Original Article
Reducing the Need for Amniocentesis in Women 35 Years of Age or Older with Serum Markers for Screening
N Engl J Med 1994; 330:1114-1118April 21, 1994
- Abstract
Background
As maternal age advances, the risk of fetal Down's syndrome increases. Pregnant women 35 years of age or older are routinely offered amniocentesis because of this risk. Recently, maternal serum markers have been reported to be useful in screening for Down's syndrome, primarily in younger women. We therefore investigated whether offering amniocentesis only to selected women 35 years of age or older who were identified by screening measurements in serum might prove a useful alternative to the current practice.
Methods
We studied 5385 women with singleton pregnancies who were 35 years of age or older and were undergoing routine amniocentesis. Along with information about the pregnancy, we obtained a serum sample for measurement of alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin. Individual estimates of the risk of Down's syndrome in the fetus were calculated for each pregnancy before the karyotype was known.
Results
If amniocentesis had been reserved for the women calculated to have a risk greater than 1 in 200 of having a fetus with Down's syndrome, 48 of the 54 cases of Down's syndrome (89 percent) would have been identified; 25 percent of the unaffected pregnancies would also have been identified as being at high risk for Down's syndrome (false positives). Seven of 15 fetuses (47 percent) with other trisomies, 11 of 25 (44 percent) with sex aneuploidy, and 1 of 9 (11 percent) with miscellaneous chromosomal abnormalities would also have been detected. In practice, such screening would have made 75 percent of the amniocenteses unnecessary, along with a proportion of the amniocentesis-associated fetal losses. If the cutoff for the risk of Down's syndrome were set higher than 1 in 200, both the rate of detection and the false positive rate would be lower. Conversely, these rates would be higher if the cutoff were set lower.
Conclusions
Prenatal screening of serum to generate individual estimates of the risk of Down's syndrome in the fetus can provide a basis for decision making in the cases of women 35 years of age or older, as it does in younger pregnant women, and is an alternative to current testing practices. .
Media in This Article
Figure 1
Rate of Detection of Down's Syndrome and the False Positive Rate on Biochemical Screening of Women 35 Years of Age or Older.Figure 2
Numbers of Amniocenteses Performed and Amniocentesis-Related Fetal Losses, According to the Rate of Detection of Down's Syndrome, in a Hypothetical Group of 10,000 Women 35 Years of Age or Older.Article Activity
- Article
It is current practice in the United States for physicians to advise pregnant women who are 35 years of age or older about the age-related risk of having a fetus with Down's syndrome. These women are then offered amniocentesis (or chorionic-villus sampling) and chromosome analysis as a way to detect fetal Down's syndrome. This practice began in the early 1970s, when amniocentesis was proved to be relatively safe and chromosome analysis became reliable1. The availability of these techniques was coupled with evidence that the risk of Down's syndrome increased steadily with maternal age2. A woman's age could therefore be used as a risk factor in screening if a cutoff were chosen (most often 35 years in the United States) that took into account both the likelihood of Down's syndrome and the risk of fetal morbidity and mortality related to amniocentesis.
In 1984, maternal serum alpha-fetoprotein concentrations were found to be lower, on average, in the presence of Down's syndrome,3 and it was demonstrated that this biochemical measurement could be used as a screening test in the second trimester4. Screening for Down's syndrome could thus be made available to younger women. The discriminatory power of this screening test in women younger than 35 years of age was estimated to be comparable to the use of maternal age alone as a screening test. Subsequent prospective intervention trials in the United States confirmed the reliability of that estimate5,6.
In 1987 and 1988, two additional serum markers, the levels of human chorionic gonadotropin7 and unconjugated estriol,8 were identified as significantly increasing the sensitivity of screening for Down's syndrome when combined with the measurement of alpha-fetoprotein. The risk of fetal Down's syndrome becomes greater as serum concentrations of human chorionic gonadotropin increase and serum concentrations of unconjugated estriol decrease. Screening protocols using these three tests and maternal age were subsequently evaluated in the United States and Europe9-13. The higher rate of detection of Down's syndrome that was achieved with this approach made a compelling case that biochemical screening might prove useful for pregnant women 35 years of age or older. We undertook this prospective study to evaluate biochemical screening in a group of women undergoing amniocentesis and chromosome analysis because of their age.
Methods
Recruitment of Subjects
The study protocol was approved by the institutional review committees at the study and recruitment centers and by the institutional review committee of the state of California. Between December 1990 and October 1992, 5425 women at least 35 years of age with singleton pregnancies were enrolled in the study at 14 prenatal diagnostic centers (see the Appendix). All the women gave informed consent before entry into the study. In the cases of 40 of the women, the indication for amniocentesis was a positive serum alpha-fetoprotein screening test; those women were excluded from the analysis. The remaining 5385 women provided information about their date of birth, race or ethnic background, weight, and other demographic and pregnancy-related factors. Estimates of gestational age were available for over 99 percent of the pregnancies, based on both the date of the last menstrual period and results of ultrasonography. Among these women, 71 percent were non-Hispanic whites, 13 percent were Hispanic whites, 10 percent were Asian, and 6 percent were black.
A blood sample was obtained and centrifuged, and the serum was refrigerated until just before shipment. The sample was shipped overnight within one to five days after its collection to a central laboratory in Scarborough, Maine, for analysis of alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin (collectively referred to hereafter as the biochemical markers). The analyses were performed within two days after the arrival of the sample, but the results were not made available for clinical purposes. The coordinating center in Berkeley, California, subsequently obtained the results of the chromosomal studies for each pregnancy and transmitted the information to Scarborough for storage and analysis. Among the 5385 women who met the eligibility criteria, 54 cases of Down's syndrome and 49 other chromosomal abnormalities in the fetuses were identified on the basis of amniotic-fluid karyotype. Balanced translocations, pseudo-mosaicisms, normal variants, and common inversions were included among the 5282 pregnancies with a normal karyotype.
