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ORIGINAL RESEARCH |
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Division of Human Genetics, Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut, and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
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Abstract |
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Methods: Using natality statistics for the United States from 1974 to 1997 of maternal-age–specific live births to women 13–49 years old, we evaluated advanced maternal age (35–49 years at delivery) and the triple serum test (maternal serum alpha-fetoprotein, hCG, and unconjugated estriol) as screening tests for Down syndrome. Efficacy was evaluated using sensitivity, false-positive rate, positive predictive value, and likelihood ratio (likelihood ratio = sensitivity/false-positive rate).
Results: In 1974, the estimated second-trimester prevalence of Down syndrome was one in 740, but by 1997 that had increased to one in 504. The proportion of Down syndrome fetuses at 16 weeks’ gestation in women 35–49 years old increased from 28.5% in 1974 to 47.3% in 1997. However, live births to women 35–49 years old increased more rapidly from 4.7% in 1974 to 12.6% in 1997. The likelihood ratio for maternal age to identify an affected pregnancy decreased during the study period and was substantially lower than that using the serum test.
Conclusion: A maternal age cutoff of 35 years in the 1990s resulted in high false-positive rates and was less efficacious based on likelihood ratio and positive predictive value. Serum testing of all pregnant women would reduce the number of amniocenteses and decrease procedure-related losses.
Down syndrome is one of the most common causes of mental retardation and congenital abnormalities. After the introduction of chromosome analysis of amniotic fluid (AF) cells in the 1970s, referrals for prenatal diagnosis were generally based on advanced maternal age or family history.1,2 In 1978, The National Institutes of Health Consensus Development Conference on Amniocentesis recommended that it be offered to pregnant women aged 35 years or over.1 More than a generation of clinicians have used maternal age of 35 years or more as a guideline for offering amniocentesis, but the choice of a specific cutoff age was never formally tested.
Maternal serum screening provides an alternative for identification of pregnancies at high risk of fetal aneuploidy. In 1988 Wald et al3 introduced the "triple" test (ie, maternal serum alpha-fetoprotein (MSAFP), estriol (E3), and hCG. The triple screen builds on the maternal age-specific a priori risk for Down syndrome and refines it using three serum markers. In contrast to a dichotomous age-based cutoff in which all women above a certain age are identified as at risk of Down syndrome, serum screening identifies a percentage of women in each year of maternal age who are at risk. The triple test has been effective for screening for Down syndrome in women of advanced maternal age.4 Palomaki et al5 estimated that 63% of all pregnant women in the United States in 1995 had serum screens for Down syndrome during the second trimester.
Precise information on the prevalence of Down syndrome is essential for evaluating various approaches to screening. Birth certificates are potential sources of information regarding Down syndrome. However, underreporting and inaccuracy are significant problems. There is a 19% sensitivity and a positive predictive value of 37% when reporting Down syndrome newborns on birth certificates.6 The expected live birth prevalence of Down syndrome, without antenatal intervention, can be estimated from the maternal age-specific incidence of Down syndrome.7 In 1983, Heuther8 noted that distribution of the reproductive population of the United States would grow older over the subsequent 15 years.8 Based on that trend he predicted an increase in Down syndrome pregnancies in the United States, which was to peak in 1995.
Our study had three objectives: 1) to estimate the 16-week prevalence of Down syndrome in the United States from 1974 to 1997, with the assumption of no antenatal intervention; 2) to determine the efficacy of maternal age cutoffs as a screen for Down syndrome at 16 weeks’ gestation; and 3) to compare efficacy of three screening protocols for detecting Down syndrome at 16 weeks’ gestation.
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Materials and Methods |
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Using United States Final Natality statistics from the Centers for Disease Control and Prevention for each year from 1974 to 1997, we recorded the number of maternal age-specific live births by year to women 13–49 years old.9,10 The number of live-born infants with Down syndrome was estimated by multiplying the maternal age-specific risk of delivering a Down syndrome infant by the number of women in each year of maternal age.7 The number of Down syndrome–affected pregnancies at 16 weeks’ gestation was calculated by dividing the number at birth by 0.843.11 That correction factor estimated a 15.7% spontaneous loss of Down syndrome fetuses from 16 weeks to term. To derive the total number of unaffected fetuses at 16 weeks’ gestation, a 0.985 adjustment factor was used. This was based on the survival in utero in 5771 controls from three series.2,12,13
Using the maternal-age specific estimates for Down syndrome at 16 weeks by year from 1974 to 1997, we evaluated maternal age as a screening tool for Down syndrome. We determined the maternal age-specific efficacy using each year of maternal age as a cutoff. This was compared with the performance of the triple test using a 1:270 second-trimester risk as the cutoff. The sensitivity and false-positive rates for the triple test were established by simulation using methods described elsewhere.14,15 We used sensitivity and false-positive rates that corresponded to ultrasound-dated pregnancies because those results more closely approximated the experience of our laboratory.15 The sensitivity and false-positive rates for the two screening approaches were expressed as receiver operating characteristic (ROC) curves (false-positive rate on the x axis and sensitivity on the y axis) or likelihood ratios (likelihood ratio = sensitivity divided by false-positive rate).16 Higher likelihood ratios indicated more efficacious screening tests.
