Skip to main content
NCBI home page
Journal of Clinical Medicine logoLink to Journal of Clinical Medicine
. 2014 Apr 8;3(2):388–415. doi: 10.3390/jcm3020388

Beyond Trisomy 21: Additional Chromosomal Anomalies Detected through Routine Aneuploidy Screening

Amy Metcalfe 1,*, Catriona Hippman 2,3, Melanie Pastuck 4, Jo-Ann Johnson 5
PMCID: PMC4449689  PMID: 26237381

Abstract

Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other than trisomy 21 with different prenatal screening tests. Non-invasive prenatal testing had the highest detection (DR) and lowest false positive (FPR) rates for trisomy 13 (DR: 90.3%; FPR: 0.2%), trisomy 18 (DR: 98.1%; FPR: 0.2%), and 45,X (DR: 92.2%; FPR: 0.1%); however, most estimates came from high-risk samples. The first trimester combined test also had high DRs for all conditions studied (trisomy 13 DR: 83.1%; FPR: 4.4%; trisomy 18 DR: 91.9%; FPR: 3.5%; 45,X DR: 70.1%; FPR: 5.4%; triploidy DR: 100%; FPR: 6.3%). Second trimester triple screening had the lowest DRs and highest FPRs for all conditions (trisomy 13 DR: 43.9%; FPR: 8.1%; trisomy 18 DR: 70.5%; FPR: 3.3%; 45,X DR: 77.2%; FPR: 9.3%). Prenatal screening tests differ in their ability to accurately detect chromosomal anomalies. Patients should be counseled about the ability of prenatal screening to detect anomalies other than trisomy 21 prior to undergoing screening.

Keywords: aneuploidy, prenatal, maternal serum, ultrasound, non-invasive testing, sensitivity, specificity

1. Introduction

Prenatal screening for fetal aneuploidy aims to identify women at increased risk of carrying a fetus with a chromosomal anomaly and limit the offer of invasive diagnostic tests (with their associated risk of miscarriage) to those women at high-risk. National practice guidelines currently recommend that all pregnant women be offered prenatal screening for aneuploidy [1,2]. Methods for prenatal screening have evolved rapidly in recent decades from screening based on maternal age alone, to serum screening, to a combination of maternal serum and ultrasound based measures, and most recently to isolated cell free fetal DNA (cffDNA) from maternal plasma [3,4,5].

Prenatal screening for fetal aneuploidy is most frequently discussed in terms of prenatal screening for trisomy 21 (Down syndrome) as this is the most common form of fetal aneuploidy and this condition has clinical implications for the health of the fetus [3,4]. However, counseling issues arise when anomalies are detected that were not discussed during the informed consent process, given that parents would be unprepared for such a result. Parents consistently report that they do not have enough information about prenatal screening, and may be surprised when they undergo a screening test for trisomy 21 only to find out that their fetus has another (and potentially more severe) anomaly [6,7,8,9]. A good understanding of prenatal screening, prior to accessing this test, is important, because if the results are positive, parents must make important and complex decisions about invasive testing which carries a small, but substantial risk of pregnancy loss, and potentially pregnancy termination [9,10]. Counseling about conditions other than trisomy 21 that may be detected through prenatal screening is complicated for a variety of reasons; the clinical implications of balanced chromosome rearrangements are not always known, the risk of specific anomalies is extremely low, and the reported detection rates and false positive rates for different anomalies vary widely in the literature [10]. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for fetal aneuploidies other than trisomy 21 using standard prenatal screening tests. This information may be helpful to care providers as they discuss the relative strengths and limitations of different forms of prenatal screening with their patients.

2. Methods

2.1. Systematic Review

Relevant English-language literature was identified through a systemic search of Medline (1946–2013) and Embase (1974–2013) in November 2013. Reference lists of included articles were examined to identify additional relevant articles that may have been missed in the electronic search. The search terms included generic terms (prenatal diagnosis, antenatal diagnosis, prenatal screening, antenatal screening) as well as specific terms related to the screening test used (first trimester screening, aneuploidy screening, integrated screening, sequential screening, non-invasive prenatal testing, serum screening, combined screening, genetic screening, quad screen) or the chromosomal anomaly (Klinefelter syndrome, tetraploidy, translocation, triploidy, trisomy 13, trisomy 18, Turner syndrome). Truncation symbols were used to include all possible variations of the search term (i.e., screen, screening, screened).

Studies were eligible for inclusion if they provided the data necessary to calculate the number of true positives, false positives, false negatives and true negatives for a chromosomal anomaly other than trisomy 21 using a currently available prenatal screening test (see Table 1). Studies that exclusively used maternal serum alpha fetoprotein (MS-AFP) or a combination of MS-AFP and human chorionic gonadotrophin (hCG) (double test) were deemed outdated and were not included in the review. Two reviewers (Amy Metcalfe, Catriona Hippman) independently reviewed all titles and abstracts for potential inclusion. Full-text review was undertaken for any article deemed potentially eligible by either reviewer. Data extraction and verification was performed by the same reviewers. Specific study elements extracted included: screening test used, detection rate, number of women screened, number of screen positive women, number of aneuploid fetuses, study location, and time period of data collection.

Table 1.

Prenatal screening tests eligible for inclusion in systematic review.

Prenatal Screening Test Biochemical and Ultrasound Components
First Trimester Combined Test NT, PAPP-A, free β hCG
Second Trimester Triple Screen AFP, hCG, uE3
Second Trimester Quadruple Screen AFP, hCG, uE3, Inhibin A
Integrated/Sequential/Contingent Screen (NT, PAPP-A, free β hCG) + (AFP, hCG, uE3, Inhibin A)
Non-Invasive Prenatal Testing (NIPT) cffDNA
Open in a new tab

AFP = alpha-fetoprotein; cffDNA = cell free fetal DNA; hCG = human chorionic gonadatrophin; NT = nuchal translucency; PAPP-A = pregnancy associated plasma protein A; uE3 = unconjugated estriol.

Guidelines for the Meta-analysis of Observational Studies in Epidemiology (MOOSE) [11] and Studies of Diagnostic Accuracy (STARD) [12] were followed.

2.2. Diagnostic Meta-Analysis

The accuracy of prenatal screening tests is typically evaluated using both the detection rate (sensitivity) and the false positive rate (1-specificity). As these measures are correlated, a bivariate random effects model was used to derive pooled estimates and generate summary receiver operating characteristic (SROC) curves [13]. Studies were weighted based on their total sample size, as large sample sizes allow for more precise estimates of sensitivity and specificity [14]. For a detailed description of the technical specifications of the model, readers are referred to [14]. A minimum of four studies were required to derive pooled detection and false positive rates. All analyses were conducting using Stata 12 SE (StataCorp LP, College Station, TX, USA).

3. Results

Sixty-five articles met all inclusion criteria and were included in the systematic review (Figure 1). Trisomy 18 was the most common aneuploidy eligible for inclusion in the meta-analysis for which literature was available, while the first trimester combined test was the most common prenatal screening test eligible for inclusion in the meta-analysis for which literature was available (Figure 1). Detailed information on all included studies can be found in the Appendix A.

Figure 1.

Figure 1

Open in a new tab

Flow diagram of study selection.

3.1. Trisomy 13 (Patau Syndrome)

Overall, 31 studies reported data on trisomy 13, including 16 studies that utilized the first trimester combined test [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30], 8 utilizing the second trimester triple screen [31,32,33,34,35,36,37,38], and 9 using non-invasive prenatal testing (NIPT) [39,40,41,42,43,44,45] (Table 2 and Appendix B). Two studies utilizing NIPT [39,45] included data on two patient groups (a training set and a validation set); hence were included as two distinct studies in the diagnostic meta-analysis.

Table 2.

Pooled results for trisomy 13.

Study Characteristics Prenatal Screening Test
1st Trimester Combined Test 2nd Trimester Triple Screen Non-Invasive Prenatal Testing
Number of Studies 16 8 9
Number of Patients 245,502 1,276,894 5840
Number of Cases 185 156 86
Median prevalence per 10,000 pregnancies (25th–75th percentile range) 5.1 (3.8–16.0) 2.2 (1.2–9.0) 263.2 (71.1–637.8)
Observed Detection Rates from Included Studies (Minimum-Maximum Range) 0%–100% 0%–100% 63.6%–100%
Observed False Positive Rates from Included Studies (Minimum-Maximum Range) 0.1%–12.5% 0.2%–26.1% 0%–1.6%
Pooled Detection Rate 83.1% (72.6–90.2) 43.9% (23.0–67.2) 90.3% (75.7–96.6)
Pooled False Positive Rate 4.4% (3.0–6.4) 8.1% (3.1–19.7) 0.2% (0.05–0.8)
Open in a new tab

Substantial variation was noted in the definition of a “screen positive” test for trisomy 13 using the first trimester combined test—definitions for specific risk levels for trisomy 13 included risks ≥1/200 [19], risks of trisomy 13 or 18 ≥1/150 [15,21] or 1/200 [25], or risks of trisomy 13, 18 or 21 ≥1/250 [24] or 1/300 [23,27]. No studies using the second trimester triple screen included a specific risk algorithm for trisomy 13; however, variation in the definition of “screen positive” for trisomy 21 or trisomy 21/trisomy 18 was observed. Studies differed in that some reported cut-off values based on the risk of trisomy 13 at the time of the test (either the first trimester or the second trimester) or at term; however, this only partially explains the differences observed in cut-off values.

