Female predominance (low sex ratio) in 47,+21 mosaics.

Data from the New York State Chromosome Registry on over 10,000 cases of Down syndrome reported from 1977 to 1996 confirm findings in the England and Wales Cytogenetic Register that in mosaic 46/47,+21 cases of Down syndrome the male/female ratio (as inferred from XY and XY karyotypes respectively) is less than 1.0 as opposed to the ratio in nonmosaic 47,+21 cases in which the ratio is close to 1.2, or in the general background population with ratio of about 1.05. These results may reflect in part differential pairing in 47,+21 somatic cells of X and Y chromosomes with a 21 chromosome and/or in in-utero selection.

Trends in the use of prenatal diagnosis in New York State and the impact of biochemical screening on the detection of Down syndrome: 1984-1993.

Our purpose was to examine trends over time in the use of prenatal cytogenetic diagnosis by New York State women from 1984 to 1993 in the context of new technologies in prenatal diagnosis and pregnancy management. Data are from the New York State Chromosome Registry and represent 95-98 per cent of all New York State women tested. Utilization rates were calculated separately for women under 35 years of age and for those aged 35 years and over. Analysis of longitudinal trends also utilized data from 1979 to 1983. Utilization by women under age 35 increased steadily over time but levelled off after 1986 among older women. Each year, there was an increase in the proportion of tests performed during the first trimester. The proportion of first-trimester tests performed with chorionic villus sampling (CVS) decreased from a maximum of 68 per cent in 1987 to 10 per cent in 1993. The percentage of tests performed due to 'advanced maternal age' decreased over time while 'suspected fetal pathology' categories increased in frequency. The increase in prenatal diagnosis tests performed because of abnormal maternal serum markers was associated with an increase over time in the number and proportion of Down syndrome fetuses detected prenatally and a slight decrease in the prevalence of Down syndrome among live births. The trends reported here parallel improvements in biochemical screening for Down syndrome and published suggestions that all women aged 30 and over are offered prenatal diagnosis.

The effects of prenatal diagnosis, population ageing, and changing fertility rates on the live birth prevalence of Down syndrome in New York State, 1983-1992.

The incidence of Down syndrome (DS) at conception is highly dependent on the maternal age distribution and age-specific pregnancy rates. The live birth prevalence of DS reflects these factors and fetal deaths. This study examined DS live birth prevalence from 1983 to 1992 in New York State and analysed the effects of demographic changes and prenatal diagnosis use on the observed live birth prevalence. Expected DS live birth prevalence without prenatal diagnosis was calculated and compared with observed. Data were obtained from birth defects registries, vital records, and population data maintained by the New York State Department of Health. Over time, DS live birth prevalence was stable at about 10.4 per 10,000 live births. The percentage and number of women in the population above age 30 increased, as did birth rates among these women. Birth rates among younger women decreased. The proportion of DS babies born to women aged 35 and over increased from 27.1 to 34.1 per cent. Use of prenatal diagnosis by this age group ranged from 39.6 to 43.2 per cent, and increased steadily from 1.8 to 4.3 per cent among women under 35. Detection of DS fetuses increased from 82 in 1985 to 233 in 1992. Without prenatal diagnosis, DS live birth prevalence in 1992 would have reached 15.3 per 10,000 live births compared to the 10.2 observed. Prenatal diagnosis has prevented an increase in DS live birth prevalence but has not been sufficient to reduce live birth prevalence significantly.

Case ascertainment for state-based birth defects registries: characteristics of unreported infants ascertained through birth certificates and their impact on registry statistics in New York state.

Cases in the New York State Congenital Malformations Registry are reported by hospitals and physicians. This study was undertaken to determine whether case finding should be expanded to include routine matching of Vital Records files to the registry in order to identify unreported children. Matching of children who were born in 1983-86 and who had a congenital malformation noted on their birth certificate yielded 2837 children who were not in the registry. The hospital of record was asked to submit a registry report if the child's medical record contained a congenital malformation. Medical records for 1267 (45%) of these children indicated that the child was normal, with no mention of a malformation. Medical records could not be located for 137. Registry reports were submitted for 1433, 67 of whom were subsequently found in the registry, leaving 1366 bona fide new cases. These new cases differ significantly from registry cases for a number of birth certificate variables and type of congenital malformation. The birth certificate cases were more likely than registry cases to have only one malformation and to have only a minor malformation. The 1366 new cases comprised 2.1% of all registry cases for 1983-86. Their addition increased the statewide prevalence of major malformations by 1.7% from 416.5 to 423.4 per 10 000 livebirths. Except for anencephaly, the prevalence of specific malformations was not altered measurably by the addition of these cases. Lengthy and continuous follow-up was required to obtain registry reports. The small number of cases found does not seem to justify the amount of resources that would be required to use birth certificates routinely to augment case finding in New York State.

