Screening with discrimination.
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Biomedical subjects
Publications and source records attributed to H S Cuckle.
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Stored amniotic fluid samples collected in Oxford and East Birmingham as part of the Collaborative Acetylcholinesterase Study were assayed for the presence of acetylcholinesterase (AChE) using a monoclonal antibody (4F19) enzyme antigen immunoassay. These results were compared with the results of a gel AChE which had been performed earlier. A total of 5689 samples from singleton pregnancies were analysed (including 36 with anencephaly, 77 with open spina bifida and 17 with anterior abdominal wall defects). The gel test yielded detection rates of 97% for anencephaly, 99% for open spina bifida and 94% for abdominal wall defects; the false positive rate (excluding pregnancies associated with serious abnormalities, miscarriages and intrauterine deaths) was 0.24%. The monoclonal test yielded similar results; using appropriate cut-off values to allow for differences in acetylcholinesterase levels in blood stained and clear samples, a similar false-positive rate of 0.22% was associated with detection rates of 97%, 95% and 71% respectively for the three types of defect. Although the detection rates and the false positive rate were slightly higher for the gel test, a result that might be explained by a decrease in AChE activity caused by storage of the samples, the monoclonal test has the advantages of requiring less interpretative expertise, it can be performed on a larger number of samples a day and it is not affected by contamination with fetal calf serum.
Two series of pregnancies were studied to investigate the relationship between maternal smoking and the risk of fetal Down's syndrome. In the first series, ascertained in the 1960s, in which smoking habits were determined after the outcome of pregnancy was known, the proportion of smokers (47 per cent) among the 461 women whose pregnancies ended in the birth of an infant with Down's syndrome was similar to that in the 461 controls (46 per cent) who had pregnancies affected by other congenital disorders. In the second series, ascertained between 1973 and 1984, smoking habits were determined by measurement of cotinine in antenatal serum samples that were routinely collected and stored or, if a serum sample was not available, from information in the antenatal notes. In this series, the proportion of smokers (14 per cent) among the 91 women who had pregnancies associated with Down's syndrome was lower than that among 413 controls (19 per cent), though this was not statistically significant. Collectively, our results provide no evidence for an association between fetal Down's syndrome and smoking. Other published studies found a deficit of smokers among women who had pregnancies associated with Down's syndrome. This may be partly due to some studies not taking adequate account of maternal age (older women are more likely to have had a Down's syndrome pregnancy but are less likely to be smokers) and partly due to the greater tendency for positive findings to be published than negative ones.
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A survey was carried out to determine the effect of prenatal screening and therapeutic abortion on births in 1985 with anencephaly and spina bifida in England and Wales. Maternal serum alpha-fetoprotein tests were done on 399,288 women (60 per cent of pregnant women): 4 per cent were reported as being screen-positive and 1 per cent had an amniocentesis. An estimated 534 pregnancies associated with anencephaly were terminated and an estimated 445 pregnancies associated with spina bifida (but without anencephaly) were terminated. Most (63 per cent) of the anencephalic pregnancies were first suspected from an ultrasound examination; 57 per cent of the spina bifida pregnancies were first suspected from a positive maternal serum alpha-fetoprotein test, 35 per cent by ultrasound, and the remaining 8 per cent by other means. The birth prevalence of anencephaly declined by 94 per cent between 1964-1972 and 1985, but when the terminations of pregnancy on account of having a fetus with anencephaly are added to the births the decline in prevalence was only 50 per cent. The birth prevalence of spina bifida declined by 68 per cent over the same period but when the terminations were added to the births the decline in prevalence was only 32 per cent. Among births with anencephaly 66 per cent had had no screening or diagnostic tests in early pregnancy, but in those that did nearly all were positive--usually in twin pregnancies where one fetus was affected but not the other. Among births with spina bifida, 48 per cent had no tests and in those that did the results were mainly negative.(ABSTRACT TRUNCATED AT 250 WORDS)
The risk of having a Down's syndrome term pregnancy was estimated using maternal age and the results of two maternal serum alpha-fetoprotein (AFP) tests carried out between 14 and 20 weeks gestation. The estimates of risk were derived from published data and the AFP results from nine affected and 145 unaffected pregnancies in which repeat testing had been carried out. Repeat AFP testing is unjustified in antenatal screening programmes for Down's syndrome, but if a second test happens to have been done, the appropriate estimate of risk that would be applicable when counselling individual patients depends on both results. For example a woman aged 35 years and 6 months with a first AFP level of 0.50 multiples of the normal median (MoM) was estimated to have a risk of 1:172. If a second test were done on a fresh sample and the AFP level were 0.80 MoM then the estimated risk would be 1:216 which is higher than the estimated risk of 1:353 obtained if the second test were regarded as the only result. Estimates of risk are given for maternal serum AFP results in first and second tests ranging from 0.40 to 2.50 MoM.
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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.
Second trimester maternal serum unconjugated oestriol levels were measured in the stored serum samples from 22 pregnancies associated with Down's syndrome and 110 unaffected control pregnancies, matched for maternal age, gestational age, duration of storage of the serum sample, smoking habits and maternal weight. The serum unconjugated oestriol level of each affected pregnancy was expressed as a multiple of the median (MoM) of its five matched controls. The unconjugated oestriol levels were significantly lower in the affected pregnancies than in the unaffected pregnancies; the median MoM was 0.79 (P less than 0.05). This association between low serum unconjugated oestriol and fetal Down's syndrome early in pregnancy raises the possibility that serum unconjugated oestriol measurement may be added to maternal age and alpha-fetoprotein measurement in the antenatal screening for Down's syndrome.
The median maternal serum unconjugated oestriol level between 13 and 27 weeks gestation in 77 pregnancies associated with Down's syndrome was lower than the median level in 385 unaffected control pregnancies matched for maternal age, gestational age, and duration of serum sample storage (P less than 0.001). The median level for the affected pregnancies was 73% of that in the controls. Low unconjugated oestriol levels can be used to detect fetal Down's syndrome; at cut-off levels selected to detect at least 35% of affected pregnancies, unconjugated serum oestriol was a better screening test than either maternal age or serum alpha-fetoprotein (AFP). The use of all three variables in combination to select women with a 1:250 or greater risk of a Down's syndrome term pregnancy would yield a 45% detection rate with a false-positive rate of 5.2%. The same detection rate using maternal age alone or using age and serum AFP in combination would yield higher false-positive rates, 15% and 9.8% respectively. The addition of unconjugated oestriol to a Down's syndrome screening programme would therefore be more efficient than the use of age and AFP alone; for a given detection rate fewer women would need an amniocentesis or, for a given percentage of women having an amniocentesis, more pregnancies with Down's syndrome would be detected.
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It has been suggested that vaginal bleeding in pregnancy is associated with an increased risk of fetal Down syndrome. To investigate this, information on vaginal bleeding, collected at the first antenatal visit, was abstracted from the medical notes of 70 pregnancies associated with Down syndrome and 140 unaffected controls matched for maternal age. Fourteen cases (20 per cent) and 23 controls (16 per cent) had some evidence of bleeding (relative risk estimated as the odds ratio = 1.3; P = 0.26, one-sided; 95 per cent confidence interval 0.6-2.8). When these results were pooled with those from the two other controlled studies already published the combined relative risk estimate was 1.8 (P = 0.02, two-sided; 95 per cent confidence interval 1.1-3.0). On the basis of present evidence, there is some reason to regard vaginal bleeding prior to the first antenatal visit as a risk factor for Down syndrome but the association and its biological significance remains uncertain.
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