- Email: [email protected]
RISKS OF MALFORMED RELATIVES
465 RISK OF DOWN SYNDROME IN RELATION TO
MATERNAL AGE
S;5—Professor Ferguson-Smith (July 31, p. 252) suggests of Down syndrome in liveborns observed in retrospective" studies such as mine’ are gross underestimates in view of the higher rates of trisomy 21 observed in studies of amniotic fluid obtained in the second trimester. This is erroneous on several counts. The rate of Down syndrome in live births may be estimated as about 0-134% in the population I reported upon, using the methods already described.’ In the other retrospective studies ; cited, the rates were z 132% in Sweden and z 145% in Australia.’3 These results may be compared with those of chromosome studies of consecutive newborns or of a prospective phenotypic survey of liveborns in which all received careful examination. In the consecutive chromosome surveys the pooled rate of trisomy 21 from about 57 000 infants in six surveys was 012. This includes one survey from Edinburgh, near where Professor Ferguson-Smith works, in which the rate was 0146%/ In the National Institutes of Health collaborative study in which mothers were ascertained before birth, the rate of Down syndrome in livebirths was 0-115%.’’ Variation in the maternal-age distributions of the populations may well account for what differences there are between these studies. And the rates that are available from these studies by five-year maternal age interval are not disparate. For example, in the 33-39 interval in my study the rate was 0.4%, in the Australian study about 0.35%, and in the N.I.H. prospective study between about 0-3% and 0.4%. The higher rates derived from studies of amniotic-fluid samples in mid-pregnancy cited by Professor Ferguson-Smith are irrelevant to the question of rates in the live born, and there are no grounds for his claim that my study or the other retrospective studies cited have grossly underestimated the true rates. The discrepancy in rates between the two types of studies may be explained by at least two factors. First, the data Professor Ferguson-Smith presents are not age adjusted appropriately. For example, he cites a rate of Down syndrome of 0-8% to mothers in the 35-39 interval: While this is based on sparse data it is higher than the rates in this age interval in the studies cited above. There are, however, more mothers aged 37 in his study than mothers aged 35, and in general, the age distribution of women aged 35 or over is skewed to the older ages compared with the distribution of all pregnant women aged 35 or over. Because of the rapid rise in the rate of Down syndrome at these maternal ages, data from studies of amniotic fluid obtained in the second trimester should be analysed by single year, not the gross intervals "35 to 39" and "40 and over" as presented by Professor Ferguson-Smith, and such’ data should be age adjusted appropriately for comparison with other studies. A difference in maternal age distribution will explain only part of the discrepancy between his study and those of liveborns, however. The remainder may be explained by the relatively high rate of fetal loss of Down syndrome and other chromosome abnormalities in late pregnancy. While only sparse data are available, they are all consistent with this trend. For example, Machin and Crolla found that 1/156 of fetuses lost late in pregnancy (including stillbirths) by mothers of all ages had trisomy 2F and Kuleshov et al. in what appears to be a BlmIlar study, found the rate to be 1/83.8 Creasy and Crolla, that the
rates
1. Hook, E. B. Lancet, 1976, ii, 33.
2 Lindsjo, A. Acta pœdiat. scand. 1974, 63, 571. 3 Collman, R D., Stoller, A. Am.J. publ. Hlth, 1962, 52, 813. 4 Hook, E B, Hamerton, J. H. Population Cytogenetics (edited by E. B. Hook and I. H. Porter). New York (in the press). 5 Jacobs, P. A., Melville, M., Ratcliffe, S., Keay, A. T., Syme, D. Ann. hum. Genet 1974, 37, 359. 6 Sever L., Gilkeson, M. R., Chen, T. C., Ley, A. C., Edmunds, D. Ann. N. YAcad Sci. 1970, 171, 328. 7 Machin, G. A., Crolla, J. A. Humangenetik, 1974, 23, 183.
who estimated that only 35% of trisomy 21 conceptuses survive gestation, found that of 8 trisomy 21 and 7 trisomy-G (i.e., trisomy 21 or 22) fetuses that had been lost between the 10th and 26th week of gestation; 3 had been lost at the 19th week or later.9 Similar considerations apply to the discrepancies in rates of other cytogenetic abnormalities. For these reasons, data derived from studies of amniotic fluid obtained in the second trimester cannot be used to estimate rates of cytogenetic abnormalities among live births. Calculations of the cost-effectiveness of prenatal diagnostic programmes cannot be based upon rates such as those of Professor Ferguson-Smith. And those doing genetic counselling should carefully distinguish the risk of an abnormality in a live birth from the risk of an abnormality detectable in mid-pregnancy. Birth Defects Institute New York State Department of Health, and
Department of Pediatrics, Albany Medical College, Albany, N.Y. 12208, U.S.A.
