Variability in predicted rates of Down syndrome associated with elevated maternal serum alpha-fetoprotein levels in older women.

Quantitative predictions of rates of Down syndrome offspring as a function of maternal serum alpha-fetoprotein (MSAFP) values and of maternal age were reviewed. Comparisons were made of 35-year-equivalent-risk values by maternal age, that is, MSAFP values (at various maternal ages) that predict the risk (of a Down syndrome offspring) equivalent to that of an average 35-year-old woman irrespective of knowledge of MSAFP. This boundary was chosen because MSAFP values that predict a greater risk than this point for younger women or a lower risk for older women are likely in many jurisdictions to alter a decision about amniocentesis that would be reached without knowledge of MSAFP. There were marked differences among available studies in these 35-year-equivalent-risk values for older women. For instance, for age 41, the values among studies vary from 1.5 MoM to 2.1 MoM and the predicted proportion of 41-year-old women likely to be affected clinically by MSAFP determinations by the above criterion is 4.4%-18%, depending on which rate schedule is used. At age 39, the variation is 1.1 to 1.9 MoM or 7.1% to 38%. Possible explanations for the variation include sampling fluctuation. Relatively few data on Down syndrome have been used to calculate the parameters of the gaussian distributions used by the studies reviewed. It is suggested that great caution be used before employing published rate schedules for genetic counseling of older women, at least until sufficient data are collected and the nature of the discrepancies among studies is clarified.     

The remarkable improvements in survival at older ages.

The belief that old-age mortality is intractable remains deeply held by many people. Remarkable progress, however, has been made since 1950, and especially since 1970, in substantially improving survival at older ages, even the most advanced ages. The pace of mortality improvement at older ages continues to be particularly rapid in Japan, even though mortality levels in Japan are lower than elsewhere. The progress in improving survival has accelerated the growth of the population of older people and has advanced the frontier of human survival substantially beyond the extremes of longevity attained in pre-industrial times. Little, however, is known about why mortality among the oldest-old has been so plastic since 1950. The little that is known has largely been learned within the past few years. New findings, especially concerning genetic factors that influence longevity, are emerging at accelerating rate.     

Down syndrome, water fluoridation, and maternal age

It has been claimed that there is a positive association between the frequency of Down syndrome and the fluoridation of drinking water. It has also been suggested that this association is most pronounced in young women. Recent congenital malformations data obtained from birth certificates from large U.S. cities have been analyzed. Some cities had fluoridated water supplies, while others had supplies deficient in fluoride. The rates of Down syndrome in the cities with fluoridated and in those with non-fluoridated water supplies were comparable. In addition, there was no indication of any maternal age-specific association.     

Differences in maternal age-specific rates of Down syndrome between Jews of European origin and of North African or Asian origin.

Rates of Down syndrome in livebirths in West Jerusalem in 1964-1975 were studied in relation to the mother's continent of birth or, if she was born in Israel, to the maternal grandfather's continent of birth. In women of European origin the crude livebirth rate of Down syndrome was 1.3 per 1,000 livebirths. This crude rate and the maternal age-specific rates in this group were very close to those observed in a Swedish study and two studies of white livebirths in the United States. For West Jerusalem women of North African or Asian origin the crude rate was about 2.4 per 1,000 livebirths, and at all maternal ages except the youngest their rates were higher than for women of European origin. The summary adjusted relative risk for a Down syndrome livebirth for all those of North African or Asian origin, compared to those for women of European origin, was about 1.56. If attention is restricted to mothers born outside of Israel, the adjusted relative risk for mothers born in Europe, the Americas or English speaking countries of the British commonwealth compared to those born in North Africa or Asia was 1.97, consistent with a two-fold difference in the likelihood of a Down syndrome livebirth between thes two groups. To our knowledge this is the first report of ethnic differences in maternal age specific rates of Down syndrome that cannot be plausibly explained by differences in ascertainment.     