Serum Measurements
Alpha-fetoprotein was measured in serum with an in-house assay14. Unconjugated estriol was measured with the Amerlex-M radioimmunoassay (RIA) kit specific for unconjugated estriol (modified to increase sensitivity15), or the Amerlex-M high-sensitivity unconjugated estriol RIA kit (Eastman Kodak, Rochester, N.Y.). Human chorionic gonadotropin was measured with the Amerlex-M extended-range HCG RIA kit or the Amerlex-M β-hCG RIA kit (Eastman Kodak). The coefficient of variation between assays was 8 percent or less for all three assays.
Statistical Analysis
At the end of the study, median values were calculated for each of the three analytes, based on estimates of gestational age derived from the date of the last menstrual period. Multiples of these median values were then calculated from the results obtained for each woman. The values for all three analytes were adjusted for maternal weight,16 and serum alpha-fetoprotein values were adjusted for race17 and the presence of insulin-dependent diabetes mellitus18. The serum unconjugated estriol values were adjusted for Hispanic and Asian women by dividing the values by 1.12 and 1.17, respectively (the median concentrations found in those groups). Individual risks of fetal Down's syndrome were then calculated from each woman's estimated age at delivery, in combination with the biochemical markers, with published values and algorithms9,19,20. A more complete description of the calculation of risk is available elsewhere10.
Results
Efficiency of Screening for Down's Syndrome
The rate of detection of Down's syndrome (n = 54) and the corresponding false positive rate in the 5282 pregnancies without chromosomal abnormalities are shown in Figure 1Figure 1
Rate of Detection of Down's Syndrome and the False Positive Rate on Biochemical Screening of Women 35 Years of Age or Older.. At 5 percent and 15 percent false positive rates, the rates of detection of Down's syndrome were 59 and 78 percent, respectively. At a false positive rate of 25 percent, the rate of detection was 89 percent; beyond that point, relatively large increases in the false positive rate yielded only small gains in detection. With the current practice of performing amniocentesis routinely in all women at least 35 years of age, all the cases of Down's syndrome are identified, but all the women with unaffected pregnancies also undergo amniocentesis.Establishing a Cutoff for Biochemical Screening Based on Individual Risk Estimates
It is routine practice to convert each woman's biochemical values, in combination with her age, into a composite estimate of the risk of Down's syndrome in her fetus. These estimates form the basis for decisions about what constitutes the high-risk population. A risk cutoff of 1 in 200 detected 89 percent of the 54 cases of Down's syndrome with a 25 percent rate of false positive results (the same rates shown in Figure 1). At a risk level of 1 in 100 the detection and false positive rates were 78 and 13 percent, respectively; at a risk of 1 in 300 they were 89 and 34 percent.
Efficiency of Biochemical Screening for Other Chromosomal Abnormalities
Table 1Table 1
Rates of Detection and False Positive Results for Chromosomal Abnormalities Other Than Down's Syndrome on Biochemical Screening. shows the detection rate and the false positive rate when three different cutoff levels were used for the risk of chromosomal abnormalities other than Down's syndrome. Among the 15 fetuses with other autosomal trisomies, 7 (47 percent) were identified at a risk cutoff of 1 in 200. In addition, 25 fetuses had sex aneuploidy, 44 percent of which were also detected at that cutoff level. Thus, the screening protocol for Down's syndrome identified other important chromosomal abnormalities at a rate higher than the 25 percent that would be expected if there was no relation between those disorders and the assigned risk of Down's syndrome. Nine fetuses had miscellaneous chromosomal abnormalities, of which one (11 percent) was detected.Rates of Detection of Down's Syndrome Using Maternal Age and Three Combinations of Biochemical Markers
Table 2Table 2
Rates of Detection of Down's Syndrome in the Study Group with Three Combinations of Serum Alpha-Fetoprotein (AFP), Unconjugated Estriol, and Human Chorionic Gonadotropin (hCG) at Three False Positive Rates. shows the detection rates associated with three false positive rates for three combinations of markers used to screen for Down's syndrome. At a 25 percent false positive rate, serum alpha-fetoprotein measurements alone detect 70 percent of the cases of Down's syndrome. When serum human chorionic gonadotropin levels are added, 85 percent of the cases are identified. When all three measures are used, 89 percent are identified.Fetal Losses Related to Amniocentesis with Biochemical Screening and Routine Amniocentesis
Figure 2Figure 2
Numbers of Amniocenteses Performed and Amniocentesis-Related Fetal Losses, According to the Rate of Detection of Down's Syndrome, in a Hypothetical Group of 10,000 Women 35 Years of Age or Older. shows the estimated number of amniocenteses and the proportional number of amniocentesis-related fetal losses among a hypothetical group of 10,000 women 35 years of age or older, expressed as functions of the rate of detection of Down's syndrome. In this calculation, the prevalence of Down's syndrome was 1 per 100 (as found in this study) and the rate of amniocentesis-related fetal loss was assumed to be 5 per 1000 procedures1,21. In this example, 50 fetal losses occurred, and all 100 cases of Down's syndrome were identified, when all 10,000 women in this hypothetical group underwent amniocentesis as currently recommended (solid circle, Figure 2). If the multiple-marker screening protocol was used with the risk cutoff set at 1 in 200, 2500 amniocenteses would be performed, 13 estimated amniocentesis-related fetal losses would occur, and 89 of the cases of Down's syndrome would be detected (open circle, Figure 2). Detecting the 11 cases of Down's syndrome that were not identified by biochemical screening would require 7500 additional amniocenteses and the loss of 37 additional unaffected fetuses.Costs of Detecting Fetal Down's Syndrome by Routine Amniocentesis or Biochemical Screening in Women 35 Years of Age or Older
Assuming that the current average cost of genetic counseling, amniocentesis, and karyotyping in the United States is $1,000, universal amniocentesis in the hypothetical group of 10,000 women described above would cost $10 million and would detect all 100 cases of Down's syndrome. Assuming the average total cost of the three serum measurements to be $75, the total cost of biochemical screening of the same 10,000 women would be $750,000, and 2500 of those women would be identified as candidates for amniocentesis. The costs of diagnostic testing and counseling for those 2500 women would be $2.5 million. The combined costs of screening and diagnosis would therefore be $3.25 million. This second approach would identify 89 of the 100 cases of Down's syndrome. The cost per case detected in the second trimester with current practices would be $100,000, as compared with $36,500 for biochemical screening. The corresponding estimated costs per live-born infant with Down's syndrome would be $130,000 and $47,000, respectively (approximately 23 percent of fetuses with Down's syndrome are spontaneously aborted in the third trimester22). This analysis does not include the additional direct health care and social costs associated with caring for the estimated eight live-born children with Down's syndrome who would not be detected by biochemical screening; the remaining three would be spontaneously lost in the third trimester. Detecting these eight cases would require an additional expenditure of $6.75 million ($840,000 per case). When these figures are extrapolated to the estimated 380,000 pregnancies occurring each year in women 35 years of age or older in the United States, the reduction in diagnostic costs resulting from the use of multiple-marker biochemical screening would be approximately $250 million (assuming total participation).
