Ak Hackshaw

First and Second Trimester Antenatal Screening for Down's Syndrome: The Results of the Serum, Urine and Ultrasound Screening Study (SURUSS):

Objectives To identify the most effective, safe and cost-effective method of antenatal screening for Downs syndrome using nuchal translucency (NT), maternal serum and urine markers in the first and second trimesters of pregnancy, and maternal age in various combinations.Design A prospective study of women who booked for their antenatal care at about 8-14 weeks of gestation, with follow-up to identify pregnancies with Downs syndrome ascertained through second trimester screening or at birth.Setting Twenty-five maternity units (24 in the UK and one in Austria) offering second trimester Downs syndrome serum screening that agreed to collect observational data in the first trimester.Participants The results were based on 47,053 singleton pregnancies, including 101 pregnancies with Downs syndrome.Measurements and tests NT measurements were included if obtained between 9 and 13 weeks of pregnancy; serum and urine samples were also taken and stored. Another pair of serum and urine samples was collected in the second trimester and included if obtained between 14 and 20 weeks. Urine and serum samples from each affected pregnancy and five matched controls were tested for:Serum:alphafetoprotein (AFP)total human chorionic gonadotrophin (hCG)unconjugated oestriol (uE(3))pregnancy associated plasma protein A (PAPP-A)free beta-hCG.dimeric inhibin-A.Urine:invasive trophoblast antigen (ITA)beta-core fragmenttotal hCGfree beta-hCG.The matching criteria were gestation (using an ultrasound crown-rump length or biparietal diameter measurement), duration of storage, and centre. Screening performance of the individual markers and combinations of markers together with maternal age was assessed using standard methods. In addition pairs of first and second trimester serum samples from 600 controls were tested to secure a larger set in which screening performance could be determined using distribution parameters based on dates (time since first day of the last menstrual period).Main outcome measures The following were determined for different combinations of markers:efficacy (by assessing screening performance, focusing on the false-positive rate (FPR) for an 85% detection rate (DR))safety (focusing on the number of fetal losses due to amniocentesis (or chorionic villus sampling) in 100,000 women screened)cost-effectiveness (focusing on the cost of screening 100,000 women and the cost per Downs syndrome pregnancy diagnosed).Results Efficacy (screening performance) The false-positive rates for an 85% detection rate for the main screening tests are shown in the above table, in decreasing order of screening performance:With the serum integrated test, 10 weeks is the preferred time in pregnancy for the PAPP-A measurement. For the integrated test and the combined test, the timing of the measurement of the first trimester markers is less critical.Safety The lower false-positive rate with the integrated test compared with other tests means that at an 85% detection rate there would be nine diagnostic procedure-related unaffected fetal losses per 100,000 women screened compared with 44 using the combined test or 45 with the quadruple test.Cost-effectiveness Screening using the integrated test is less costly than might be expected because the extra screening costs tend to be offset by savings in the cost of diagnosis arising from the low false-positive rate. It was estimated that to achieve an 85% detection rate the cost to the UK NHS would be pound15,300 per Downs syndrome pregnancy detected. The corresponding cost using the second trimester quadruple test would be pound16,800 and using the first trimester combined test it would be pound19,000.Conclusions Implications for healthcare The results showed that screening performance in the first trimester of pregnancy was virtually the same as that in the second trimester, and in either it was much less effective than integrating screening measurements from both trimesters into a single test. In applying these results to screening practice several conclusions can be drawn. The following tests offer the most effective and safe method of screening:overall: the integrated testif an NT measurement is not available: the serum integrated testfor women who do not attend for antenatal care until the second trimester of pregnancy: the quadruple testfor women who choose to have a screening test in the first trimester: the combined test.At a constant detection rate, the cost-effectiveness of these four tests is broadly similar, any extra screening costs tending to be offset by fewer diagnostic costs. The evidence presented in this report does not support retaining the double test, the triple test, or NT measurements on their own (with or without maternal age) because each would lead to many more women having invasive diagnostic tests, without increasing the proportion of Downs syndrome pregnancies detected.

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 Downs 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 womans risk of having a pregnancy affected by Downs 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 Downs 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 Downs 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 Downs syndrome with a much lower false positive rate than the best currently available test.

When can a risk factor be used as a worthwhile screening test

One of the most important areas of medical inquiry is the identification of risk factors for specific disorders. Such research is usually aimed at discovering new causes of a disease, but risk factors can also be used as screening tests. The fact that a risk factor must be very strongly associated with a disorder if it is to be a worthwhile screening test is not widely recognised. If this were better understood, fewer risk factors would be proposed unnecessarily as screening tests. Serum cholesterol measurement, for example, would probably never have been considered seriously as a screening test for ischaemic heart disease. Although a high cholesterol concentration is a strong risk factor for ischaemic heart disease in aetiological terms, the association is not sufficiently strong for it to be used as a screening test—in practice, its screening performance is poor.1 In this article we specify the quantitative relation between risk factors and screening tests and show how strongly a risk factor needs to be associated with a disease before it is likely to be a useful screening test. For simplicity, we consider only risk factors with a Gaussian distribution, though the general principles we present can be applied to all frequency distributions. #### Summary points To be a worthwhile screening test, a risk factor must be strongly associated with a disorder The strength of association between a risk factor and a disorder can be quantified by the relative risk or relative odds (odds ratio) A risk factor can also be considered as a screening test, and its association with the disorder can be quantified as the detection rate for a specified false positive rate There is a direct numerical equivalence between the relative odds and the detection rate for specified false positive rate that does not depend on the incidence or prevalence …

Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study

Abstract Objective: To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. Design: Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21 515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. Subjects: Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. Main outcome measure: The difference in mortality from ischaemic heart disease for a 0.6 mmol/1 difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. Results: The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/1 in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/1 in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. Conclusions: The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.