NIPT exhibited the strongest overall test performance with a pooled detection rate of 90.3% and a false positive rate <1% (Table 2). The first trimester combined test had a significantly higher detection rate (83.1% vs. 43.9%) and a lower false positive rate (4.4% vs. 8.1%) than the second trimester triple screen, although statistical significance was not achieved for the false positive rate (p > 0.05) (Table 2).

3.2. Trisomy 18 (Edward Syndrome)

Trisomy 18 was the most frequently reported condition in eligible studies. Data was obtained from 61 studies, including 30 that utilized the first trimester combined test [15,16,17,18,19,20,21,23,24,25,26,27,28,29,30,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60], 17 that used the second trimester triple screen [31,32,33,34,35,36,37,38,61,62,63,64,65,66,67,68,69], 12 that contained data on NIPT [40,41,42,43,44,45,70,71,72,73,74], 3 studies that used the second trimester quadruple screen [47,75,76], and 2 studies that reported data on patients undergoing integrated or sequential screening [52,77] (Table 3 and Appendix B). One of the studies reporting on NIPT included data from two separate patient groups [72], and is included as two separate studies in the diagnostic meta-analysis.

Table 3.

Pooled results for trisomy 18.

Study Characteristics Prenatal Screening Test
1st Trimester Combined Test 2nd Trimester Triple Screen Non-Invasive Prenatal Testing
Number of Studies 30 17 12
Number of Patients 325,808 1,752,184 10,778
Number of Cases 581 693 302
Median prevalence per 10,000 pregnancies (25th–75th percentile range) 13.9 (8.3–21.3) 4.8 (3.0–22.5) 454.2 (134.8–801.3)
Observed Detection Rates from Included Studies (Minimum-Maximum Range) 50%–100% 0%–100% 90%–100%
Observed False Positive Rates from Included Studies (Minimum-Maximum Range) 0.4%–15.8% 0.2%–35.7% 0%–2.0%
Pooled Detection Rate 91.9% (85.8–95.6) 70.5% (60.9–78.6) 98.1% (95.1–99.2)
Pooled False Positive Rate 3.5% (2.5–4.9) 3.3% (3.1–3.6) 0.2% (0.1–0.4)
Open in a new tab

Similar to screening for trisomy 13, substantial heterogeneity was observed in the definition for a “screen positive” test for trisomy 18. Positive risk scores for the first trimester combined screen ranged from risks ≥1/100 to ≥1/300. Approximately half of the studies using the second trimester triple screen that reported their definition for “screen positive” results used a patient-specific risk (risks ≥1/100 or ≥1/200), while the remaining studies used a fixed cut-off level based on levels of serum analytes (typically AFP ≤ 0.75 MoM, hCG ≤ 0.55 MoM, and uE3 ≤ 0.60 MoM). Again, studies differed in that some reported cut-off values based on the risk of trisomy 18 at the time of the test (either the first trimester or the second trimester) or at term.

NIPT exhibited the best overall test performance with a pooled detection rate of 98.1% and false positive rate of <1% (Table 3). The first trimester combined test outperformed the second trimester triple screen, as it had a significantly higher detection rate (91.9% vs. 70.5%), with no difference in the false positive rate (p > 0.05) (Table 3). There were an insufficient number of studies to derive pooled estimates on the detection rate and false positive rate for trisomy 18 using the second trimester quadruple test, but the observed detection rate ranged from 44.4% to 100% with false positive rates ranging from 0.5% to 9.6% [47,75,76]. Pooled results from the triple screen population may be generalizable to women screened with the quadruple test, as Inhibin A is not part of the trisomy 18 screening protocol.

There were an insufficient number of studies using integrated/sequential screening to determine pooled detection and false positive rates; however, the observed detection rate was 100% in both studies using integrated/sequential screening, while the observed false positive rates ranged from 3.7% to 7.3% [52,77].

3.3. 45,X (Turner Syndrome)

Twenty studies included data on Turner syndrome, 6 that utilized the first trimester combined screen [19,23,26,30,49,51], 9 that used the second trimester triple screen [31,32,33,34,35,36,66,78,79], 4 that involved NIPT [40,42,43,45], and a single study that used the second trimester quadruple screen [76] (Table 4 and Appendix B).

Table 4.

Pooled results for 45,X.

Study Characteristics Prenatal Screening Test
1st Trimester Combined Test 2nd Trimester Triple Screen Non-Invasive Prenatal Testing
Number of Studies 6 9 4
Number of Patients 95,159 1,385,296 1491
Number of Cases 37 290 30
Median prevalence per 10,000 pregnancies (25th–75th percentile range) 4.2 (2.5–9.3) 3.2 (2.5–6.1) 397.5 (206.9–583.1)
Observed Detection Rates from Included Studies (Minimum-Maximum Range) 0%–100% 0%–100% 75%–100%
Observed False Positive Rates from Included Studies (Minimum-Maximum Range) 4.3%–7.2% 5.1%–26.1% 0%–0.2%
Pooled Detection Rate 70.1% (51.8–83.7) 77.2% (59.9–88.5) 92.2% (91.6–92.8)
Pooled False Positive Rate 5.4% (4.7–6.3) 9.3% (6.7–12.8) 0.1% (0.11–0.12)
Open in a new tab

With the exception of NIPT, none of the other screening tests involved a specific risk cut-off to identify patients at increased risk of carrying a fetus with Turner syndrome. Turner syndrome is considered an incidental finding amongst patients who screen positive for trisomy 13, 18 or 21 with the first trimester combined test and the second trimester triple and quadruple screens. This has implications for the interpretation of test results in a clinical setting.

NIPT had the best overall test performance with a detection rate of 92.2% and a false positive rate of <0.1% (Table 4). A significant difference was not observed between the first trimester combined test and the second trimester triple screen for detection rate, although the first trimester combined test had a significantly lower false positive rate (p < 0.05) (Table 4). The single study that used the second trimester quadruple screen had an observed detection rate of 66.7% and a false positive rate of 9.6% [76].

3.4. Triploidy

Finally, 11 studies provided data on triploidy: 7 of which used the first trimester combined test [19,20,23,24,27,30,51], 3 utilized the second trimester triple screen [32,33,35] and 1 used the second trimester quadruple screen [76]. Triploidy was an incidental finding amongst women who were screen positive for trisomy 13, 18 or 21. This has implications for the interpretation of test results in a clinical setting and how patients should be counseled following a positive screening test.

Seven studies, representing 93,796 women and 15 affected fetuses, contained data on the first trimester combined screen and could be pooled using diagnostic meta-analysis [19,20,23,24,27,30,51]. These studies had a pooled detection rate of 100.0% (99.9–100.0) and a pooled false positive rate of 6.3% (4.9–8.0) (Appendix B). Comparable results were also observed for the other screening tests, even though sufficient data were not available to derive pooled estimates. Observed detection rates ranged from 98.1% to 100% with observed false positive rates of 2.6%–10.6% for the second trimester triple screen [32,33,35]; while the single study that used the quadruple screen reported a detection rate of 100% and a false positive rate of 9.6%.

4. Discussion

The results of this systematic review and diagnostic meta-analysis confirm the general consensus that for all conditions, NIPT is a superior test in terms of detection rate and false positive rate than other screening tests for aneuploidies, with the caveat that most studies have been performed in high risk populations. However, NIPT is subject to a higher rate of test failures than other prenatal screening tests and currently only provides results for a limited number of aneuploidies. The dramatically higher median prevalence of aneuploidies used in studies of NIPT to date has important implications on test performance in a low-risk setting. While this is unlikely to impact the overall detection rate and false positive rate, positive predictive values (odds of being affected given a positive result) are particularly sensitive to the prevalence of the condition being studied [80,81]. Additionally, pooled results for NIPT did not display 100% detection rates for any condition, indicating the importance of confirmatory invasive testing. Furthermore, due to the high cost of NIPT, many centers continue to utilize other forms of prenatal screening. Nonetheless, having data on pooled detection rates and false positives rates may be helpful when counseling patients.

