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First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18

First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18
Authors:
Geralyn M Messerlian, PhD
Antonio Farina, MD
Glenn E Palomaki, PhD
Section Editor:
Louise Wilkins-Haug, MD, PhD
Deputy Editor:
Vanessa A Barss, MD, FACOG
Literature review current through: Jan 2023. | This topic last updated: May 02, 2022.

INTRODUCTION — First-trimester and integrated screening tests for Down syndrome (trisomy 21) and trisomy 18 will be reviewed here. Other aspects of fetal aneuploidy screening are discussed separately:

(See "Down syndrome: Overview of prenatal screening".)

(See "Prenatal screening for common aneuploidies using cell-free DNA".)

(See "Laboratory issues related to maternal serum screening for Down syndrome".)

(See "Sonographic findings associated with fetal aneuploidy".)

A glossary of terms describing the various tests used in first- and second-trimester screening for Down syndrome is provided in the table (table 1A).

The discussion in this topic is consistent with screening guidelines published by the American College of Obstetricians and Gynecologists in 2020 [1].

COMBINED TEST

Components — Measurement of the following three markers comprise the "combined test" and together with maternal age provides a patient-specific risk for Down syndrome [2-6]:

Maternal serum beta-human chorionic gonadotropin (total beta-hCG or free beta-hCG subunit)

Maternal serum pregnancy-associated plasma protein A (PAPP-A)

Ultrasound measurement of nuchal translucency (NT)

Pattern — The pattern in pregnancies affected by Down syndrome is increased hCG, decreased PAPP-A, and enlarged NT (table 2).

Performance — The combined test detects approximately 85 percent of Down syndrome (ie, detection rate [DR] = sensitivity = 85 percent) with a false-positive rate (FPR) of 5 percent [3,7-16]. As described below, it can also detect trisomy 18. (See 'Detection of trisomy 18' below.)

The combined test performs slightly better than the second-trimester quadruple test (ie, the DR is higher and/or the FPR is lower) when the comparison has been calculated after adjustment for the expected natural losses of Down syndrome fetuses between the first and second trimesters (table 3) [17,18].

Timing of blood sample and ultrasound — First-trimester Down syndrome screening is performed in the late first trimester, usually between 10+0 and 13+6 weeks of gestation, depending on which markers are used [19]. The blood tests and ultrasound examination for the combined test are most commonly performed on the same day between 11+0 and 13+6 weeks of gestation. Some protocols opt for blood collection as early as 9+0 weeks of gestation so that the chemistry results are available for immediate reporting when the ultrasound is performed a week or more afterwards.

First-trimester testing should not be offered if chorionic villus sampling (CVS) is not available to establish a definite diagnosis. Such patients are better off having a serum integrated test with amniocentesis as the follow-up diagnostic test. (See 'Serum integrated test' below.)

Beta-hCG

Hormone – hCG is part of the glycoprotein hormone family, together with the luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone. These hormones are heterodimers that share a common alpha-subunit and varying degrees of homology in their beta-subunits.

Level in Down syndrome – Beta-hCG levels are, on average, twice as high in pregnancies affected with Down syndrome than in euploid pregnancies. Beta-hCG can be assayed in its free or total form.

Measurement – The test for free beta-hCG for Down syndrome screening is effective at 9+0 to 13+6 weeks, and screening performance improves as gestational age advances within this interval [20].

The test for total beta-hCG for Down syndrome screening is effective at 11+0 to 13+6 weeks, and screening performance improves as gestational age advances within this interval [7,8,17].

Between 11+0 and 13+6 weeks, there is no consensus as to whether free beta-hCG performs significantly better than total beta-hCG for Down syndrome screening when interpreted in conjunction with maternal age and measurement of PAPP-A and NT [7,8,20]. (See "Down syndrome: Overview of prenatal screening".)

PAPP-A

Hormone – PAPP-A is a complex, high molecular weight glycoprotein.

Level in Down syndrome – PAPP-A levels, on average, are lower in pregnancies affected with Down syndrome.

Measurement – PAPP-A performance as a screening marker for Down syndrome decreases with advancing gestational age between 9+0 and 13+0 weeks [8,17,18,21].

