacco smoke intake. Volunteers first switched to a cigarette brand yielding around 10% less tar than their usual brand to identify smokers able to change brand. The 434 subjects who successfully switched were then randomly allocated to one of three groups: (a) "fast reduction" group which changed to a brand of cigarettes with a tar yield of about half that of their usual brand; (b) "slow reduction" group which reduced to the same level in steps over several months; and (c) a control group which continued smoking cigarettes with a tar yield 10% lower than their usual brand. RESULTS: Over the course of the trial cigarette consumption declined slightly in all three groups. In both the "fast reduction" and the "slow reduction" groups, intake of COHb and cotinine was reduced, though not to the same extent as the yield reduction. Comparison of the results before randomisation with those at the end of the trial showed that a reduction in carbon monoxide yield of 45% was associated with a decrease in carbon monoxide intake of 19% (95% confidence interval 14% to 24%) and that a reduction in nicotine yield of 40% was associated with an 11% (6% to 16%) reduction in nicotine intake, reflecting relative intakes of about 1.5 for both carbon monoxide and nicotine in the "fast reduction" group. Results were similar in the "slow reduction" group with a 42% reduction in carbon monoxide yield, a 16% (11% to 22%) reduction in carbon monoxide intake, a 37% reduction in nicotine yield, and a 6% (0% to 13%) reduction in nicotine intake. Estimates of compensation derived from these results were 65% for carbon monoxide, 79% for nicotine, and 62% for tar. CONCLUSIONS: Compensation, demonstrated when switching from a high tar cigarette to a low tar one, was incomplete. Advising people who have failed to give up smoking to switch to low tar cigarettes will reduce the intake of smoke constituents to a small extent. This would be expected to decrease their risk of smoking-related diseases, although by a smaller amount than would be achieved by giving up smoking altogether.

Occupational exposure to hydrazine and subsequent risk of cancer.

OBJECTIVES: The aim was to examine the cause specific mortality of men exposed to hydrazine. METHODS: Hydrazine was produced at a factory in the east midlands between 1945 and 1971. The cohort of all 427 men who were employed there for at least six months with varying degrees of occupational exposure to hydrazine were followed up until the end of January 1992. RESULTS: By the end of July 1982 49 deaths had occurred and the observed mortality was found to be close to that expected at each level of exposure. By the end of January 1992 a further 37 deaths had occurred. Again the observed mortality was close to that expected for all causes and also for lung cancer, cancers of the digestive system, other cancers, and all other causes, irrespective of the level of exposure. CONCLUSIONS: The results weigh against there having been any material hazard of occupational exposure to hydrazine. The small number of men studied means, however, that a relative risk as high as 3.5 for lung cancer cannot confidently be excluded.

Maternal serum free alpha- and free beta-human chorionic gonadotrophin in pregnancies with insulin-dependent diabetes mellitus: implications for screening for Down's syndrome.

A study was performed to investigate the concentrations of the alpha and beta free sub-units of human chorionic gonadotrophin (free alpha-hCG and free beta-hCG) 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 free alpha-hCG level in the IDDM pregnancies was 0.86 multiples of the median (MOM) for pregnancies without IDDM at the same gestational age (P < 0.002) (95 per cent confidence interval 0.80-0.94). The corresponding free beta-hCG level was 0.96 MOM (95 per cent confidence interval 0.85-1.09). These results enable free alpha-hCG values to be adjusted so that antenatal screening for Down's syndrome can be performed using this marker in IDDM pregnancies as well as in non-diabetic pregnancies.

Four-marker serum screening for Down's syndrome.

The value of measuring the separate sub-units of human chorionic gonadotrophin (free alpha-hCG and free beta-hCG) instead of total hCG together with alpha-fetoprotein (AFP) and unconjugated oestriol (uE3) was examined to determine the effect on the performance of serum screening for Down's syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples relating to 75 singleton pregnancies with fetal Down's syndrome and 367 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the serum sample, supplemented by data from 970 white women with unaffected pregnancies. Using the four serum markers AFP, uE3, free beta-hCG, and free alpha-hCG, in addition to maternal age, 65 per cent of Down's syndrome pregnancies were detected for a 5 per cent false-positive rate compared with 59 per cent with the conventional triple test (AFP, uE3, total hCG with maternal age). If gestation was based on an ultrasound scan examination, the detection rate was 72 per cent using the four serum markers compared with 67 per cent with the triple test. As an alternative illustration, if the detection rate was kept at 60 per cent and gestation was estimated by an ultrasound scan examination the four-marker test reduced the false-positive rate by one-third from 3 per cent using the triple test to 2 per cent with the four-marker test. Screening performance was hardly affected by adjusting marker levels for maternal weight.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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 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.

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.

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.

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.