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Background
Historically in the United States, risk assessment for Down syndrome (DS) and other fetal chromosomal abnormalities had varies by maternal age. Invasive genetic testing, either amniocentesis or chorionic villus sampling (CVS), were offered towomen 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). See CPB 464 - Serum Marker Screening for Down Syndrome.
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. See CPB 358 - Prenatal Diagnosis of Genetic Diseases. Although invasive testing (amniocentesis or CVS) detects 100% of fetal chromosomal abnormalities, it is associated with an increased risk of pregnancy loss compared to noninvasive testing. Maternal serum testing with the quad screen in the second trimester is safe but only maximally detects 79% of DS cases.
First trimester non-invasive 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 Down syndrome (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 & 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 11-13 weeks (Canick & 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 three 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 & Wald, 2001; Malone & 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 Down syndrome (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 percent at a 5 percent 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 three outcomes: screen positive, screen negative, and 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 Down syndrome 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 percent 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 cannot 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 & 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 Down syndrome (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 & D’Alton, 2003; ACOG, 2004).
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 one tenth of one millimeter -- 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):
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Appropriate ultrasound training and ongoing quality monitoring programs are in place, and
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Sufficient information and resources are available to provide comprehensive counseling to women regarding the different screening options and limitations of these tests, and
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Access to an appropriate diagnostic test is available where screening test results are positive.
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.
Credentialing Process for NT measurements in the US
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/.
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