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ORIGINAL RESEARCH |
From the *Division of Human Genetics, Department of Genetics and Developmental Biology, and the Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut; and the Departments of Radiology, Epidemiology and Biostatistics, and Obstetrics, Gynecology, and Reproductive Medicine, University of California, San Francisco, San Francisco, California.
Address reprint requests to: Peter A. Benn, PhD, Division of Human Genetics, Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030–6140; e-mail: benn{at}nso1.uchc.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We reviewed all amniotic fluid and chorionic villus samples (CVS) processed by the University of Connecticut Health Center's cytogenetics laboratory for the years 1991 to 2002. We evaluated trends in the use of prenatal testing, referral indications, and the numbers of cytogenetic abnormalities identified.
RESULTS: The number of women receiving amniocentesis or CVS declined more than 50% from 1,988 in 1991 to 933 in 2002 (P < .001), despite an increase in the number of women of advanced maternal age in the population served. There was a 68% decline in the number of women who underwent invasive prenatal testing solely on the basis of their age (1,314 in 1991 to 423 in 2002, P < .001). The number of Down syndrome fetuses detected prenatally increased from 20 to 31 (P = .08), representing approximately one half of the affected pregnancies present in the population served. Between 1991 and 2002, the proportion of antenatal cytogenetic tests with a significant chromosomal abnormality increased from 1 in 43 (2.3%) to 1 in 14 (7.0%; P < .001).
CONCLUSION: Advances in maternal serum screening and second-trimester ultrasonography have resulted in more judicious use of amniocentesis and chorionic villus sampling.
LEVEL OF EVIDENCE: II-2
Current U.S. professional guidelines issued by the American College of Obstetricians and Gynecologists and the American College of Medical Genetics recommend that these invasive tests be offered to all women aged 35 years or older and to younger women who have positive maternal serum screening test results.1,2 Because of the growing number of women who are delaying or extending their childbearing years, the policy of using maternal age alone to identify women who should undergo invasive testing would result in increasing numbers of invasive tests with fewer than 1% of the tests showing a trisomy 21 (Down syndrome) karyotype.3 The guidelines do not take into consideration recent advances in prenatal screening such as the addition of inhibin-A,4,5 the availability of nuchal translucency measurement,6 first-trimester serum screening tests,7 or the use of second-trimester ultrasonography to identify anomalies or markers associated with aneuploidy.8
Actual patterns of practice may depart substantially from the professional guidelines. For example, serum and ultrasound screening has been advocated for older women rather than using maternal age alone as a reason for testing.9–11 Women's acceptance of testing is also an important factor in the determination of the net proportion of chromosomal abnormalities that will be identified prenatally. The decision to accept or reject invasive testing appears to be dependent on the level of risk presented to individual patients, maternal and gestational ages at the time of screening, race/ethnicity, and probably other factors.12 Thus, the actual impact of prenatal screening and diagnosis on a population may differ markedly from the theoretic sensitivity and false-positive rates cited for the various screening protocols.13,14
A review of the trends in the indications for tests referred to cytogenetics laboratories and the frequency of abnormal karyotypes provides an opportunity to assess the overall impact of developments in prenatal screening and diagnosis. In this study, we summarize these trends for a 12-year period for one New England laboratory.
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MATERIALS AND METHODS |
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Our data were compiled from the cytogenetics laboratory's database that was used to track and report all prenatal and postnatal test results from January 1991 to December 2002. A karyotype result was present in more than 99% of all tests performed, and we are unaware of any misdiagnoses. In all cases in which there was an abnormal cytogenetic result, we reviewed multiple demographic fields to ensure that duplicate cases were not included.
We considered autosomal trisomies, mosaicism, unbalanced translocations, sex chromosome abnormalities, nonfamilial marker chromosomes, or other chromosomal imbalances abnormal. We categorized balanced translocations and inversions (including apparently de novo cases) and all familial marker chromosomes as normal.