Multiple studies have indicated that up to half of the chromosomal anomalies identified through invasive testing for abnormal prenatal screening results or increased maternal age are not autosomal aneuploidies [15,82,83]. Several authors have expressed concern that moving away from serum and ultrasound based screening to prenatal screening based exclusively on NIPT might miss the detection of rare chromosomal anomalies [5,73,84]. Furthermore, extreme levels of serum analytes are associated with adverse obstetrical outcomes and may be useful to help triage patients into higher levels of prenatal care [85,86,87,88]. Contingent screening with NIPT might provide a compromise in terms of maintaining the benefits of existing prenatal screening programs, while reducing the number of women who proceed onto invasive testing, but the current costs of NIPT make this prohibitive to implement in many population-based screening programs. While the costs of NIPT will likely decrease over time, the current cost of NIPT is $795 (Canadian dollars) in contrast to $303 for the first trimester combined test and $15 for the second trimester triple screen [89,90].

Current clinical practice guidelines recommend that prenatal screening should be offered through an informed consent process; in particular, the Society of Obstetricians and Gynecologists of Canada has issued counseling recommendations specifically detailing that all women who are offered prenatal screening should be told that all women have some risk of having a fetus affected by trisomy 21, 18, or 13 [91]. We suggest additional pre-screening counseling recommendations that women should be informed that, while prenatal screening tests have been developed to specifically target the detection of trisomy 21, 18, and 13, other chromosomal anomalies and obstetrical risks may be detected by the screen as well. In particular, it would be worth discussing sex chromosome aneuploidy and triploidy in light of available data, but some mention of the breadth of unexpected results would enhance the informed consent process.

This study has limitations. The search specifically excluded terms related to trisomy 21—this was done on purpose to restrict the number of abstracts identified and because the goal of this review was to look at chromosomal anomalies other than trisomy 21. This may have resulted in some relevant articles not being identified in the initial search; however, the reference lists of accepted articles were hand searched to identify other relevant articles. The quality of the pooled results is a direct reflection of the data included in the original articles; the authors of many studies made the assumption that false negative cases would be brought to their attention through cytogenetic databases or birth certificates and did not actively follow-up all women screened. Additionally, the raw data on true positives, false positives, false negatives and true negatives sometimes had to be back-calculated based on reported detection and false positive rates; this may have resulted in some minor inaccuracies. The model used to generate pooled detection and false positive rates does not specifically account for differences in cut-off values or the specific screening algorithm used to define a positive or negative screening test [14]. However, this is reflected in the different estimates of sensitivity and specificity obtained from individual studies and the heterogeneity of these estimates is directly modeled and used to derive the pooled estimates [14]. Multiple between-study differences were observed in terms of the maternal age distribution, inclusion of pregnancies that ultimately resulted in spontaneous abortion and of multiple gestation pregnancies, test uniformity (specifically related to the use of free β hCG vs. total hCG), and test quality standards (specifically related to the use of nuchal translucency). While a random effects model was used to derive pooled estimates, this model addresses statistical heterogeneity, not clinical heterogeneity in the underlying populations. Finally, the search was limited to English language articles which may limit the generalizability of the results. However, the included studies came from North America, Europe, Australia and Asia, indicating wide geographic coverage.

5. Conclusions

In conclusion, while prenatal screening tests are often described to patients in terms of trisomy 21, they do (to varying degrees) identify other chromosomal anomalies. Providing this information to patients prior to screening can help them make an informed choice about accessing prenatal screening and, in some contexts, which screening test is preferable to them.

Acknowledgments

Amy Metcalfe holds a fellowship award from the Canadian Institutes of Health Research. Catriona Hippman is supported by the Women’s Health Research Institute.

Appendix

Appendix A.

Included studies.

