Clinical Policy Bulletin: Noninvasive Down Syndrome Screening
Aetna considers the following noninvasive screening schemes for fetal aneuploidy medically necessary:
First-trimester nuchal translucency (NT) testing alone (without serum analyte screening) for multiple gestations; or
First-trimester NT measurements results combined with the results of first trimester serum analyte tests that include pregnancy-associated plasma protein A (PAPP-A) plus beta-human chorionic gonadotropin (hCG)*; or
Integrated, sequential, or contingent screening: First-trimester triple test (NT, PAPP-A, and hCG*) plus second-trimester quadruple test (maternal serum alfa-fetoprotein (MSAFP, unconjugated estriol, inhibin A, and hCG*) screening; or
Serum integrated screening for pregnancies where NT measurement is not available or can not be obtained: First-trimester (PAPP-A plus hCG*) plus second-trimester quad (MSAFP, uncongugated estriol, inhibin A, and hCG*) screening; or
*For purposes of this policy, these various forms of hCG are considered interchangeable: free beta subunit of hCG, total hCG, or hyperglycosylated hCG (also known as invasive trophoblast antigen [ITA]).
Note: All screening schemes that involve NT testing are considered medically appropriate only when performed in a setting of demonstrated ultrasound credentialing and ongoing quality monitoring.
Historically in the United States, risk assessment for Down syndrome (DS) and other fetal chromosomal abnormalities had varied by maternal age. Invasive genetic testing, either amniocentesis or chorionic villus sampling (CVS), were offered to women who would be older than age 35 at the time of delivery with singleton pregnancies. Second trimester maternal serum testing ("analyte testing") was offered to women younger than 35 years at time of delivery with singleton pregnancies, or those older than age 35 but who decline invasive testing. The serum tests performed in the second trimester are either a "triple" screen" (maternal age plus maternal serum alpha-fetal protein (MSAFP), unconjugated estriol, and free or total beta-hCG) or a "quad" screen (maternal age plus MSAFP, estriol, free or total beta-hCG, and dimeric inhibin A).
More recently, guidelines from the American College of Obstetricians and Gynecologists (ACOG, 2007) and the American College of Medical Genetics (ACMG) (Palomaki et al, 2007) state that all women, regardless of age, should have the option of invasive testing. Although invasive testing (amniocentesis or CVS) detects 100 % of fetal chromosomal abnormalities, it is associated with an increased risk of pregnancy loss compared to non-invasive testing. Maternal serum testing with the quad screen in the second trimester is safe but only maximally detects 79 % of DS cases.
First Trimester Noninvasive Screening
Recent advances in prenatal screening have been focused on first trimester non-invasive screening. According to the American College of Obstetricians and Gynecologists (ACOG), non-invasive first trimester screening for chromosomal abnormalities, such as DS, offers several potential advantages over second trimester screening. First trimester screening provides for earlier diagnosis of fetal aneuploidy. For women with affected fetuses who elect termination of pregnancy, the procedure is safer and results in fewer maternal complications when performed early in pregnancy. Women who have negative test results may elect to forego invasive testing thus avoiding the potential complication of unintended fetal loss due to procedure-related complications.
Several population-based studies have evaluated the effectiveness of non-invasive first trimester screening for the detection of DS using a combination of first trimester serum markers with measurement of fetal nuchal translucency (NT) (i.e., ultrasonographic measurement of the fluid accumulation behind the fetal neck,). A large, National Institutes of Health (NIH)-sponsored, prospective, multi-center study called the Blood, Ultrasound, and Nuchal Translucency (BUN) Trial determined that an algorithm that combined the results an NT measurement in the first trimester (between 11 weeks' and 1 day and 13 weeks' and 6 days' gestation) with the results of maternal serum tests (free-beta hCG and PAPP-A) performed in the first trimester detected about 79 % of all DS cases with a false-positive rate of 5 % (Wapner et al, 2003). A nested, case-controlled British trial called the Serum, Urine and Ultrasound Screening Study (SURUSS) evaluated both first and second trimester markers for DS in singleton pregnancies. Results for first trimester screening found that NT in combination with free or total beta-hCG plus PAPP-A detected 85 % of DS with a false-positive rate of 5 % (Wald et al, 2003). A United States-based, NIH-funded First and Second Trimester Estimation of Risk (FaSTER) Study was an intervention trial involving more than 38,000 pregnancies that compared first and second trimester markers in the same women. Published results of the first trimester analysis of NT combined with free beta-hCG plus PAPP-A found DS detection rates of 85 % with a false-positive rate of 5 % (Malone and D'Alton, 2003). The DS detection rates described in these studies are comparable or better than those for second-trimester "quad" screening using four serum markers (MSAFP, total or intact beta-hCG, unconjugated estradiol, and serum inhibin A).