Combining ultrasound and biochemistry in first-trimester screening for Down's syndrome.

Data on pregnancies with and without Downs syndrome between 10 and 14 weeks of pregnancy were used to determine the performance of combined ultrasound and biochemical markers in prenatal screening for Downs syndrome. We used three datasets: one published by Pandya et al. (1995) on nuchal translucency measurement in 86 Downs syndrome pregnancies; one published by Wald et al. (1996a) on free beta human chorionic gonadotrophin (hCG) and pregnancy‐associated plasma protein A (PAPP‐A) in 77 affected pregnancies and 385 unaffected pregnancies; and the third from Schuchter et al. on 561 unaffected pregnancies with nuchal translucency measurement. Combining the data from these three datasets showed that screening between 10 and 14 weeks by combining the serum markers with nuchal translucency measurement had a detection rate of 80 per cent for a 5 per cent false‐positive rate, better than maternal age with two serum markers (62 per cent for 5 per cent) or maternal age with nuchal translucency measurement (63 per cent for 5 per cent). At this time in pregnancy, it appears that screening using the combined test is better than second‐trimester serum screening (76 per cent for 5 per cent), though these estimates do not allow for any association between the markers and spontaneous fetal loss, an issue that needs to be clarified by further research. Meanwhile, these results provide a reasonable working estimate of screening performance using different combinations of these markers.

Antenatal screening for Down's syndrome with the quadruple test

Second trimester screening for Downs syndrome is widely practised throughout the world. We assessed the performance of antenatal serum screening for Downs syndrome with the quadruple test in 46193 pregnancies from 14 hospitals over 5 years. Women who screened positive (risk > or =1 in 300) were offered diagnostic amniocentesis or chorionic villus sampling. Of 88 observed Downs syndrome pregnancies, 71 (81%) had a positive screening result (81% detection rate, 95% CI 72-89), and of 46105 unaffected pregnancies, 3200 tested positive (7% false-positive rate). These results show that the quadruple test is a better method of screening for Downs syndrome than use of maternal age alone (51% detection rate, 14% false-positive rate) and is more effective than other second trimester screening tests. Therefore, we conclude that the quadruple test should be the test of choice in second trimester screening for Downs syndrome.

SURUSS in perspective.

Background  Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Downs Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Downs Syndrome pregnancies, and discuss their implications.

Empirical validation of risk screening for Down's syndrome.

Objective— To validate individual risk estimates in antenatal serum screening for Downs syndrome. Methods— Women screened for Downs syndrome using maternal serum a fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophs (hCG) with maternal age (the triple test) or AFP, uE3, free β subunit and free a subunit of hCG with maternal age (the quadruple test) were grouped according to their predicted risk of having an affected pregnancy. The mean predicted risk in each category was then compared with the observed prevalence based on the number of affected and unaffected pregnancies in each category. Subjects— About 100 000 pregnant women screened for Downs syndrome from 1989 to 1995. Results— There was close agreement between the predicted term risk and the prevalence at birth for both the triple test and the quadruple test. For example, with the quadruple test the predicted risk in the highest risk group was 1 in 3.3 and the prevalence was 1 in 2.6; in the lowest risk group these were 1 in 3000 and 1 in 2300 respectively. Conclusion— Risk estimates based on multiple marker screening for Downs syndrome are accurate. The technique used to demonstrate this is simple and offers a useful empirical check on screening performance.

Folic acid and miscarriage: An unjustified link

The letter by Windham et al., [2000] cannot be taken as showing that folic acid causes miscarriage, and Professor Hook’s interpretation of the results to this effect in his editorial comment [Hook, 2000] is unjustified. Windham and her colleagues compare the rates of miscarriage in women who took multivitamins early in pregnancy with women who did not. The rates were, respectively, 10.3% and 9%, a difference that was not statistically significant (reported relative risk 1.14, with a 95% confidence interval of 0.96–1.36). In his editorial, Professor Hook gives a P value for this difference of 0.06 but this is based on a one-tailed test, which is inappropriate. Even if there were a result that could not be explained by chance, there would be no reason to conclude that this was due to folic acid because many other vitamins were included in the multivitamin preparation. The MRC Vitamin Study [Wald et al., 1991] is the only large randomized, controlled trial capable of examining the specific effect of folic acid on miscarriage, and overall it provided no suggestion of an effect (relative risk of 1.06 with a 95% confidence interval of 0.79– 1.43, P 4 0.70) [Wald and Hackshaw, 1997]. If the data were restricted to compare those women who were only given folic acid with those given neither folic acid nor multivitamins, the relative risk is 0.98 (95% confidence interval 0.64–1.49, P 4 0.91). There is not even a suggestion that folic acid supplementation is a cause of miscarriage. The negative evidence is all the more compelling given that the MRC trial used a high dose of folic acid (4 mg), approximately 10 times greater than that used in supplements available over the counter.

Maternal Serum Prostate-specific Antigen and Down Syndrome in the First and Second Trimesters of Pregnancy

It has been suggested that high levels of maternal serum prostate‐specific (PSA) may be associated with fetal Down syndrome. We retrieved stored blood samples from 102 singleton Down syndrome pregnancies at 8–14 weeks’ gestation and 99 at 15–22 weeks’ gestation, together with samples from five unaffected singleton control pregnanceis matched for gestational age. PSA was measured using an ultrasensitive assay. Contrary to earlier reports, PSA levels were similar in affected and unaffected pregnancies in both the first and second trimester of pregnancy; 1.1 and 0.9 multiple of the normal median, respectively, in affected pregnancies. There was no indication that PSA would be a useful screening marker. Copyright