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Antenatal screening for Down's syndrome
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE
Antenatal screening for Down’s syndrome Sir—James Haddow’s Aug 1 commentary1 correctly points out that the 268 (82%) of 326 recognised Down’s syndrome pregnancies detected in the Fetal Medicine Foundation Study (Aug 1, p 343)2 of ultrasound nuchal translucency screening is a biased estimate of the detection rate. In any prospective intervention trial of this kind the proportion detected will overestimate the detection rate because of unrecognised affected pregnancies. This overestimate arises because most affected pregnancies, viable and nonviable, with abnormal screening results are terminated, whereas cases with normal results that miscarry are not recognised. Haddow’s suggested alternative method seems to underestimate the detection rate. He divides the number of detected cases by the expected number of affected pregnancies, assumed to be 40% more than the expected number of births, derived from the maternal age distribution (60%=268/(1·40⫻266)). A more direct alternative method is adopted in Snijders and colleagues’ report2 from the Fetal Medicine Foundation Study. The observed number of affected births divided by the expected number is subtracted from 100% (78%=100%–58/266). Statistical modelling techniques, which have been shown to be reliable in planning screening policy for Down’s syndrome, yield a predicted detection rate much closer to 78% then 60%. With adjustment to allow for non-viable cases,3 the predicted detection rate for an 8% false-positive rate (that found in the Fetal Medicine Foundation Study) is 77%, based on the maternal age distribution for England and Wales in 1991–95.4 There are now sufficient published data on both nuchal translucency and first-trimester maternal serum markers to reliably model a combined screening approach. The simplest combined protocol is to obtain a blood sample at 9–11 weeks and schedule an ultrasound for 12–13 weeks. In Leeds we have shown this approach to be
1144
feasible: the nuchal-translucency measurement is telephoned to the laboratory and a combined risk of Down’s syndrome is immediately faxed to the sonographer. With serum markers based on a meta-analysis of 44 studies I have calculated that the predicted detection rate is 91% for an 8% false-positive rate and 88% for a 5% false-positive rate. The UK’s Department of Health National Screening Committee is currently considering the possibility of a national Down’s syndrome screening programme based on second-trimester serum markers. They should consider programmes in the first and second trimester of pregnancy. Howard Cuckle Centre for Reproduction, Growth and Development, School of Medicine, University of Leeds, Leeds LS2 9NZ, UK 1
2
3
4
Haddow JE. Antenatal screening for Down’s syndrome: where are we and where next? Lancet 1998; 352: 336. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchaltranslucency thickness at 10–14 weeks of gestation. Lancet 1998; 352: 343–46. Nicolaides KH, Snijders RJM, Cuckle HS. Correct estimation of parameters for ultrasound nuchal translucency screening. Prenat Diagn 1998; 14: 203–08. Office of Population Censuses and Surveys. Birth Stat Ser FM1 1993; 97: 20–24.
Author’s reply Sir—Howard Cuckle’s comment about methods to calculate detection rates in interventional trials offers an opportunity to explain further why my method of calculating a 60% detection rate is likely to be accurate. The critical number to be determined is the total number of affected fetuses in the screened population during the first trimester. R J M Snijders and colleagues 1 provide the estimated number of cases at birth, based on the maternal age distribution of women in their study. This represents 60% of the cases present in the first trimester
(266/0·6=443). In calculating their detection rate, however, the investigators do not use this number as the denominator. Instead, they combine the number of affected pregnancies identified by screening with the number identified at birth. That total is 365, after taking into account spontaneous losses (268+58/0·6). The discrepancy between these two estimates of the number of Down’s syndrome pregnancies in the first trimester is quite large (78). The most probable explanation is that the authors did not find all the cases missed by screening. Cuckle’s calculation of 78% detection also assumes that the number of Down’s syndrome cases identified at birth is correct and, thus has the same limitation as Snijders’ estimate. In studies as large as that of Snijders and co-workers, the number of cases of Down’s syndrome ascertained (after correction) should be in reasonable agreement with the number estimated by the maternal age distribution. For example, in a cohort of 226 000 births in Maine, the expected number of Down’s syndrome births was 253. After adjustment for the trimester of ascertainment, we identified 245 cases.2 As a second example, we did a meta-analysis that involved 16 second-trimester intervention trials of serum screening for Down’s syndrome.3 Among the 224 000 pregnancies collectively screened, 355 second-trimester affected pregnancies were estimated by the maternal age distributions; 367 were ascertained (after correction to the second trimester). James E Haddow Foundation for Blood Research, PO BOX 190, Scarborogh, ME 04070, USA 1
2
Snijders RJM, Noble P, Sebire N, Souka A. Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Lancet 1998; 352: 343–46. Palomaki GE, Haddow JE, Beauregard LJ. Prenatal screening for Down’s syndrome in Maine, 1980 to 1993. N Engl J Med 1996; 334: 1409–10.