ERNEST B. HOOK
RISKS OF MALFORMED RELATIVES
SIR,-Professor Edwards (June 19, p. 1348) gave a series of formulae for calculating the risks for multifactorial conditions such as spina bifida to second-degree and third-degree relatives. These formulae make use of estimates of the incidences of the condition in first-degree relatives (11) and in the general population (P). In instances in which the former is not known, it would seem reasonable to substitute the commonly used approximations, 11 10 If this is done, the risk to third-degree relatives, 12, becomes Pand the risk to third-degree relatives, I3, becomes P 1. Theseapproximations, which form an interesting power series, may be more convenient for ready calculation. =
Department of Pediatrics, University of California, San Francisco, California
94143, U.S.A.
CHARLES J. EPSTEIN
’PERSANTIN’-ASPIRIN REINFARCTION STUDY
SiR,—Thrombosis may be an important factor in the intimal thickening of the arteries found in the late stages of atherosclerotic disease, and blood-platelet aggregation may play a fundamental role in initiating thrombus formation in arteries. It has been suggested that acute myocardial infarction and sudden death may be a result of platelet aggregation forming in atherosclerotic arteries or in the microcirculation of the heart. If the incidence of thrombosis and embolisation is reduced, then as a consequence mortality and morbidity from myocardial infarction might be expected to be reduced also. Dipyridamole (’Persantin’) and aspirin are promising antithrombotic agents for prophylactic use in preventing arterial thrombosis in man, and their effects on platelet aggregation indicate that a clinical trial is warranted. Only through a largescale controlled clinical trial can we learn whether aspirin alone or in combination with dipyridamole are useful in the secondary prevention of coronary heart disease. The Persantin-Aspirin Reinfarction Study (PARIS) is a randomised controlled trial designed to test and compare the efficacy of aspirin, and of the combination of dipyridamole and aspirin in the long-term therapy of coronary heart-disease in men and women with a previous myocardial infarction. Assessment covers mortality-rates and the incidence of cardiovascular events, especially recurrent myocardial infarctions. Kuleshov, N. P., Alekhin, N. I., Egolina, N. A., Karetmkova, N. A. Genetika, 1975, 11, 107. 9. Creasy, M. R., Crolla, J. A. Lancet, 1974, i, 473. 10. Edwards, J. H. Acta genet. 1960, 10, 63. 8.
MATERNAL AGE
S;5—Professor Ferguson-Smith (July 31, p. 252) suggests of Down syndrome in liveborns observed in retrospective" studies such as mine’ are gross underestimates in view of the higher rates of trisomy 21 observed in studies of amniotic fluid obtained in the second trimester. This is erroneous on several counts. The rate of Down syndrome in live births may be estimated as about 0-134% in the population I reported upon, using the methods already described.’ In the other retrospective studies ; cited, the rates were z 132% in Sweden and z 145% in Australia.’3 These results may be compared with those of chromosome studies of consecutive newborns or of a prospective phenotypic survey of liveborns in which all received careful examination. In the consecutive chromosome surveys the pooled rate of trisomy 21 from about 57 000 infants in six surveys was 012. This includes one survey from Edinburgh, near where Professor Ferguson-Smith works, in which the rate was 0146%/ In the National Institutes of Health collaborative study in which mothers were ascertained before birth, the rate of Down syndrome in livebirths was 0-115%.’’ Variation in the maternal-age distributions of the populations may well account for what differences there are between these studies. And the rates that are available from these studies by five-year maternal age interval are not disparate. For example, in the 33-39 interval in my study the rate was 0.4%, in the Australian study about 0.35%, and in the N.I.H. prospective study between about 0-3% and 0.4%. The higher rates derived from studies of amniotic-fluid samples in mid-pregnancy cited by Professor Ferguson-Smith are irrelevant to the question of rates in the live born, and there are no grounds for his claim that my study or the other retrospective studies cited have grossly underestimated the true rates. The discrepancy in rates between the two types of studies may be explained by at least two factors. First, the data Professor Ferguson-Smith presents are not age adjusted appropriately. For example, he cites a rate of Down syndrome of 0-8% to mothers in the 35-39 interval: While this is based on sparse data it is higher than the rates in this age interval in the studies cited above. There are, however, more mothers aged 37 in his study than mothers aged 35, and in general, the age distribution of women aged 35 or over is skewed to the older ages compared with the distribution of all pregnant women aged 35 or over. Because of the rapid rise in the rate of Down syndrome at these maternal ages, data from studies of amniotic fluid obtained in the second trimester should be analysed by single year, not the gross intervals "35 to 39" and "40 and over" as presented by Professor Ferguson-Smith, and such’ data should be age adjusted appropriately for comparison with other studies. A difference in maternal age distribution will explain only part of the discrepancy between his study and those of liveborns, however. The remainder may be explained by the relatively high rate of fetal loss of Down syndrome and other chromosome abnormalities in late pregnancy. While only sparse data are available, they are all consistent with this trend. For example, Machin and Crolla found that 1/156 of fetuses lost late in pregnancy (including stillbirths) by mothers of all ages had trisomy 2F and Kuleshov et al. in what appears to be a BlmIlar study, found the rate to be 1/83.8 Creasy and Crolla, that the