Discussion
In this study, the rate of detection of Down's syndrome when we used multiple biochemical markers was 89 percent, with a 25 percent false positive rate, among women 35 years of age or older. Gestational ages were estimated on the basis of the dates of the last menstrual period. The use of gestational ages determined by ultrasonography did not substantially reduce the false positive rate, because incorrectly dated pregnancies account for a relatively small proportion of the high false positive rate in this age group (data not shown). In addition, adding serum measurements of unconjugated estriol to the screening protocol contributes less to its efficiency in this age group than it does among younger women. The rate of detection of Down's syndrome is lower in these women, providing greater opportunity to identify additional cases by measuring unconjugated estriol (Table 3Table 3
Estimated Gain in Detection of Down's Syndrome with the Use of Serum Unconjugated Estriol Levels in Addition to Serum Alpha-Fetoprotein and Human Chorionic Gonadotropin Levels, According to Maternal Age.).The practice of offering amniocentesis to all pregnant women 35 years of age or older is based on a documented increase in the risk of Down's syndrome in the fetus with each additional year of maternal age. This screening practice is equivalent to offering amniocentesis to all women with a second-trimester risk of Down's syndrome at or above 1 in 270 (the risk at the age of 35). The biochemical markers provide additional independent information about the risk of Down's syndrome. This new information can be combined with the risk based on age alone to provide more accurate individual estimates of risk. For example, all 38-year-old pregnant women are currently counseled that their age-related risk of having a fetus with Down's syndrome in the second trimester is 1 in 140. After measurements of the biochemical markers, however, their individual estimated risks can range from 1 in 10 to less than 1 in 10,000.
One argument against replacing current practice with a policy based on biochemical screening is that the latter will detect only 9 of every 10 cases of Down's syndrome, whereas routine amniocentesis detects all 10 cases. This fact needs to be weighed, however, against the large reduction in the number of women requiring amniocentesis that can be achieved with biochemical screening and, as a consequence, the reduction in fetal losses related to the procedure.
An additional argument for maintaining current practice is that other chromosomal abnormalities, some of them medically important, are also detected by amniocentesis. In our study, 47 percent of the fetuses with other autosomal trisomies were identified when amniocentesis was offered to 25 percent of the women. A supplementary protocol specifically designed to determine the risk of trisomy 18 further increases this rate of detection, with a negligible increase in the number of amniocenteses24. These other autosomal trisomies are not compatible with life, and affected fetuses are usually lost spontaneously before term22. Forty-four percent of the fetuses with a sex aneuploidy were identified with multiple-marker biochemical screening. The detection of sex aneuploidy is generally viewed as a byproduct of prenatal chromosome analysis; the consequences of these abnormalities for health are not substantial and, in and of themselves, they do not justify amniocentesis25. When the diagnosis of a sex-chromosome aneuploidy is made, however, 50 percent or more of the pregnancies are electively terminated26,27. Among the nine fetuses with miscellaneous chromosomal abnormalities, an estimated 80 to 90 percent of those born alive would not have a mental or physical disability28.
A third argument in support of maintaining current practice is that the medical and social costs necessary to maintain patients with Down's syndrome are high. Although accurate measurement of these costs is difficult, few take issue with the validity of this claim. The considerable savings in diagnostic costs that can be achieved with multiple-marker biochemical screening will, as a consequence, be at least partially offset by the costs of maintaining the 10 percent of fetuses with Down's syndrome who are not identified prenatally.
On the basis of this study, three health care policy options might be considered for pregnant women 35 years of age or older: continue the current policy of universal amniocentesis, replace this policy with a policy of using multiple-marker biochemical screening, or allow women a choice between these two options. Deciding among these options involves weighing the advantages of screening (more accurate information about individual risks of Down's syndrome, fewer procedure-related fetal losses, and lower overall diagnostic costs) against the disadvantages (failure to detect 10 percent of the cases of Down's syndrome, failure to detect a proportion of other chromosomal disorders, and added costs for maintaining the children born in the missed cases).
Supported by a grant (MCJ-237014-02-2) from the Maternal and Child Health Bureau, Department of Health and Human Services, and from the National Institute of Child Health and Human Development.
Source Information
From the Foundation for Blood Research, Scarborough, Me. (J.E.H., G.E.P., G.J.K.); the California Department of Health Services, Genetic Disease Branch, Berkeley (G.C.C., L.S.L.); and the California Public Health Foundation, Berkeley (P.A.B.).