Nuchal translucency

Anatomy – NT refers to the hypoechoic space in the posterior fetal neck. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Anatomy'.)

Measurement – NT thickness is measured by ultrasound between 10+3 and 13+6 gestational weeks. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Procedure'.)

Enlargement in Down syndrome – The NT measurement is, on average, increased in fetuses with Down syndrome [9,22,23]. There is a slight reduction in the NT median MoM from 10+0 to 13+0 weeks. However, there is a concomitant decrease in the spread of the observations at each week (standard deviation) [23]. Overall, this leads to an increase in NT performance as a screening marker for Down syndrome with advancing gestation between 10+0 and 13+0 weeks [8,18,24,25]. Specifically, NT provides 51 percent detection of Down syndrome for a 5 percent FPR at 10 weeks, 59 percent at 11 weeks, and 62 percent at 12 to 13 weeks [24]. Thus, although NT performs well as a screening marker throughout the first trimester, measurements are ideally performed at 12 or 13 weeks of gestation. With the combination of multiple markers, including PAPP-A and hCG/free beta-hCG, screening performance is very similar at 11 to 13 weeks, and targeting 12 weeks is reasonable.

Performance of NT as a screening marker has not been consistent from study to study, presumably because of variability in operator expertise and quality of equipment [26]. For this reason, proper training and ongoing quality management are essential components of screening programs that involve measurement of NT [27].

The best interpretation of NT is by screening programs that combine its measurement with maternal age and first trimester serum markers to provide a patient specific risk of Down syndrome. One exception to this recommendation is for fetuses with a cystic hygroma or significantly enlarged NT. These pregnancies are at particularly high risk of aneuploidy. Many experts proceed directly to karyotype (some choose microarray) assessment in these cases, rather than checking maternal serum biochemical marker levels. The optimum threshold for proceeding to chromosomal analysis without maternal serum screening is unclear. NT thresholds in the range of 3.0 to 4.0 mm have been suggested, given the relatively high risk of Down syndrome at this level. Enlarged NT has also been associated with other structural malformations. These issues are discussed in more detail separately. (See "Enlarged nuchal translucency and cystic hygroma".)

Advantages and disadvantages of the combined test — There are obvious advantages to performing Down syndrome screening early in pregnancy. Early risk assessment and diagnosis of fetal abnormalities allow maximum time for decision-making; privacy, since others may not be aware of the pregnancy; and, if chosen, safer methods of pregnancy termination. However, this assumes that a screen-positive result can be further assessed by a diagnostic test; the combined test should not be offered if CVS is not available for immediate diagnostic testing.

Less obvious consequences include the identification of a fetus with Down syndrome that would have been spontaneously lost (approximately 15 percent of all Down syndrome pregnancies are spontaneously lost between 11 and 16 weeks of gestation compared with less than 2 percent of euploid pregnancies).

Other first-trimester serum and sonographic markers of Down syndrome

hCG, PAP-A, PlGF, AFP, and NT – The performance of the first-trimester combined test can be enhanced by adding placental growth factor (PlGF) and alpha-fetoprotein (AFP) to the combined test [28,29]. PlGF and AFP levels are, on average, lower in pregnancies affected with fetal Down syndrome. Several studies have shown that a combination of four serum markers (PlGF, AFP, beta-human chorionic gonadotropin [hCG], and pregnancy-associated plasma protein A) between 11+0 and 13+0 weeks of gestation can detect up to 90 percent of Down syndrome pregnancies but with an FPR of approximately 20 percent [28,30,31]. Such testing would only be reasonable with reflexive cell-free DNA testing for those with initial screen-positive results [32] and may be useful in areas where NT is unreliable, unavailable, or too costly for routine use.

Additional sonographic markers (eg, absent nasal bone) – First-trimester combined screening can also be improved by assessing two or three ultrasound markers in addition to NT, such as nasal bone (present versus absent) and bladder size (megacystis [defined by longitudinal bladder length ≥7 mm at 10 to 14 weeks of gestation] present versus absent). Disadvantages include the additional expertise and costs involved. Additional markers are described separately. (See "Sonographic findings associated with fetal aneuploidy".)