Indications for prenatal diagnosis had been entered into the database from the information provided on test requisition forms. In many instances, more than one indication was present. For simplicity, we reduced multiple indications to a single indication using the following priority order: 1) "fetal demise"; 2) "abnormal ultrasound" (anomalies or markers); 3) "abnormal serum" screening results, including patients who were screen-positive for Down syndrome, trisomy 18, or an open neural tube defect; 4) "family history" of aneuploidy or known presence of a translocation or inversion segregating in the family; 5) "maternal age" of 35 years or older; and 6) "other" cases including prenatal biochemical or molecular referrals, history of spontaneous abortion, anxiety, etc.
We extracted the maternal age distributions for Connecticut women giving birth in each year from 1991 to 2002 from birth certificate data.17 Using Bray et al's18 8-series curve for maternal age–specific prevalence for Down syndrome, we calculated the expected number of Down syndrome births and pregnancies19 each year for Connecticut assuming no prenatal diagnosis.
To evaluate whether our ascertainment of Down syndrome cases was substantially complete, proportional annual changes in the calculated number of Down syndrome births were applied to our 1991 laboratory number to generate the expected number of Down syndrome diagnoses made by the laboratory in subsequent years. We assumed that the proportion of the population served by the laboratory was constant over the years of the study and that the maternal age distribution mirrored that of the entire Connecticut population. After excluding cases in which fetal demise was known to have occurred before the time of prenatal diagnosis, we further adjusted the number of first- and second-trimester diagnoses of Down syndrome to reflect the fact that a proportion of affected pregnancies would not be expected to survive to full term.19
We also used the maternal age distributions for Connecticut to estimate the expected changes in the number of women screen-positive for Down syndrome by the second-trimester triple test based on a 1:270 second-trimester cutoff and assuming that all women received this screening.20
We performed linear regression analyses using SPSS for Windows (SPSS Inc, Chicago, IL) with analyses of variance used to evaluate the significance of trends and 
2 tests to compare rates. For tests of significance, a P value of less than 0.05 was considered significant.
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RESULTS |
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Over the same time interval, the number of amniotic fluid samples referred to our laboratory declined by more than 50% (P < .001) as did the number of CVS tests (P < .05; Table 1). Only 4.3% of all prenatal samples were obtained through CVS. Figure 1 shows this overall decline in the number of prenatal diagnostic tests performed. The proportional increase in the advanced-maternal-age women (aged 35 years or older at delivery) in Connecticut and the proportional increase in the number of women expected to be screen-positive by the triple test are shown for comparison.
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Referrals on the basis of maternal age alone declined by 68% from 1,314 in 1991 to 423 in 2002 (P < .001) despite a 58% increase in the number of advanced-maternal-age women in Connecticut over the same period (Table 2). By factoring in this increase in the number of advanced-maternal-age women, there was a net 80% decline in the proportion of referrals on the basis of maternal age alone. The number of women undergoing amniocentesis because of positive maternal serum screening results also showed a 23% decline from 455 in 1991 to 350 in 2002. Because maternal age is incorporated into serum screening risks, the number of women with an indication for amniocentesis on the basis of being screen-positive by the triple test would have been expected to increase by 14% over the same period (Figure 1).
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The number of Down syndrome cases prenatally detected increased from 20 in 1991 to 31 in 2002 (P = .08; Table 1). We found a similar trend for all chromosomal abnormalities combined which also failed to reach statistical significance (P = .12). In 1991, abnormal karyotypes were present in 2.3% (1 in 43) of the cases, and in 2002 an abnormal karyotype was found in 7.0% (1 in 14) of all prenatal tests (P < 0.001). When limited to the detection of Down syndrome alone, the proportion of invasive tests that showed a Down syndrome diagnosis increased 3-fold, from 1.0% to 3.3% (P < .001).