The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: new data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes.

We report the results of an ongoing survey of rates of spontaneous death of fetuses with chromosome abnormalities detected at second-trimester amniocentesis in which the mother did not elect abortion. Estimated excess risks (and conservative 90% confidence intervals) of spontaneous fetal death for various cytogenetic abnormalities are as follows: 47,+21, 25.6% (18.0%-34.0%); 47,+18, 63.8% (49.3%-79.8%); 47,+13, 36.5% (11%-69.7%); 45,X, 65.3% (41.0%-84.2%); and mosaic 45,X/46,XX, 10.8% (1.0%-26.8%). There is little evidence for an excess risk of fetal death, at least following amniocentesis, for 47,XXX, 47,XXY, or 47,XYY. The excess risks of fetal death were adjusted for the likelihood that a fetus of normal karyotype would undergo spontaneous fetal death in a population of older maternal age similar to that in which prenatal cytogenetic diagnosis is undertaken. The absolute fetal death rates when this factor is ignored are about 3.5% higher (i.e., may be derived by adding 3.5% to the values given). The excess risks are those which are most appropriate for use in estimating the contribution of chromosome abnormalities to spontaneous fetal death.

Maternal age-specific rates of 47,+21 and other cytogenetic abnormalities diagnosed in the first trimester of pregnancy in chorionic villus biopsy specimens: comparison with rates expected from observations at amniocentesis.

Results are presented on chromosome analyses made on 4,481 embryos or fetuses studied through chorionic villus sampling (CVS) in whom there was no known bias to presence of a chromosome abnormality except advanced parental age. We excluded from the analysis most cases in which mosaicism was diagnosed or in which there were cytogenetic discrepancies among samples obtained from the conceptus. There remain 48 cases of 47,+21, 39 cases of other nonlethal abnormalities, and 12 lethal abnormalities diagnosed in 4,481 studied. A regression analysis (restricted to the 3,848 cases diagnosed in the 35-49-year maternal age interval) was done on rates of (1) 47,+21, (2) other abnormalities excluding lethals or (3) including them, and (4) all abnormalities excluding lethals or (5) including them. The model used was y = exp(bx + c), where y is the rate of abnormality, x is maternal age at time of CVS (the modal age of the procedure was 10 gestational weeks from the last menstrual period), and b and c were, respectively, (1) 0.288 and -15.527; (2) 0.272 and -15.173; (3) 0.253 and -14.141; (4) 0.282 and -14.753; and (5) 0.271 and -14.195. We also derived rates of abnormalities at the time of CVS that would be predicted from rates (of nonmosaics) at amniocentesis after adjustment for the difference in gestational age between the usual times that these two procedures are done. The difference between the numbers of abnormalities predicted on the basis of these adjusted amniocentesis rates and the numbers observed at CVS provides an estimate of the spontaneous loss of embryos and fetuses between the usual gestational ages of these procedures. In these data, for 47,+21 the estimated proportion lost is 21% but the result is not significant at the .05 level. For other abnormalities excluding lethals the estimated spontaneous loss is 29% (P approximately .05); including lethals it is 44%. For all abnormalities, excluding lethals, pooled together, the estimate is 24%; including lethals it is 33%. The last three values are all significant at the .05 level or lower. The observed rates of abnormalities at CVS would be approximately 10% to 15% higher if one pooled diagnosed mosaics with the nonmosaics, but the estimated proportion of spontaneous fetal loss would be lower.

Maternal cigarette smoking, Down syndrome in live births, and infant race.

