Original Article
Prenatal Screening for Down's Syndrome with Use of Maternal Serum Markers
N Engl J Med 1992; 327:588-593August 27, 1992
- Abstract
- Abstract
Background.
Approximately 35 percent of all cases of Down's syndrome in fetuses can be detected by measuring maternal serum alpha-fetoprotein during the second trimester in the general population of pregnant women. Recent case–control studies indicate that this detection rate could be approximately doubled by measuring serum levels of unconjugated estriol and chorionic gonadotropin, which are abnormally low and abnormally high, respectively, in women carrying fetuses affected by Down's syndrome.
Methods.
We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Down's syndrome with an algorithm that took into account measurements of all three serum markers in combination with maternal age. On this basis, 1661 subjects (6.6 percent) were initially assigned a second-trimester risk of fetal Down's syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestational age. Gestational age was determined on the basis of the first day of the last menstrual period or, when available, by ultrasonography.
Results.
Among the 760 women and adolescents who chose amniocentesis, 20 cases of fetal Down's syndrome were detected, along with 7 other chromosomal disorders. There was 1 additional case of Down's syndrome among the 202 women who chose not to have amniocentesis. The rate of detection of fetal Down's syndrome was thus 58 percent (21 of 36 expected cases), and the frequency of identifying a fetus with Down's syndrome in women undergoing amniocentesis was 1 per 38 amniocenteses (95 percent confidence interval, 1 in 25 to 1 in 62).
Conclusions.
Measuring serum alpha-fetoprotein, chorionic gonadotropin, and estriol is more effective in screening for fetal Down's syndrome than measuring maternal serum alpha-fetoprotein alone. Such an expanded protocol can readily be incorporated into existing prenatal screening programs. (N Engl J Med 1992;327:588–93.)
Article Activity
- Article
BEFORE 1984, prenatal screening for Down's syndrome (if there was no family history of the disorder) was restricted to asking a pregnant woman her age and then offering amniocentesis and chromosomal analysis if she was 35 years old or older. This approach was based on the well-documented trend of an increasing risk of Down's syndrome in fetuses as maternal age increased.1 In the United States in 1988, 8 percent of all pregnant women were 35 years of age or older,2 and 25 to 30 percent of all cases of Down's syndrome would be estimated to occur in the fetuses of these women.
The first opportunity to expand screening to include pregnant women under the age of 35 came with reports that maternal serum alpha-fetoprotein concentrations at midtrimester were approximately 25 percent lower in pregnancies affected by Down's syndrome than in unaffected pregnancies.3 , 4 With the use of these measurements in combination with the woman's age, the estimated detection rate in pregnant women younger than 35 was 20 percent at a screening cutoff value that initially identified 5 percent of the women as being at high risk. This estimate was subsequently confirmed by prospective intervention trials.5 , 6
More recently, average maternal serum concentrations of chorionic gonadotropin were found to be at least two times higher than normal and those of unconjugated estriol 25 percent lower than normal in the presence of fetal Down's syndrome.7 , 8 In a confirmatory study, maternal serum concentrations of alpha-fetoprotein, chorionic gonadotropin, and unconjugated estriol were found to be largely independent predictors of Down's syndrome, and all were independent of maternal age.9 Thus, the use of these three biochemical measurements could substantially increase the rate of detection without increasing the rate of initially positive screening results, even though the biologic rationale for the altered concentrations of these substances has not yet been clearly defined.
This report summarizes the effect of adding these two measurements, of serum unconjugated estriol and chorionic gonadotropin, to routine prenatal screening protocols in two New England centers. We also compare the findings with the performance of the earlier screening protocol described in a collaborative study from New England6 in which only a combination of maternal serum alpha-fetoprotein levels and age was used.