Study Screening Test N Detection Rate False Positive Rate Cut-Off to Define a Positive Screening Test Location
Trisomy 13
Alamillo 2013 [15] First Trimester Combined Test 23,329 100.0 6.3 T21: 1/300
T13/T18: 1/150		 USA
Berktold 2013 [29] First Trimester Combined Test 14,862 83.3 4.7 Germany
Hormansdorfer 2009 [16] First Trimester Combined Test 2202 0 5.8 1/230 Germany
Kagan 2008 [17] First Trimester Combined Test 56,954 93.4 3.1 UK
Karadozov-Orlic 2012 [18] First Trimester Combined Test 4172 81.8 5.3 Serbia
Marttala 2011 [19] First Trimester Combined Test 56,076 54.5 4.5 T21: 1/250
T13/T18: 1/200		 Finland
Merz 2008 [28] First Trimester Combined Test 40,802 92.3 5.0 Germany
Ochshorn 2001 [26] First Trimester Combined Test 1408 66.7 7.1 Israel
Orlandi 1997 [20] First Trimester Combined Test 2010 50.0 12.5 Italy
Scott 2004 [30] First Trimester Combined Test 2053 100.0 7.2 Australia
Sorensen 2011 [21] First Trimester Combined Test 19,694 72.7 1.0 T21: 1/300
T13/T18: 1/150		 Denmark
Spencer 2000 [22] First Trimester Combined Test 989 83.3 0.1 England
Spencer 2000 [27] First Trimester Combined Test 3762 100.0 6.7 T13/T18/T21: 1/300 England
Spencer 2003 [23] First Trimester Combined Test 11,105 100.0 5.2 T13/T18/T21: 1/300 England
Stenhouse 2004 [24] First Trimester Combined Test 5084 100.0 6.2 T13/T18/T21: 1/250 Scotland
Valinen 2012 [25] First Trimester Combined Test 1000 66.7 4.6 T13/T18: 1/200 Finland
Benn 1996 [31] Second Trimester Triple Screen 26,364 20.0 8.7 T21: 1/270
T18: AFP ≤ 0.75 MoM,
Hcg ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Burton 1993 [32] Second Trimester Triple Screen 8233 0 0.2 T21: 1/270
T18: AFP ≤ 0.7 MoM,
hCG ≤ 0.5 MoM,
uE3 ≤ 0.55 MoM		 USA
Kazerouni 2009 [33] Second Trimester Triple Screen 752,686 36.0 6.6 T21: 1/190
T18: 1/100		 USA
Onda 2000 [34] Second Trimester Triple Screen 32,925 100.0 14.5 T21: 1/295
T18: 1/100		 Japan
Summers 2003 [35] Second Trimester Triple Screen 423,895 60.0 9.7 T21: 1/385 at term
T18: 1/100		 Canada
Suzumori 1997 [37] Second Trimester Triple Screen 1078 50.0 20.3 T21: 1/299 Japan
Wenstrom 1995 [36] Second Trimester Triple Screen 1423 0 26.1 T21: 1/190
T18: AFP ≤ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Wortelboer 2008 [38] Second Trimester Triple Screen 30,290 50.0 13.1 T21: 1/200
T18: 1/200		 Netherlands
Ashoor 2013 [39] Non-invasive prenatal testing 156 63.6 0 England
Ashoor 2013 [39] Non-invasive prenatal testing 1949 80.0 0.1 England and USA
Bianchi 2012 [40] Non-invasive prenatal testing 532 78.6 0 USA
Chen 2011 [41] Non-invasive prenatal testing 392 100.0 1.1 Hong Kong,
Netherlands,
UK
Jiang 2012 [42] Non-invasive prenatal testing 903 100.0 0 China
Lau 2012 [43] Non-invasive prenatal testing 108 100.0 0 Japan
Palomaki 2012 [44] Non-invasive prenatal testing 1688 91.7 1.0 z score ≥ 3 Argentina, Australia, Canada, Czech Republic, Hungary, Ireland, Italy, Spain, USA
Sehnert 2011 [45] Non-invasive prenatal testing 47 100.0 0 >2.5 standard deviations of the mean USA
Sehnert 2011 [45] Non-invasive prenatal testing 65 100.0 1.6 >2.5 standard deviations of the mean USA
Trisomy 18
Alamillo 2013 [15] First trimester combined test 23,329 100.0 6.3 T21: 1/300
T13/18: 1/150		 USA
Berktold 2013 [29] First trimester combined test 14,862 100.0 4.7 Germany
Borrell 2004 [46] First trimester combined test 2765 75.0 3.3 T21: 1/250 Spain
Breathnach 2007 [47] First trimester combined test 35,974 82.1 6.0 T21: 1/150
T18: 1/100		 USA
Centini 2005 [48] First trimester combined test 408 100.0 15.8 Italy
Chou 2009 [49] First trimester combined test 10,811 50.0 5.4 T21: 1/270 Taiwan
Dhaifalah 2006 [50] First trimester combined test 686 100.0 5.1 1/250 Czech Republic
Gaffari 2012 [51] First trimester combined test 13,706 100.0 4.7 1/300 Iran
Guanciali-Franchi 2011 [52] First trimester combined test 7292 66.7 4.2 Italy
Hormansdorder 2009 [16] First trimester combined test 2202 50.0 5.7 1/230 Germany
Jacques 2007 [53] First trimester combined test 15,243 66.7 0.4 T21: 1/300
T18: 1/250		 Australia
Kagan 2008 [17] First trimester combined test 56,954 96.7 2.4 UK
Karadzov-Orlic 2012 [18] First trimester combined test 4172 85.7 5.3 Serbia
Krantz 2000 [54] First trimester combined test 5718 100.0 0.8 T18: 1/150 USA
Martinez-Morillo 2012 [55] First trimester combined test 18,801 100.0 0.4 1/250 Spain
Marttala 2011 [19] First trimester combined test 56,076 74.1 4.5 T21: 1/250
T13/18: 1/200		 Finland
Merz 2008 [28] First trimester combined test 40,802 94.1 5.0 Germany
Ochshorn 2001 [26] First trimester combined test 1408 66.7 7.1 Israel
Orlandi 1997 [20] First trimester combined test 2010 100.0 12.3 Italy
Perni 2006 [56] First trimester combined test 4615 100.0 1.0 USA
Scott 2004 [30] First trimester combined test 2053 100.0 7.2 Australia
Sorensen 2011 [21] First trimester combined test 19,694 91.3 1.5 T21: 1/300
T13/18: 1/150		 Denmark
Spencer 2000 [27] First trimester combined test 3762 100.0 6.6 T13/18/21: 1/300 England
Spencer 2003 [23] First trimester combined test 11,105 100.0 5.1 T13/18/21: 1/300 England
Spencer 2007 [57] First trimester combined test 521 96.2 1.3 T21: 1/300
T13/18: 1/100		 UK
Stenhouse 2004 [24] First trimester combined test 5084 100.0 6.1 T13/18/21: 1/250 Scotland
Tsai 2001 [58] First trimester combined test 1514 50.0 6.3 T21: 1/400 Taiwan
Tul 1999 [59] First trimester combined test 997 90.0 1.1 England
Valinen 2012 [25] First trimester combined test 1000 73.7 4.6 T13/18: 1/200 Finland
Wapner 2003 [60] First trimester combined test 8216 100.0 2.0 T21: 1/270
T18:1/150		 USA
Barkai 1993 [61] Second trimester triple screen 5502 66.7 0.3 T21: 1/300
T18: 1/100		 Israel
Benn 1996 [31] Second trimester triple screen 26,364 62.5 8.6 T21: 1/270
T18: AFP ≥ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Benn 1999 [62] Second trimester triple screen 41,565 92.3 0.4 T21: 1/270
T18: 1/100		 USA
Burton 1993 [32] Second trimester triple screen 8233 100.0 0.2 T21: 1/270
T18: AFP ≥ 0.7 MoM,
hCG ≤ 0.5 MoM,
uE3 ≤ 0.55 MoM		 USA
Hogge 2001 [63] Second trimester triple screen 45,145 66.7 0.5 1/100 USA
Kazerouni 2009 [33] Second trimester triple screen 752,686 82.5 6.6 T21: 1/190
T18: 1/100		 USA
Kellner 1995 [64] Second trimester triple screen 8649 66.7 0.2 T18: AFP ≥ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Kishida 2000 [65] Second trimester triple screen 1055 60.0 35.7 T21: 1/299 or AFP ≥ 2.5 MoM Japan
McDuffie 1996 [66] Second trimester triple screen 6197 100.0 0.2 T21: 1/295
T18: AFP ≥ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Meier 2003 [67] Second trimester triple screen 382,598 62.2 0.2 1/30 (2nd Trimester) or 1/100 at term Canada
Onda 2000 [34] Second trimester triple screen 32,925 96.4 0.5 T21: 1/295
T18: 1/100		 Japan
Palomaki 1995 [68] Second trimester triple screen 10,620 65.2 0.2 USA
Summers 2003 [35] Second trimester triple screen 423,895 52.8 0.2 T21: 1/385 (at term)
T18: 1/100		 Canada
Suzumori 1997 [37] Second trimester triple screen 1078 0 20.4 T21: 1/299 Japan
Wenstrom 1995 [36] Second trimester triple screen 1423 75.0 25.9 T21: 1/190
T18: AFP ≥ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Wenstrom 1997 [69] Second trimester triple screen 5327 41.7 1.8 T21: 1/190
T18: AFP ≥ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Wortelboer 2008 [38] Second trimester triple screen 30,290 67.9 13.1 T21: 1/250
T18: 1/200		 Netherlands
Breathnach 2007 [47] Second trimester quadruple screen 35,120 100.0 8.9 T21: 1/300
T18: 1/100		 USA
Jacques 2006 [75] Second trimester quadruple screen 16,607 44.4 0.5 T21: 1/250
T18: 1/200		 Australia
Kwon 2012 [76] Second trimester quadruple screen 9435 100.0 9.6 T21: 1/270
T18: 1/100		 Korea
Ashoor 2012 [74] Non-invasive prenatal testing 397 980 0 UK
Bianchi 2012 [40] Non-invasive prenatal testing 532 97.2 0 USA
Chen 2011 [41] Non-invasive prenatal testing 392 91.9 2.0 Hong Kong,
Netherlands,
UK
Dan 2012 [70] Non-invasive prenatal testing 3000 100.0 0.03 China
Jiang 2012 [42] Non-invasive prenatal testing 903 100.0 0.1 China
Lau 2012 [43] Non-invasive prenatal testing 108 90.0 0 Japan
Nicolaides 2012 [73] Non-invasive prenatal testing 1949 100.0 0. Risk ≥1% UK
Norton 2012 [71] Non-invasive prenatal testing 3080 97.4 0.1 1/100 USA, Netherlands, Sweden
Palomaki 2012 [44] Non-invasive prenatal testing 1971 100.0 0.3 z score ≥ 3 Argentina,
Australia,
Canada,
Czech Republic,
Hungary,
Ireland,
Italy,
Spain,
USA
Sehnert 2011 [45] Non-invasive prenatal testing 65 100.0 1.6 >2.5 standard deviations of the mean USA
Sparks 2012 [72] Non-invasive prenatal testing 167 100.0 0.6 USA
Sparks 2012 [72] Non-invasive prenatal testing 163 100.0 0 USA
Benn 2007 [77] Integrated screening 1203 100.0 7.3 USA
Guanciali-Franchi 2011 [52] Integrated screening 7292 100.0 3.7 1/250 Italy
45,X
Chou 2009 [49] First trimester combined test 10,811 80.0 5.4 T21: 1/270 Taiwan
Ghaffari 2012 [51] First trimester combined test 13,706 100.0 4.7 1/300 Iran
Marttala 2011 [19] First trimester combined test 56,076 57.1 4.3 T21: 1/250
T13/T18: 1/200		 Finland
Ochshorn 2001 [26] First trimester combined test 1408 60.0 7.1 Israel
Scott 2004 [30] First trimester combined test 2053 0 7.2 Australia
Spencer 2003 [23] First trimester combined test 11,105 100.0 5.2 T13/T18/T21: 1/300 England
Benn 1996 [31] Second trimester triple screen 26,364 75.0 8.7 T21: 1/270
T18: AFP ≤ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Burton 1993 [32] Second trimester triple screen 8233 60.0 10.6 T21: 1/270
T18: AFP ≤ 0.7 MoM,
hCG ≤ 0.5 MoM,
uE3 ≤ 0.55 MoM		 USA
Kazerouni 2009 [33] Second trimester triple screen 752,686 79.4 6.6 T21: 1/190
T18: 1/100		 USA
McDuffie 1996 [66] Second trimester triple screen 6197 50.0 5.6 T21: 1/295
T18: AFP ≤ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Onda 2000 [34] Second trimester triple screen 32,925 75.0 14.5 T21: 1/295
T18: 1/100		 Japan
Ruiz 1999 [78] Second trimester triple screen 130,595 63.2 5.1 T21: 1/225 USA
Summers 2003 [35] Second trimester triple screen 423,895 97.3 9.7 T21: 1/385 (at term)
T18: 1/100		 Canada
Valerio 1996 [79] Second trimester triple screen 2978 100.0 7.1 T21: 1/270 Italy
Wenstrom 1995 [36] Second trimester triple screen 1423 0 26.1 T21: 1/190
T18: AFP ≤ 0.75 MoM,
hCG ≤ 0.55 MoM,
uE3 ≤ 0.6 MoM		 USA
Kwon 2012 [76] Second trimester quadruple screen 9435 66.7 9.6 T21: 1/270
T18: 1/100		 Korea
Bianchi 2012 [40] Non-invasive prenatal testing 433 93.8 0.2 USA
Jiang 2012 [42] Non-invasive prenatal testing 903 75.0 0.2 China
Lau 2012 [43] Non-invasive prenatal testing 108 100.0 0 Japan
Sehnert 2011 [45] Non-invasive prenatal testing 47 100.0 0 >2.5 standard deviations of the mean USA
Triploidy
Ghaffari 2012 [51] First trimester combined test 13,706 100.0 4.8 1/300 Iran
Marttala 2011 [19] First trimester combined test 56,076 50.0 4.3 T21: 1/250
T13/T18: 1/200		 Finland
Orlandi 1997 [20] First trimester combined test 2010 100.0 12.4 Italy
Scott 2004 [30] First trimester combined test 2053 100.0 7.2 Australia
Spencer 2000 [27] First trimester combined test 3762 100.0 6.7 T13/T18/T21: 1/300 England
Spencer 2003 [23] First trimester combined test 11,105 100.0 5.2 T13/T18/T21: 1/300 England
Stenhouse 2004 [24] First trimester combined test 5084 100.0 6.2 T13/T18/T21: 1/250 Scotland
Burton 1993 [32] Second trimester triple screen 8233 100.0 10.6 T21: 1/270
T18: AFP ≤ 0.7 MoM,
hCG ≤ 0.5 MoM,
uE3 ≤ 0.55 MoM		 USA
Kazerouni 2009 [33] Second trimester triple screen 752,686 98.1 6.6 T21: 1/190
T18: 1/100		 USA
Summers 2003 [35] Second trimester triple screen 423,895 100.0 9.7 T21: 1/385 at term
T18: 1/100		 Canada
Kwon 2012 [76] Second trimester quadruple screen 9435 100.0 9.6 T21: 1/270
T18: 1/100		 Korea
Open in a new tab