In fetuses with DS, NT measurements are increased, serum total and free beta-hCG are increased and PAPP-A is decreased compared to fetuses without DS in the gestational age window of 11 to 13 weeks (Canick and Kellner, 1999). The performance of each of the markers, individually, varies as gestational age progresses. For example, the performance of NT and PAPP-A declines and total and free beta-hCG increases as gestational age proceeds through the end of the first trimester and early second trimester. In order to achieve the detection rates described in the 3 large trials described above, first trimester non-invasive screening should involve all markers (NT, PAPP-A, and total or free beta-hCG) and be performed in the time window of 11 to 13 weeks gestation.
Two analytes for hCG, "free" beta-hCG and "total" or "intact" beta-hCG, are currently employed in first trimester risk assessment. The efficacy of the free beta-hCG analyte has been more extensively studied. Both the BUN and FaSTER trials support the efficacy of free beta-hCG. Support for the efficacy of the total or intact beta-hCG analyte is provided by the SURUSS study. As individual markers, NT is the most informative followed by PAPP-A (Wald et al, 2003). As an individual marker, free beta-hCG outperforms total beta-hCG in detecting DS affected pregnancies. Recent guidelines from the ACMG (Palomaki et al, 2007) state that all screening schemes that involve measurement of hCG in first or first and second trimester fetal aneuploidy screening should consider free beta subunit of hCG, total hCG, or hyperglycosylated hCG (also known as invasive trophoglast antigen (ITA)) interchangeable.
The Society for Maternal Fetal Medicine (SMFM) and ACMG have provided guidance on follow-up of normal first trimester combination screening. Specifically, women should not undergo independent sequential "triple" or "quad" screening in the second trimester of pregnancy to further assess aneuploidy risk if results of combined first trimester NT and serum analyte testing are negative (normal) (Driscoll, 2004). Independent sequential testing of this sort is associated with an unacceptably high false-positive rate (Hackshaw and Wald, 2001; Malone and D'Alton, 2003). Instead, women who want a higher detection rate can have an integrated or sequential screening test, which combines both first- and second-trimester screening results (ACOG, 2007). An integrated approach to screening uses both first-trimester and second-trimester markers to adjust a woman's age-relatd risk of having a child with DS (ACOG, 2007). The results are reported only after both first- and second-trimester screening tests are completed. In the FASTER (First- and Second-Trimester Evaluation of Risk) trial, the detection rate with "integrated screening" was 94 to 96 % at a 5 % screen-positive rate (Malone et al, 2005). Although integrated screening has the highest sensitivity and lowest false-positive rate of noninvasive screening methods, the main disadvantage of integrated screening lies in the need to wait 3 to 4 weeks between initiation and completion of the screening. This may result in patient anxiety and the potential for patients to fail to complete the second-trimester portion of the screening test after performing the first-trimester component. Another disadvantage is that the patient loses the opportunity to consider CVS if the first-trimester screening indicates a high risk of fetal aneuploidy.
Sequential screening approaches that obviate some of the disadvantages of integrated screening have been developed (ACOG, 2007). With this strategy, the patient is informed of the first-trimester screening result. Those at highest risk might opt for an early diagnostic procedure, and those at lower risk can still take advantage of the higher detection rate achieved with additional second-trimester screening.
Guidelines from the ACMG have introduced the concept of contingent screening (Palomaki et al, 2007). ACMG guidelines explain that contingent screening, like sequential screening, incorporates aspects of first trimetser screening and integrated screening. However, in contingent screening, the first trimester results are divided into 3 outcomes: (i) screen positive, (ii) screen negative, and (iii) intermediate/pending risk. Those patients at intermediate risk will then provide a second trimester sample for testing in order to computed integrated risk. ACMG guidelines explain that this strategy allows for early diagnosis of DS among a small, high-risk group (screen positives) and early reassurance to a large, low-risk group (screen negatives). It attempts to maintain high performance by having those with intermediate/pending first trimester risks benefit from the integrated test (Palomaki et al, 2007).