Methods
Enrollment and Follow-up of Study Subjects
We studied women and adolescents ranging in age from 16 to 41 who chose to undergo prenatal screening for open neural-tube defects and Down's syndrome between September 1989 and June 1991 in Rhode Island and between September 1990 and June 1991 in Maine. Women and adolescents with multiple gestations and those who had already had chromosomal studies were excluded. Table 1Table 1
Characteristics of the Pregnant Women and Adolescents Screened in Maine and Rhode Island. lists selected characteristics of the women and adolescents enrolled. All subjects in the second trimester of pregnancy whose initial screening values placed them in the high-risk category for carrying a fetus with Down's syndrome were reported to the data-coordinating center; a code was used to protect the subjects' confidentiality. Second-trimester risk differs from term risk, because 23 percent of fetuses with Down's syndrome are spontaneously aborted between the second trimester and term.10 Subsequent relevant follow-up information, including the results of diagnostic studies and pregnancy outcomes, was obtained for over 98 percent of the subjects whose pregnancies were in the high-risk category. Detailed birth-outcome data were not routinely sought for subjects classified as being at low risk, but specific information about the delivery of infants with Down's syndrome by these subjects was sought from the individual physicians and health centers and from laboratories providing chromosome-testing services. The number of cases identified was then compared with the number predicted, exclusively on the basis of published age-specific estimates.11 Protocols for Decision Making
Maternal serum alpha-fetoprotein measurements were corrected for maternal weight, race, and the presence of insulin-dependent diabetes mellitus.12 The second-trimester risk of Down's syndrome was calculated with a published trivariate gaussian algorithm that combined information from the three biochemical measurements and maternal age.9 The maternal age-specific risk was calculated with a published equation that uses maternal age at the estimated date of delivery.11
As an example, a 24-year-old pregnant woman has a risk of 1 in 1070 of fetal Down's syndrome on the basis of her age alone. Her serum measurements (expressed as multiples of the median values in women with unaffected pregnancies) are as follows: alpha-fetoprotein, 0.62; unconjugated estriol, 0.62; and human chorionic gonadotropin, 2.17. Individually, each of these measurements indicates an increased risk of fetal Down's syndrome (1.6, 2.6, and 2.4 times the age-associated risk, respectively). If the three markers were completely independent, the product of these three likelihood ratios (10.0) would be multiplied by the woman's age-related risk to yield a new risk of 1 in 107 (10 in 1070). There are slight pairwise correlations between the values, however, and these are taken into account by the trivariate gaussian algorithm. This algorithm assigns a lower likelihood ratio of 8.3, resulting in a more accurate risk of fetal Down's syndrome of 1 in 130 (8.3 in 1070). Within a general population of pregnant women, the risks assigned with the use of this algorithm range from more than 1 in 10 to less than 1 in 10,000.
Figure 1Figure 1
Protocol for Screening for Fetal Down's Syndrome with the Use of Measurements of Alpha-Fetoprotein, Unconjugated Estriol, and Chorionic Gonadotropin in Maternal Serum. shows the protocol used for the women and adolescents who were screened. A positive screening result was defined as a risk of at least 1 in 190 of Down's syndrome in the fetus. The choice of this risk represents a balance between the rate of detection of Down's syndrome and the rate of false positive tests. When a subject in whom gestational age was calculated on the basis of the date of the last menstrual period was identified as having a positive screening result, ultrasonography was recommended to verify gestational age, because of the strong dependency of the three serum measurements on gestational age. If the ultrasound-derived gestational dates confirmed the dates based on the last menstrual period (within 8 days in Maine and 10 days in Rhode Island), amniocentesis for chromosomal analysis was offered. If gestational age was not confirmed by ultrasonography, the risk of Down's syndrome was recalculated on the basis of the new estimate of gestational age. After the risk was recalculated, the subject might remain in the group at high risk for fetal Down's syndrome, but more often she would be reclassified as having a negative screening result (a risk of less than 1 in 190). Most often, the revised estimates of gestational age indicated that it was too early in gestation for the tests to yield a reliable interpretation (less than 15 weeks' gestation). If so, retesting was recommended. During the study period the Rhode Island testing center actually used a risk of at least 1 in 270 to identify subjects at high risk for fetal Down's syndrome, allowing assessment of the effect of lowering the cutoff value to include subjects with risks between 1 in 190 and 1 in 270.Maternal Serum Alpha-Fetoprotein, Unconjugated Estriol, and Chorionic Gonadotropin Assays
Serum samples were analyzed with the AFP/Ob radioimmunoassay (Kallestad Diagnostics, Austin, Tex.) in Rhode Island and an in-house alpha-fetoprotein assay13 in Maine; both centers used an Amerlex-M Specific Oestriol (unconjugated) radioimmunoassay (Amersham, Arlington Heights, Ill.), modified to increase sensitivity for unconjugated estriol,14 and an Amerlite HCG-60 assay (Amersham) for human chorionic gonadotropin. The between-assay coefficients of variation were 8 percent or less for all three assays over the range of values used for clinical interpretation.