We next examined the efficacy of various second-trimester Down syndrome screening strategies. In the first protocol, termed advanced maternal age, all women 35–49 years old at delivery were considered risk positive. The second protocol, universal triple screening, assumed all women had the triple test to determine risk-positive patients. The third protocol, combination screening, considered all women 35–49 years old risk positive in combination with all women 13–34 years old who are risk positive by the triple test.
Risk-positive women in each protocol were assumed to have been offered amniocentesis, with 79% having chosen to accept the procedure.17 We also assumed that the amniocentesis rate was not affected by introduction of fetal ultrasound examinations to identify markers associated with Down syndrome (however, in our experience the amniocentesis rate did decline with increased use of this fetal biometric and anatomic evaluation.)18 We estimated the number of amniocenteses done and procedure-related losses. Losses were calculated by multiplying the number of positive screening tests by 0.79, the amniocentesis rate, and that product by 0.05, the procedure-related risk.13 The calculations were done on a spreadsheet.
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Results |
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The estimated 16-week prevalence of Down syndrome in the United States in 5-year intervals from 1975 to 1995 and for 1997 is shown in Table 1
. The estimated number of 16-week-old Down syndrome fetuses carried by women 35–49 years old increased 3.1 times from 1975 to 1997. The estimated 16-week prevalence of Down syndrome for the entire population increased 1.5 times from one in 735 in 1974 to one in 504 in 1997. In 1997, 47.3% of all 16-week Down syndrome fetuses were carried by women 35–49 years old. The maternal age-specific distribution of Down syndrome fetuses at 16 weeks in 5-year intervals from 1975 to 1995 and for 1997 in the United States is shown in Figure 1.
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depicts the ROC curves using each year of maternal age as a cutoff in 1974 and 1997. Curves were generated for intervening years and fell almost entirely between the two curves. Sensitivity and false-positive rates varied inversely with the maternal age cutoff. A low age cutoff, eg, 20 years old, had a high sensitivity and false-positive rate because almost the entire population was screen positive and almost all Down syndrome fetuses were carried by women 20 years or older. A high age cutoff, eg, 45 years old, had a low sensitivity and false-positive rate because very few fetuses, with or without Down syndrome, were carried by women 45 years or older. There was no apparent point of inflection in either curve to identify a specific maternal age as the most efficacious cutoff. The sensitivities and false positive rates changed annually because the population distribution changed each year. The efficacy, in 5-year intervals from 1975 to 1995 and for 1997, for a maternal age cutoff of 35 years old, is given in Table 2.
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. Sensitivity and false-positive rates representing each year of maternal age from 13–49 years old are plotted. In contrast to maternal age cutoffs, sensitivity and false-positive rates for the triple test varied directly with maternal age, ie, younger women have lower rates compared with older women. Although the maternal age-specific sensitivities and false-positive rates were constant from year to year, the cumulative population rates varied with annual shifts in the population distribution.
The increasing sensitivity for advanced maternal age from 1975 to 1997 in Table 2 illustrates that screening by maternal age alone resulted in detection of a progressively larger proportion of Down syndrome–affected fetuses. During that same period, however, the false-positive rate increased at a faster pace. The numeric value of the likelihood ratio declined, indicating that maternal age has become a less efficacious screening test. A modest decrease was also seen in the positive predictive value. Table 2 also shows the efficacy of screening with the two other protocols. The triple test resulted in the most efficacious screening, as evaluated by the likelihood ratio and positive predictive value. The current, widely used protocol of offering amniocentesis to all women 35 years or older and to women 13–34 years old who have positive triple tests had a very high false-positive rate (17.3% in 1997) and was less efficacious than universal triple testing when evaluated by the likelihood ratio.
Not all women choose the triple test. Amniocentesis also might be refused by women at increased risk of an affected pregnancy, so we evaluated the effect of screening in terms of amniocenteses performed, affected pregnancies detected, and procedure-related losses (Table 3). Under any of those screening strategies, less than two thirds of all affected pregnancies were diagnosed prenatally. Table 3 shows that the number of procedure-related fetal losses is lowest when all women use the triple test. In the subset of pregnant women 35–49 years old, we estimated that for the 1997 maternal age population distribution, 3267 of the 3699 affected pregnancies (88.3%) would be identified by the triple test. If 79% of the risk-positive women chose amniocentesis, the number of amniocenteses would be reduced by 190,888 (79.3%) compared with advanced maternal age alone, and there would be 1971 fewer procedure-related losses using a loss rate of 1:200.
