From the Pregnancy Outcome Unit, Epidemiology Branch, South Australian Department of Human Services, Adelaide, South Australia 5000, Australia.
Received for publication April 17, 2003; accepted for publication April 22, 2003.
Abbreviations: Abbreviation: BERD, Birth Events Record Database.
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INTRODUCTION |
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It is well-known that risk of a Downs syndrome pregnancy increases with maternal age (2, 3). Since the 1970s, pregnant women aged 35 years or more have been offered amniocentesis and karyotyping of their fetuses so they can have the option of terminating the pregnancy if Downs syndrome is detected. Chorionic villus sampling for detection of fetal Downs syndrome became available during the mid-1980s; it has the advantage that it can be performed earlier in pregnancy (usually at 1012 weeks gestation as compared with 1518 weeks for amniocentesis), but it involves a greater risk of miscarriage (4). Prenatal diagnosis of Downs syndrome was largely confined to older women until the late 1980s and 1990s, when maternal serum screening for Downs syndrome became available. Diagnosis of Downs syndrome among those pregnancies found to involve "increased risk" in maternal serum screening had to be undertaken by amniocentesis. With the availability of maternal serum screening to pregnant women of all ages, a much larger proportion of Downs syndrome was detected prenatally and an increasing proportion of these pregnancies were terminated, resulting in decreased birth prevalence of Downs syndrome (59). However, total prevalence of Downs syndrome (including births and terminations of pregnancy) has been increasing because of the older age of mothers. Thus, in all studies aimed at identifying associations between various factors and the risk of Downs syndrome, it is essential to include both births and terminations among fetuses with Downs syndrome.
Doria-Rose et al. found it difficult to explain why investigators in some other studies (10, 11) concluded that there was no association between parity and Downs syndrome risk after adjusting for age. However, they identified most of the reasons for this in their Discussion (1).
Inclusion of terminations for Downs syndrome
Doria-Rose et al. included only births with Downs syndrome in their analysis. The prevalence of Downs syndrome in Washington State for the entire study period was 8.1 per 10,000 livebirths, with a trend towards a decreasing prevalence over the period (1). Downs syndrome prevalences quoted for Doria-Rose et al.s study and for the entire United States for 19831990 (9.2 per 10,000 livebirths) (12) are birth prevalences; therefore, they are low in comparison with total prevalences from Australia for the same period. In three Australian states with birth defects registers and access to statewide cytogenetic diagnoses, the total prevalences based on both births and terminations increased over the study years of 19841998, from 11.7 per 10,000 births to 17.9 per 10,000 births in Western Australia (8, 13), from 10.4 to 24.6 in South Australia (9, 14), and from 16.0 to 21.5 in Victoria (15), with an increase in maternal age (8, 9, 14). On the other hand, birth prevalences in Australia fell considerably, by up to 60 percent, because of increased prenatal diagnosis and termination of pregnancy (8, 9). Thus, a substantial proportion of Downs syndrome babies, of women who availed themselves of prenatal diagnosis and pregnancy termination, were excluded from Doria-Rose et al.s analysis, especially in the later years. The women left in the analysis, who had births of Downs syndrome babies, included larger proportions of Hispanic women, high-parity women, and women with fewer previous pregnancy terminations in comparison with controls. It was in this group that the authors found an association between parity and risk of Downs syndrome. While similar results were obtained using data sets for different years and with or without BERD, all of these analyses used only birth data.
Ascertainment of Downs syndrome births
Doria-Rose et al. identified Downs syndrome births from birth certificate records for Washington State and BERD, but BERD data were included for only 10 of the 15 years of the study. Although the authors report that the prevalence in 19871989 was similar to that of a birth defects surveillance program, this was for years in which the birth certificate information was supplemented by the BERD information. Data from birth certificate records have been shown to underascertain Downs syndrome, with sensitivity being only 19 percent in Atlanta, Georgia, in a comparison with birth defects registry records (16). Doria-Rose et al.s data also show that ascertainment of Downs syndrome births by BERD was incomplete. Thus, for at least 5 study years, a proportion of Downs syndrome births was excluded from the analysesthat is, births to women for whom the condition was not recorded on birth certificates. Those children not diagnosed before birth registration also would not have been included (12).
