1 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
2 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Received for publication October 15, 2002; accepted for publication March 3, 2003.
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ABSTRACT |
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case-control studies; Down syndrome; parity; prenatal diagnosis; prevalence; risk factors
Abbreviations: Abbreviation: BERD, Birth Events Record Database.
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INTRODUCTION |
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Downs syndrome is one of the most frequently reported birth defects in the United States, with a prevalence of 9.2 cases per 10,000 livebirths (1). Advanced maternal age is strongly associated with an increased risk of Downs syndrome; however, other risk factors are less well established. Investigators from several studies have reported a positive association between parity and Downs syndrome (26), although several other groups did not find an association (79). The interpretation of many of these studies has been hindered by certain methodological issues (10). Because parity is closely correlated with maternal age, and because several early studies examining the relation between parity and Downs syndrome used broad (5-year) categories in controlling for maternal age (25), it has been suggested that at least part of the apparent effect of parity is due to residual confounding (4, 10). Additionally, there is some evidence that women of higher parity are less likely to undergo prenatal screening for Downs syndrome by amniocentesis or chorionic villus sampling (6, 8, 1113) and therefore are less likely to choose to terminate a Downs syndrome pregnancy than women of lower parity. This would result in an excess of Downs syndrome livebirths among multiparous women, even in the absence of a true biologic association with parity.
The purpose of this study was to examine increasing parity as an independent risk factor for Downs syndrome, while attempting to minimize the possibility of residual confounding by age, and to evaluate the potential effect of differential pregnancy termination practices between high-parity and low-parity women.
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MATERIALS AND METHODS |
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Five controls were matched to each case on the basis of exact maternal age (in years) and infant birth year. Controls were selected randomly from children born without Downs syndrome, as indicated by both the birth record and the BERD database or by birth record only for the years for which BERD was not available. Exact matching on maternal age was used to minimize the potential for residual confounding. For two cases, only four controls could be identified; thus, there were 4,488 controls in total.
All cases and controls were limited to infants with mothers aged 20 years or more (because of the small number of women under age 20 with a parity greater than two) for whom information on parity was available on the birth certificate. Twelve case infants with missing parity information were excluded (1.3 percent of all identified cases); a small proportion from the control pool (2.6 percent) were similarly excluded because of a missing value for parity.
Exposure status was ascertained using parity information from the birth certificate records. Five different levels of parity were examined: zero, one, two, three, and four or more previous livebirths. Additionally, information on potentially confounding factors was obtained from the birth records. Potential confounders that were considered included infants race, maternal smoking during pregnancy, and a variety of variables related to the reproductive history of the mother, for both previous pregnancies (prior fetal death or prior induced termination) and the index pregnancy (whether amniocentesis was performed).
Conditional logistic regression was used to assess the risk of Downs syndrome associated with increasing parity. Odds ratios and their corresponding 95 percent confidence intervals were calculated, using a parity of zero as the reference category. Linear tests of trend (two-sided) were also conducted. Preliminary analyses suggested that the association between parity and Downs syndrome differed by maternal age; therefore, odds ratios were calculated separately for women under age 35 years and women aged 35 years or more. Likelihood ratio tests were used to determine the significance of the interaction between maternal age and parity (two-sided tests with an alpha level of 0.05). All analyses were carried out using the statistical software package Stata, version 7.0 (Stata Corporation, College Station, Texas).
Because women of higher parity may have a lower likelihood of choosing to terminate a pregnancy in which they are carrying a Downs syndrome fetus (6, 8, 1113), we conducted a second analysis in which Downs syndrome infants and controls were excluded if amniocentesis during the index pregnancy was reported on the birth certificate. Women not receiving amniocentesis would probably not know of any genetic abnormalities in the fetus, and thus any association between parity and Downs syndrome in this group would be less likely to be due to differential likelihood of pregnancy termination. For this analysis, odds ratios and 95 percent confidence intervals were calculated and trend tests and likelihood ratio tests were conducted as above. This subanalysis was based on information from 763 cases and 3,276 controls.