INTEGRATED TESTS — Integrated screening tests use markers measured in both the first and second trimesters to provide a single patient-specific estimate of risk for a Down syndrome pregnancy.

Full integrated test

Components and timing – A serum sample is assayed for pregnancy-associated plasma protein A between 10+0 and 13+6 weeks and an ultrasound measurement of NT, along with estimation of gestational age by crown-rump length, is performed between 11+0 and 13+6 weeks. The information is not analyzed until a second-trimester serum sample is drawn and the quadruple test markers are measured (alpha-fetoprotein, unconjugated estriol, inhibin A, and beta-human chorionic gonadotropin [hCG]) at 15+0 to 22+6 weeks (table 1B). Beta-hCG can be used as a marker in either the first or second trimester, but it is routinely measured in the second trimester when its performance is better.

The six marker values are used, together with maternal age, to calculate a single patient-specific risk for Down syndrome, and a report is generated.

Pattern – The pattern in pregnancies affected by Down syndrome is decreased PAPP-A, enlarged NT, decreased AFP, decreased unconjugated estriol, increased inhibin A and increased hCG (table 2).

Performance – The full integrated test achieves an 85 percent detection rate (DR) at a 1 percent false positive-rate (FPR). If a 90 percent DR is the target, the FPR will be 2 percent (table 3) [17].

Advantages and disadvantages – The advantage of the integrated test is that at an equivalent DR, it has a substantially lower FPR than the combined or quadruple test [33]. A reduction in the FPR in screening tests is highly desirable. Any reduction in false positives while maintaining a high DR will increase the safety of the screening process because there will be fewer procedure-related miscarriages per Down syndrome pregnancy identified. A lower FPR will also decrease the number of patients who are anxious due to a false positive result; such anxiety appears to decrease participation in Down syndrome screening in the next pregnancy [34].

The disadvantage of the integrated test is that final test results are not available until the second trimester. This problem can be largely mitigated by using a sequential approach, but if used, chorionic villus sampling (CVS) should be available, otherwise there is little advantage of providing the first-trimester results. (See 'Sequential screening' below.)

Like the combined test, the integrated test can also detect trisomy 18, which is associated with a different pattern of test results (table 2). (See 'Detection of trisomy 18' below.)

Serum integrated test

Components and timing – The serum integrated test is the same as the full integrated test but without ultrasound measurement of NT. (See 'Full integrated test' above.)

Performance – This test has the highest DR among screening tests that do not include NT measurement or cell-free DNA (table 3). (See 'Choice of screening test' below.)

Advantages and disadvantages – The advantages and disadvantages of screening across two trimesters are discussed above. (see 'Full integrated test' above) An advantage of the serum-integrated test is that it provides an option to patients in areas where expertise in measurement of NT is not available.

Sequential screening

Components and timing – The sequential screening process involves performing the first-trimester portion of the integrated screen and then offering counseling and CVS to patients whose results place them at very high risk (eg, ≥1 in 50, or approximately the highest 0.5 percent) of an affected fetus. Patients whose screen does not place them at very high risk do not receive early results and go on to complete the second-trimester portion of the test.

Performance – One investigator estimated an 86 percent DR was achieved at a 2 percent FPR in a sequential test in which the first-trimester cut-off for offering invasive testing was set at 1 in 40 and the integrated cut-off was set at 1 in 110 [35]. In the FASTER trial discussed below, sequential screening detected 95 percent of Down syndrome fetuses with an FPR of 5 percent (2.5 percent in the first-trimester portion and 2.5 percent in the integrated portion of the test) [18]. These rates approach those of full integrated screening but have the benefit of availability of early results for the highest risk patients [19]. Issues related to this type of sequential testing have been reviewed elsewhere [33,35].

Advantages and disadvantages – The rationale for not releasing first-trimester risk results to patients in the group with risks less than the cut-off is that this information may lead to diagnostic testing in those at moderate risk and increase the actual FPR of the sequential test without a substantial increase in detection. Many patients with somewhat elevated risks in the first trimester will have quite low risks once the results of second-trimester testing are included.