Appendix B—Summary Receiver Operator Characteristic (SROC) Curves

The Summary Receiver Operator Characteristic (SROC) curves below plot the sensitivity (detection rate) of a given test against 1-specificity (false positive rate) of a given test for detecting the condition of interest [13]. Circles represent the point estimate from included studies; the size of the circle is related to the sample size of the study [13]. Diamonds represent the pooled detection rate and false positive rate [13]. The dashed lines represent the 95% confidence region surrounding the pooled effect estimate, while the dotted lines represent the 95% prediction region that would encompass the true detection rate and false positive rates in future studies [13]. The HSROC curve represents the summary receiver operator characteristic curve obtained from the model [13].

Appendix Figure B1.

Appendix Figure B1

Open in a new tab

Summary Receiver Operator Characteristic (SROC) Curves for the detection of trisomy 13 using (A) first trimester combined test; (B) second trimester triple screen; and (C) non-invasive prenatal testing.

Appendix Figure B2.

Appendix Figure B2

Open in a new tab

Summary Receiver Operator Characteristic (SROC) Curves for the detection of trisomy 18 using (A) first trimester combined test; (B) second trimester triple screen; and (C) non-invasive prenatal testing.

Appendix Figure B3.

Appendix Figure B3

Open in a new tab

Summary Receiver Operator Characteristic (SROC) Curves for the detection of 45,X using (A) first trimester combined test; (B) second trimester triple screen; and (C) non-invasive prenatal testing.

Appendix Figure B4.

Appendix Figure B4

Open in a new tab

Summary Receiver Operator Characteristic (SROC) Curves for the detection of triploidy using the first trimester combined test.

Conflicts of Interest

The authors declare no conflict of interest.