Results
Risk Classification and Decisions about Amniocentesis
The percentages of women and adolescents initially classified as having a risk of at least 1 in 190 are shown in Table 2Table 2
Percentage of Women and Adolescents with Initially Positive Screening Results for Fetal Down's Syndrome, According to a Second-Trimester Risk Cutoff of 1 in 190.. The results are stratified according to whether the initial risks were based on gestational ages derived from ultrasonography or from the date of the last menstrual period. Considerably fewer subjects for whom gestational ages were based on ultrasonographic results were initially classified as at high risk. Overall, 6.6 percent (1661) of the women and adolescents were initially identified as being at high risk — a number that is slightly higher than the predicted rate of 5.1 percent.9 Of these 1661 subjects, 699 were subsequently reclassified as not being at high risk, and therefore amniocentesis was not recommended. Serum samples from 523 of these 699 subjects (75 percent) had been obtained too early in gestation (before 15 weeks) for reliable interpretation, and in an additional 105 subjects (15 percent), the gestational age was estimated inaccurately with use of the date of the last menstrual period, leading to a recalculation and lowering of the risk after ultrasonography. The remaining 71 women and adolescents (10 percent) were reclassified as having a low risk of fetal Down's syndrome or were excluded from further analysis for a variety of other reasons.
Amniocentesis was offered to the 962 subjects (3.8 percent) remaining in the high-risk group and was chosen by 760, for an overall acceptance rate of 79 percent. Women and adolescents assigned a final risk of greater than 1 in 50 chose amniocentesis more often than those assigned lower risks, irrespective of age (Table 3Table 3
Percentage of Women and Adolescents Who Agreed to Undergo Amniocentesis, Stratified According to the Risk of Down's Syndrome and Maternal Age.*). Conversely, women who were at least 35 years of age, regardless of risk classification, chose amniocentesis less often than younger women.Down's Syndrome and Other Chromosomal Disorders Identified by Amniocentesis
Among the 760 subjects who chose amniocentesis, Down's syndrome was identified in 20 fetuses (1 affected fetus per 38 amniocenteses; 95 percent confidence interval, 1 in 25 to 1 in 62). Fifteen of the 20 subjects chose to terminate the pregnancy. Six cases of sex aneuploidy were also identified (three with 45,X; one with 47,XXX; one with 47,XXY; and one with mosaic 47,XXY), along with one case of trisomy 13. These cases increased the total number of chromosomal disorders identified to 27 (1 affected fetus per 28 amniocenteses; 95 percent confidence interval, 1 in 20 to 1 in 46). In addition, five familial balanced chromosomal rearrangements were found.
Incidence of Fetal Down's Syndrome among Women and Adolescents Who Refused Amniocentesis and Those Whose Risk Was Reclassified
Outcome information was available for 98 percent of the women and adolescents who refused amniocentesis and those who were reclassified as being at low risk. One fetus with Down's syndrome was subsequently identified at birth from among the group of the 202 high-risk subjects who chose not to have amniocentesis. In addition, 2 cases of fetal Down's syndrome were identified at birth among the group of 699 subjects whose risks were reclassified. The first of these subjects had been classified as having a risk of less than 1 in 190 on the basis of follow-up ultrasonography. The second was found to have been tested before 15 weeks of gestation and, when tested at the appropriate time in gestation, was assigned a risk of less than 1 in 190.
Estimated Total Cases of Fetal Down's Syndrome Identified in the Second Trimester and the Detection Rate at a Risk Cutoff of 1 in 190
The total number of pregnant women and adolescents enrolled in the study, according to their estimated age at delivery, is shown in Table 4Table 4
Expected Cases of Fetal Down's Syndrome in the Second Trimester, According to the Number of Subjects Screened at Each Age in the Study.. For each age, the number of subjects is multiplied by the second-trimester age-specific risk of fetal Down's syndrome10 , 11 to derive the expected number of cases. Among the 25,207 pregnant adolescents and women screened, 36 cases were predicted. Within the group of 1661 women and adolescents in whom the initial risk was estimated to be at least 1 in 190, 23 cases of fetal Down's syndrome were ultimately identified (64 percent, or 23 of 36 expected cases). Twenty-one cases of fetal Down's syndrome were found in the group of 962 women and adolescents whose risks remained high after subsequent evaluation and who were offered amniocentesis (58 percent, or 21 of 36 expected cases).Predicted versus Actual Cases of Fetal Down's Syndrome among Low-Risk Subjects
The risk of fetal Down's syndrome was lower than 1 in 190 in 23,546 women. Given the published estimate of a 61 percent rate of detection,9 14 of the 36 expected cases of fetal Down's syndrome were predicted to occur in this low-risk group. Three of the 14 fetuses with Down's syndrome (approximately 23 percent10) were expected to be spontaneously aborted in the third trimester, resulting in 11 live births. Twelve infants with Down's syndrome were actually identified at follow-up in this low-risk group, agreeing closely with the 11 predicted.