The highest rates of abnormality were present in cases with abnormal ultrasound findings (1 in 6 tests) and fetal death (1 in 9 tests) (Table 3). Chromosomal abnormality was twice as common in tests performed because of positive serum screening results (1 in 25 tests) compared with the rate seen in the maternal age group (1 in 51).
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Over the same 12-year period, in our laboratory there were 222 neonatal diagnoses of Down syndrome, 17 babies with trisomy 13, and 10 with trisomy 18. We found a significant decline over time in the number of trisomy 13 diagnoses (P = .03). No significant trends were apparent in the numbers of Down syndrome cases (P = .96) or trisomy 18 cases (P = .22).
Prenatal and postnatal diagnoses of Down syndrome were combined, after adjusting for the number of known fetal demises at the time of prenatal diagnosis and those expected to spontaneously abort had these pregnancies continued to full term (Table 4). These data indicated that approximately 49% of the potentially viable Down syndrome cases were identified through prenatal diagnosis. This proportion did not show any significant trend over the study period (P = .59).
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A linear regression of the number of Down syndrome diagnoses provided a stabilized estimate of the cases for each year. For 1991, the regressed number of affected cases was 34, which was equivalent to the provision of cytogenetic laboratory services for approximately 21,400 births per year or 44% of all Connecticut births. Based on this estimate for 1991 and allowing for the subsequent changes in the numbers of Connecticut births and the maternal age distribution of the population, 455 Down syndrome cases were expected over the 12-year period. A total of 436 cases was documented. Thus, we found little evidence for underascertainment of Down syndrome births or pregnancies despite the major reduction in the number of invasive prenatal tests performed.
On the basis of prenatal and postnatal cytogenetic services provided for 44% of Connecticut births, the 1,988 prenatal diagnoses performed in 1991 was equivalent to the provision of invasive prenatal testing in approximately 9.6% of all pregnancies. After allowing for changes in the overall number of pregnancies, the corresponding rate for the year 2002 was approximately 5.2%.
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DISCUSSION |
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The reduction of invasive tests is largely attributable to a departure from the policy of using maternal age alone as a primary basis for assessing risk. Serum screening and ultrasonography can assist all women, regardless of their age, in the decision whether to accept invasive testing.11 In women aged 35 years or older, approximately 10% of Down syndrome–affected pregnancies are not detected by second-trimester maternal serum screening tests.20 However, this number should be lower when second-trimester ultrasound examinations are also provided to these women.15
Our cytogenetic test referral data are not sufficiently detailed to allow us to determine the relative contributions of individual improvements in maternal serum screening and second-trimester ultrasonography in the overall changes in the use of invasive testing. The simplification of the indications for testing into a single reason for each referral resulted in a bias in favor of assigning the detection of abnormality to particular categories when multiple factors were present. The exact figures provided in Table 2 must therefore be interpreted cautiously. However, it seems clear from these data that both serum screening and use of second-trimester ultrasonography have substantially contributed to the more effective use of invasive testing. The increased use of second-trimester ultrasonography may explain the reduction in neonatal diagnoses of trisomy 13.
Changes in hospital affiliations or insurance participation that increased referrals to competing laboratories could have contributed to the decline in the overall numbers of tests. However, no new cytogenetics laboratories opened in our area, and the total number of Down syndrome cases identified each year was close to the number expected on the assumption that the use of the laboratory had remained stable. Furthermore, the annual number of women receiving maternal serum Down syndrome screening tests by our laboratory has remained within the narrow range of 19.1–21.3% of the total Connecticut pregnancy population from 1992 to 2002. We therefore believe that any alteration in laboratory use was minor.
Approximately 50% of all potentially viable Down syndrome pregnancies were diagnosed prenatally. This proportion did not seem to change substantially over the past 12 years and is less than might have been expected, given the improvements in screening over that time. It is important to establish whether this reflects patients’ attitudes toward prenatal testing, a desire not to know whether the fetus is affected, or if there are substantial access barriers to the serum screening tests, advanced ultrasound services, counseling, and cytogenetics.