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RESULTS |
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Selected characteristics of cases and controls are shown in table 1. Approximately one third of Downs syndrome cases were born to mothers over age 35. Even after age-matching, case mothers were more likely to be of higher parity than controls; this relation was particularly strong among older women (aged 35 years or more). Patterns of amniocentesis usage also differed by maternal age. Older control mothers were much more likely to receive amniocentesis than mothers of Downs syndrome infants. This association was reversed in younger women (under age 35 years), with a slight excess in utilization among case mothers. Case mothers were also slightly less likely to report a previous induced pregnancy termination than control mothers.
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DISCUSSION |
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There are several limitations to using birth certificate data that must be considered when interpreting the results of this study. First, birth defects are underreported on birth certificates, even after the conversion of open-ended questions to a check-box format on the 1989 revision of the US Standard Certificate of Live Birth (14). In a validation study using Georgia birth certificates from 1989 and 1990, the sensitivity of Downs syndrome reporting was only 19 percent in comparison with a population-based birth defects registry (15). We attempted to minimize any potential bias of Downs syndrome underreporting by identifying additional cases of Downs syndrome using BERD. The addition of BERD data seemed to identify a majority of the cases not reported on the birth certificate, at least for the years for which statewide surveillance data were available. Our estimated prevalence of Downs syndrome was similar to the prevalence reported by a population-based birth defects registry for the years 19871989 (1). Furthermore, the source of case identification did not seem to affect the association with parity, since trends were observed regardless of whether the cases were identified by birth certificate only, by BERD only, or by both methods.
Secondly, we were unable to exclude all individuals who had received prenatal diagnosis for Downs syndrome from the subgroup analysis. Previous studies have also shown amniocentesis to be underreported on birth certificates. In an evaluation of Tennessee birth certificates from 1989, the sensitivity of amniocentesis reporting ranged from approximately 50 percent (for very low birth weight babies) to 60 percent (for normal weight babies) in comparison with abstraction of subjects medical records (16). Additionally, even if reporting of amniocentesis were completely accurate, we failed to exclude anyone who received prenatal diagnosis by chorionic villus sampling, which is not reported on the birth certificate. However, in analysis of 19941998 data from the statewide system of regional genetic clinics for Washington State, amniocentesis accounted for more than 95 percent of procedures performed for prenatal diagnosis of Downs syndrome (D. Lochner Doyle, Washington State Department of Health, personal communication, 2001).
Two different strategies were used to account for the differential use of prenatal diagnosis between low- and high-parity women. First, we examined the risk of Downs syndrome among multiparous women under the age of 35 years. Prenatal diagnosis is performed infrequently in this group; in our data, amniocentesis was reported in only 2 percent of control mothers under 35 years of age. Therefore, differential elective termination of Downs syndrome fetuses would be unlikely to result in an appreciable bias in the odds ratios. The second strategy was to perform a subanalysis restricted to those women who had not received amniocentesis during the index pregnancy, according to the birth certificate. This restriction resulted in a decrease in the odds ratios for older women. Had we been able to identify all women receiving prenatal diagnosis, it seems likely that the odds ratios for older women would have been further blunted, becoming even more similar to the odds ratios observed for younger women. In fact, the interaction between parity and age was no longer significant after women reporting amniocentesis were excluded, despite the fact that we were unable to eliminate the impact of the diagnosis and termination of Downs syndrome pregnancies. Thus, these data seem consistent with a moderate biologic association between parity and Downs syndrome that does not differ by maternal age and with the possibility that the interaction with age that we observed was due to the differential use of prenatal diagnosis among older women. However, it was impossible to verify this without having complete ascertainment of prenatal diagnosis usage.
Prior studies of parity and Downs syndrome have not reported associations as strong as those observed in this study. Several studies (25) reported more modest associations with parity, despite the use of 5-year age categories to control for confounding. The use of broader maternal age intervals would tend to bias the resulting measures of association upwards, because of residual confounding. Of the two studies that have controlled for exact maternal age (in years) (6, 8), only one found an association with parity (6), and this was restricted to women aged 35 years or more, leading the authors to conclude that differential usage of prenatal diagnosis between low- and high-parity women was probably responsible for the association.