References

  • 1.Chitayat D., Langlois S., Wilson R.D. Prenatal screening for fetal aneuploidy in singleton pregnancies. J. Obstet. Gynaecol. Can. 2011;33:736–750. doi: 10.1016/S1701-2163(16)34961-1. [DOI] [PubMed] [Google Scholar]
  • 2.ACOG Committee on Practice Bulletins ACOG practice bulletin no. 77: Screening for fetal chromosomal abnormalities. Obstet. Gynecol. 2007;109:217–227. doi: 10.1097/00006250-200701000-00054. [DOI] [PubMed] [Google Scholar]
  • 3.Vassy C. From a genetic innovation to mass health programmes: The diffusion of Down’s syndrome prenatal screening and diagnostic techniques in France. Soc. Sci. Med. 2006;63:2041–2051. doi: 10.1016/j.socscimed.2006.04.032. [DOI] [PubMed] [Google Scholar]
  • 4.Patterson D., Costa A.C. Down syndrome and genetics—A case of linked histories. Nat. Rev. Genet. 2005;6:137–147. doi: 10.1038/nrg1525. [DOI] [PubMed] [Google Scholar]
  • 5.Chitty L.S., Hill M., White H., Wright D., Morris S. Noninvasive prenatal testing for aneuploidy-ready for prime time? Am. J. Obstet. Gynecol. 2012;206:269–275. doi: 10.1016/j.ajog.2012.02.021. [DOI] [PubMed] [Google Scholar]
  • 6.Skirton H., Barr O. Antenatal screening and informed choice: A cross-sectional survey of parents and professionals. Midwifery. 2010;26:596–602. doi: 10.1016/j.midw.2009.01.002. [DOI] [PubMed] [Google Scholar]
  • 7.Chiang H.H., Chao Y.M., Yuh Y.S. Informed choice of pregnant women in prenatal screening tests for Down’s syndrome. J. Med. Ethics. 2006;32:273–277. doi: 10.1136/jme.2005.012385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Favre R., Duchange N., Vayssiere C., Kohler M., Bouffard N., Hunsinger M.C., Kohler A., Mager C., Neumann M., Viville B., et al. How important is consent in maternal serum screening for Down syndrome in France? Information and consent evaluation in maternal serum screening for Down syndrome: A French study. Prenat. Diagn. 2007;27:197–205. doi: 10.1002/pd.1656. [DOI] [PubMed] [Google Scholar]
  • 9.Rowe H.J., Fisher J.R., Quinlivan J.A. Are pregnant Australian women well informed about prenatal genetic screening? A systematic investigation using the multidimensional measure of informed choice. Aust. N. Z. J. Obstet. Gynaecol. 2006;46:433–439. doi: 10.1111/j.1479-828X.2006.00630.x. [DOI] [PubMed] [Google Scholar]
  • 10.Sheridan E., Williams J., Caine A., Morgan R., Mason G., Mueller R.F. Counselling implications of chromosomal abnormalities other than trisomy 21 detected through a maternal serum screening programme. Br. J. Obstet. Gynaecol. 1997;104:42–45. doi: 10.1111/j.1471-0528.1997.tb10647.x. [DOI] [PubMed] [Google Scholar]
  • 11.Stroup D.F., Berlin J.A., Morton S.C., Olkin I., Williamson G.D., Rennie D., Moher D., Becker B.J., Sipe T.A., Thacker S.B. Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of observational studies in epidemiology (moose) group. JAMA. 2000;283:2008–2012. doi: 10.1001/jama.283.15.2008. [DOI] [PubMed] [Google Scholar]
  • 12.Bossuyt P.M., Reitsma J.B., Bruns D.E., Gatsonis C.A., Glasziou P.P., Irwig L.M., Lijmer J.G., Moher D., Rennie D., de Vet H.C. Towards complete and accurate reporting of studies of diagnostic accuracy: The stard initiative. The standards for reporting of diagnostic accuracy group. Croat. Med. J. 2003;44:635–638. [PubMed] [Google Scholar]
  • 13.Harbord R.M., Whiting P. Metandi: Meta-analysis of diagnostic accuracy using hierarchical logistic regression. Stata J. 2009;9:211–229. [Google Scholar]
  • 14.Reitsma J.B., Glas A.S., Rutjes A.W., Scholten R.J., Bossuyt P.M., Zwinderman A.H. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J. Clin. Epidemiol. 2005;58:982–990. doi: 10.1016/j.jclinepi.2005.02.022. [DOI] [PubMed] [Google Scholar]
  • 15.Alamillo C.M., Krantz D., Evans M., Fiddler M., Pergament E. Nearly a third of abnormalities found after first-trimester screening are different than expected: 10-year experience from a single center. Prenat. Diagn. 2013;33:251–256. doi: 10.1002/pd.4054. [DOI] [PubMed] [Google Scholar]
  • 16.Hormansdorfer C., Scharf A., Golatta M., Vaske B., Hillemanns P., Schmidt P. Preliminary analysis of the new “prenatal risk calculation (PRC)” software. Arch. Gynecol. Obstet. 2009;279:511–515. doi: 10.1007/s00404-008-0743-z. [DOI] [PubMed] [Google Scholar]
  • 17.Kagan K.O., Wright D., Valencia C., Maiz N., Nicolaides K.H. Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free β-hCG and pregnancy-associated plasma protein-A. Hum. Reprod. 2008;23:1968–1975. doi: 10.1093/humrep/den224. [DOI] [PubMed] [Google Scholar]
  • 18.Karadzov-Orlic N., Egic A., Milovanovic Z., Marinkovic M., Damnjanovic-Pazin B., Lukic R., Joksic I., Curkovic A., Mikovic Z. Improved diagnostic accuracy by using secondary ultrasound markers in the first-trimester screening for trisomies 21, 18 and 13 and turner syndrome. Prenat. Diagn. 2012;32:638–643. doi: 10.1002/pd.3873. [DOI] [PubMed] [Google Scholar]
  • 19.Marttala J., Peuhkurinen S., Ranta J.K., Laitinen P., Kokkonen H.L., Honkasalo T., Ryynanen M. Screening and outcome of chromosomal abnormalities other than trisomy 21 in Northern Finland. Acta Obstet. Gynecol. Scand. 2011;90:885–889. doi: 10.1111/j.1600-0412.2011.01174.x. [DOI] [PubMed] [Google Scholar]
  • 20.Orlandi F., Damiani G., Hallahan T.W., Krantz D.A., Macri J.N. First-trimester screening for fetal aneuploidy: Biochemistry and nuchal translucency. Ultrasound Obstet. Gynecol. 1997;10:381–386. doi: 10.1046/j.1469-0705.1997.10060381.x. [DOI] [PubMed] [Google Scholar]
  • 21.Sorensen S., Momsen G., Sundberg K., Friis-Hansen L., Jorgensen F.S. First-trimester risk calculation for trisomy 13, 18, and 21: Comparison of the screening efficiency between 2 locally developed programs and commercial software. Clin. Chem. 2011;57:1023–1031. doi: 10.1373/clinchem.2010.161299. [DOI] [PubMed] [Google Scholar]
  • 22.Spencer K., Ong C., Skentou H., Liao A.W., Nicolaides K.N. Screening for trisomy 13 by fetal nuchal translucency and maternal serum free β-hCG and PAPP-A at 10–14 weeks of gestation. Prenat. Diagn. 2000;20:411–416. doi: 10.1002/(SICI)1097-0223(200005)20:5<411::AID-PD822>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  • 23.Spencer K., Spencer C.E., Power M., Dawson C., Nicolaides K.H. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: A review of three years prospective experience. Br. J. Obstet. Gynaecol. 2003;110:281–286. doi: 10.1046/j.1471-0528.2003.02246.x. [DOI] [PubMed] [Google Scholar]
  • 24.Stenhouse E.J., Crossley J.A., Aitken D.A., Brogan K., Cameron A.D., Connor J.M. First-trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice. Prenat. Diagn. 2004;24:774–780. doi: 10.1002/pd.980. [DOI] [PubMed] [Google Scholar]
  • 25.Valinen Y., Marttala J., Sahravand M., Jarvela I., Honkasalo T., Laitinen P., Ryynanen M. Adding ADAM12 in risk calculation program does not improve the detection rate of trisomies 18 and 13 in first trimester screening. J. Matern. Fetal Neonatal Med. 2012;25:822–825. doi: 10.3109/14767058.2011.590559. [DOI] [PubMed] [Google Scholar]
  • 26.Ochshorn Y., Kupferminc M.J., Wolman I., Orr-Urtreger A., Jaffa A.J., Yaron Y. First trimester PAPP-A in the detection of non-Down syndrome aneuploidy. Prenat. Diagn. 2001;21:547–549. doi: 10.1002/pd.105. [DOI] [PubMed] [Google Scholar]
  • 27.Spencer K., Spencer C.E., Power M., Moakes A., Nicolaides K.H. One stop clinic for assessment of risk for fetal anomalies: A report of the first year of prospective screening for chromosomal anomalies in the first trimester. Br. J. Obstet. Gynaecol. 2000;107:1271–1275. doi: 10.1111/j.1471-0528.2000.tb11619.x. [DOI] [PubMed] [Google Scholar]
  • 28.Merz E., Thode C., Alkier A., Eiben B., Hackeloer B.J., Hansmann M., Huesgen G., Kozlowski P., Pruggmaier M., Wellek S. A new approach to calculating the risk of chromosomal abnormalities with first-trimester screening data. Ultraschall Med. 2008;29:639–645. doi: 10.1055/s-2008-1027958. [DOI] [PubMed] [Google Scholar]
  • 29.Berktold L., von Kaisenberg C.S., Hillemanns P., Vaske B., Schmidt P. Analysis of the impact of PAPP-A, free β-hCG and nuchal translucency thickness on the advanced first trimester screening. Arch. Gynecol. Obstet. 2013;287:413–420. doi: 10.1007/s00404-012-2585-y. [DOI] [PubMed] [Google Scholar]
  • 30.Scott F., Peters H., Bonifacio M., McLennan A., Boogert A., Kesby G., Anderson J. Prospective evaluation of a first trimester screening program for Down syndrome and other chromosomal abnormalities using maternal age, nuchal translucency and biochemistry in an Australian population. Aust. N. Z. J. Obstet. Gynaecol. 2004;44:205–209. doi: 10.1111/j.1479-828X.2004.00205.x. [DOI] [PubMed] [Google Scholar]