THE LANCET • Vol 352 • October 3, 1998
COMMENTARY
CORRESPONDENCE
Antenatal screening for Down’s syndrome Sir—James Haddow’s Aug 1 commentary1 correctly points out that the 268 (82%) of 326 recognised Down’s syndrome pregnancies detected in the Fetal Medicine Foundation Study (Aug 1, p 343)2 of ultrasound nuchal translucency screening is a biased estimate of the detection rate. In any prospective intervention trial of this kind the proportion detected will overestimate the detection rate because of unrecognised affected pregnancies. This overestimate arises because most affected pregnancies, viable and nonviable, with abnormal screening results are terminated, whereas cases with normal results that miscarry are not recognised. Haddow’s suggested alternative method seems to underestimate the detection rate. He divides the number of detected cases by the expected number of affected pregnancies, assumed to be 40% more than the expected number of births, derived from the maternal age distribution (60%=268/(1·40⫻266)). A more direct alternative method is adopted in Snijders and colleagues’ report2 from the Fetal Medicine Foundation Study. The observed number of affected births divided by the expected number is subtracted from 100% (78%=100%–58/266). Statistical modelling techniques, which have been shown to be reliable in planning screening policy for Down’s syndrome, yield a predicted detection rate much closer to 78% then 60%. With adjustment to allow for non-viable cases,3 the predicted detection rate for an 8% false-positive rate (that found in the Fetal Medicine Foundation Study) is 77%, based on the maternal age distribution for England and Wales in 1991–95.4 There are now sufficient published data on both nuchal translucency and first-trimester maternal serum markers to reliably model a combined screening approach. The simplest combined protocol is to obtain a blood sample at 9–11 weeks and schedule an ultrasound for 12–13 weeks. In Leeds we have shown this approach to be
1144
feasible: the nuchal-translucency measurement is telephoned to the laboratory and a combined risk of Down’s syndrome is immediately faxed to the sonographer. With serum markers based on a meta-analysis of 44 studies I have calculated that the predicted detection rate is 91% for an 8% false-positive rate and 88% for a 5% false-positive rate. The UK’s Department of Health National Screening Committee is currently considering the possibility of a national Down’s syndrome screening programme based on second-trimester serum markers. They should consider programmes in the first and second trimester of pregnancy. Howard Cuckle Centre for Reproduction, Growth and Development, School of Medicine, University of Leeds, Leeds LS2 9NZ, UK 1
2
3
4
Haddow JE. Antenatal screening for Down’s syndrome: where are we and where next? Lancet 1998; 352: 336. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchaltranslucency thickness at 10–14 weeks of gestation. Lancet 1998; 352: 343–46. Nicolaides KH, Snijders RJM, Cuckle HS. Correct estimation of parameters for ultrasound nuchal translucency screening. Prenat Diagn 1998; 14: 203–08. Office of Population Censuses and Surveys. Birth Stat Ser FM1 1993; 97: 20–24.
Author’s reply Sir—Howard Cuckle’s comment about methods to calculate detection rates in interventional trials offers an opportunity to explain further why my method of calculating a 60% detection rate is likely to be accurate. The critical number to be determined is the total number of affected fetuses in the screened population during the first trimester. R J M Snijders and colleagues 1 provide the estimated number of cases at birth, based on the maternal age distribution of women in their study. This represents 60% of the cases present in the first trimester
(266/0·6=443). In calculating their detection rate, however, the investigators do not use this number as the denominator. Instead, they combine the number of affected pregnancies identified by screening with the number identified at birth. That total is 365, after taking into account spontaneous losses (268+58/0·6). The discrepancy between these two estimates of the number of Down’s syndrome pregnancies in the first trimester is quite large (78). The most probable explanation is that the authors did not find all the cases missed by screening. Cuckle’s calculation of 78% detection also assumes that the number of Down’s syndrome cases identified at birth is correct and, thus has the same limitation as Snijders’ estimate. In studies as large as that of Snijders and co-workers, the number of cases of Down’s syndrome ascertained (after correction) should be in reasonable agreement with the number estimated by the maternal age distribution. For example, in a cohort of 226 000 births in Maine, the expected number of Down’s syndrome births was 253. After adjustment for the trimester of ascertainment, we identified 245 cases.2 As a second example, we did a meta-analysis that involved 16 second-trimester intervention trials of serum screening for Down’s syndrome.3 Among the 224 000 pregnancies collectively screened, 355 second-trimester affected pregnancies were estimated by the maternal age distributions; 367 were ascertained (after correction to the second trimester). James E Haddow Foundation for Blood Research, PO BOX 190, Scarborogh, ME 04070, USA 1
2
Snijders RJM, Noble P, Sebire N, Souka A. Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Lancet 1998; 352: 343–46. Palomaki GE, Haddow JE, Beauregard LJ. Prenatal screening for Down’s syndrome in Maine, 1980 to 1993. N Engl J Med 1996; 334: 1409–10.
THE LANCET • Vol 352 • October 3, 1998