Reporting a first-trimester Down syndrome risk and a separate and independent second-trimester Down syndrome risk is relatively uncommon but has important disadvantages. These were illustrated in a multicenter study of the first-trimester combined test sponsored by the National Institute of Child Health and Human Development [36]. Independent first- and second-trimester testing (the results of first-trimester screening were not incorporated into the total risk assessment) resulted in a very high DR (overall approximately 98 percent) but at an inappropriately high FPR (approximately 17 percent). Reporting both risks leads to physician and patient confusion and unpredictable screening performance.

CHOICE OF SCREENING TEST — Patients can be informed:

The full integrated test (first-trimester NT, pregnancy-associated plasma protein A [PAPP-A], and second-trimester alpha-fetoprotein [AFP], unconjugated estriol [uE3], beta-human chorionic gonadotropin [hCG], and inhibin A) is the most efficient serum-based screening test (high detection rate [DR], low false-positive ratio [FPR]). The rate of procedure-related unaffected fetal loss would be 9 losses per 100,000 patients screened compared with approximately 45 losses per 100,000 when either the combined test or the second-trimester quadruple test is performed. Sequential screening, a variant of the integrated test, approximates the performance of the full integrated test and may be a valuable alternative because it reports very high risk results in the first trimester.

If NT testing is not available, the serum-integrated test (first-trimester PAPP-A and second-trimester AFP, uE3, beta-hCG, and inhibin A) is the next most efficient choice.

The quadruple test (second-trimester AFP, uE3, beta-hCG, and inhibin A) is the best available option for individuals who present for prenatal care in the second trimester.

First-trimester combined screening (NT, PAPP-A and beta-hCG) is a reasonable approach for individuals who desire earliest possible screening and diagnosis. This assumes that chorionic villus sampling (CVS) is available if diagnostic testing is indicated.

Evidence — These conclusions are based on results of The Serum, Urine and Ultrasound Screening Study (SURUSS) and First and Second Trimester Evaluation of Risk (FASTER) trial, which evaluated Down syndrome screening in both the first and second trimesters of the same individual. A summary of results from these trials, including FPRs for various detection rates (DRs), is provided in the tables (table 3).

MANAGEMENT

Screen-positive first-trimester combined test results

Defining screen-positive – A screen-positive test result indicates that the individual's risk of having a child with Down syndrome is equal to, or exceeds, a specific cut-off level that was predetermined by the laboratory based on the performance characteristics of the chosen screening test. This cut-off level is program/laboratory-specific and based on the combination of markers used, among other factors. A typical cut-off for the combined test is the term risk of Down syndrome of ≥1 in 300. This is associated with a false-positive rate (FPR) of approximately 5 percent (eg, approximately 5 per 100 screened patients will have risks higher than 1 in 300, such as 1 in 250 or 1 in 75). The odds of Down syndrome in this group of patients is approximately 1 in 20 (eg, for every 20 patients who are screen-positive, 1 will have a Down syndrome fetus and 19 will have a normal fetus) (table 4). (See "Laboratory issues related to maternal serum screening for Down syndrome", section on 'Effect of maternal age'.)

Giving the information to the patient – The patient's risk of having an affected fetus/child is calculated from their age and screening test results and provided in the report (eg, Down syndrome risk 1 in 90). This can be explained to the patient as, "Your screening test result for Down syndrome is 1 in 90, meaning that among a group of 90 individuals with this test result, one will have a fetus with Down syndrome, while the remaining 89 will not."

It is important to note whether the risks reported are at term (ie, chance of an infant with Down syndrome at birth), at mid-trimester (the chance that an amniocentesis will identify and affected fetus), or in the late first trimester (chance that chorionic villus sampling [CVS] will identify an affected fetus). For example, a term risk of 1 in 90 translates to a mid-trimester risk of approximately 1 in 68 and a late first-trimester risk of 1 in 61. These differences reflect the ongoing risk of fetal loss associated with Down syndrome pregnancies [37].

Genetic counseling – After a positive screening test, it is helpful to have a genetic counselor meet with the parents to discuss the results along with diagnostic and management options. This would include information about the natural history of Down syndrome. Nondirective information enables the parents to balance the risks, limitations, and benefits of prenatal screening and diagnostic testing with the medical, educational and social issues involved in raising a child with Down syndrome or pregnancy termination.

Diagnostic testing versus secondary screening – Patients with positive screening results are offered definitive fetal chromosomal analysis (karyotype, microarray) by CVS if they present prior to 14 weeks of gestation. Alternatively, they may choose to undergo secondary screening using a maternal plasma-based test for cell-free DNA (cfDNA). Although not diagnostic, the high sensitivity and specificity of the cfDNA test will reassure many individuals whose cfDNA test suggests a very low risk of Down syndrome, and thus allow them to avoid the cost and risk associated with an invasive diagnostic test. For those patients with a positive cfDNA test, the risk of Down syndrome is increased but still requires confirmation by an invasive diagnostic test (CVS, amniocentesis). (See "Down syndrome: Overview of prenatal screening", section on 'Screen-positive test result' and "Prenatal screening for common aneuploidies using cell-free DNA".)

These two approaches were compared in a multicenter trial that explored the outcomes of individuals with a positive first-trimester combined test randomly assigned to follow-up with secondary cfDNA screening or an invasive diagnostic test [38]. No Down syndrome pregnancies were missed. There were 11 (1.5 percent) additional chromosome anomalies identified among the 751 individuals who underwent invasive testing; however, only two abnormalities with potential clinical consequences would have been missed. Four of the 11 genetic abnormalities would not be associated with clinical consequences and five could have been identified with a more complete cfDNA test (two mosaic trisomy 13, three sex chromosome aneuploidy). As expected, the number of invasive procedures performed in each group was dramatically different (84 [8 percent] in the cfDNA group versus 751 [77 percent] in the no cfDNA group). Seven of 751 patients (0.93 percent) in the invasive testing group who underwent an invasive procedure had a miscarriage versus none of the 84 patients who had an invasive procedure performed after a positive cfDNA test result; however, there was no significant difference between groups in overall miscarriage rates before 24 weeks (0.8 percent for both groups). A major limitation of the trial was that patient compliance with the study protocol differed dramatically: 99 percent of the individuals allocated to cfDNA screening complied while only 74 percent complied with immediate invasive testing. In addition, the trial was underpowered to identify the procedure-related risk of invasive testing (approximately 0.2 percent) cited in large contemporary observational studies.

Screen-positive integrated test results

Defining screen-positive – A positive test result means the patient's risk of having a baby with Down syndrome is greater than a specified cut-off level; it does not provide a definitive diagnosis of Down syndrome. The cut-off chosen for screen-positive in the integrated test is often higher than that of the combined or quadruple test in order to obtain this test's low FPR while still maintaining a high detection rate (DR). A typical cut-off for the integrated test is a midpregnancy risk of Down syndrome of ≥1 in 100. This cut-off is associated with an FPR of 1 to 2 percent and odds of Down syndrome among the screen-positive individuals is approximately 1 in 5 to 1 in 10 (table 4).

Counseling and management – The same counseling issues that apply to patients with first-trimester screen-positive results are applicable to those with a screen-positive integrated test result, except that amniocentesis is the diagnostic test offered instead of CVS since the screening result is provided in the early second trimester. Alternatively, as discussed above, they may choose to undergo secondary screening using a maternal plasma-based test for cfDNA. Although not diagnostic, the high sensitivity and specificity of this test will reassure many of these patients and allow them to avoid the risk associated with an invasive diagnostic test. (See 'Screen-positive first-trimester combined test results' above.)

Screen-negative first-trimester or integrated test results — A negative test result means the patient's risk of having a baby with Down syndrome is less than a specified cut-off level; it does not exclude the possibility of Down syndrome. The patient's risk is usually provided in the report (eg, Down syndrome risk 1 in 9000) and this number can be given to the patient with a discussion of its meaning. With regard to Down syndrome screening, no further testing is recommended.

Additional screening to detect structural anomalies — Down syndrome screening does not obviate the need for second-trimester fetal assessment, including second-trimester ultrasound for fetal anatomic survey, with or without serum alpha-fetoprotein (AFP) screening for neural tube defects. Sonographic evaluation for detection of fetal structural anomalies is commonly performed at 18 to 20 weeks for optimal visualization. Serum AFP screening can be performed reliably at 16 to 18 weeks. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management" and "Overview of ultrasound examination in obstetrics and gynecology", section on 'Obstetric sonography'.)

DETECTION OF TRISOMY 18

Background — Trisomy 18 occurs in approximately 1 in 4000 births [39] and is more prevalent in older, compared with younger, mothers. The prevalence is three- to fivefold higher in the first and second trimesters than at birth because many affected fetuses spontaneously die in utero.

Ninety-five percent of affected infants die within the first year of life; 50 percent die within the first week. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome'.)

First-trimester combined test

Pattern – The first-trimester biochemical marker pattern characteristic of trisomy 18 is a very low beta-human chorionic gonadotropin (hCG), a very low pregnancy-associated plasma protein A (PAPP-A), and an enlarged NT measurement (table 2) [12,40,41].

Performance – In a study that screened over 8500 singleton pregnancies in the first trimester the use of maternal age, NT, beta-hCG, and PAPP-A detected 10 of 11 fetuses with trisomy 18. The single false negative case was screen-positive for trisomy 21 [12]. Thus, screening identified 91 percent of the 11 cases of trisomy 18, with a false-positive rate (FPR) of 2 percent using a risk cut-off of 1 in 150. Of course, due to the high spontaneous loss rate in affected pregnancies, some missed cases might spontaneously abort and never be identified as a false negative. In the FASTER trial, 9 of 15 (60 percent) of trisomy 18 cases were identified using a similar first-trimester algorithm, at a 0.1 percent FPR [42].

When screening for trisomy 18, it is appropriate to keep the FPR very low (less than 0.5 percent) so that only a small number of very high-risk individuals will be offered invasive diagnostic testing to detect a fetal abnormality that is often spontaneously lost (72 percent frequency of miscarriage or stillbirth between 12 weeks and term [43]). If the FPR is kept too low, the detection rate (DR) will also be reduced but many cases will be detected sonographically in the second trimester (see "Sonographic findings associated with fetal aneuploidy", section on 'Trisomy 18 (Edward syndrome)'). Among term trisomy 18 live births, the majority die within a few days and over 95 percent die by one year.

Integrated test

Performance – The serum-integrated test is highly efficient in identifying cases of trisomy 18. In one study that used a second-trimester risk cut-off of 1 to 100, four serum markers (first-trimester PAPP-A with second-trimester beta-hCG, alpha-fetoprotein, and unconjugated estriol) in combination with maternal age detected 90 percent of trisomy 18 pregnancies at an FPR of 0.1 percent [44]. The risk of a trisomy 18 pregnancy among screen-positive individuals was 1 in 4.

The addition of NT to a trisomy 18 screening algorithm (full integrated test) will further improve the performance of the test.

Additional findings — The presence of anatomic findings suggestive of trisomy 18 on ultrasound examination is highly dependent upon gestational age and most reliable at ≥20 weeks of gestation (DR 93 versus 76 percent at <20 weeks [45]). Thus, a scan at 19 to 20 weeks is a practical approach. Nearly all cases of trisomy 18 will have some ultrasound finding, but a portion of these will be only a "soft marker" that is also commonly seen in unaffected pregnancies. (See "Sonographic findings associated with fetal aneuploidy", section on 'Trisomy 18 (Edward syndrome)'.)

Management of patients with screen-positive trisomy 18 results — As with Down syndrome, individuals with screen-positive trisomy 18 results should receive genetic counseling and the offer of secondary screening with cell-free DNA or invasive diagnostic testing. (See 'Screen-positive first-trimester combined test results' above and 'Screen-positive integrated test results' above.)