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Discussion |
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That major demographic change translated into a markedly higher fetal prevalence of Down syndrome. Between 1974 and 1997, we estimated a 1.8 times increase in the number of 16-week Down syndrome fetuses, from 4364 to 7826 births. That change warrants a critical re-evaluation of the recommendation to use maternal age alone as a screening tool for Down syndrome.1,20,21 The 1994 ACOG Committee Opinion that recommended continued use of maternal age as a screening tool for Down syndrome based its conclusions on data that indicated that only 5–8% of live births were to women aged 35–49 years.21 Those rates were accurate for the 1970s and mid 1980s but not for the 1990s. With 12.6% of women in the advanced maternal age group in 1997, the number of additional amniocenteses must be considered (Table 3) because of procedure-related losses and costs. From 1974 to 1997, the likelihood ratio for advanced maternal age to identify fetal Down syndrome has actually declined, further challenging the appropriateness of the existing policy.
Maternal serum screening was offered as a substitute for advanced maternal age by Wald et al2 in 1988 and its effectiveness demonstrated by Haddow et al3 in 1994. Screening provides a rational and appropriate solution to the burgeoning number of amniocenteses that would be offered on the basis of maternal age alone.20,21 For example, the data in Table 3 show that in 1997 there would have been 154,756 fewer amniocenteses, 1556 more Down syndrome fetuses detected, and 773 fewer procedure-related losses if all pregnant women had had triple screens rather than simply using a maternal age of 35–49 years as the screening tool. A cost-benefit analysis by Beazoglou et al22 concluded that there were substantial net benefits of prenatal triple screening for Down syndrome at advanced maternal ages. The use of additional ultrasound markers for fetal aneuploidy23 and inhibin-A in the second trimester24 and the introduction of first-trimester ultrasound and biochemical testing will result in greater efficacy.24,25 The triple test currently provides a benchmark for the evaluation of those new approaches.
The increased risk of chromosome abnormalities other than trisomy 21 has been used as an argument for retaining maternal age alone as a screening tool. In fact, high sensitivities and low false-positive rates are available with serum screening for trisomy 18.26 In addition, serum screening will preferentially identify a proportion of cases of Turner syndrome,27 triploidy,28 and trisomy 16,29 but not trisomy 1330 or Klinefelter syndrome.31 Chromosomal abnormalities that are of lesser clinical significance and that might cause high levels of anxiety for patients (eg, some other sex chromosome abnormalities, inherited translocations, markers, etc)31 do not appear to be selectively identified through screening, which some view as advantageous. Serum screening does not provide identification of all abnormalities, so women should be advised of the limitations of screening, regardless of age.
Rowley noted that "the aim of genetic screening programs and prenatal cytogenetic diagnosis should be to maximize the options available to families rather than to reduce the prevalence of genetic diseases."32 Options will be maximized while minimizing procedure-related losses and costs when risk estimates are based on maternal serum screening before a decision is made regarding amniocentesis. The maternal age demographic, which was the basis for the initial recommendation to use age 35 years as the cutoff in 1978, has changed dramatically in the United States from 1974 to 1997.1,9,10 We suggest that the practice21,22 of offering routine amniocentesis to women 35 years of age or older without first performing maternal serum screening is an anachronism that should be abandoned.
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Footnotes |
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Received April 17, 2000. Received in revised form July 3, 2000. Accepted August 4, 2000.
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References |
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2. National Institutes of Child Health and Human Development National Registry for Amniocentesis Study Group. Midtrimester amniocentesis for prenatal diagnosis: Safety and accuracy. JAMA 1976;236;1471–6.[Abstract]
3. Wald NJ, Cuckle HS, Demsem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down syndrome in early pregnancy. BMJ 1988;297:883–7.
4. Haddow JE, Palomaki GE, Knight GJ, Cunningham GC, Lustig LS, Boyd PA. Reducing the need for amniocentesis in women 35 years of age or older with serum markers for screening. N Engl J Med 1994;330:1114–8.
5. Palomaki GE, Knight GJ, McCarthy JE, Haddow JE, Donhowe JM. Maternal serum screening for Down syndrome in the United States: A 1995 survey. Am J Obstet Gynecol 1997;176:1046–51.[Medline]
6. Watkins ML, Edmonds L, McLeam A, Mullins L, Mulinare J, Khouri M. The surveillance of birth defects: The usefulness of the revised U.S. standard birth certificate. Am J Public Health 1996;86: 731–3.
7. Bray I, Wright DE, Davies C, Hook EB. Joint estimation of Down syndrome risk and ascertainment rates: A meta-analysis of nine published data sets. Prenat Diagn 1988;18:9–20.