Deformed nasal septa and relaxed selection

Abstract

Demographic studies undertaken in several Andean countries have found that women residing at high altitudes have significantly fewer live births than do their low altitude counterparts. This reduction has been explained as being due to various factors: the debilitating effects of hypoxia upon the reproductive system; the effects of sociocultural factors which vary with altitude and which affect reproductive behavior; and errors in data collection. In order to examine the validity of some of these hypotheses, the fertility of a group of 906 Bolivian women residing at low, medium, and high altitudes was examined. The women were selected from the lower socioeconomic strata and reported never having used any method of contraception. A detailed analysis of the fertility of these women showed no significant altitude‐related differences in the number of live births. However, as a result of significantly higher childhood mortality rates at altitude, there was a significant reduction in numbers of living children. The results of this study suggest that the collection and analysis of census data that ignores socioeconomic differences within a population or differences among census units in neonatal or early childhood mortality may bias or complicate the study of the impact of altitude on human fertility. Although the present research does not prove that hypoxic stress does not affect the reproductive system, the results suggest that if altitude does reduce fecundity, the reduction is not great and is likely to be shown only through studies of reproductive physiology.     

A maternal serum screen for trisomy 18: an extension of maternal serum screening for Down syndrome.

The feasibility of extending second-trimester maternal blood screening for Down syndrome so as to include screening for trisomy 18 was examined using stored maternal serum samples collected for neural tube-defect screening. There were 12 samples from trisomy 18 pregnancies and 390 controls. The median maternal serum concentration of alpha-fetoprotein, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, intact human chorionic gonadotrophin, total estriol, unconjugated estriol, estradiol, human placental lactogen, and progesterone were lowered in those pregnancies affected by trisomy 18 when compared with unaffected pregnancies matched for racial origin, maternal age, gestational age, and sample-storage duration. At an estimated odds risk of 1:400, 83.3% of affected pregnancies were detected using an algorithm which combines the maternal age-related risk with the maternal serum concentrations of unconjugated estriol, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, estradiol, and human placental lactogen. The associated false-positive rate was 2.6%. At high risk odds of 1:10, the detection rate was 58.3%, with an associated false-positive rate of 0.3%. beta-Subunit human chorionic gonadotrophin and unconjugated estriol were the most powerful discriminators. It is possible to incorporate into existing Down syndrome screening programs an algorithm for detecting trisomy 18 with high sensitivity and specificity.     

Down syndrome and maternal age: the effect of erroneous assignment of parental origin.

It is tempting to assume that the maternal age effect in trisomy 21 is confined to cases arising from errors of maternal gametogenesis. However, it has been suggested that this hypothesis is incompatible with the results of studies, based on the subjective assessment of chromosome polymorphisms, of the parental origin of the additional chromosome. Contrary to the hypothesis, these studies appear to indicate that the ratio of maternal to paternal errors does not depend significantly on maternal age. I show here that the hypothesis need not be rejected if the proportion of published parental assignments that are incorrect is greater than or equal to 8%, a figure regarded as realistic by some experienced cytogeneticists.     

Down syndrome in British Columbia, 1952-73: incidence and mean maternal age.

Records of children with Down syndrome (DS) at the BC Health Surveillance Registry were linked to their Birth Registrations to derive maternal ages. Incidence and maternal-age specific rates were calculated for 1952-73. Mean maternal age has declined both for normal and DS children, the latter to a marked degree, so that in 1972-73 80% were born to women under 35 years. Using maternal age of 40 and over as an indication for amniocentesis would only detect 10% of DS children. The crude incidence rate (mean 1.28/1000 livebirths) has not changed appreciably over the study period except for 1969 in which a statistically significant peak occurred. The standarized rate showed an increasing trend but it is not clear whether this was a true biological increase or resulted from better ascertainment.     

Paternal age and Down syndrome.

The frequency of Down syndrome (DS) in infants of older fathers has been examined in two sets of data. The effect of maternal age was controlled by single years of age. Lack of tight control has been an important weakness of other studies on this subject. Data obtained in metropolitan Atlanta by an intensive case-ascertainment program showed no overall excess of DS infants born to older fathers. Nor was there evidence of such an effect in recent birth certificate data made available by the National Center for Health Statistics. The Atlanta data suggest an increased number of DS infants born to older fathers who had children by women less than or equal to 34 years. However, there was a small deficiency of DS infants born to older fathers by women greater than or equal to 35 years. The possibility of a paternal-age effect remains open, but the available data suggest that, if it exists, it is quite small.     

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.