In attempts to remove the effects of differential pregnancy termination, two previous studies of parity and Downs syndrome risk have used information from both pregnancies that resulted in livebirths and pregnancies that did not. The first study, by Haddow and Palomaki (7), used results from second-trimester karyotype analysis of 54 cases of Downs syndrome and 5,282 pregnancies with a normal karyotype in a cohort of women aged 35 years or more in Minnesota. In the second, conducted in Australia, Chan et al. (8) had access to a birth defects registry that included karyotype results from both liveborn and electively aborted fetuses. Their analysis was based on 284 cases of Downs syndrome and almost 200,000 livebirths. Interestingly, neither of these studies reported an association between parity and Downs syndrome after controlling for maternal age, though only one (8) calculated an age-adjusted relative risk (for each additional livebirth, the relative risk was 0.96 (95 percent confidence interval: 0.78, 1.20)). Another study that examined gravidity of four or more as a risk factor for Downs syndrome (17) noted a reduction in odds ratios (from 1.41 to 1.15) when spontaneous fetal losses and terminations were included (as compared with livebirths only).
One potential drawback of using information from pregnancies that do not result in livebirth in this type of analysis is that a large majority of Downs syndrome fetuses, usually an estimated 75 percent or more (18, 19), are spontaneously aborted. At the time of elective termination of a Downs syndrome fetus, it is impossible to know whether the pregnancy would have resulted in a livebirth. If the association between parity and Downs syndrome were due to a reduced likelihood of pregnancy loss by women of higher parity, as has been proposed (10, 20), the inclusion of all Downs syndrome pregnancies that did not result in livebirth would eliminate any association, even if one were truly present. Women of proven ability to carry a pregnancy to completion, as measured by number of prior livebirths, may be more likely to do so even in the presence of fetal chromosomal abnormalities. If this were the case, it could explain part of the seemingly contradictory results between our analyses and those of Haddow and Palomaki (7) and Chan et al. (8), since the latter studies included some cases of Downs syndrome in which spontaneous abortion would have occurred had the pregnancies been allowed to continue. If spontaneous loss of a Downs syndrome fetus were more likely to occur among women of lower parity, the inclusion of case fetuses that were destined to be spontaneously aborted would bias any true association towards the null.
Still, the inclusion of these cases is unlikely to account for all of the differences between our analyses and those of Haddow and Palomaki (7) and Chan et al. (8). Downs syndrome pregnancy loss is believed to be more common earlier in gestation. After the time of amniocentesis (usually 1518 weeks gestation), loss rates have been estimated to be 1025 percent (2123). Thus, at most, one fourth of the case fetuses in the Haddow and Palomaki study and one tenth of the case fetuses in the Chan et al. study (one fourth of the 113 terminated cases included) would have been spontaneously aborted. This is an insufficient number of cases to fully account for the differences from our study. Nevertheless, if spontaneous Downs syndrome fetal loss differs by parity, our method of accounting for differential termination practices by restricting the data to women not receiving prenatal diagnosis is not susceptible to the particular bias introduced by the inclusion of terminated cases. In practice, however, we were hindered in carrying out this approach because of underreporting of prenatal diagnosis on the birth certificate.
It is unclear why our findings differ from those of Haddow and Palomaki (7) and Chan et al. (8). We cannot rule out the possibility of uncontrolled confounding or other bias leading to a spurious association. However, the magnitude of the association observed in this study, even among younger women, is strong enough that additional studies in populations in which prenatal diagnosis may be more reliably ascertained are warranted.
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ACKNOWLEDGMENTS |
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The authors thank Drs. Christine Velicer and Noel Weiss for their helpful comments on an earlier version of the manuscript and William OBrien for his assistance with the birth record and BERD databases.
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NOTES |
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REFERENCES |
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