Integrated screening can be performed using only first-and second-trimester serum markers ("serum integrated screening"), without incorporating an NT measurement. In the FASTER trial, the serum integrated screen resulted in an 85 to 88 % detection rate (Malone et al, 2005). ACOG (2007) guidelines state that a serum integrated screening approach is ideal for patients without access to NT measurement or for whom reliable NT measurements can not be obtained.
First trimester NT testing alone is less sensitive than either first trimester combined screening or second trimester “quad” screening and, thus, should not be used in isolation for routine fetal aneuploidy screening in singleton pregnancies (Malone and D’Alton, 2003). In multiple gestations, however, serum analyte testing is unreliable and NT screening alone is medically appropriate. It should be noted that the identification of a cystic hygroma during first trimester is a very powerful predictor of fetal aneuploidy. In one large, prospective study, a septated cystic hygroma was associated with a 51 % likelihood of DS (Malone et al, 2005). This finding should immediately prompt counseling and consideration for diagnostic testing and should not be delayed by serum analyte measurement and further risk calculation.
First trimester serum analyte testing alone (with any combination of analytes) is also not sufficiently sensitive to be used for routine fetal aneuploidy screening (Wald et al, 2003; Malone and D’Alton, 2003; ACOG, 2004).
Rosen et al (2007), on behalf of the Nuchal Translucency Oversight Committee/Maternal Fetal Medicine Foundation, stated that recent studies have suggested that adding ultrasound assessment of the nasal bone to nuchal translucency thickness and maternal serum analytes in the first-trimester will improve performance. The authors evaluated the literature and discussed practical issues that must be addressed before widespread implementation of nasal bone screening in the United States. Furthermore, in a review on screening for fetal abnormalities with ultrasound, Flood and Malone (2008) noted that the limitations of first-trimester nasal bone measurement were reiterated while its measurement has been shown to be beneficial in the second-trimester, especially when calculated with multiples of the median. The authors concluded that screening for fetal abnormalities continues to evolve with the introduction of novel techniques and the further refinement of previously proposed screening tools. How these modalities are implemented into routine clinical practice remains to be seen.
Miron et al (2010) ascertained maternal plasma levels of follistatin-related gene protein (FLRG) in the first trimester of pregnancy and assessed its potential role as a marker for pre-natal screening of DS. Maternal plasma levels of FLRG were determined in 100 pregnant women with normal fetuses in their first trimester of pregnancy (i.e., 11th to 15th weeks). These results were compared with 20 cases with DS fetuses, taking into consideration clinical and demographic variables, such as maternal age, maternal weight, gestational age, smoking status and ethnicity. Maternal plasma median of FLRG in the normal population was 1.41 ng/ml with 95 % confidence interval (CI) of 1.37 to 1.70 and inter-quartile range (IQR) of 0.88, during the 11th to 15th weeks of pregnancy. Maternal age and weight were the only variables significantly related to FLRG levels (p = 0.030 and 0.020, respectively). Only maternal and gestational ages were related to DS (p = 0.039 and p = 0.006, respectively). Maternal plasma levels of FLRG were not significantly different in the presence of DS fetuses compared to normal population (p = 0.63). The authors concluded that FLRG can be successfully detected in maternal plasma in the first trimester of pregnancy. However, its levels are not significantly altered in the presence of DS fetuses.
Li and colleagues (2010) compared the difference in maternal serum anti-Mullerian hormone (AMH) level between DS pregnancies and unaffected pregnancies, and evaluated its performance as a screening marker for DS pregnancy. A total of 145 pregnancies affected by fetal DS and 290 unaffected controls matched with maternal age and gestational age were selected, and their archived first or second trimester serum retrieved for AMH assay. There was no significant difference in maternal serum AMH level between pregnancies affected and unaffected by fetal DS. The first trimester serum samples had higher AMH concentration compared to second trimester samples. The authors concluded that maternal serum AMH level, as a marker of ovarian age, is not superior to chronological age in predicting DS pregnancies. Despite the cross-sectional nature of this study, the variation of maternal serum AMH concentration with gestational age warrants further investigation.