Previous studies have suggested that maternal smoking is negatively associated with a Down syndrome live birth. We analyzed the data of the U.S. Perinatal Collaborative Study in a search for racial variation in Down syndrome risk factors. There were 22 cases in 25,346 live births to smoking mothers (4/10,780 blacks, 18/13,320 whites, and 0/1,246 other races) and 42/29,130 live births to nonsmoking mothers (24/14,665 blacks, 14/11,694 whites, and 4/2,771 others). The crude overall rates per 1,000 live births were 0.4 in black smokers and 1.6 in black nonsmokers but 1.4 in white smokers and 1.2 in white non-smokers. Adjusted for maternal age, the summary relative risk for a Down syndrome live birth to a smoking mother was 0.2 in blacks (95% interval 0.1-0.7) but 1.2 in whites (95% interval 0.6-2.5). Stratification on variables associated with socioeconomic status or gestational age at time of entry into the study did not alter the racial difference. A comparison of smokers with those who never smoked revealed essentially the same trends. Among all nonsmokers the ratio of the maternal age-adjusted risks for a Down syndrome live birth in whites compared with blacks was 0.7 (95% interval 0.3-1.3), and among all smokers this ratio was 3.6 (95% interval 1.3-9.9). If the results are not attributable to statistical fluctuation or undetected confounding, then differences in the probability of intrauterine survival of the Down syndrome fetus would appear to be one plausible explanation for the difference.

An analysis of paternal age and 47,+21 in 35,000 new prenatal cytogenetic diagnosis data from the New York State Chromosome Registry: no significant effect.

In 35,680 fetuses of women who had prenatal cytogenetic diagnosis done upon amniotic fluid specimens obtained during 2nd trimester amniocentesis and in whom there was no increased cytogenetic risk except for age, there was no statistically significant evidence for an increase of 47,+21 at any paternal age after adjustment for maternal age. The ratio of observed-to-expected numbers in fathers less than 30 years old was 1.0 and in fathers 40 years or older was 0.9 when compared with numbers derived from maternal-age-specific rates in men 30-39 years old. The ratio was 1.1 for those younger than 34 years when compared with rates in fathers aged 34-39 years old. Only for men 55 years or older was there any, even suggestive, increase. The ratio was roughly 1.5 (9 observed to about 6 expected). This was not statistically significant, and moreover, the increase such as it was, was in men married to women 37-42 years old. Regression analyses using several additive parental age models introducing a parabolic function for paternal age, failed to reveal any paternal age contribution.

Extra structurally abnormal chromosomes (ESAC) detected at amniocentesis: frequency in approximately 75,000 prenatal cytogenetic diagnoses and associations with maternal and paternal age.

We analyzed rates of extra structurally abnormal chromosomes (ESAC) detected in prenatal cytogenetic diagnoses of amniotic fluid reported to the New York Chromosome Registry. These karyotypes include both extra unidentified structurally abnormal chromosomes (EUSAC)--often denoted as "markers"--and extra identified structurally abnormal chromosomes (EISAC). The rate of all EUSAC was 0.64/1,000 (0.32-0.40/1,000 mutant and 0.23-0.32 inherited), and that of all EISAC was 0.11/1,000 (0.07/1,000 mutant and 0.04/1,000 inherited). The rate of all ESAC was approximately 0.8/1,000-0.4-0.5/1,000 mutant and 0.3-0.4/1,000 inherited. Mean +/- SD maternal age of mutant cases was 37.5 +/- 2.9, significantly greater than the value of 35.8 years in controls. A regression analysis indicated a rate of change of the log of the rate of about +0.20 with each year of maternal age between 30 and 45 years. When paternal age was introduced, the maternal age coefficient increased to about +0.25--close to that seen for 47, +21--but the paternal age coefficient was -0.06. After being matched for maternal age and year of diagnosis, the case-control difference in paternal age for 24 mutant cases was -2.4 with a 95% confidence interval of -4.6 to -0.1 years. In a regression analysis of the effects of both parental ages on the (log) rate, the maternal age coefficient was +0.25 and the paternal age coefficient was -0.06. These results are consistent with a (weak) negative paternal age effect in the face of a strong maternal age effect. Since ESAC include a heterogeneous group of abnormalities, the maternal age and paternal age trends, if not the result of statistical fluctuation or undetected biases, may involve different types of events. Data in the literature suggest that chromosomes with de novo duplicated inversions of 15p have a strong maternal age effect (but little paternal age effect). Such chromosomes, however, do not account for the active maternal age trends seen in the data analyzed here. Inherited ESAC exhibited no such trends.

Rates of mutant and inherited structural cytogenetic abnormalities detected at amniocentesis: results on about 63,000 fetuses.

We report data on diagnoses made on amniotic fluid specimens from 1977 to 1984 as reported to the New York State Chromosome Registry. The rate of all de novo (presumed mutant) abnormalities was about 2 per 1,000 in about 61,000 fetuses in which results are unlikely to be biased by the reason for amniocentesis (except for maternal age). This includes about 0.5 per 1,000 de novo markers, about 0.5 per 1,000 other de novo unbalanced, and about 1.0 per 1,000 de novo balanced rearrangements. In about 55,000 fetuses in which rates of inherited abnormalities could be evaluated without apparent bias, the rate of all inherited rearrangement was about 2.9 per 1,000. This includes about 0.3 per 1,000 inherited markers, about 0.2 per 1,000 other inherited unbalanced rearrangements, and about 2.4 per 1,000 inherited balanced abnormalities. Only mutant markers showed a clear association with maternal age (37.6 +/- 2.7 in 24 cases v. 35.8 +/- 3.6 in controls). Inherited markers did not exhibit this trend (35.8 +/- 2.0 in 12 cases v. 36.4 +/- 2.8 in controls). Paternal age does not appear to account for the association. Among abnormalities of known origin, the ratio of mutant to inherited cases is for markers 64:36, for other unbalanced rearrangements 73:27, and for all balanced abnormalities 29:71. In a subgroup of about 55,000 fetuses, of 263 total abnormalities there were 8 instances of apparent true somatic mosaics (5 mutant and 3 of unknown origin but almost certainly mutant). There were also 20 instances of markers in which presumptive somatic loss had resulted in mosaicism (10 mutant, 6 of unknown origin and 4 inherited) and 13 other instances of mosaicism associated with apparent somatic loss (9 mutant, 3 of unknown origin, and 1 inherited). The sex ratio (Y to non-Y karyotypes) for all abnormalities detected was 228:210 (1.09), not different from controls. Only deletions (5:14) and 'other' unbalanced rearrangements (5:13) exhibited a suggestive deviation from this trend. The rates of mutant chromosome rearrangements reported from 1977 to 1983 showed no apparent time cluster, with the possible exception of a peak of markers in 1977, a trend that may be due to higher maternal age in this year. Among fetuses studied because of maternal exposure to putative mutagens there was a non-significant excess of mutants (2.9-5.7 per 1,000 v. 1.7-2.2 per 1,000) and a borderline significant excess of inherited rearrangements (8.6-11.5 per 1,000 v. 2.6-3.1 per 1,000).(ABSTRACT TRUNCATED AT 400 WORDS)

Cigarette smoking and Down syndrome.

A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the normal controls but not for the defect controls. The risk ratios for the association of cigarette smoking around the time of conception with Down syndrome was 0.58 (90% confidence interval of 0.34-0.98) in the case-defect control comparison and 0.56 (90% confidence interval of 0.33-0.95) in the case-normal control comparison. Stratification by alcohol ingestion and maternal age did not abolish the negative trend to association. The results are contrary to that of an earlier study of others that found a positive association of older age and trisomy in spontaneous abortions. In fact, among mothers of Down syndrome cases over age 30 in this analysis, the risk ratio was lower than for younger mothers. (For case-normal control comparisons, the value was 0.39 [90% confidence interval of 0.17-0.87]). If not due to chance or confounding, the negative association in our data may be attributable to, among other factors, a selective effect of smoking upon survival or fertilizability of +21 gametes prior to conception or upon survival of +21 conceptuses after fertilization.

False-positive reporting of Down syndrome on Ohio and New York birth certificates.