DETECTION OF OTHER ANEUPLOIDIES — Trisomy 13, an even more severe and less common disorder (birth prevalence of approximately 1:7000) [39] than trisomy 18, has first-trimester biochemical and ultrasound findings similar to those of trisomy 18. Thus, there is no need for a special screening program for trisomy 13. Most will be identified as being positive for trisomy 18, with a similarly poor prognosis. In one series of 26 ongoing pregnancies with trisomy 13, there were 12 intrauterine deaths (46.2 percent) [46]. Among term births, neonatal death on day 1 of life occurred in 79 percent, the overall early neonatal mortality rate was 93 percent, and no infant survived longer than six weeks. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome'.)

The FASTER trial found that first-trimester combined screening detected 78 percent of all non-Down syndrome aneuploidies, with an overall false-positive rate (FPR) of 6 percent [42]. These patients were identified as being at high risk for Down syndrome or trisomy 18, or presented with cystic hygroma in the first trimester. In another prospective study, more than 90 percent of trisomy 21, 18, and 13 pregnancies could be detected using a specific algorithm, with an overall FPR of 3.1 percent [47].

NT alone is a marker of various chromosome abnormalities. In one study, approximately half of the chromosome abnormalities identified by increased NT measurements were not trisomy 21 [48]. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Clinical significance'.)

PREDICTION OF ADVERSE PREGNANCY OUTCOME — Abnormal maternal Down syndrome screening tests are also associated with obstetric complications, but the predictive values for these outcomes are low. Further investigation is needed to determine whether any type of monitoring and intervention protocol would improve pregnancy outcome and be cost effective in managing these pregnancies. In the absence of such data, changes in clinical management are not indicated.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal screening and diagnosis" and "Society guideline links: Down syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Should I have a screening test for Down syndrome during pregnancy? (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Screening tests – The terms describing the various tests used in first- and second-trimester screening for Down syndrome are provided in the table (table 1A-B).

Choice of Down syndrome screening test (See 'Choice of screening test' above.)

First-trimester combined test – First-trimester combined screening is most appropriate for patients who place a high value on identifying Down syndrome during the first trimester and accept a higher risk of procedure-related pregnancy loss from first-trimester invasive diagnostic testing. NT measurement should be performed by a properly trained and qualified individual and chorionic villus sampling (CVS) should be readily available for individuals with a screen-positive combined test.

Full integrated test – The full integrated test is the most efficient serum-based screening test (high detection rate [DR], low false-positive rate [FPR]). It is most appropriate for patients who place a higher value on minimizing the risk of procedure-related pregnancy loss from invasive diagnostic testing than on first-trimester identification of an affected pregnancy.

Serum-integrated test – If nuchal translucency (NT) testing is not available, the serum-integrated test is the next most efficient choice. It is more efficient than the second-trimester quadruple test. At the same DR, the serum-integrated test has a lower FPR than the quadruple test.

Quadruple test – The quadruple test is the best available option for individuals who present for prenatal care in the second trimester.

Performance of screening tests – The performance of Down syndrome screening tests can be viewed is shown in the table (table 3). (See 'Performance' above and 'Integrated tests' above.)

Management of patients who screen-positive Individuals who receive a screen-positive result for any of the screening tests discussed should be offered the choice of an invasive test for definitive diagnosis (CVS through 14 weeks, amniocentesis at ≥15 weeks) or a secondary screening test based on cell-free DNA. A negative secondary screen reduces the proportion of patients going on to invasive testing by ≥90 percent, but a positive screen needs to be confirmed by invasive testing. The odds of Down syndrome after a positive test result is shown in the table (table 4). (See 'Management' above.)

Detection of trisomy 18 and 13 and other syndromes – The combined and integrated tests are also effective in identifying fetuses at high risk of trisomy 18 and trisomy 13. Biochemical markers used for Down syndrome screening may detect pregnancies at high risk for other fetal syndromes, such as triploidy and conditions related to very low estriol, such as Smith-Lemli-Opitz syndrome, steroid sulfatase deficiency, and its associated contiguous gene deletion syndrome (table 2). (See 'Detection of trisomy 18' above.)

Screening for anatomic abnormalities – Individuals who choose first-trimester screening should be offered screening for open neural tube defects in the second trimester. (See 'Additional screening to detect structural anomalies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Jacob A Canick, who contributed to earlier versions of this topic review.

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Topic 422 Version 38.0

References

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