A disintegrin and metalloprotease 12 (ADAM12-S) has previously been reported to be significantly reduced in maternal serum from women with fetal aneuploidy early in the first trimester and to significantly improve the quality of risk assessment for fetal trisomy 21 in prenatal screening. Torring and colleagues (2010) examined if ADAM12-S is a useful serum marker for fetal trisomy 21 using the mixture model. In this case control study, ADAM12-S was measured by KRYPTOR ADAM12-S immunoassay in maternal serum from gestational weeks 8 to 11 in 46 samples of fetal trisomy 21 and in 645 controls. Comparison of sensitivity and specificity of first trimester screening for fetal trisomy 21 with or without ADAM12-S included in the risk assessment using the mixture model. The concentration of ADAM12-S increased from week 8 to 11 and was negatively correlated with maternal weight. Log multiples of median (MoM) ADAM12-S was positively correlated with log MoM PAPP-A (r = 0.39, p < 0.001), and with log MoM free beta hCG (r = 0.21, p < 0.001). The median ADAM12-S MoM in cases of fetal trisomy 21 in gestational week 8 was 0.66 increasing to approximately 0.9 MoM in week 9 and 10. The use of ADAM12-S along with biochemical markers from the combined test (PAPP-A, free beta-hCG) with or without nuchal translucency measurement did not affect the detection rate or false positive rate of fetal aneuploidy as compared to routine screening using PAPP-A and free beta-hCG with or without nuchal translucency. The authors concluded that these findings show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8 to 11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21.
Liao et al (2010) evaluated the potential of maternal serum using ADAM12 as a marker for trisomy 21 in Chinese pregnant women. Serum samples were collected and stored from women having a viable singleton pregnancy undergoing first trimester screening for trisomy 21 between 2006 and 2007. Serum concentration of ADAM12 was measured using an automated time-solved immuno-fluorometric assay from 608 stored serum samples (601 euploidy and 7 trisomy 21). Regression analysis was used to determine the expected median in euploidy pregnancies after adjusting for pregnancy characteristics. The level of ADAM12 MoM was compared between trisomy 21 and euploidy pregnancies. Expected median levels in Chinese were compared to that published for Caucasians and Afro-Caribbeans. In euploidy pregnancies, the concentration of ADAM12 increased with crown-rump length and decreased with maternal weight. The expected median level of ADAM12 in Chinese was significantly lower than Caucasian and Afro-Caribbeans (F = 14.2, p < 0.0001). There was a significant correlation between log10 ADAM12 MoM both log10 PAPP-A MoMs (r = 0.46; p < 0.001) and log10 free beta-hCG MoMs (r = 0.08; p = 0.048). The median ADAM12 MoM in trisomy 21 pregnancies was not significantly different from that in euploidy pregnancies (z = 0.18; p = 0.88). The authors concluded that ADAM12 concentrations in Chinese are lower than those of Caucasians and Afro-Carribeans; that ADAM12 MoM levels in euploidy and trisomy 21 pregnancies were not statistically different.
Valinen et al (2010) examined the correlation between ADAM12 and PAPP-A and free beta-hCG during the first trimester of pregnancy. ADAM12, PAPP-A and free beta-hCG were measured in 225 serum samples of randomly chosen pregnancies with completely normal outcome. The samples were taken between pregnancy weeks 9+0 and 12+6. The ADAM12 levels tended to increase with advanced gestational age and the highest levels were detected at pregnancy week 12. The ADAM12 levels correlated with PAPP-A levels. After weight correction and logarithmic transformation the MoM of ADAM12 still correlated with the MoMs of PAPP-A and also with the MoMs of free beta-hCG. Smokers had lower ADAM12 levels than non-smokers. The authors concluded that secretion of ADAM12 seems to resemble the secretion of PAPP-A in the end of the first trimester. Accordingly ADAM12 appears not to be a separate marker independent of PAPP-A. They stated that it remains to be assessed whether adding ADAM12 in DS screening risk calculation will reduce the false positive rate during the first trimester of pregnancy.