Address reprint requests to Dr. Haddow at the Foundation for Blood Research, Scarborough, ME 04074.
Appendix
The centers and investigators that collaborated in this study are as follows: Alfigen-The Genetics Institute, Pasadena, Calif. -- J.C. Kelly and G.R. DeVore; University of Iowa Hospitals and Clinics, Iowa City -- S. Grant and K. Wenstrom; University of California, San Francisco -- M.S. Golbus and J.D. Goldberg; Pennsylvania Hospital, Philadelphia -- A.E. Donnenfeld; Cedars-Sinai Medical Center, Los Angeles -- D.E. Carlson and L.D. Platt; Loma Linda University Medical Center, Loma Linda, Calif. -- H. Brar and D. Abad; Children's Hospital Oakland, Oakland, Calif. -- A. Bastian and S. Sherman; Children's Hospital Los Angeles, Los Angeles -- R.E. Falk and K.A. Wendt; Kaiser Permanente of Southern California, Pasadena -- H.N. Bass and C. Francisco; Fetal Diagnostic Center, Laguna Hills, Calif. -- D.C. Lagrew, Jr., and C. Roquemore; Prenatal Diagnostic Center of Southern California, Los Angeles -- J. Williams III and C.H. Rubin; Jefferson Medical College, Philadelphia -- A. Johnson and R.J. Wapner; University of Tennessee, Memphis -- S. Elias and J.L. Simpson; and University of Connecticut Health Center, Storrs -- L. Ciarleglio and A. Craffey.
- References
References
1
The NICHD National Registry for Amniocentesis Study Group, Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy
CrossRef | Web of Science2
Hook EB. Down syndrome: frequency in human populations and factors pertinent to variation in rates. In: de la Cruz FF, Gerald PS, eds. Trisomy 21 (Down syndrome): research perspectives. Baltimore: University Park Press, 1981:3-18.
3
Merkatz IR ,Nitowsky HM ,Macri JN ,Johnson WE . An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol 1984;148:886-894
Web of Science | Medline4
Cuckle HS ,Wald NJ ,Lindenbaum RH . Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984;1:926-929
CrossRef | Web of Science | Medline5
Combining maternal serum alpha-fetoprotein measurements and age to screen for Down syndrome in pregnant women under age 35: New England Regional Genetics Group Prenatal Collaborative Study of Down Syndrome Screening
Web of Science | Medline6
DiMaio MS ,Baumgarten A ,Greenstein RM ,Saal HM ,Mahoney MJ . Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N Engl J Med 1987;317:342-346
Full Text | Web of Science | Medline7
Bogart MH ,Pandian MR ,Jones OW . Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn 1987;7:623-630
CrossRef | Web of Science | Medline8
Canick JA ,Knight GJ ,Palomaki GE ,Haddow JE ,Cuckle HS ,Wald NJ . Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome. Br J Obstet Gynaecol 1988;95:330-333
CrossRef | Medline9
Wald NJ ,Cuckle HS ,Densem JW , et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297:883-887[Erratum, BMJ 1988;297:1029.]
CrossRef | Web of Science | Medline10
Haddow JE ,Palomaki GE ,Knight GJ , et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med 1992;327:588-593
Full Text | Web of Science | Medline11
Wald NJ ,Kennard A ,Densem JW ,Cuckle HS ,Chard T ,Butler L . Antenatal maternal serum screening for Down's syndrome: results of a demonstration project. BMJ 1992;305:391-394
CrossRef | Web of Science | Medline12
Cheng EY ,Luthy DA ,Zebelman AM ,Williams MA ,Lieppman RE ,Hickok DE . A prospective evaluation of a second-trimester screening test for fetal Down syndrome using maternal serum alpha-fetoprotein, hCG, and unconjugated estriol. Obstet Gynecol 1993;81:72-77
Web of Science | Medline13
Phillips OP ,Elias S ,Shulman LP ,Andersen RN ,Morgan CD ,Simpson JL . Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hCG, and unconjugated estriol: a prospective 2-year study. Obstet Gynecol 1992;80:353-358
Web of Science | Medline14
Knight GJ. Alpha-fetoprotein. In: Pesce AJ, Kaplin L, eds. Methods in clinical chemistry. St. Louis: C.V. Mosby, 1987:459-65.
15
Canick JA . Screening for Down syndrome using maternal serum alpha-fetoprotein, unconjugated estriol and HCG. J Clin Immunoassay 1990;13:30-33
Web of Science16
Palomaki GE ,Panizza DS ,Canick JA . Screening for Down syndrome using AFP, uE3 and hCG: effect of maternal weight. Am J Hum Genet 1990;47:Suppl:A282-A282 abstract.17
Crandall BF ,Lebherz TB ,Schroth PC ,Matsumoto M . Alpha-fetoprotein concentrations in maternal serum: relation to race and body weight. Clin Chem 1983;29:531-533
Web of Science | Medline18
Greene MF ,Haddow JE ,Palomaki GE ,Knight GJ . Maternal serum alpha-fetoprotein levels in diabetic pregnancies. Lancet 1988;2:345-346
CrossRef | Web of Science | Medline19
Wald NJ ,Cuckle HS ,Densem JW ,Kennard A ,Smith D . Maternal serum screening for Down's syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight. Br J Obstet Gynaecol 1992;99:144-149
CrossRef | Medline20
Wald NJ ,Densem JW . Use of unconjugated oestriol in screening for Down's syndrome. Prenat Diagn 1993;13:1149-1153
CrossRef | Web of Science | Medline21
Tabor A ,Philip J ,Madsen M ,Bang J ,Obel EB ,Norgaard-Pedersen B . Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1:1287-1293
CrossRef | Web of Science | Medline22
Hook EB ,Cross PK ,Schreinemachers DM . Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:2034-2038
CrossRef | Web of Science | Medline23
National Center for Health Statistics. Vital statistics of the United States, 1988. Vol. I. Natality. Washington, D.C.: Government Printing Office, 1990:89. (DHHS publication no. (PHS) 90-1100).