Lesser use of prenatal diagnosis by women of high parity
Women of higher parity (three and above) have been shown to use amniocentesis less frequently than women of lower parity (17, 18). Doria-Rose et al. tried to correct for this bias by excluding cases for which the mother had undergone amniocentesis, as self-identified in the birth certificate record. However, amniocentesis has been shown to be underreported on birth certificates, with a sensitivity of 5061 percent in comparison with hospital medical records (19). Furthermore, in excluding these women, Doria-Rose et al. were presumably excluding those who had Downs syndrome diagnosed prenatally but continued with their pregnancies. Thus, the authors second analysis of cases was limited largely to births to a select group of women who did not avail themselves of prenatal diagnosis and gave birth to a Downs syndrome baby.
"Error" which may be introduced by inclusion of pregnancy terminations in the analysis
Inclusion of terminations of pregnancy for Downs syndrome in the analysis may introduce the error of overascertainment, since some of these fetuses may be spontaneously lost before birth. The vast majority of prenatal diagnoses are made by amniocentesis rather than chorionic villus sampling. In South Australia during the years 19941998, amniocentesis accounted for a slightly lower proportion of these prenatal diagnostic procedures than in Washington State: approximately 88 percent (9, 14) as compared with more than 95 percent (1). Spontaneous loss of Downs syndrome fetuses after the time of amniocentesis at 1518 weeks gestation and before birth has been estimated to be 1224 percent (2023). An Australian study (20) found spontaneous losses of 17 percent between chorionic villus sampling (at 1012 weeks gestation) and amniocentesis and 13 percent between amniocentesis and 20 weeks gestation. Spontaneous losses based on these figures were estimated in the South Australian study for Downs syndrome pregnancies that were terminated in 19861995 (9). We found that this would have resulted in the loss of 18 fetuses out of the 284 births and terminations (6 percent) included in the study (11), mainly in the later years. This is a relatively small proportion, but it comprises 16 percent of the 113 pregnancy terminations. In that study (11), the mean length of gestation among the terminated Downs syndrome pregnancies was 18.3 weeks (median 19 weeks), and because notification is required for all births of at least 20 weeks gestation, including stillbirths (which are fetal losses), the loss would have been even less than that calculated from the time of the prenatal diagnostic procedure. Admittedly, this proportion of fetuses that would have been spontaneously lost might increase in the future with earlier prenatal diagnosis and termination of pregnancy.
Other studies that have found this association between parity and risk of Downs syndrome (2426) have also been based on analysis of data on Downs syndrome births only. Two studies (24, 25) used 5-year age intervals in the analysis, and it has been suggested that the findings of those studies were due to truncation of maternal age (2527). Kallen (26) concluded that the association found among older mothers of high parity in his study was related to their lesser use of prenatal diagnosis. In our study (11), we found that when births alone were analyzed, there was a statistically significant increase in risk with increasing parity, but when we adjusted for age there was no association. However, when we included terminations with births, there was no association between parity and risk of Downs syndrome (11). Our study used data on Downs syndrome births and terminations obtained directly from a birth defects register and a cytogenetics database for the entire state of South Australia, in which data on all births and pregnancy terminations, including information on age, parity, and gestation, are required to be reported under legislation. The birth data have also been demonstrated in two validation studies to have a very high level of reliability when compared with hospital case records for the variables of interest, namely maternal age ( = 0.97) and parity (
= 0.97) (28, 29).
While Doria-Rose et al. must be commended for using various strategies to try to identify and correct sources of error, the deficiencies in the available data were considerable. For a study to determine the association between parity and risk of Downs syndrome, it would be necessary to have access to complete population data on births (including maternal age and parity) and complete data on all births and pregnancy terminations for Downs syndrome (maternal age and parity and gestational age) from a birth defects register with access to a cytogenetics database.
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NOTES |
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REFERENCES |
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