Cowans et al (2010) examined placental growth factor (PlGF) levels in first trimester maternal serum in trisomy 21 pregnancies and investigated the potential value of PlGF in a first trimester screening test. First trimester maternal serum from 70 trisomy 21 cases and 375 euploid controls were retrospectively analyzed for PlGF using a DELFIA Xpress immunoassay platform. Results were expressed as MoM for comparison. PlGF levels were significantly decreased in pregnancies with trisomy 21, 0.76 MoM versus 0.98 MoM in controls. Inclusion of PlGF into the first trimester combined test (maternal age, PAPP-A, free beta-hCG) and nuchal translucency would increase the detection rate by 0.5 % at a 5 % false-positive rate. The authors concluded that PlGF at 11 weeks to 13 weeks 6 days has the potential to be included as a marker for the detection of pregnancies with trisomy 21.
Nuchal Translucency Measurement
Correct performance of the NT measurement is critical to the accuracy, safety, and effectiveness of the new non-invasive screening schemes. First trimester NT screening involves the ultrasound measurement of the echo-free area of the back of the fetal neck measured between 10 and 14 weeks gestation. The NT measurement is highly dependent on experience of the ultrasonographer, Small differences -- less than 1/10 of 1 mm -- in NT measurements can characterize the difference between a screen negative or “normal” and screen positive or “abnormal” test result. The increased detection rates seen with non-invasive first and second trimester screening compared to older screening schemes is mostly due to the contribution of the NT measurement. All the published trials that have demonstrated superior detection rates of the new screening strategies the incorporate NT measurements have relied on NT measurements performed by highly trained and credentialed ultrasonographers.
Recognizing the potential magnitude of the problem that would result from the performance of NT measurement by untrained ultrasonographers, the SMFM has recommended that first trimester screening not be made widely available until a national program of quality review and oversight is established for the United States. Similarly, ACOG, the ACMG, the American Institute for Ultrasound in Medicine, and the National Institute of Child Health and Development (NICHD) of the NIH have cautioned that screening based on NT measurements should only be made available in the setting of quality credentialing and oversight monitoring (ACOG, 2004). Specifically, ACOG concluded that, in order for first-trimester screening for DS and trisomy 18 to be an option, it should be offered only if the following criteria are met (ACOG, 2004):
Access to an appropriate diagnostic test is available where screening test results are positive; and
Appropriate ultrasound training and ongoing quality monitoring programs are in place; and
Sufficient information and resources are available to provide comprehensive counseling to women regarding the different screening options and limitations of these tests.
Nuchal translucency credentialing and quality oversight review process have been established in the NT Oversight Committee (NTOC) of the Maternal Fetal Medicine Foundation (MFMF). A wide range of national, regional, and local genetics laboratory providers will only provide risk assessment using the components of NT measurement and serum analyte values if the sonographers demonstrate evidence of NT credentialing. Non-invasive first trimester nuchal translucency testing for fetal aneuploidy is considered medically appropriate only under such a credentialing program.
Maternal Plasma MicroRNA for Down Syndrome Screening
Kamhieh-Milz et al (2014) hypothesized that different fetal developmental processes might be reflected by extra-cellular microRNAs (miRNAs) in maternal plasma and may be utilized as biomarkers for the non-invasive pre-natal diagnosis of chromosomal aneuploidies. In this proof-of-concept study, these investigators reported on the identification of extra-cellular miRNAs in maternal plasma of DS pregnancies. Using high-throughput quantitative PCR (HT-qPCR), a total of 1,043 miRNAs were investigated in maternal plasma via comparison of 7 DS pregnancies with age- and fetal sex-matched controls. A total of 695 miRNAs were identified; 36 significantly differentially expressed mature miRNAs were identified as potential biomarkers. Hierarchical cluster analysis of these miRNAs resulted in the clear discrimination of DS from euploid pregnancies. Gene targets of the differentially expressed miRNAs were enriched in signaling pathways such as mucin type-O-glycans, ECM-receptor interactions, TGF-beta, and endocytosis, which have been previously associated with DS. The authors concluded that miRNAs are promising and stable biomarkers for a broad range of diseases and may allow a reliable, cost-efficient diagnostic tool for the non-invasive prenatal diagnosis of DS.
Furthermore, an UpToDate review on “Down syndrome: Prenatal screening overview” (Messerlian and Palomaki, 2014) does not mention microRNA as a tool for non-invasive prenatal diagnosis of DS.