Down's Syndrome Screening Performance with a Risk Cutoff of 1 in 270
A risk cutoff of 1 in 270 was used in Rhode Island. It is therefore possible to evaluate the extent to which this lower cutoff might influence both the detection rate and the initial positive rate of Down's syndrome as compared with the cutoff of 1 in 190. With a cutoff of 1 in 270, an additional 2.3 percent of pregnant women and adolescents were initially classified as having positive screening results, and 1.2 percent more of the total number of subjects were recommended for amniocentesis (Table 5Table 5
Effect of Using a Lower Cutoff for Risk on the Detection and Initial Positive Rates of Down's Syndrome.*). This led to an increase in the rate of detection from 56 to 60 percent (1 additional case identified among an estimated 23.4 second-trimester cases expected). Detecting that case required the classification of an additional 367 subjects as being at high risk and the performance of an additional 192 amniocenteses.Comparison of the Screening Methods for Fetal Down's Syndrome
We compared the performance of the three biochemical tests (risk cutoff, 1 in 190) with that of maternal serum alpha-fetoprotein measurements alone (risk cutoff, 1 in 270) described in an earlier collaborative study (Table 6Table 6
Comparison of Results from the Current Study with an Earlier Study in Which the Screening Protocol Was Based on Maternal Age and Serum Alpha-Fetoprotein Levels in Women Less Than 35 Years Old.*).6 The earlier study included only women under the age of 35; therefore, we restricted the analysis to this age group. The percentage of women with positive screening results was slightly higher in the current than the earlier study (6.1 percent vs. 4.7 percent). After verification of gestational age, the proportion of women remaining in the high-risk category was also slightly higher, as was the proportion of women who chose amniocentesis. Among the women who chose amniocentesis, 18 cases of fetal Down's syndrome were identified in 77,273 women in the earlier study, as opposed to 17 cases in 23,975 women in the current study. The ratio of amniocenteses performed to cases of Down's syndrome detected was significantly higher in the current study (38:1 vs. 89:1; chi-square, 7.7; P = 0.01), and the rate of detection of Down's syndrome was twice as high (P = 0.002 by Fisher's exact test).Rate of Detection of Down's Syndrome with Three versus Two Biochemical Markers
Among the 35 women and adolescents whose fetuses had Down's syndrome, the median values for serum alpha-fetoprotein, unconjugated estriol, and chorionic gonadotropin were 0.77, 0.72, and 2.50 multiples of the median values for an unaffected population of pregnant women, respectively, and the pair-wise correlations were small (r2 < 0.07). At a risk cutoff of 1 in 190, the removal of measurements of serum unconjugated estriol from the algorithm resulted in a net loss in detection of three cases (four cases missed and one additional case detected). By adjusting the risk cutoff for the two-marker protocol (alpha-fetoprotein and chorionic gonadotropin) such that the initial positive rate was equal to the 6.6 percent found with the use of three markers, the removal of unconjugated estriol from the algorithm resulted in a net loss of two cases (a reduction from 64 to 58 percent).
Discussion
We found that routine prenatal screening for Down's syndrome during the second trimester can be carried out effectively in pregnant women with a combination of three biochemical markers and maternal age. This practice is more effective than current protocols that use maternal serum alpha-fetoprotein measurements and maternal age alone. Any screening protocol for Down's syndrome needs to balance the ability to detect Down's syndrome against the risk of amniocentesis. The present protocol provides a favorable ratio of cases detected ( 1 per 38 amniocenteses) to the risk of fetal loss (estimated to be as high as 1 per 100 amniocenteses).
The performance of the combined biochemical-marker protocol — a detection rate of 64 percent and an initial positive rate of 6.6 percent — closely approximates that predicted from a model developed in an earlier case–control study — a 61 percent rate of detection and a 5.1 percent initial positive rate.9 The model rates were based on the total group of women with initially positive screening results; the potential effect of follow-up ultrasound studies and subsequent reclassification could not be addressed. The use of ultrasonography as a follow-up procedure to verify gestational age in the current study reduced the positive rate from 6.6 to 3.8 percent (leading to a major reduction in the need for amniocentesis) but also reduced the detection rate from 64 to 58 percent (a difference of two cases).