24
Palomaki GE ,Knight GJ ,Haddow JE ,Canick JA ,Saller DN ,Panizza DS . Prospective intervention trial of a screening protocol to identify fetal trisomy 18 using maternal serum alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotropin. Prenat Diagn 1992;12:925-930
CrossRef | Web of Science | Medline25
Robinson A, Bender BG, Linden MG. Prenatal diagnosis of sex chromosome abnormalities. In: Milunsky A, ed. Genetic disorders and the fetus: diagnosis, prevention, and treatment. 3rd ed. Baltimore: Johns Hopkins University Press, 1992:211-39.
26
Robinson A ,Bender BG ,Linden MG . Decisions following the intrauterine diagnosis of sex chromosome aneuploidy. Am J Med Genet 1989;34:552-554
CrossRef | Web of Science | Medline27
Holmes-Siedle M ,Ryynanen M ,Lindenbaum RH . Parental decisions regarding termination of pregnancy following prenatal detection of sex chromosome abnormality. Prenat Diagn 1987;7:239-244
CrossRef | Web of Science | Medline28
Warburton D . De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 1991;49:995-1013
Web of Science | Medline
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CrossRef4
Chan-Kyung J. Cho, Eleftherios P. Diamandis. (2011) Application of proteomics to prenatal screening and diagnosis for aneuploidies. Clinical Chemistry and Laboratory Medicine 49:1, 33-41
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G. R. DeVore. (2010) Genetic sonography: the historical and clinical role of fetal echocardiography. Ultrasound in Obstetrics and Gynecology 35:5, 509-521
CrossRef6
Francisco Álvarez-Nava, Marisol Soto, Alisandra Morales-Machín, Alicia Rojas, Karelis Urdaneta, Jenny Cañizález. (2008) Prospective prenatal serum screening for Down syndrome in Venezuela. International Journal of Gynecology & Obstetrics 103:3, 241-245
CrossRef7
Zvi Vaknin, Orit Reish, Ido Ben-Ami, Eli Heyman, Arie Herman, Ron Maymon. (2008) Prenatal Diagnosis of Sex Chromosome Abnormalities: The 8-Year Experience of a Single Medical Center. Fetal Diagnosis and Therapy 23:1, 76-81
CrossRef8
C.V. Bellieni, M. Maffei, A. Brogna, A. Plantulli, E. Cervo, M. Reda, L. Signorini, G. Buonocore, F. Petraglia. (2008) Consumerism in Prenatal Diagnosis? A Local Italian Study. Fetal Diagnosis and Therapy 24:1, 29-34
CrossRef9
Thomas M Jenkins, Dawnette Lewis. 2007. Screening for aneuploidy and prenatal diagnosis. , 30-39.
CrossRef10
Peter R. Muller, Robert Cocciolone, Eric A. Haan, Chris Wilkinson, Heather Scott, Leonie Sage, Renata Bird, Rhonda Hutchinson, Annabelle Chan. (2007) Trends in state/population-based Down syndrome screening and invasive prenatal testing with the introduction of first-trimester combined Down syndrome screening, South Australia, 1995-2005. American Journal of Obstetrics and Gynecology 196:4, 315.e1-315.e7
CrossRef11
NG Anderson, B Luehr, R Ng. (2006) Normal obstetric ultrasound reduces the risk of Down syndrome in fetuses of older mothers. Australasian Radiology 50:5, 429-434
CrossRef12
Yiu Man Chan, Tse Ngong Leung, Tak Yeung Leung, Tak Yuen Fung, Lin Wai Chan, Tze Kin Lau. (2006) The utility assessment of Chinese pregnant women towards the birth of a baby with Down syndrome compared to a procedure-related miscarriage. Prenatal Diagnosis 26:9, 819-824
CrossRef13
B. Khoshnood, C. De Vigan, B. Blondel, A. Lhomme, V. Vodovar, M. Garel, F. Goffinet. (2006) Women's interpretation of an abnormal result on measurement of fetal nuchal translucency and maternal serum screening for prenatal testing of Down syndrome. Ultrasound in Obstetrics and Gynecology 28:3, 242-248
CrossRef14
Miriam Kuppermann, Lee A. Learman, Elena Gates, Steven E. Gregorich, Robert F. Nease, James Lewis, A Eugene Washington. (2006) Beyond Race or Ethnicity and Socioeconomic Status. Obstetrics & Gynecology 107:5, 1087-1097
CrossRef15
Katharine D. Wenstrom. (2005) Evaluation of Down Syndrome Screening Strategies. Seminars in Perinatology 29:4, 219-224
CrossRef16
Ray O. Bahado-Singh, Utko A. Oz, Inanc Mendilcioglu, Maurice J. Mahoney. (2005) The Mid-Trimester Genetic Sonogram. Seminars in Perinatology 29:4, 209-214
CrossRef17
Ronald J. Wapner. (2005) First Trimester Screening: The BUN Study. Seminars in Perinatology 29:4, 236-239
CrossRef18
Fady Khoury-Collado, Ammar N. Wehbeh, Allan J. Fisher, Allan T. Bombard, Zeev Weiner. (2005) Prenatal diagnosis of 47,XXX. American Journal of Obstetrics and Gynecology 192:5, 1469-1471
CrossRef19
Katharine D. Wenstrom. 2005. Prenatal aneuploidy screening. .
CrossRef20
Babak Khoshnood, B
atrice Blondel, G
CrossRef21
Miriam Kuppermann, Mary E. Norton. (2005) Prenatal Testing Guidelines:. Gynecologic and Obstetric Investigation 60:1, 6-10
CrossRef22
Peter A. Benn, James F. X. Egan, Min Fang, Rebecca Smith-Bindman. (2004) Changes in the Utilization of Prenatal Diagnosis. Obstetrics & Gynecology 103:6, 1255-1260
CrossRef23
Babak Khoshnood, Catherine Vigan, Veronique Vodovar, Janine Goujard, Francois Goffinet. (2004) A population-based evaluation of the impact of antenatal screening for Down's syndrome in France, 1981-2000. BJOG: An International Journal of Obstetrics and Gynaecology 111:5, 485-490
CrossRef24
Aaron B. Caughey, A Eugene Washington, Virginia Gildengorin, Miriam Kuppermann. (2004) Assessment of Demand for Prenatal Diagnostic Testing Using Willingness to Pay. Obstetrics & Gynecology 103:3, 539-545
CrossRef25
Cristina B Netto, Ionara R Siqueira, Cı́ntia Fochesatto, Luis V Portela, Maria da Purificação Tavares, Diogo O Souza, Roberto Giugliani, Carlos-Alberto Gonçalves. (2004) S100B content and SOD activity in amniotic fluid of pregnancies with Down syndrome. Clinical Biochemistry 37:2, 134-137
CrossRef26
Ryan A Harris, A Eugene Washington, Robert F Nease, Miriam Kuppermann. (2004) Cost utility of prenatal diagnosis and the risk-based threshold. The Lancet 363:9405, 276-282
CrossRef27
Wilfried J.A. Gyselaers, Annie J. Vereecken, Erik van Herck, Dany P.L. Straetmans, Eric T.M. de Jonge, Willem U.A.M. Ombelet, Jan G. Nijhuis. (2004) Single-Step Maternal Serum Screening for Trisomy 21 in the Era of Combined or Integrated Screening. Gynecologic and Obstetric Investigation 58:4, 221-224
CrossRef28
Wapner, Ronald, Thom, Elizabeth, Simpson, Joe Leigh, Pergament, Eugene, Silver, Richard, Filkins, Karen, Platt, Lawrence, Mahoney, Maurice, Johnson, Anthony, Hogge, W. Allen, Wilson, R. Douglas, Mohide, Patrick, Hershey, Douglas, Krantz, David, Zachary, JuliaSnijders, Rosalinde, Greene, Naomi, Sabbagha, Rudy, MacGregor, Scott, Hill, Lyndon, Gagnon, Alain, Hallahan, Terrence, Jackson, Laird, . (2003) First-Trimester Screening for Trisomies 21 and 18. New England Journal of Medicine 349:15, 1405-1413
Full Text29
Nancy E Budorick, Mary K O'Boyle. (2003) Prenatal diagnosis for detection of aneuploidy: the options. Radiologic Clinics of North America 41:4, 695-708
CrossRef30
Greggory R. DeVore. (2003) Is genetic ultrasound cost-effective?. Seminars in Perinatology 27:2, 173-182
CrossRef31
Lami Yeo, Anthony M. Vintzileos. (2003) The use of genetic sonography to reduce the need for amniocentesis in women at high-risk for Down syndrome. Seminars in Perinatology 27:2, 152-159
CrossRef32
J. Hartnett, A. F. Borgida, P. A. Benn, D. M. Feldman, M. E. DeRoche, J. F. X. Egan. (2003) Cost analysis of Down syndrome screening in advanced maternal age. Journal of Maternal-Fetal and Neonatal Medicine 13:2, 80-84
CrossRef33
Fran
CrossRef34
Tina Marini, Jan Sullivan, Rizwan Naeem. (2002) Decisions about amniocentesis by advanced maternal age patients following maternal serum screening may not always correlate clinically with screening results: Need for improvement in informed consent process. American Journal of Medical Genetics 109:3, 171-175
CrossRef35
D. J. D. Rosen, I. Kedar, A. Amiel, T. Ben-Tovim, Y. Petel, H. Kaneti, M. Tohar, M. D. Fejgin. (2002) A negative second trimester triple test and absence of specific ultrasonographic markers may decrease the need for genetic amniocentesis in advanced maternal age by 60%. Prenatal Diagnosis 22:1, 59-63
CrossRef36
Ryan A. Harris, A. Eugene Washington, David Feeny, Miriam Kuppermann. (2001) Decision Analysis of Prenatal Testing for Chromosomal Disorders: What Do the Preferences of Pregnant Women Tell Us?. Genetic Testing 5:1, 23-32
CrossRef37
Greggory R. DeVore. (2001) The genetic sonogram: its use in the detection of chromosomal abnormalities in fetuses of women of advanced maternal age. Prenatal Diagnosis 21:1, 40-45
CrossRef38
Martin J. N. Weinans, Annemarie M. G. Huijssoon, Tjeerd Tymstra, Mignon C. F. Gerrits, Johan R. Beekhuis, Albert Mantingh. (2000) How women deal with the results of serum screening for Down syndrome in the second trimester of pregnancy. Prenatal Diagnosis 20:9, 705-708
CrossRef39
Yung Hang Lam, Mary Hoi Yin Tang, Chin Peng Lee, Sai Yuen Sin, Rebecca Tang, Hong Soo Wong, Sai Fun Wong. (2000) Acceptability of serum screening as an alternative to cytogenetic diagnosis of Down syndrome among women 35 years or older in Hong Kong. Prenatal Diagnosis 20:6, 487-490
CrossRef40
Anna Locatelli, Maria Giovanna Piccoli, Patrizia Vergani, Eloisa Mariani, Alessandro Ghidini, Silvana Mariani, John C. Pezzullo. (2000) Critical appraisal of the use of nuchal fold thickness measurements for the prediction of Down syndrome. American Journal of Obstetrics and Gynecology 182:1, 192-197
CrossRef41
Kristen Karlberg. 2000. The work of genetic care providers: Managing uncertainty and ambiguity. , 81-97.
CrossRef42
Agustin Conde-Agudelo, Ana C. Kafury-Goeta. (1999) Triple-Marker Test As Screening for Down Syndrome: A Meta-Analysis. Obstetrical & Gynecological Survey 54:Supplement, 147-155
CrossRef43
William Cusick, Anthony M. Vintzileos. (1999) Fetal Down syndrome screening: A cost effectiveness analysis of alternative screening programs. The Journal of Maternal-Fetal Medicine 8:6, 243-248
CrossRef44
Katharine D. Wenstrom, John Owen, D.C. Chu, Larry Boots. (1999) Prospective evaluation of free β-subunit of human chorionic gonadotropin and dimeric inhibin A for aneuploidy detection. American Journal of Obstetrics and Gynecology 181:4, 887-892
CrossRef45
M Kuppermann, J D Goldberg, R F Nease, A E Washington. (1999) Who should be offered prenatal diagnosis? The 35-year-old question.. American Journal of Public Health 89:2, 160-163
CrossRef46
A. Antsaklis, N. Papantoniou, S. M Eso. (1999) Pregnant women of 35 years of age or more: maternal serum markers or amniocentesis?. Journal of Obstetrics & Gynaecology 19:3, 253-256
CrossRef47
R. A. KADIR, T. PEPERA, D. L. ECONOMID. (1999) Second trimester maternal serum biochemical screening for Down's syndrome: experience of a single obstetric unit. Journal of Obstetrics & Gynaecology 19:4, 373-376
CrossRef48
Tryfon Beazoglou, Dennis Heffley, John Kyriopoulos, Anthony Vintzileos, Peter Benn. (1998) Economic evaluation of prenatal screening for Down syndrome in the U.S.A.. Prenatal Diagnosis 18:12, 1241-1252
CrossRef49
Andrew I. Sokol, Ralph L. Kramer, Yuval Yaron, Joseph E. O’Brien, Francoise Muller, Mark P. Johnson, Mark I. Evans. (1998) Age-specific variation in aneuploidy incidence among biochemical screening programs. American Journal of Obstetrics and Gynecology 179:4, 971-973
CrossRef50
Katharine D. Wenstrom, D.C. Chu, John Owen, Larry Boots. (1998) Maternal serum α-fetoprotein and dimeric inhibin A detect aneuploidies other than Down syndrome. American Journal of Obstetrics and Gynecology 179:4, 966-970
CrossRef51
Bor-Ching Sheu, Ming-Kwang Shyu, Chien-Nan Lee, Bo-Jein Kuo, Yun-Ying Tseng, Fon-Jou Hsieh. (1998) Maternal age-specific risk of Down syndrome in an Asian population: a report of the Taiwan Down syndrome screening group. Prenatal Diagnosis 18:7, 675-682
CrossRef52
MARK I. EVANS, JOSEPH E. O'BRIEN, GREGORY CRITCHFIELD. (1998) Detection of Anomalies: Alternatives to Ultrasound. Annals of the New York Academy of Sciences 847:1 ULTRASOUND SC, 191-199
CrossRef53
Agustin Conde-Agudelo, Ana C. Kafury-Goeta. (1998) Triple-Marker Test As Screening for Down Syndrome. Obstetrical & Gynecological Survey 53:6, 369-376
CrossRef54
Pietro Cavalli, Enrico Gnocchi, Alessandro Pennacchio, Brunello Morrica. (1998) Dual analyte screening for fetal Down syndrome in pregnant women over 35 years of age. Prenatal Diagnosis 18:6, 637-638
CrossRef55
George J. Knight, Glenn E. Palomaki, Louis M. Neveux, Karen K. Fodor, James E. Haddow. (1998) hCG and the free β-subunit as screening tests for Down syndrome. Prenatal Diagnosis 18:3, 235-245
CrossRef56
Diane B. Paul. (1998) Genetic Services, Economics, and Eugenics. Science in Context 11:3-4,
CrossRef57
Carolyn L. Olsen, Philip K. Cross. (1997) Trends in the use of prenatal diagnosis in New York State and the impact of biochemical screening on the detection of Down syndrome: 1984–1993. Prenatal Diagnosis 17:12, 1113-1124
CrossRef58
Katharine D. Wenstrom, John Owen, D.C. Chu, Larry Boots. (1997) Elevated second-trimester dimeric inhibin A levels identify Down syndrome pregnancies. American Journal of Obstetrics and Gynecology 177:5, 992-996
CrossRef59
L. H. Kornman, M. J. M. Wortelboer, J. R. Beekhuis, L. P. Morssink, A. Mantingh. (1997) Women's opinions and the implications of first- versus second-trimester screening for fetal Down's syndrome. Prenatal Diagnosis 17:11, 1011-1018
CrossRef60
Katharine D. Wenstrom, John Owen, D.C. Chu, Larry Boots. (1997) α-Fetoprotein, free β-human chorionic gonadotropin, and dimeric inhibin A produce the best results in a three-analyte, multiple-marker screening test for fetal Down syndrome. American Journal of Obstetrics and Gynecology 177:5, 987-991
CrossRef61
Kaoru Suzumori, Mitsuyo Tanemura, Isamu Murakami, Setsuo Okada, Michiya Natori, Mamoru Tanaka, Tsukasa Takagi, Akio Sato. (1997) A Retrospective Evaluation of Maternal Serum Screening for the Detection of Fetal Aneuploidy. Prenatal Diagnosis 17:9, 861-866
CrossRef62
W. J. Van Der Veen, J. R. Beekhuis, M. C. Cornel, A. Mantingh, H. E. K. De Walle, B. T. H. M. de Wolf. (1997) A Demographic Approach to the Assessment of Down Syndrome Screening Performance. Prenatal Diagnosis 17:8, 717-724
CrossRef63
Georgine Lamvu, Jeffrey A. Kuller. (1997) Prenatal Diagnosis Using Fetal Cells From the Maternal Circulation. Obstetrical & Gynecological Survey 52:7, 433-437
CrossRef64
Glenn E. Palomaki. (1996) Down's syndrome epidemiology and risk estimation. Early Human Development 47, S19-S26
CrossRef65
JOHN W. SEEDS. (1996) The Routine or Screening Obstetrical Ultrasound Examination. Clinical Obstetrics and Gynecology 39:4, 814-830
CrossRef66
Sheau-Wen Jan, Chih-Ping Chen, Lian-Hua Huang, Fu-Yuan Huang, Chung-Chi Lan. (1996) Attitudes toward maternal serum screening in Chinese women with positive results. Journal of Genetic Counseling 5:4, 169-180
CrossRef67
George J. Knight. (1996) Quality assessment of a prenatal screening program. Early Human Development 47, S49-S53
CrossRef68
Ray O. Bahado-Singh, Özgür Deren, Ann Tan, Roberto Levi D'Ancona, David Hunter, J.A. Copel, M.J. Mahoney. (1996) Ultrasonographically adjusted midtrimester risk of trisomy 21 and significant chromosomal defects in advanced maternal age. American Journal of Obstetrics and Gynecology 175:6, 1563-1568
CrossRef69
L.H. Kornman, J.R. Beekhuis, B.T.H.M.de Wolf. (1996) Screening should not be compared with diagnosis. American Journal of Obstetrics and Gynecology 174:6, 1941
CrossRef70
Jerome Yankowitz, Donald M. Howser, John W. Ely. (1996) Differences in practice patterns between obstetricians and family physicians: Use of serum screening. American Journal of Obstetrics and Gynecology 174:4, 1361-1365
CrossRef71
Chandice Covington, Phyllis Gieleghem, Frances Board, Kimberly Madison, Daphne Nedd, Linda Miller. (1996) Family Care Related to Alpha-Fetoprotein Screening. Journal of Obstetric, Gynecologic, <html_ent glyph="@amp;" ascii="&"/> Neonatal Nursing 25:2, 125-130
CrossRef72
L. S. M. RIBBERT, L. H. KORNMAN, B. T. H. M. DE WOLF, A. H. M. SIMONS, C. A. M. JANSEN, J. R. BEEKHUIS, A. MANTINGH. (1996) MATERNAL SERUM SCREENING FOR FETAL DOWN SYNDROME IN IVF PREGNANCIES. Prenatal Diagnosis 16:1, 35-38
CrossRef73
Glenn E Palomaki, Louis M Neveux, James E Haddow. (1995) Are DADs (discriminant aneuploidy detection) as good as MOMs (multiples of the median)?. American Journal of Obstetrics and Gynecology 173:6, 1895-1896
CrossRef74
Thomas E. J. Ind, N. M. Fisk. (1995) Fetal nuchal translucency: ultrasound screening for fetal trisomy in the first trimester of pregnancy. BJOG: An International Journal of Obstetrics and Gynaecology 102:9, 758-759
CrossRef75
Jean-Claude Forest, Jacques Massé, François Rousseau, Jean-Marie Moutquin, Natalie-Anne Brideau, Micheline Bélanger. (1995) Screening for Down syndrome during the first and second trimesters: Impact of risk estimation parameters. Clinical Biochemistry 28:4, 443-449
CrossRef76
Peter A. Benn, Donna Horne, Susan Briganti, Robert M. Greenstein. (1995) Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome. American Journal of Obstetrics and Gynecology 173:2, 496-501
CrossRef77
Jeanine Loncar, Vanessa M. Barnabei, John W. Larsen. (1995) Advent of Maternal Serum Markers for Down Syndrome Screening. Obstetrical & Gynecological Survey 50:4, 316-320
CrossRef78
Mark I. Evans, Lawrence Chik, Joseph E. O'Brien, Bernadette Chin, Elena Dvorin, Mazin Ayoub, Eric L. Krivchenia, Joel W. Ager, Mark P. Johnson, Robert J. Sokol. (1995) MOMs (multiples of the median) and DADs (disciminant aneuploidy detection): Improved specificity and cost-effectiveness of biochemial screening for aneuploidy with DADs. American Journal of Obstetrics and Gynecology 172:4, 1138-1149
CrossRef79
Leonard H. Kellner, Robert R. Weiss, Zeev Weiner, Marsha Neuer, Gregory M. Martin, Harold Schulman, Stanley Lipper. (1995) The advantages of using triple-marker screening for chromosomal abnormalities. American Journal of Obstetrics and Gynecology 172:3, 831-836
CrossRef80
(1995) Review article. Journal of Perinatal Medicine 23:6, 421-436
CrossRef81
Joe Leigh Simpson, Sherman Elias. (1994) Isolating fetal cells in maternal circulation for prenatal diagnosis. Prenatal Diagnosis 14:13, 1229-1242
CrossRef82
JamesE. Haddow, GlennE. Palomaki. (1994) Multiparity and Down's syndrome. The Lancet 344:8927, 956
CrossRef83
Fiona J. Bamforth. (1994) Laboratory screening for genetic disorders and birth defects. Clinical Biochemistry 27:5, 333-342
CrossRef84
(1994) Triple-Marker Screening of Serum for Down's Syndrome. New England Journal of Medicine 331:10, 681-682
Full Text85
Glenn E. Palomaki, James E. Haddow. (1994) Comparison of two Down syndrome screening strategies for women aged 35 and older. Prenatal Diagnosis 14:9, 898-899
CrossRef86
JOE LEIGH SIMPSON, SHERMAN ELIAS. (1994) Fetal Cells in Maternal Blood.. Annals of the New York Academy of Sciences 731:1 Fetal Cells i, 1-8
CrossRef87
Pauker, Susan P., , Pauker, Stephen G., . (1994) Prenatal Diagnosis -- Why Is 35 a Magic Number?. New England Journal of Medicine 330:16, 1151-1152
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