Philip K. Cross

Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births

SummaryData were analyzed on the results of 19675 prenatal cytogenetic diagnoses reported to two chromosome registries on women aged 35 or over for whom there was no known cytogenetic risk for a chromosome abnormality except parental age. The expected rates at amniocentesis of 47,+21; 47,+18; 47,+13; XXX; XXY; XYY; and other clinically significant cytogenetic defects by maternal age were obtained from a regression analysis on the observed rates, using a first degree exponential model. After an adjustment for maternal age, these rates were compared with previously estimated rates by maternal age in live births. The rates of 47,+21 at amniocentesis and live birth are approximately parallel, with the latter about 80% of the amniocentesis rates. The rates of 47,+18 at amniocentesis and live birth are approximately parallel, with the live birth rates about 30% of the amniocentesis rates, consistent with high fetal mortality of 47,+18 after amniocentesis. The rates of 47,+13 at amniocentesis indicate an increase in maternal age that is not as marked as thar previously estimated in live births. The rates at amniocentesis for XXX and XXY increase with maternal age, with the rates of XXY almost identical to those estimated previously in live births, suggesting no late fetal mortality of XXY. The rates of XYY show a slight decrease with maternal age also consistent with little late fetal mortality of XYY. No consistent trend with age is seen for the pooled group of other clinically significant defects.

Paternal age and Down's syndrome genotypes diagnosed prenatally: No association in New York State data

SummaryAn investigation of a paternal age effect independent of maternal age was undertaken for 98 cases of Downs syndrome genotypes diagnosed prenatally compared to 10,329 fetuses with normal genotype diagnosed prenatally in data reported to the New York State Chromosome Registry. The mean of the difference (delta) in paternal age of cases compared to those with normal genotypes after controlling for maternal age, was slightly negative,-0.27 with a 95% confidence interval of-1.59 to +1.06. A regression analysis was also done in which the data were first fit to an equation of the type lny=(bx+c) and then to the equation ln y=(bx+dz+c) where y = rate of Downs syndrome, x = maternal age, z = paternal age, and b, d, and c are parameters. This also revealed no evidence for a paternal age effect. The value of d (the paternal age coefficient) was in fact slightly negative,-0.0058, with an asymptotic 95% confidence interval of-0.0379 to +0.0263. Lastly, multiple applications of the Mantel-Haenszel test considering various boundaries in paternal age also revealed no statistically significant evidence for a paternal age effect independent of maternal age. These results are at variance with claims of others elsewhere of a very strong paternal age effect detected in studies at prenatal diagnoses. Five different hypotheses are suggested which may account for discrepancies among studies to date in findings on paternal age effects for Downs syndrome: (i) there are temporal, geographic, or ethnic variations in paternal age effects, (ii) there is no paternal age effect and statistical fluctuation accounts for all trends to date; (iii) methologic artifacts have obscured a paternal age effect in some studies which did not find a positive outcome; (iv) methodologic artifacts are responsible for the positive results in some studies to date; (v) there is a rather weak paternal age effect independent of maternal age in most if not all populations, but because of statistical fluctuation the results are significant only in some data sets. The results of all data sets to date which we have been able to analyze by one year intervals are consistent with a mean delta of +0.04 to +0.48 and in the value of d (the paternal age coefficient) of +0.006 to +0.017, and it appears the fifth hypothesis cannot be excluded. Projections based on this assumption are presented.

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

SummaryWe 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 data. 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.

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.

Data quality and the spatial analysis of disease rates: congenital malformations in New York State

Spatial analyses of disease rates are increasing as the hardware and software used in disease surveillance and cluster investigations become more accessible and easier to use. The results of these analyses should be interpreted with caution since inconsistencies in health outcome reporting and population estimates may lead to erroneous conclusions. In this report we provide an example, using data on congenital malformations in New York State, to show how under-reporting of malformations by some New York City hospitals can lead to apparent clusters of malformations in other areas of the state where reporting is more complete. We illustrate how spatial analysis techniques can be used to locate under-reporting problems and determine the extent to which the problem exists.

Down Syndrome: Interaction between Culture, Demography, and Biology in Determining the Prevalence of a Genetic Trait

The incidence of Down syndrome (DS) at conception is highly dependent upon the maternal age distribution and age-specific pregnancy rates. Live-birth prevalence of DS reflects these factors and fetal deaths. Since the introduction of prenatal diagnosis in the early 1970s, the role of fetal deaths in the equation has increased. Between 1920 and the early 1980s, DS live-birth prevalence decreased in many populations due to declining fertility rates, particularly among older women. In the late-1970s the trend reversed, as the median age of populations and birth rates among older women steadily increased. This paper illustrates these interactions using data we have analyzed for New York State (NYS) and comparative data obtained from the literature. Between 1983 and 1997 DS live-birth prevalence in NYS remained stable at about 9.9 per 10,000 live births. The number of prenatal tests performed increased by 158%, and the number of DS fetuses detected prenatally more than quadrupled. Fertility rates of women aged 35-49 continued to increase. The proportion of DS cases born to these older mothers increased from 23% in 1985 to 43% in 1997. We estimated that without prenatal diagnosis, DS live-birth prevalence would have been 17.0 per 10,000 live births by 1995. Cultural factors influence demographic trends, birthing technologies, physician practices, and womens decision-making regarding prenatal screening and diagnosis for DS.

Spontaneous abortion and subsequent Down syndrome livebirth

SummaryAnalyses 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.

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

SummaryIn 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.

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.

Factual, statistical and logical issues in the search for a paternal age effect for Down syndrome.

There has been a long exchange on the existence and extent, if any, of a relationship of paternal age to the prevalence rate of Down syndrome either in livebirths or conceptuses diagnosed at amniocentesis. (See Hook 1987 for a summary and Stene and Stene 1989 for more recent references.) Cross and Hook (1987) in this journal concluded that in a series of data on 35,680 fetuses there were no grounds to infer an increase of 47,+21 at any paternal age after adjustment for maternal age. But in recent comments upon statistical issues in investigation of such effects Stene and Stene (1989) claimed in essence to have rebutted these conclusions. The claims and implications of the Stenes are, however, erroneous on factual, statistical, and logical grounds.