The use of the three biochemical markers effectively identifies women whose pregnancies are less advanced than estimated on the basis of the date of the last menstrual period. In such women, the pattern of measurements mimics that found with Down's syndrome. When gestational age is estimated by ultrasonography before screening, the rate of initial high-risk classification is strikingly lower. Universal dating by ultrasonography before screening would greatly lessen the number of women who are wrongly told that their pregnancies are high risk, and it would allow subsequent diagnostic steps to be undertaken more expeditiously. It would also preclude missing an occasional case of fetal Down's syndrome because of a reclassification of the risk after follow-up ultrasonography. Biparietal-diameter measurements are recommended for determining gestational age, because such measurements are not altered in the presence of Down's syndrome.15
Selecting a screening cutoff is a fundamental policy decision for any screening program. A cutoff that results in an appropriate initial positive rate for one screening method (e.g., serum alpha-fetoprotein screening in women under the age of 35) will not necessarily result in the same initial positive rate when used with another screening method. In this study, a risk cutoff of 1 in 270 (the risk of fetal Down's syndrome in a 35-year-old woman in the second trimester) was used in Rhode Island to maintain consistency with the existing cutoff for alpha-fetoprotein screening and with existing obstetrical practice. This cutoff was projected to yield an initial positive rate of 7 to 8 percent when applied to women of all ages. In Maine the cutoff was selected to yield an initial positive rate of approximately 5 percent (a risk of 1 in 190). The lower cutoff of 1 in 270 led to 192 additional amniocenteses (a 36 percent increase) and resulted in the detection of 1 additional case of fetal Down's syndrome.
In addition to the cases of fetal Down's syndrome identified by this screening protocol, several other chromosomal disorders were found. Too few of these occurred individually to determine whether the screening protocol was responsible for selecting them or whether they occurred by chance. We assume that they occurred by chance, with the possible exception of the three cases of Turner's syndrome.
The earlier method of screening for fetal Down's syndrome, which used serum alpha-fetoprotein measurements and maternal age, also identified a proportion of the cases of trisomy 18. The current screening protocol does not detect trisomy 18, since this condition is associated with low, rather than high, maternal serum chorionic gonadotropin concentrations. There is, however, a separate and highly efficient protocol based on low levels of all three biochemical markers that can detect approximately 60 percent of such cases.16 This supplementary protocol is projected to lead to an additional 5 women per 1000 (0.5 percent) being offered amniocentesis and to identify 1 case of trisomy 18 per 16 amniocenteses.
Some programs now use an alternative protocol that combines maternal age with serum alpha-fetoprotein and chorionic gonadotropin measurements. The model developed in an earlier case–control study9 indicated that not using unconjugated estriol values would lead to a 5 percent reduction in the rate of detection (from 61 to 56 percent) with an initial positive rate of 5 percent. We found a 6 percent reduction in the rate of detection (from 64 to 58 percent) at an initial positive rate of 6.6 percent. A more clinically relevant comparison of the two protocols would include the number of amniocenteses performed per case of fetal Down's syndrome identified. However, the number of amniocenteses performed with use of the alternative protocol cannot be determined in this study, because some subjects who would have been classified as being at high risk without the use of unconjugated estriol values did not undergo follow-up studies.
Funded in part by a grant to the New England Regional Genetics Group (Project MCJ-251003–06) from the Maternal and Child Health Bureau, Department of Health and Human Services.
We are indebted to Laurent J. Beauregard, Ph.D. (Eastern Maine Medical Center), and Brian Ward, Ph.D. (Integrated Genetics), for their assistance in providing cytogenetic outcome data; and to Kathie Foss, M.S. (Foundation for Blood Research), and Amy Goldstein, M.S., Diane Panizza, B.A., and Marea Tumber, B.A. (Women and Infants Hospital), for their assistance in collecting screening information.
Source Information
From the Foundation for Blood Research, Scarborough, Me. (J.E.H., G.E.P., G.J.K., J.W., A.P.), and Women and Infants Hospital and Brown University, Providence, R.I. (J.A.C., D.N.S., G.B.B.). Address reprint requests to Dr. Haddow at the Foundation for Blood Research, P.O. Box 190, Scarborough, ME 04070–0190.
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