Although correction for underreporting of congenital malformations on birth certificates is included in most studies, inaccuracy of reporting has not been widely examined. Two separate investigations were conducted on the inaccuracy of Down syndrome (DS) reporting on birth certificates; ie, false-positive cases in which an individual coded as DS did not in fact have DS. In Ohio, 824 individuals were coded as DS on their birth certificate during 1970-1981. Of these, a definitive determination as to whether or not they had DS was made on 778 by using cytogenetic data, medical records, the state's birth defects registry, school records, and by questioning physicians. Fifty-seven false-positives were found, indicating a 7.8% level of coding inaccuracy for all races and 6.9% for whites only. Nine of these arose from miscodings during data processing; 48 were misdiagnosed as DS. This can be contrasted with false-negatives also studied in Ohio, where 66.1% of DS cases were not reported on the birth certificate. No statistical differences were observed between false-positives and true DS in the distribution of sexes, in population size of county of birth, or in year of birth (although there was a declining false-positive rate over the 12 year period). The percentage of DS false-positives, however, was significantly higher for younger maternal ages (greater than or equal to 30 years) than older ones (greater than or equal to 30 years) and for nonwhites compared to whites. Further, there was a strong negative correlation between the percentage of false-positives and the degree of certainty expressed in reporting DS on the birth certificate.

Inherited structural cytogenetic abnormalities detected incidentally in fetuses diagnosed prenatally: frequency, parental-age associations, sex-ratio trends, and comparisons with rates of mutants.

Rates of structural chromosome abnormalities were analyzed in 24,951 fetuses studied prenatally in which there were no grounds to suspect an inherited abnormality. In about one in 200 prenatal cytogenetic diagnoses, an unexpected structural abnormality was found. The observed rate was 5.3 per 1,000, of which 1.7 per 1,000 were unbalanced and 3.6 per 1,000 balanced. The rate of inherited abnormalities was 3.1-3.7 per 1,000 (0.4-0.9 per 1,000 for unbalanced abnormalities and 2.6-2.8 per 1,000 for balanced abnormalities). The rate of mutants in this series was, by contrast, 1.6-2.2 per 1,000 (0.8-1.2 per 1,000 for unbalanced abnormalities and 0.8-1.0 per 1,000 for balanced abnormalities). The rate of balanced Robertsonian translocation carriers was 0.6 per 1,000 (about 0.25 per 1,000 for mutants and 0.35 per 1,000 for inherited abnormalities), and for other balanced abnormalities, 3.0 per 1,000 (about 0.6 per 1,000 for mutants and 2.4 per 1,000 for inherited abnormalities). The rates of unbalanced Robertsonian translocations was about 0.1 per 1,000, almost all of which were mutants. For supernumerary rearrangements, the rate was 0.9 per 1,000 (about 0.4 per 1,000 inherited and 0.5 per 1,000 mutant). The rates of all unbalanced (nonmosaic) inherited abnormalities (4.0-5.2 per 10,000) were intermediate between higher rates estimated in all conceptuses (9.1-15.8 per 10,000) and rates observed in newborns (1.5-2.5 per 10,000). This trend is probably attributable to fetal mortality associated with unbalanced rearrangements. The rates of balanced (nonmosaic) inherited abnormalities (26.0-28.0 per 10,000), however, were considerably higher than the rates in all conceptuses (13-16.7 per 10,000) or in all live births (12.2-16.0 per 10,000). The major difference was in the rate of inversions. The use of "banding" methods in the studies of amniocentesis but not in most of the live births or abortus studies probably contributes to at least some of these differences. One trend in parental age among the inherited abnormalities was noteworthy. Paternal age was elevated for inherited balanced reciprocal structural abnormalities of paternal origin but not of maternal origin. With regard to sex ratio, there was a greater proportion of females than males among the unbalanced rearrangements both inherited and mutant. There was no obvious sex difference among the balanced rearrangements.

Changes in rates of spontaneous fetal deaths reported in Upstate New York vital records by gestational age, 1968-78.

Between 1968 and 1978, the rates for spontaneous deaths, recorded on Upstate New York fetal death certificates, that occurred after 28 or more weeks of gestation dropped 37 percent, and the rates for deaths that occurred at 20 to 27 completed weeks of gestation dropped 12 percent. However, the rates of reported spontaneous fetal deaths after 16 to 19 weeks gestation dropped only 4 percent. The rates for such deaths at 12-15 weeks of gestation increased by 21 percent and by 55 percent at less than 12 weeks of gestation. The decline in the late fetal death rate is probably attributable, at least in part, to medical and social advances during this period. The reported rise in early fetal deaths may be due, among other factors, to changes in reporting practices or to earlier deaths of conceptuses that formerly would have been lost after 20 weeks of gestation.