rates
1. Hook, E. B. Lancet, 1976, ii, 33.
2 Lindsjo, A. Acta pœdiat. scand. 1974, 63, 571. 3 Collman, R D., Stoller, A. Am.J. publ. Hlth, 1962, 52, 813. 4 Hook, E B, Hamerton, J. H. Population Cytogenetics (edited by E. B. Hook and I. H. Porter). New York (in the press). 5 Jacobs, P. A., Melville, M., Ratcliffe, S., Keay, A. T., Syme, D. Ann. hum. Genet 1974, 37, 359. 6 Sever L., Gilkeson, M. R., Chen, T. C., Ley, A. C., Edmunds, D. Ann. N. YAcad Sci. 1970, 171, 328. 7 Machin, G. A., Crolla, J. A. Humangenetik, 1974, 23, 183.
who estimated that only 35% of trisomy 21 conceptuses survive gestation, found that of 8 trisomy 21 and 7 trisomy-G (i.e., trisomy 21 or 22) fetuses that had been lost between the 10th and 26th week of gestation; 3 had been lost at the 19th week or later.9 Similar considerations apply to the discrepancies in rates of other cytogenetic abnormalities. For these reasons, data derived from studies of amniotic fluid obtained in the second trimester cannot be used to estimate rates of cytogenetic abnormalities among live births. Calculations of the cost-effectiveness of prenatal diagnostic programmes cannot be based upon rates such as those of Professor Ferguson-Smith. And those doing genetic counselling should carefully distinguish the risk of an abnormality in a live birth from the risk of an abnormality detectable in mid-pregnancy. Birth Defects Institute New York State Department of Health, and
Department of Pediatrics, Albany Medical College, Albany, N.Y. 12208, U.S.A.
ERNEST B. HOOK
RISKS OF MALFORMED RELATIVES
SIR,-Professor Edwards (June 19, p. 1348) gave a series of formulae for calculating the risks for multifactorial conditions such as spina bifida to second-degree and third-degree relatives. These formulae make use of estimates of the incidences of the condition in first-degree relatives (11) and in the general population (P). In instances in which the former is not known, it would seem reasonable to substitute the commonly used approximations, 11 10 If this is done, the risk to third-degree relatives, 12, becomes Pand the risk to third-degree relatives, I3, becomes P 1. Theseapproximations, which form an interesting power series, may be more convenient for ready calculation. =
Department of Pediatrics, University of California, San Francisco, California
94143, U.S.A.
CHARLES J. EPSTEIN
’PERSANTIN’-ASPIRIN REINFARCTION STUDY
SiR,—Thrombosis may be an important factor in the intimal thickening of the arteries found in the late stages of atherosclerotic disease, and blood-platelet aggregation may play a fundamental role in initiating thrombus formation in arteries. It has been suggested that acute myocardial infarction and sudden death may be a result of platelet aggregation forming in atherosclerotic arteries or in the microcirculation of the heart. If the incidence of thrombosis and embolisation is reduced, then as a consequence mortality and morbidity from myocardial infarction might be expected to be reduced also. Dipyridamole (’Persantin’) and aspirin are promising antithrombotic agents for prophylactic use in preventing arterial thrombosis in man, and their effects on platelet aggregation indicate that a clinical trial is warranted. Only through a largescale controlled clinical trial can we learn whether aspirin alone or in combination with dipyridamole are useful in the secondary prevention of coronary heart disease. The Persantin-Aspirin Reinfarction Study (PARIS) is a randomised controlled trial designed to test and compare the efficacy of aspirin, and of the combination of dipyridamole and aspirin in the long-term therapy of coronary heart-disease in men and women with a previous myocardial infarction. Assessment covers mortality-rates and the incidence of cardiovascular events, especially recurrent myocardial infarctions. Kuleshov, N. P., Alekhin, N. I., Egolina, N. A., Karetmkova, N. A. Genetika, 1975, 11, 107. 9. Creasy, M. R., Crolla, J. A. Lancet, 1974, i, 473. 10. Edwards, J. H. Acta genet. 1960, 10, 63. 8.