8. Huether CA. Projection of Down syndrome births in the United States 1979–2000, and the potential effects of prenatal diagnosis. Am J Public Health 1983;73:1186–9.
9. National Center for Health Statistics. Vital statistics of the United States, Natality, 1974–1993; Hyattsville, MD; 1977–1996.
10. National Center for Health Statistics CD-ROM: 1994–1997 Natality Data Set, Series 21, Nos. 4–9, 1997–1999. Atlanta: Centers for Disease Control and Prevention.
11. Cuckle H. Down syndrome fetal loss rate in pregnancy. Prenat Diagn 1999;19:1177–9.
12. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pederson B. Randomised controlled trial of genetic amniocentesis in 4606 low risk women. Lancet 1986;1:1287–93.[Medline]
13. Elias S, Simpson JL. Amniocentesis. In: Milunsky A, ed. Genetic disorders and the fetus. 3rd ed. Baltimore: Johns Hopkins University Press, 1992:33–57.
14. Reynolds TM, Penney MD. The mathematical basis of multivariate risk screening: With special reference to screening for Down’s syndrome associated pregnancy. Ann Clin Biochem 1989;27:452–8.
15. Benn PA, Rodis JF, Beazoglou T. Cost-effectiveness of estimating gestational age by ultrasonography in Down syndrome screening. Obstet Gynecol 1999;94:29–33.
16. Dawson-Saunders B, Trapp RG. Basic and clinical biostatistics. 2nd ed. Norwalk, Connecticut: Appleton and Lange, 1994: 232–48.
17. Haddow JE, Palomaki GE, Knight GJ, Williams J, Pukkinen A, Canick JA, et al. Prenatal screening for Down’s syndrome with the use of maternal serum markers. N Engl J Med 1992;327:588–93.[Abstract]
18. Chen J, Heffley D, Beazoglou T, Benn PA. Utilization of amniocentesis by women screening positive for Down syndrome with the second-trimester triple test. Community Genet 2000;3:24–30.
19. One hundred fifieth registration report for year ending December 31, 1997. Feb 1999:60–1; Hartford, Connecticut: The Connecticut Department of Public Health.
20. American College of Obstetricians and Gynecologists. Down syndrome screening. ACOG committee opinion no. 141. Washington, DC: American College of Obstetricians and Gynecologists, 1994.
21. American College of Medical Genetics Position Statement on Multiple Marker Screening in women 35 or older. http://www.faseb.org/genetics/acmg/pol-15.htm.
22. Beazoglou T, Heffley D, Kyriopoulos J, Vintzileos AM, Benn PA. Economic evaluation of prenatal screening for Down syndrome in the USA. Prenat Diagn 1998;18:1241–52.[Medline]
23. Vintzileos AM, Ananth CV, Fisher AJ, Smulian JC, Day-Salvatore D, Beazoglou T, et al. An economic evaluation of second trimester genetic ultrasonography for prenatal detection of Down syndrome. Am J Obstet Gynecol 1998;179:1214–9.[Medline]
24. Haddow JE, Palomaki GE, Knight GJ, Foster DL, Neveux LM. Second trimester screening for Down syndrome using maternal serum dimeric inhibin A. J Med Screening 1998;5:115–9.
25. Wald NJ, Watt HC, Hacksaw AK. Integrated screening for Down’s syndrome based on tests performed during the first and second trimesters. N Engl J Med 1999;341:461–7.
26. Benn PA, Leo MV, Rodis JF, Beazoglou T, Collins R, Horne D. Maternal serum screening for fetal trisomy 18: A comparison of fixed cutoff and patient-specific risk protocols. Obstet Gynecol 1999;93:707–11.
27. Wenstrom KD, Williamson RA, Grant SS. Detection of Turner syndrome with multiple-marker screening. Am J Obstet Gynecol 1994;170:570–3.[Medline]
28. Schmidt D, Shaffer LG, McCaskill MS, Rose E, Greenberg F. Very low maternal serum chorionic gonadotropin levels in association with fetal triploidy. Am J Obstet Gynecol 1994;170:770–80.[Medline]
29. Benn PA. Trisomy 16 and trisomy 16 mosaicism: A review. Am J Hum Genet 1998;79:121–33.
30. Saller DN, Canick J, Blitzer MG, Palomaki GE, Schwartz S, Blakemore KJ, et al. Second-trimester maternal serum analyte levels associated with fetal trisomy 13. Prenat Diagn 1999;19: 813–6.[Medline]
31. Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple screen marker testing as screen positive for Down syndrome. Am J Obstet Gynecol 1995;173:496–501.[Medline]
32. Rowley PT. Genetic screening: Marvel or menace? Science 1984; 225:138–44.
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