Credentialing Process for NT Measurements in the U.S.
In December 2004, NICHD, SMFM, ACOG, and the March of Dimes co-sponsored a "State of the Science" workshop where all extant data were reviewed by national and international experts. Shortly thereafter, the MFMF was founded. Functioning under the auspices of the MFMF, the NT Oversight Committee developed an educational, training, and quality review program that was initiated in February 2005. This program, known as the Nuchal Translucency Quality Review Program (NTQR), is one rof two recognized credentialing systems for the United States. Information about the MFMF credentialing process and on-line registration can be found at the NTQR website at http://www.NTQR.org.
The Fetal Medicine Foundation - United States (FMS-US) offers another recognized credentialing system for the United States for screening for aneuploidy with nuchal translucency measurements. FMF-US has been offering an education, training, credentialing, and ongoing quality review program that was initiated in the United States more than 5 years ago. The FMF-US is affiliated with its European counterpart, the Fetal Medicine Foundation - United Kingdom (FMF-UK). Information about the FMF-US credentialing process and on-line registration can be found at the FMF-US website at http://fetalmedicine.com/usa/.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria is met:
Ultrasound, pregnant uterus, real time with image documentation, first trimester fetal nuchal translucency measurement, transabdominal or transvaginal approach; single or first gestation
each additional gestation (List separately in addition to code for primary procedure)
Fetal congenital abnormalities, biochemical assays of three proteins (PAPP-A, hCG [any form], DIA), utilizing maternal serum, algorithm reported as a risk score
Fetal congenital abnormalities, biochemical assays of three analytes (AFP, uE3, hCG [any form]), utilizing maternal serum, algorithm reported as a risk score
Fetal congenital abnormalities, biochemical assays of four analytes (AFP, uE3, hCG [any form], DIA) utilizing maternal serum, algorithm reported as a risk score (may include additional results from previous biochemical testing)
Fetal congenital abnormalities, biochemical assays of five analytes (AFP, uE3, total hCG, hyperglycosylated hCG, DIA) utilizing maternal serum, algorithm reported as a risk score
Gonadotropin, chorionic (hCG); free beta chain
CPT codes not covered for indications listed in the CPB:
Immunoassay, analyte quantitative; not otherwise specified [first-trimester maternal serum anti-Mullerian hormone level] [first trimester serum A disintegrin and metalloprotease 12 (ADAM 12-S)] [first trimester maternal serum placental growth factor]
Other CPT codes related to the CPB:
Chorionic villus sampling, any method
Alpha-fetoprotein (AFP); serum
Pregnancy-associated plasma protein-A (PAPP-A)
Gonadotropin, chorionic (hCG); quantitative
ICD-9 codes covered if selection criteria are met:
758.0 - 758.9
V28.81 - V28.89
Other specified antenatal screening
Other ICD-9 codes related to the CPB:
Encounter for routine screening for malformation using ultrasonics
Other genetic screening
The above policy is based on the following references:
American College of Obstetricians and Gynecologists (ACOG). Maternal serum screening. ACOG Technical Bulletin No. 228. Washington, DC: ACOG; September 1996.
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Ewigman BG, Crane JP, Frigoletto FD, et al. Effect of prenatal ultrasound screening on perinatal outcome. N Eng J Med. 1993;329:821-827.
American College of Obstetricians and Gynecologists (ACOG). First-trimester screening for fetal anomalies with nuchal translucency. ACOG Committee Opinion No. 223. Washington, DC: ACOG; October 1999.
Malone FD, Berkowitz RL, Canick JA, et al. First-trimester screening for aneuploidy: Research or standard of care? Am J Obstet Gynecol. 2000;182(3):490-496.
American College of Obstetricians and Gynecologists Committee on Practice Bulletins -- Obstetrics. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol. 2001;97(5 Pt 1):suppl 1-12.
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Carvalho MH, Brizot ML, Lopes LM, et al. Detection of fetal structural abnormalities at the 11-14 week ultrasound scan. Prenat Diagn. 2002;22(1):1-4.
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Institute for Clinical Systems Improvement (ICSI). First trimester prenatal testing for Down syndrome using nuchal translucency. Technology Assessment Report. Bloomington, MN: ICSI; 2002.
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