  • 31.Benn P.A., Horne D., Craffey A., Collins R., Ramsdell L., Greenstein R. Maternal serum screening for birth defects: Results of a connecticut regional program. Connect. Med. 1996;60:323–327. [PubMed] [Google Scholar]
  • 32.Burton B.K., Prins G.S., Verp M.S. A prospective trial of prenatal screening for Down syndrome by means of maternal serum α-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. Am. J. Obstet. Gynecol. 1993;169:526–530. doi: 10.1016/0002-9378(93)90613-N. [DOI] [PubMed] [Google Scholar]
  • 33.Kazerouni N.N., Currier B., Malm L., Riggle S., Hodgkinson C., Smith S., Tempelis C., Lorey F., Davis A., Jelliffe-Pawlowski L., et al. Triple-marker prenatal screening program for chromosomal defects. Obstet. Gynecol. 2009;114:50–58. doi: 10.1097/AOG.0b013e3181a9479e. [DOI] [PubMed] [Google Scholar]
  • 34.Onda T., Tanaka T., Yoshida K., Nakamura Y., Kudo R., Yamamoto H., Sato A., Yanagida K., Takai Y., Uemura H., et al. Triple marker screening for trisomy 21, trisomy 18 and open neural tube defects in singleton pregnancies of native Japanese pregnant women. J. Obstet. Gynaecol. Res. 2000;26:441–447. doi: 10.1111/j.1447-0756.2000.tb01355.x. [DOI] [PubMed] [Google Scholar]
  • 35.Summers A.M., Farrell S.A., Huang T., Meier C., Wyatt P.R. Maternal serum screening in Ontario using the triple marker test. J. Med. Screen. 2003;10:107–111. doi: 10.1258/096914103769010987. [DOI] [PubMed] [Google Scholar]
  • 36.Wenstrom K.D., Desai R., Owen J., DuBard M.B., Boots L. Comparison of multiple-marker screening with amniocentesis for the detection of fetal aneuploidy in women > or = 35 years old. Am. J. Obstet. Gynecol. 1995;173:1287–1292. doi: 10.1016/0002-9378(95)91372-6. [DOI] [PubMed] [Google Scholar]
  • 37.Suzumori K., Tanemura M., Murakami I., Okada S., Natori M., Tanaka M., Takagi T., Sato A. A retrospective evaluation of maternal serum screening for the detection of fetal aneuploidy. Prenat. Diagn. 1997;17:861–866. doi: 10.1002/(SICI)1097-0223(199709)17:9<861::AID-PD169>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  • 38.Wortelboer E.J., Koster M.P., Stoutenbeek P., Loeber J.G., Visser G.H., Schielen P.C. Fifteen years of triple tests in the Netherlands; the life cycle of a screening test. Prenat. Diagn. 2008;28:950–955. doi: 10.1002/pd.2091. [DOI] [PubMed] [Google Scholar]
  • 39.Ashoor G., Syngelaki A., Wang E., Struble C., Oliphant A., Song K., Nicolaides K.H. Trisomy 13 detection in the first trimester of pregnancy using a chromosome-selective cell-free DNA analysis method. Ultrasound Obstet. Gynecol. 2013;41:21–25. doi: 10.1002/uog.12299. [DOI] [PubMed] [Google Scholar]
  • 40.Bianchi D.W., Platt L.D., Goldberg J.D., Abuhamad A.Z., Sehnert A.J., Rava R.P. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet. Gynecol. 2012;119:890–901. doi: 10.1097/AOG.0b013e31824fb482. [DOI] [PubMed] [Google Scholar]
  • 41.Chen E.Z., Chiu R.W., Sun H., Akolekar R., Chan K.C., Leung T.Y., Jiang P., Zheng Y.W., Lun F.M., Chan L.Y., et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS One. 2011;6:e21791. doi: 10.1371/journal.pone.0021791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Jiang F., Ren J., Chen F., Zhou Y., Xie J., Dan S., Su Y., Yin B., Su W., Zhang H., et al. Noninvasive fetal trisomy (NIFTY) test: An advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med. Genomics. 2012;5 doi: 10.1186/1755-8794-5-57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Lau T.K., Chen F., Pan X., Pooh R.K., Jiang F., Li Y., Jiang H., Li X., Chen S., Zhang X. Noninvasive prenatal diagnosis of common fetal chromosomal aneuploidies by maternal plasma DNA sequencing. J. Matern. Fetal Neonatal Med. 2012;25:1370–1374. doi: 10.3109/14767058.2011.635730. [DOI] [PubMed] [Google Scholar]
  • 44.Palomaki G.E., Deciu C., Kloza E.M., Lambert-Messerlian G.M., Haddow J.E., Neveux L.M., Ehrich M., van den Boom D., Bombard A.T., Grody W.W., et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: An international collaborative study. Genet. Med. 2012;14:296–305. doi: 10.1038/gim.2011.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Sehnert A.J., Rhees B., Comstock D., de Feo E., Heilek G., Burke J., Rava R.P. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin. Chem. 2011;57:1042–1049. doi: 10.1373/clinchem.2011.165910. [DOI] [PubMed] [Google Scholar]
  • 46.Borrell A., Casals E., Fortuny A., Farre M.T., Gonce A., Sanchez A., Soler A., Cararach V., Vanrell J.A. First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study. Prenat. Diagn. 2004;24:541–545. doi: 10.1002/pd.949. [DOI] [PubMed] [Google Scholar]
  • 47.Breathnach F.M., Malone F.D., Lambert-Messerlian G., Cuckle H.S., Porter T.F., Nyberg D.A., Comstock C.H., Saade G.R., Berkowitz R.L., Klugman S., et al. First- and second-trimester screening: Detection of aneuploidies other than Down syndrome. Obstet. Gynecol. 2007;110:651–657. doi: 10.1097/01.AOG.0000278570.76392.a6. [DOI] [PubMed] [Google Scholar]
  • 48.Centini G., Rosignoli L., Scarinci R., Faldini E., Morra C., Petraglia F. Re-evaluation of risk for Down syndrome by means of the combined test in pregnant women of 35 years or more. Prenat. Diagn. 2005;25:133–136. doi: 10.1002/pd.1036. [DOI] [PubMed] [Google Scholar]
  • 49.Chou C.Y., Hsieh F.J., Cheong M.L., Lee F.K., She B.Q., Tsai M.S. First-trimester Down syndrome screening in women younger than 35 years old and cost-effectiveness analysis in Taiwan population. J. Eval. Clin. Pract. 2009;15:789–796. doi: 10.1111/j.1365-2753.2008.01095.x. [DOI] [PubMed] [Google Scholar]
  • 50.Dhaifalah I., Santavy J., Zapletalova J. Screening for chromosomal anomalies in the first trimester: A report on the first year of prospective screening for chromosomal anomalies in the first trimester in the Czech Republic. Biomed. Pap. 2006;150:275–278. doi: 10.5507/bp.2006.041. [DOI] [PubMed] [Google Scholar]
  • 51.Ghaffari S.R., Tahmasebpour A.R., Jamal A., Hantoushzadeh S., Eslamian L., Marsoosi V., Fattahi F., Rajaei M., Niroomanesh S., Borna S., et al. First-trimester screening for chromosomal abnormalities by integrated application of nuchal translucency, nasal bone, tricuspid regurgitation and ductus venosus flow combined with maternal serum free β-hCG and PAPP-A: A 5-year prospective study. Ultrasound Obstet. Gynecol. 2012;39:528–534. doi: 10.1002/uog.10051. [DOI] [PubMed] [Google Scholar]
  • 52.Guanciali-Franchi P., Iezzi I., Palka C., Matarrelli B., Morizio E., Calabrese G., Benn P. Comparison of combined, stepwise sequential, contingent, and integrated screening in 7292 high-risk pregnant women. Prenat. Diagn. 2011;31:1077–1081. doi: 10.1002/pd.2836. [DOI] [PubMed] [Google Scholar]
  • 53.Jaques A.M., Halliday J.L., Francis I., Bonacquisto L., Forbes R., Cronin A., Sheffield L.J. Follow up and evaluation of the victorian first-trimester combined screening programme for Down syndrome and trisomy 18. Br. J. Obstet. Gynaecol. 2007;114:812–818. doi: 10.1111/j.1471-0528.2007.01349.x. [DOI] [PubMed] [Google Scholar]
  • 54.Krantz D.A., Hallahan T.W., Orlandi F., Buchanan P., Larsen J.W., Jr., Macri J.N. First-trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstet. Gynecol. 2000;96:207–213. doi: 10.1016/S0029-7844(00)00881-4. [DOI] [PubMed] [Google Scholar]
  • 55.Martinez-Morillo E., Prieto B., Moreno F., Alvarez F.V. Improvement of a prenatal screening program for trisomy 18 in the first trimester of gestation. Clin. Chem. Lab. Med. 2012;50:1973–1977. doi: 10.1515/cclm-2012-0198. [DOI] [PubMed] [Google Scholar]
  • 56.Perni S.C., Predanic M., Kalish R.B., Chervenak F.A., Chasen S.T. Clinical use of first-trimester aneuploidy screening in a United States population can replicate data from clinical trials. Am. J. Obstet. Gynecol. 2006;194:127–130. doi: 10.1016/j.ajog.2005.06.068. [DOI] [PubMed] [Google Scholar]
  • 57.Spencer K., Cowans N.J. ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy. J. Matern. Fetal Neonatal Med. 2007;20:645–650. doi: 10.1080/14767050701483389. [DOI] [PubMed] [Google Scholar]
  • 58.Tsai M.S., Huang Y.Y., Hwa K.Y., Cheng C.C., Lee F.K. Combined measurement of fetal nuchal translucency, maternal serum free β-hCG, and pregnancy-associated plasma protein a for first-trimester Down’s syndrome screening. J. Formos. Med. Assoc. 2001;100:319–325. [PubMed] [Google Scholar]
  • 59.Tul N., Spencer K., Noble P., Chan C., Nicolaides K. Screening for trisomy 18 by fetal nuchal translucency and maternal serum free β-hCG and PAPP-A at 10–14 weeks of gestation. Prenat. Diagn. 1999;19:1035–1042. doi: 10.1002/(SICI)1097-0223(199911)19:11<1035::AID-PD694>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  • 60.Wapner R., Thom E., Simpson J.L., Pergament E., Silver R., Filkins K., Platt L., Mahoney M., Johnson A., Hogge W.A., et al. First-trimester screening for trisomies 21 and 18. N. Engl. J. Med. 2003;349:1405–1413. doi: 10.1056/NEJMoa025273. [DOI] [PubMed] [Google Scholar]