The frequency of 47,+21,47,+18, and 47,+13 at the uppermost extremes of maternal ages: results on 56,094 fetuses studied prenatally and comparisons with data on livebirths.

We examined the proportions (or so called "rates") of fetuses with 47,+21, 47,+18, or 47,+13 diagnosed prenatally in women at the upper extremes of age. Our analysis was prompted by results from a large scale European study of amniocentesis which indicated that after increasing exponentially from age 35 years, the proportions of the autosomal trisomies reached a peak at a specific age and then leveled off or declined at the upper end of the age range. We analyzed North American data on 56,075 fetuses studied because of no known cytogenetic risk factor (aside from maternal age). This is the largest series to date. For 47,+21, the data from amniocentesis studies provide no evidence for any drop in the rate of change of proportion with maternal age up to 49 years. There is, if anything, a trend in our data to a steepening in the exponential rate of change at the upper extreme of age (above 46 years). Data from livebirths on the Down syndrome phenotype are at least consistent with an exponential rate of increase in proportion affected up to age 49 years. For 47,+18 our data from prenatal diagnoses are more consistent with an exponential increase up to age 43 years and a level proportion (or "rate") after that. For 47,+13 no cases were observed above age 42 years, consistent with the drop in proportion affected above this age observed in the European series. We emphasize the possible effect of sampling fluctuation and reporting error upon these apparent trends.

Chromosomal abnormality rates at amniocentesis and in live-born infants.

Regression-smoothed maternal age-specific rates of six different categories of cytogenetic abnormalities in recent large-scale prenatal cytogenetic studies were multiplied by independently derived fetal selection coefficients--factors that adjust for the excess likelihood of spontaneous loss of cytogenetically abnormal fetuses--to obtain estimated maternal age-specific rates of these categories of cytogenetic abnormalities in live-born infants. The derived rates apply to women whose only risk factor is advanced maternal age. The categories analyzed were 47,+21 (Down's syndrome), 47,+18 (Edwards' syndrome), 47,+13 (Patau's syndrome), 47,XXY (Klinefelter's syndrome), 47,XXX, and the group of other clinically significant abnormalities considered collectively. The rate of all clinically significant abnormalities considered together derived in this study was about five per 1,000 at age 35 years, 15 per 1,000 at age 40 years, and 50 per 1,000 at age 45 years.

Spontaneous abortion and subsequent Down syndrome livebirth.

Analyses of two data sets are presented, one based on nationwide hospital discharges for the USA for 1970-1971, the other for Upstate New York vital record data for 1976-1981. Summary relative risks of a Down syndrome livebirth were calculated within the three maternal age categories below 20, 20-29, and 30 years and above for those with a history of one spontaneous abortion and for those with a history of two or more, compared to those with no reported previous abortions. There was significant heterogeneity by age and reproductive history in the relative risk of an affected child. In general the trends revealed that the younger the mother and the more the number of abortions, the higher the relative risk of a Down syndrome livebirth compared to the rates for women of the same age for those with no previous abortions. Extrapolation from average maternal age specific rates on Down syndrome imply a rate per 1000 livebirths somewhere in the range of 1.1 to 11.4 for women under 20 years with a history of one spontaneous abortion, of 5.2 to 13.4 for women under 20 years with a history of two or more spontaneous abortions, and of 1.0 to 2.4 for women 20 to 29 years with a history of two or more spontaneous abortions. (Average "background" livebirth rates in women under 30 years are, in contrast, in the range of about 0.5 to 1.0 per 1000 and for the average woman aged 35 years, at which prenatal diagnosis is usually felt to be indicated, 2.7 per 1000.) For those in the other categories these data did not reveal clinically significant effects upon average maternal age specific rates. It is emphasized that because of limitations in the data it is not possible to refine these risks by adjusting for karyotype, the age at which the abortions occurred, or other biologic and social factors associated with embryonic and fetal death. The implications of the analyses here for genetic counseling should be regarded as preliminary and tentative.