Ideally, prenatal aneuploidy screening would achieve levels of efficacy such that invasive testing was only needed to confirm, or precisely define, a chromosomal abnormality that had been established as being present by noninvasive techniques.14 Our results show that there has been substantial progress toward this objective.
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Footnotes |
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Received December 10, 2003. Received in revised form February 19, 2004. Accepted March 11, 2004.
10.1097/01.AOG.0000127008.14792.14
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REFERENCES |
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2. American College of Medical Genetics. ACMG position statement on multiple marker screening in women 35 and older, 1994. Available at: http://www.acmg.net/resources/policies/pol-022.asp. Retrieved October 6, 2003.
3. Egan JFX, Benn P, Borgida AF, Rodis JF, Campbell WA, Vintzileos AM. Efficacy of screening for Down syndrome in the United States from 1974 to 1997. Obstet Gynecol 2000;96:979–85.
4. Benn PA, Fang M, Egan JFX, Horne D, Collins R. Incorporation of inhibin-A in second-trimester screening for Down syndrome. Obstet Gynecol 2003;101:451–4.
5. Wald NJ, Huttley WJ, Hackshaw AK. Antenatal screening for Down's syndrome with the quadruple test. Lancet 2003;361:835–6.[Medline]
6. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998;352:343–6.[Medline]
7. Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome. J Med Screen 1997;4:181–246.[Medline]
8. Shipp TD, Benacerraf BR. Second trimester ultrasound screening for chromosomal abnormalities. Prenat Diagn 2002;22:296–307.[Medline]
9. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297:883–7.[Medline]
10. 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.
11. Benn PA. Improved antenatal screening for Down's syndrome. Lancet 2003;361:794–5.[Medline]
12. Chen J, Heffley D, Beazoglou T, Benn P. Utilization of amniocentesis by women screening positive for Down syndrome on the second-trimester triple test. Commun Genet 2000;3:24–30.
13. Benn PA. Advances in prenatal screening for Down syndrome: I. General principles and second trimester testing. Clin Chim Acta 2002;323:1–16.[Medline]
14. Benn PA. Advances in prenatal screening for Down syndrome: II. First trimester testing and future directions. Clin Chim Acta 2002;324:1–11.[Medline]
15. Egan JFX, Malakh L, Turner G, Markenson G, Wax J, Benn PA. Role of ultrasound for Down syndrome screening of the advanced maternal age population. Am J Obstet Gynecol 2001;185:1028–31.[Medline]
16. Nyberg DA, Luthy DA, Resta RG, Nyberg BC, Williams MA. Age-adjusted ultrasound risk assessment for fetal Down's syndrome during the second trimester: description of the method and analysis of 142 cases. Ultrasound Obstet Gynecol 1998;12:8–14.[Medline]
17. National Center for Health Statistics (US). Vital statistics of the United States, 1991–2001. Hyattsville, MD: Natality Data Set; 1997–2003.
18. 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 1998;18:9–20.[Medline]
19. Cuckle H. Down syndrome fetal loss rate in early pregnancy. Prenat Diagn 1999;19:1177–9.[Medline]
20. Benn PA, Ying J, Beazoglou T, Egan JFX. Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross-identification and double-positive results. Prenat Diagn 2001;21:46–51.[Medline]
21. The NICHD National Registry for Amniocentesis Study Group. Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy. J Am Med Assoc 1976;236:1471–6.[Abstract]
22. Medical Research Council Working Party on Amniocentesis. An assessment of the hazards of amniocentesis. Br J Obstet Gynaecol 1978;85:1–41.[Medline]
23. Tabor A, Madsen M, Obel EB, Bang J, Obel EB, Norgaard-Pedersen B. Randomized controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1:1287–92.[Medline]
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