  • 61.Barkai G., Goldman B., Ries L., Chaki R., Zer T., Cuckle H. Expanding multiple marker screening for Down’s syndrome to include Edward’s syndrome. Prenat. Diagn. 1993;13:843–850. doi: 10.1002/pd.1970130908. [DOI] [PubMed] [Google Scholar]
  • 62.Benn P.A., Leo M.V., Rodis J.F., 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;93:707–711. doi: 10.1016/S0029-7844(98)00554-7. [DOI] [PubMed] [Google Scholar]
  • 63.Hogge W.A., Fraer L., Melegari T. Maternal serum screening for fetal trisomy 18: Benefits of patient-specific risk protocol. Am. J. Obstet. Gynecol. 2001;185:289–293. doi: 10.1067/mob.2001.116728. [DOI] [PubMed] [Google Scholar]
  • 64.Kellner L.H., Weiss R.R., Weiner Z., Neuer M., Martin G.M., Schulman H., Lipper S. The advantages of using triple-marker screening for chromosomal abnormalities. Am. J. Obstet. Gynecol. 1995;172:831–836. doi: 10.1016/0002-9378(95)90007-1. [DOI] [PubMed] [Google Scholar]
  • 65.Kishida T., Hoshi N., Hattori R., Negishi H., Yamada H., Okuyama K., Hanatani K., Takagi T., Sagawa T., Fujimoto S. Efficacy of maternal serum screening in the prenatal detection of fetal chromosome abnormalities in Japanese women. Fetal Diagn. Ther. 2000;15:112–117. doi: 10.1159/000020987. [DOI] [PubMed] [Google Scholar]
  • 66.McDuffie R.S., Jr., Haverkamp A.D., Stark C.F., Haverkamp C., Barth C.K. Prenatal screening using maternal serum α-fetoprotein, human chorionic gonadotropin, and unconjugated estriol: Two-year experience in a health maintenance organization. J. Matern. Fetal Neonatal Med. 1996;5:70–73. doi: 10.1002/(SICI)1520-6661(199603/04)5:2<70::AID-MFM4>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  • 67.Meier C., Huang T., Wyatt P.R., Summers A.M. Accuracy of trisomy 18 screening using the second-trimester triple test. Prenat. Diagn. 2003;23:443–446. doi: 10.1002/pd.614. [DOI] [PubMed] [Google Scholar]
  • 68.Palomaki G.E., Haddow J.E., Knight G.J., Wald N.J., Kennard A., Canick J.A., Saller D.N., Jr., Blitzer M.G., Dickerman L.H., Fisher R. Risk-based prenatal screening for trisomy 18 using α-fetoprotein, unconjugated oestriol and human chorionic gonadotropin. Prenat. Diagn. 1995;15:713–723. doi: 10.1002/pd.1970150806. [DOI] [PubMed] [Google Scholar]
  • 69.Wenstrom K.D., Owen J., Brumfield C.G., Davis R.O., Dubard M., Garcia T. Significance of a false-positive trisomy 18 multiple-marker screening test. Obstet. Gynecol. 1997;90:938–942. doi: 10.1016/S0029-7844(97)00478-X. [DOI] [PubMed] [Google Scholar]
  • 70.Dan S., Wang W., Ren J., Li Y., Hu H., Xu Z., Lau T.K., Xie J., Zhao W., Huang H., et al. Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat. Diagn. 2012;32:1225–1232. doi: 10.1002/pd.4002. [DOI] [PubMed] [Google Scholar]
  • 71.Norton M.E., Brar H., Weiss J., Karimi A., Laurent L.C., Caughey A.B., Rodriguez M.H., Williams J., III, Mitchell M.E., Adair C.D., et al. Non-invasive chromosomal evaluation (NICE) study: Results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 2012;207:e1–e8. doi: 10.1016/j.ajog.2012.05.021. [DOI] [PubMed] [Google Scholar]
  • 72.Sparks A.B., Struble C.A., Wang E.T., Song K., Oliphant A. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: Evaluation for trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 2012;206:e1–e9. doi: 10.1016/j.ajog.2012.01.030. [DOI] [PubMed] [Google Scholar]
  • 73.Nicolaides K.H., Syngelaki A., Ashoor G., Birdir C., Touzet G. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am. J. Obstet. Gynecol. 2012;207:e1–e6. doi: 10.1016/j.ajog.2012.08.033. [DOI] [PubMed] [Google Scholar]
  • 74.Ashoor G., Syngelaki A., Wagner M., Birdir C., Nicolaides K.H. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 2012;206:e1–e5. doi: 10.1016/j.ajog.2012.01.029. [DOI] [PubMed] [Google Scholar]
  • 75.Jaques A.M., Collins V.R., Haynes K., Sheffield L.J., Francis I., Forbes R., Halliday J.L. Using record linkage and manual follow-up to evaluate the victorian maternal serum screening quadruple test for Down’s syndrome, trisomy 18 and neural tube defects. J. Med. Screen. 2006;13:8–13. doi: 10.1258/096914106776179782. [DOI] [PubMed] [Google Scholar]
  • 76.Kwon J.Y., Park I.Y., Kwon S.M., Kim C.J., Shin J.C. The quadruple test for Down syndrome screening in pregnant women of advanced maternal age. Arch. Gynecol. Obstet. 2012;285:629–633. doi: 10.1007/s00404-011-2052-1. [DOI] [PubMed] [Google Scholar]
  • 77.Benn P.A., Campbell W.A., Zelop C.M., Ingardia C., Egan J.F. Stepwise sequential screening for fetal aneuploidy. Am. J. Obstet. Gynecol. 2007;197:e1–e5. doi: 10.1016/j.ajog.2007.06.054. [DOI] [PubMed] [Google Scholar]
  • 78.Ruiz C., Lamm F., Hart P.S. Turner syndrome and multiple-marker screening. Clin. Chem. 1999;45:2259–2261. [PubMed] [Google Scholar]
  • 79.Valerio D., Aiello R., Altieri V., Fagnoni P. Maternal serum screening of fetal chromosomal abnormalities by AFP, UE3, hCG and free-beta hCG. Prospective and retrospective results. Minerva Ginecol. 1996;48:169–173. [PubMed] [Google Scholar]
  • 80.Schlattmann P., Schuetz G.M., Dewey M. Influence of coronary artery disease prevalence on predictive values of coronary CT angiography: A meta-regression analysis. Eur. Radiol. 2011;21:1904–1913. doi: 10.1007/s00330-011-2142-2. [DOI] [PubMed] [Google Scholar]
  • 81.Giorgi-Rossi P., Franceschi S., Ronco G. HPV prevalence and accuracy of HPV testing to detect high-grade cervical intraepithelial neoplasia. Int. J. Cancer. 2012;130:1387–1394. doi: 10.1002/ijc.26147. [DOI] [PubMed] [Google Scholar]
  • 82.Grati F.R., Barlocco A., Grimi B., Milani S., Frascoli G., di Meco A.M., Liuti R., Trotta A., Chinetti S., Dulcetti F., et al. Chromosome abnormalities investigated by non-invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. Am. J. Med. Genet. 2010;152:1434–1442. doi: 10.1002/ajmg.a.33370. [DOI] [PubMed] [Google Scholar]
  • 83.Drugan A., Dvorin E., Koppitch F.C., III, Greb A., Krivchenia E.L., Evans M.I. Counseling for low maternal serum α-fetoprotein should emphasize all chromosome anomalies, not just Down syndrome. Obstet. Gynecol. 1989;73:271–274. [PubMed] [Google Scholar]
  • 84.Hui L., Hyett J. Noninvasive prenatal testing for trisomy 21: Challenges for implementation in Australia. Aust. N. Z. J. Obstet. Gynaecol. 2013;53:416–424. doi: 10.1111/ajo.12117. [DOI] [PubMed] [Google Scholar]
  • 85.McPherson E., Thomas G.D., Manlick C., Zaleski C.A., Reynolds K.K., Rasmussen K., Giampietro P.F., Wiley C., Mascola M. Extreme values of maternal serum analytes in second trimester screening: Looking beyond trisomy and NTD’s. J. Genet. Couns. 2011;20:396–403. doi: 10.1007/s10897-011-9364-y. [DOI] [PubMed] [Google Scholar]
  • 86.Metcalfe A., Langlois S., Macfarlane J., Vallance H., Joseph K.S. Prediction of obstetrical risk using maternal serum markers and clinical risk factors. Prenat. Diagn. 2014;34:172–179. doi: 10.1002/pd.4281. [DOI] [PubMed] [Google Scholar]
  • 87.Hui D., Okun N., Murphy K., Kingdom J., Uleryk E., Shah P.S. Combinations of maternal serum markers to predict preeclampsia, small for gestational age, and stillbirth: A systematic review. J. Obstet. Gynaecol. Can. 2012;34:142–153. doi: 10.1016/S1701-2163(16)35157-X. [DOI] [PubMed] [Google Scholar]
  • 88.Morris R.K., Cnossen J.S., Langejans M., Robson S.C., Kleijnen J., Ter Riet G., Mol B.W., van der Post J.A., Khan K.S. Serum screening with Down’s syndrome markers to predict pre-eclampsia and small for gestational age: Systematic review and meta-analysis. BMC Pregnancy Childbirth. 2008;8 doi: 10.1186/1471-2393-8-33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Metcalfe A., Currie G., Johnson J.A., Bernier F., Lix L.M., Lyon A.W., Tough S.C. Impact of observed versus hypothesized service utilization on the incremental cost of first trimester screening and prenatal diagnosis for trisomy 21 in a Canadian province. Prenat. Diagn. 2013;33:429–435. doi: 10.1002/pd.4082. [DOI] [PubMed] [Google Scholar]
  • 90.Gekas J., Gagne G., Bujold E., Douillard D., Forest J.C., Reinharz D., Rousseau F. Comparison of different strategies in prenatal screening for Down’s syndrome: Cost effectiveness analysis of computer simulation. BMJ. 2009;338 doi: 10.1136/bmj.b138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Cartier L., Murphy-Kaulbeck L., Wilson R.D., Audibert F., Brock J.A., Carroll J., Gagnon A., Johnson J.A., Langlois S., Okun N., et al. Counselling considerations for prenatal genetic screening. J. Obstet. Gynaecol. Can. 2012;34:489–493. doi: 10.1016/S1701-2163(16)35248-3. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Medicine are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES