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Laboratory issues related to maternal serum screening for Down syndrome

Laboratory issues related to maternal serum screening for Down syndrome
Authors:
Geralyn M Messerlian, PhD
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 11, 2022.

INTRODUCTION — Maternal serum marker screening is used to estimate a pregnant woman's risk of having a fetus with Down syndrome. This allows the woman to make an informed choice about invasive diagnostic testing, which is associated with a small risk of pregnancy loss and may be costly. A variety of serum markers are used to screen for Down syndrome in the first and/or second trimesters.

Some genetic abnormalities other than Down syndrome have also been associated with alterations in first- and second-trimester marker levels (table 1). One group concluded that detection of genetic anomalies other than Down syndrome is a particular advantage of serum screening protocols [1]. They estimated that 17 percent of abnormalities identified as high risk by serum screening would be missed by cell-free DNA-based screening methods. However, these claims have been challenged [2].

This topic will review laboratory issues related to use of maternal serum markers used in Down syndrome screening. Other topics related to Down syndrome screening, including use of cell-free DNA in maternal blood, are available separately:

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

(See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)

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

TYPES AND TIMING OF SERUM MARKER SCREENING TESTS

Quadruple marker test — The quadruple test is performed in the early second trimester (optimally at 15+0 to 18+6 weeks of gestation, but it can be done as late as 22+6 weeks). Four markers are measured:

Alpha-fetoprotein (AFP)

Unconjugated estriol (uE3)

Total/intact human chorionic gonadotropin (hCG) or the free beta subunit of hCG (free beta hCG)

Inhibin A (InhA)

Clinical use of this test is reviewed separately. (See "Down syndrome: Overview of prenatal screening", section on 'Second-trimester quadruple test'.)

A first-trimester quadruple test also exists, but data on performance and use are limited [3].

Combined test — The combined test is performed in the late first trimester and includes:

Sonographic determination of fetal nuchal translucency (NT) measured at 11+0 to 13+6 weeks and

Two serum markers:

Pregnancy-associated plasma protein A (PAPP-A)

Total/intact hCG or free beta hCG

Blood for the serum markers can be drawn between 10+3 and 13+6 weeks; however, some programs that use total/intact hCG rather than free beta hCG use 11+0 weeks of gestation as the earliest gestational age for drawing blood because the hCG distributions in unaffected and Down syndrome pregnancies are nearly overlapping in the 10th week of gestation. (See 'Total/intact versus free beta hCG' below.)

Serum may be drawn days to weeks prior to the ultrasound examination or on the same day. In "one-stop" clinics, the serum and ultrasound results are available within an hour.

Clinical use of this test is reviewed separately. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Combined test'.)

Full integrated test — The full integrated test includes:

NT measured at 11+0 to 13+6 weeks and

PAPP-A measured at 10+0 to 13+6 weeks and

Measurement of four serum markers at 15+0 to 22+6 weeks:

AFP

uE3

Total/intact hCG or free beta hCG

InhA

Clinical use of this test is reviewed separately. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Integrated tests'.)

Serum integrated test — The serum integrated test includes all of the serum markers of the full integrated test (PAPP-A, AFP, uE3, total/intact hCG or free beta hCG, and InhA) as described above (see 'Full integrated test' above) but does not include measurement of NT (ie, ultrasound is not performed).

Clinical use of this test is reviewed separately. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Serum integrated test'.)

Stepwise sequential test — For stepwise sequential screening:

Perform the first-trimester portion of the integrated screen.

NT measured at 11+0 to 13+6 weeks and

PAPP-A measured at 10+0 to 13+6 weeks

Based on this result, offer chorionic villus sampling to women at very high risk of having an affected fetus (eg, risk ≥1 in 50).

The remaining women, who are at lower risk, go on to complete the second-trimester portion of the integrated test (AFP, uE3, total/intact hCG or free beta hCG, InhA) at 15+0 to 22+6 weeks.

Clinical use of this test is reviewed separately. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Sequential screening'.)

Sequential testing that does not include results of previous testing is not recommended. This is called "independent sequential screening." For example, a second-trimester quadruple test is performed at 15+0 to 22+6 weeks and reported without taking the first-trimester markers NT and PAPP-A into account.

TOTAL/INTACT VERSUS FREE BETA hCG — Measurement of the human chorionic gonadotropin (hCG) component of these screening tests may utilize intact hCG (alpha and beta together), total hCG (alpha and beta together plus the free beta subunit), or the free beta subunit of hCG alone. Regardless of the choice, the multiple marker tests will perform similarly.

Laboratories in the United States tend to use total/intact hCG because commercial kits to measure the free beta subunit alone are not readily available. Another factor to consider is that the total hCG is 100 times more abundant than the free beta subunit in pregnancy serum [4-6]. If the serum sample is exposed to high temperatures or long transit time, the intact hCG can dissociate and cause artificial increases in the free beta subunit measurements that result in incorrect test results and lead to additional false-positive results.

It is for this reason that some laboratories using the free beta subunit rely on dried blood spots rather than serum for their sample type.

hCG biochemistry and isoforms are reviewed in detail separately. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease".)

SERUM MARKER SCREENING FOR OPEN NEURAL TUBE DEFECTS — Blood for screening for open neural tube defects (NTDs), which also uses alpha-fetoprotein (AFP) test results, should only be drawn and interpreted at ≥15+0 weeks. This is one of the reasons that Down syndrome screening tests using AFP are only recommended at ≥15+0 weeks.

If the first-trimester combined test is performed to screen for Down syndrome, a second sample of blood should be drawn at ≥15+0 weeks for open NTD screening. Many programs suggest drawing blood samples for testing between 16+0 and 18+6 weeks, which optimizes testing for both Down syndrome and NTDs and allows ample time for follow-up testing in screen-positive pregnancies. However, second-trimester screening tests for Down syndrome can be drawn and interpreted up to 22+6 weeks, and for NTDs up to 23+6 weeks, depending on the laboratory.

Alternatively, targeted ultrasound screening for NTDs can be performed. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Ultrasound examination'.)

CHANGES IN MARKER LEVELS ACROSS GESTATION — Changes in serum marker levels are shown in the figures (figure 1A-E).

Regressed data should show that, in the early second trimester, alpha-fetoprotein increases by 15 to 20 percent per week and unconjugated estriol by 20 to 25 percent per week.

Levels of total/intact human chorionic gonadotropin (hCG) and free beta hCG reach a peak at approximately 10 weeks of gestation and decline through the remainder of the first trimester. Free beta hCG levels decline faster than total/intact hCG (by approximately 10 to 30 percent and 5 to 10 percent per week, respectively).

Inhibin A exhibits a shallow, U-shaped curve with its nadir at 17 weeks of gestation.

First-trimester pregnancy-associated plasma protein A levels increase by 30 to 50 percent per week between 10+0 and 13+6 weeks of gestation.

MARKER LEVELS IN SELECTED SYNDROMES

Down syndrome

First trimester – Median levels for first-trimester markers of Down syndrome by gestational age are shown in the figure (figure 2). Unlike the second trimester, the overlapping distributions in unaffected and Down syndrome pregnancies change systematically when measured between 10+3 and 13+6 weeks of gestation (figure 3). This change in marker performance should be accounted for in the calculation of patient-specific risk [7]. Pregnancy-associated plasma protein A (PAPP-A), free beta human chorionic gonadotropin (hCG), and total/intact hCG are also Gaussian (normal) on a logarithmic scale. Median PAPP-A rises from approximately 0.4 multiples of the median (MoM) at 10 weeks to approximately 0.7 MoM at 13 weeks, so the performance of PAPP-A decreases as gestation progresses. Median free beta hCG and total/intact hCG also rise during this period, which improves the performance of these markers since they are both elevated in Down syndrome pregnancies. These two effects tend to cancel each other out so that performance is relatively constant over the indicated time period.

Second trimester – The overlapping distributions of second-trimester alpha-fetoprotein (AFP), unconjugated estriol (uE3), total/intact hCG, free beta hCG, and inhibin A (InhA) MoM values in both unaffected and Down syndrome pregnancies are shown in the figure (figure 4).

The median MoM levels for all markers in unaffected pregnancies are, by definition, 1.0. Levels of AFP and uE3 are, on average, lower by 30 to 35 percent (0.70 to 0.75 MoM) in Down syndrome pregnancies. Therefore, these distributions are shifted to the left of the unaffected population. Second-trimester levels of hCG, free beta hCG, and InhA are approximately twice as high (2.0 MoM) and are shown shifted to the right. In examining these overlapping distributions, the power of each marker to discriminate between unaffected and affected pregnancies is a function of both the distance between the medians (peaks) and the widths (log standard deviations [SD]) of the two distributions. If one distribution is taller than another at its peak, the log SD is smaller. The more "separate" and "tighter" the distributions are, the better the marker's screening performance. The median MoM values of the second-trimester markers in Down syndrome pregnancy are constant over the gestational ages of interest (14+0 to 22+6 weeks) [8].

The reasons for altered maternal serum markers in Down syndrome pregnancy are poorly understood. Placental secretory products, such as the clinically important markers free beta hCG and InhA (as well as other products such as progesterone [9], human placental lactogen [10], and pregnancy-specific glycoprotein 1 [11]), are generally increased in the second trimester of Down syndrome pregnancy [8,12-14]. However, PAPP-A is also a placental secretory product, and its levels are low in the first trimester and not different from unaffected fetuses in the second trimester [7]. None of the genes for these placental products resides on chromosome 21, thereby eliminating a simple dose effect to explain the increased or decreased concentrations. Placental dimensions and weight are comparable in Down syndrome and unaffected pregnancies [15,16]. There may be an increase in the synthesis of specific placental proteins in Down syndrome, as suggested by free beta hCG and inhibin mRNA and protein studies [17-19]. Deficient syncytiotrophoblast formation may also have a role in abnormal placental secretion in affected pregnancies [20].

By comparison, secretory products synthesized in the fetus or requiring the combined fetoplacental unit are, on average, low in second-trimester maternal serum from Down syndrome pregnancies. As an example, levels of AFP derived from the fetal liver are reduced, as are maternal serum and amniotic fluid concentrations of the fetoplacental steroid, uE3 [21,22], and its fetal androgen precursor molecules, dehydroepiandrosterone sulfate (DHEA-S) [22] and 16-alpha-hydroxyDHEA-S [23].

The mechanisms leading to this phenomenon of increased placental and decreased fetal products in second-trimester maternal serum of Down syndrome pregnancy are actively being investigated [17-20,24-26]. One hypothesis is that the serum marker pattern is related to poorly functioning fetal tissue in affected fetuses with compensatory placental hyperfunction.

Trisomy 18

First trimester – The first-trimester marker pattern of trisomy 18 is very low PAPP-A (median 0.1 to 0.2 MoM), very low free beta hCG and total/intact hCG (median 0.2 to 0.4 MoM) and increased NT (median 1.8 to 3.7 MoM) (table 1) [27-29]. It is estimated that approximately 90 percent of trisomy 18 pregnancies can be identified by first-trimester screening, with a false-positive rate <1 percent [27,29,30]. However, these estimates are less confident than those for Down syndrome due to potential ascertainment biases in many of the published studies. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)

Second trimester – In the second trimester, the marker pattern suggestive of trisomy 18 is low levels of AFP, uE3, free beta hCG and total/intact hCG. The reduction in levels is, on average, 40 percent for AFP, 60 percent for uE3, and 70 percent for total/intact hCG and free beta hCG [31]. The concentration of InhA is only slightly reduced (by 12 to 16 percent), and this is insufficient for it to be used in screening for trisomy 18 [32,33]. Based on this marker pattern, maternal age and levels of AFP, uE3, and hCG (table 2) can be used to generate a patient-specific risk for trisomy 18. The detection rate would be 60 to 80 percent, with a screen-positive rate of approximately 0.5 percent [31].

Trisomy 13

First trimester – The first-trimester marker pattern of trisomy 13 is similar to that of trisomy 18 but is more variable. It is characterized by low to very low PAPP-A (median 0.36 MoM). The free beta hCG levels are also lower (median 0.41 MoM) while the NT is modestly increased (median 1.17 MoM, range 0.63 to 4.5) (table 1) [28]. Performance of trisomy 13 screening should be similar to, or perhaps lower than, that for trisomy 18. However, one study estimated that 87 percent of trisomy 13 cases could be detected in the first trimester with a 0.2 percent false-positive rate [34]. Since the pattern of trisomy 13 is similar to that of trisomy 18, programs can implement screening for trisomy 18 with the knowledge that trisomy 13 pregnancies will also be detected.

Second trimester – In the second trimester, the prenatal serum screening markers are not strongly associated with trisomy 13 and are not useful for detection of affected pregnancies.

Turner syndrome — Turner syndrome will be opportunistically identified in women undergoing diagnostic testing because of a high risk of Down syndrome or trisomy 18. There are no reliable published estimates of the performance of screening markers for Turner syndrome alone.

First trimester – Pregnancies affected by fetal Turner syndrome (45X, monosomy X) have relatively normal serum PAPP-A levels (median 0.99 MoM), with slightly increased total/intact hCG and free beta hCG measurements (median 1.20 MoM) as well as increased NT (median 1.38 MoM) levels. One study from Taiwan reported that 9 of 11 (81 percent) of Turner syndrome cases were detected after first-trimester serum screening, with a false-positive rate of 5.4 percent; however, some affected pregnancies may have been missed, particularly those that miscarried [35].

Second trimester – In the second trimester, fetal Turner syndrome is associated with a particular marker pattern depending on the presence or absence of hydrops. However, based on data from the California screening program and known prevalence of the common sex chromosome aneuploidies, the second-trimester screening performance was found to be only slightly better than chance (5.7 percent detection rate at a 4.6 percent false-positive risk) [36].

Fetal Turner syndrome complicated by hydrops has a maternal serum marker pattern similar to that observed with Down syndrome, with relatively low uE3 (median 0.61 MoM) and elevated total/intact hCG and free beta hCG measurements (median 5.05 MoM). InhA levels are also elevated (median 3.91 MoM) [33,37,38]. AFP levels are low or normal (median range 0.8 to 1.0 MoM).

Turner syndrome without hydrops is characterized by moderately reduced levels of all markers [33,37,38], similar to the pattern seen with trisomy 18. Median levels of AFP, uE3 and InhA are approximately 0.6 MoM while median total/intact hCG and free beta hCG levels are only slightly reduced (0.8 MoM) [33].

Triploidy — Triploidy (69,XXX; 69,XXY; 69,XYY) can affect markers measured in Down syndrome screening. The two types of triploidy are based upon the parental origin of the extra set of chromosomes.

Type I – Type I triploidy (diandric) originates from an extra set of paternal chromosomes and is characterized by a large cystic placenta and fetal loss early in gestation. In one study, first-trimester median levels were 8.7 MoM for free beta hCG and 0.74 MoM for PAPP-A [39].

If a pregnancy affected by triploidy continues to the second trimester, screening results for cases of Type I triploidy (diandric) will often indicate a high risk of Down syndrome because of low uE3 and elevated hCG and InhA concentrations [40,41]. AFP levels in triploidy are not predictable; they may be high, low, or unremarkable.

Type II – Type II triploidy (digynic) originates from an extra set of maternal chromosomes and is characterized by a small fetus, small placenta, and intrauterine survival late into pregnancy. First-trimester marker median levels were extremely low: 0.16 MoM for free beta hCG and 0.06 MoM for PAPP-A [39]. In these digynic triploidy cases, the risk algorithms for trisomy 21, 18, and 13 in combination resulted in detection of 84 percent of cases at a 3.1 percent false-positive rate. Maternal serum levels of uE3 are extremely low (usually less than 20 percent of normal values) in Type II triploidy (digynic) and free beta hCG and InhA are also reduced [40,41]. AFP levels are not predictable. These cases may be identified by second-trimester trisomy 18 screening protocols.

Smith-Lemli-Opitz syndrome — Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive defect in a cholesterol biosynthetic enzyme, C7-reductase, that leads to intellectual disability, poor growth, and a variety of phenotypic abnormalities (variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly) [42]. Although the gene alterations responsible for SLOS are relatively common and suggest a high prevalence, the second-trimester and birth prevalence of SLOS is quite low (1:80,000 or lower). This is likely due to a high fetal loss rate in early pregnancy. In one study, the carrier frequency was found to be between 1 in 43 (Ashkenazi Jews) and 1 in 54 (Northern Europeans), but the low birth incidence suggests fetal loss rates of 42 to 88 percent [43]. The second-trimester marker pattern associated with SLOS is a very low uE3 level (median 0.21 MoM) [44] because the steroid precursors required for estriol synthesis are deficient in the fetus (figure 5), with only modest reductions in AFP (median 0.72 MoM) and hCG (median 0.76 MoM).

Maternal serum screening for SLOS with AFP, uE3, and hCG is expected to be very efficient, with a detection rate of approximately 60 percent at a 0.3 percent false-positive rate [45]. A trial that attempted to identify pregnancies with SLOS in conjunction with prenatal screening for Down syndrome included over 1 million pregnant women and reported an 83 percent detection rate at a 0.3 percent false-positive rate. The estimated prevalence of SLOS was 1 in 100,000 White women [46]. Although the prevalence of SLOS was very low, women who were screen positive for SLOS were at very high risk for other major fetal abnormalities, including a variety of aneuploidies and anatomic abnormalities [47]. For this reason, some laboratories continue to offer an estimate of risk for SLOS.

Prenatal diagnosis of SLOS can be performed by amniocentesis with amniotic fluid measurement of cholesterol and its precursors, 7- and 8-dehydrocholesterol [48]. Prenatal diagnosis by molecular and mutation analyses is under investigation [49,50]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Smith-Lemli-Opitz syndrome' and "Causes of differences of sex development", section on 'Smith-Lemli-Opitz syndrome'.)

BLOOD SAMPLE PREPARATION AND TESTING — The levels of first- and second-trimester Down syndrome screening markers can be measured reliably when the blood sample is centrifuged within an hour and the serum is kept refrigerated and received by the testing laboratory within a week of being drawn [51].

Each of the serum markers used in prenatal screening is measured using immunoassay technology, most often by automated methods.

REPORTING RESULTS

Units — Marker values are initially measured as standardized mass units. For the five maternal serum markers used in Down syndrome screening, the units most commonly used in the United States are:

Alpha-fetoprotein (AFP) – ng/mL or IU/mL

Unconjugated estriol (uE3) – ng/mL

Total/intact human chorionic gonadotropin (hCG) – mIU/mL or IU/mL

Free beta hCG – ng/mL

Inhibin A (InhA) – pg/mL

Pregnancy-associated plasma protein A (PAPP-A) – ng/mL or mIU/mL

Multiples of the median — Since the serum levels of each marker change by gestational age, the mass values for each are converted to multiples of the median (MoM) [52]. This process of normalization requires that each screening laboratory develop sufficient data to generate reliable gestational age-specific medians, usually gestational day-specific. Medians should be generated by testing fresh serum samples from women with singleton pregnancies between 15+0 and 22+6 gestational weeks for second-trimester markers and between 10+0 or 11+0 weeks to 13+6 weeks for first-trimester markers.

A specific woman's individual result divided by the median appropriate for the estimated gestational age results in a set of MoM levels for the markers measured. This eliminates the effects of proportional assay differences and variation due to gestational age. As an example, an AFP mass value of 25 IU/mL measured at 15+0 weeks of gestation might result in a normalized value of 1.0 MoM (assuming the regressed median for AFP in the population at 15+0 weeks is 25 IU/mL). An AFP mass value twice as high (50 IU/mL) measured at 20+0 weeks might also result in a MoM of 1.0 (assuming the regressed median for AFP in the population at 20+0 weeks is 50 IU/mL). Thus, the AFP levels measured at these two different gestational ages are comparable once they have been normalized for gestational age. This conversion also accounts for differences between laboratories (or assays). For example, in Laboratory A, the regressed median at 16+0 weeks may be 32 IU/mL and the woman's result is 16 IU/mL, resulting in a MoM of 0.5. This same woman's sample measured in Laboratory B might be 20 IU/mL (25 percent higher), but the corresponding median AFP in this laboratory would also be 25 percent higher at 40 IU/mL, resulting in the same MoM of 0.5.

Conversion to MoMs also provides a relatively simple way to compare an individual with the entire population being screened. By definition, the central value in unaffected singleton pregnancy is 1.0 MoM; thus, 2.0 MoM indicates that the woman is at twice the central value, while 0.50 MoM indicates that the woman is at one-half the central value. Since the distribution is Gaussian only after a logarithmic transformation, equal numbers/proportions of women would be expected to have values below 0.5 MoM and above 2.0 MoM.

Prior to clinical implementation of any screening marker, the distribution of its levels in unaffected and affected pregnancies must be thoroughly described. Most laboratories cannot assess marker levels in an unbiased set of affected (Down syndrome) pregnancies because of limited access to sufficient numbers of such samples. As a result, they must use data reported in the scientific literature [7,53,54] or from commercial providers of software used in prenatal screening. However, each screening laboratory can and should examine the distribution of MoM levels in its screened population, almost all of it derived from unaffected pregnancies (known twins could be removed). The parameters of the population distribution (the center of the distribution or antilog of the mean of log MoM values and the breadth of the distribution or standard deviation of the log MoM values after appropriate trimming of outliers) should be consistent with published parameters of such distributions. It would not be necessary to identify and remove the few pregnancies affected by Down syndrome or open neural tube defects to obtain reliable estimates for the unaffected population parameters for each marker.

Assessment of patient-specific risk — Prenatal serum screening results are evaluated using a patient-specific risk-based assessment. A woman's a priori risk is determined based on her chronological age at the estimated date of delivery and history of a previous Down syndrome pregnancy. This baseline risk is then increased (or decreased) by a factor called the "likelihood ratio" (LR). The LR is determined by comparing each of her serum marker MoM values with the reference distributions (figure 4 and figure 3) after accounting for the degree of independence between each pair of markers (measured as an R value after log transformation of the marker MoMs). The final reported risk is her calculated patient-specific risk of having a fetus affected by Down syndrome in that pregnancy. These risks have been validated as being correct, on average [55]. For example, among a group of 1000 pregnancies having an average risk of 1 in 100, 10 affected pregnancies were identified.

The typical cutoff for a screen-positive result and recommendation to offer diagnostic testing was, by convention, the risk of Down syndrome pregnancy in a 35-year-old woman (1:350 at term, 1:270 second trimester). However, as tests improve in sensitivity and specificity, higher risk cutoffs (eg, 1:100 second trimester) are being used. This allows for higher performance tests, like the integrated test, to obtain lowered false-positive rates while still providing high detection.

The goal is to optimize the trade-off between higher detection rates and lower false-positive rates. However, overall test performance is also dependent on the prevalence of the disorder in the population being screened. For example, testing the oldest 5 percent of pregnant women in the general population identifies 30 percent of all Down syndrome pregnancies. The screen-positive group will have a sixfold higher risk (30/5) than the general population. Since the birth prevalence of Down syndrome is approximately 1 in 500, these screen positives will have a group risk of 1 in 83 (ie, 1 in 500/6). This result, expressed as a percentage (1.2 percent), is the positive predictive value. A better screening test, such as one that identifies 90 percent of Down syndrome pregnancies with only 2 percent false-positive rate (eg, the Integrated screen), will yield a smaller screen-positive group with a 45-fold higher risk (90/2). Thus, screen positives in this group will, on average, have a risk of 1 in 11 (ie, 1 in 500/45). Of course, an individual woman would be interested in her specific risk, not the group risk.

FACTORS TO CONSIDER FOR TEST PERFORMANCE AND INTERPRETATION

Selection of the risk cutoff — As described above, each patient is given the specific numerical risk of Down syndrome (eg, 1 in 100) calculated based on the patient's age, family history, and screening test results. (See 'Assessment of patient-specific risk' above.)

The risk cutoff chosen for test interpretation (ie, identifying patients as screen negative or screen positive) determines the detection and false-positive rates for Down syndrome (table 3). For a given test, as the risk cutoff becomes higher (eg, 1:100 versus 1:250), fewer women are screen positive and fewer affected pregnancies will be identified. However, the positive predictive value (PPV) will increase. If less stringent risk cutoffs are chosen, a greater number of affected pregnancies will be identified, but there will be more false-positive tests and the PPV will decrease. This would lead to a larger number of couples experiencing parental anxiety and having to consider costly and potentially risky diagnostic procedures. Thus, there is always a trade-off between a higher detection and a tolerable false-positive rate.

Term risk versus first-trimester versus second-trimester risk — The risk of Down syndrome is stated as either the risk of giving birth to an affected baby (term risk), the risk of carrying an affected fetus in the second trimester (second-trimester risk), or the risk of carrying an affected fetus in the first trimester (first-trimester risk).

Term risk is lower than second-trimester risk at all maternal ages due to loss of affected fetuses in the late second and the third trimesters (table 4). Looked at in another way, intrauterine demise occurs in more than one-third of Down syndrome fetuses between 12 weeks and term and in 20 to 25 percent between 16 weeks and term [56,57]. Thus, a second-trimester risk of Down syndrome of 1 in 190 is equivalent to a term risk of 1 in 250. First-trimester risks are even higher than second-trimester risks.

Term risk can be interpreted as the risk of having a live affected birth, while a first- or second-trimester risk indicates the likelihood of identifying an affected pregnancy if diagnostic fetal testing is undertaken at that time. Laboratories should clearly state whether they are providing first-trimester, second-trimester, or term risks for Down syndrome in all of their patient reports and use one of these conventions consistently. Approximately three-quarters of screening programs in the United States report second-trimester risk. Programs that rely on first-trimester combined screening often report first-trimester risk. There is no advantage of reporting one type of risk over another, but it is essential to clearly state which is being used.

Effect of maternal age — Each woman's initial risk at screening is based upon her age-related risk for having a child with Down syndrome (table 4). Since older women start at higher risk, they are more often screen positive than their younger counterparts. This also leads to a higher Down syndrome detection rate in older women. However, in the largest study to date, the risk of a Down syndrome birth did not increase further after the age of 45 years, likely because of higher miscarriage rates in this age group [58].

Prior pregnancy history — Geneticists generally tell patients the recurrence risk of aneuploidy is at least 1 percent if a woman has had a prior Down syndrome pregnancy (non-inherited type). This figure is based on data published in the 1980s [59]. Subsequent analyses of North American data [60] and of previously published studies [61,62] have suggested that the overall incremental risk of recurrence is less than 1 percent and that the excess risk is higher for younger than for older women [60,63]. For example, data from the United Kingdom National Down Syndrome Cytogenetic Register clearly show that the recurrence risk for younger women (under 27 years old) is approximately 4 or 5 per 1000 births, and that the risk drops to 2 or 3 per 1000 in women in their early 30s [63]. By ages 36 to 42, the excess risk is only 1 per 1000 births, and by age 44, there is no excess risk of recurrence.

The risk of recurrence of inherited (ie, translocation) Down syndrome is usually much higher, but depends upon the specific translocation. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)'.)

Method of gestational age determination — Error in the estimation of gestational age is the most common reason for a false-positive result. If the true gestational age is earlier than reported, alpha-fetoprotein (AFP), unconjugated estriol (uE3), and pregnancy-associated plasma protein A (PAPP-A) multiples of the median (MoM) values will be falsely interpreted as low and human chorionic gonadotropin (hCG) will be falsely interpreted as elevated, a pattern replicating that seen in Down syndrome pregnancy (figure 6).

A screen-positive result initially based on last menstrual period (LMP) should be adjusted if a subsequent ultrasound estimation of gestational age is substantially different (eg, 10 days or more) and the estimated date of delivery is revised (table 5). Adjustment of screen-positive reports based on a small ultrasound/LMP discrepancy may provide false reassurance and should be avoided.

Sonographic measurement of biparietal diameter (second trimester) or crown rump length (first trimester) are the most appropriate methods of gestational age assessment for the screening population and are reliable even in pregnancies with Down syndrome. Ultrasound dating results in a narrower distribution of serum marker values in both affected and unaffected pregnancies, leading to improved performance. In one study, at a fixed 5 percent false-positive rate, the Down syndrome detection rate using the quadruple test increased by 9 percentage points when ultrasound rather than LMP dating was used [8]. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

Adjustments to the multiples of the median — A variety of factors can affect serum marker concentrations. While the impact on overall screening performance is improved only slightly by adjusting for each of these factors, adjustment is recommended because each will improve the estimate of an individual's risk [54,64] and overall screening performance. These variables include:

Maternal weight

Maternal race

Multiple gestation

Previous false-positive result

Conception by in vitro fertilization

Smoking

Diabetes mellitus

Maternal weight — Serum marker concentrations decrease as maternal body weight increases because the additional blood volume dilutes the amount of marker that is present. Each marker should be corrected for maternal body weight, measured ideally on the day the sample was drawn [65-67]. Even though the overall impact is small, weight adjustment can have a substantial effect for individual results, especially for very light or obese women. Large differences can also occur when assigning trisomy 18 risks due to its typical marker pattern.

Maternal race — Concentrations of maternal serum AFP, PAPP-A, total hCG, and free beta hCG are increased and inhibin A (InhA) levels are decreased in Black versus White women. In Black women, the AFP is commonly adjusted for race because it is the sole marker used in screening for neural tube defects. Differences in marker levels for other races have been reported [68-70], but adjustments may be difficult to implement because of limitations in patient self-reporting of race/ethnicity or insufficient data regarding the effect size. Laboratories that provide services to many women of other races may be able to determine their median data for these women. If not, adjustment of screening markers for race provides only relatively small changes in Down syndrome risk.

Multiple gestation — In first-trimester combined testing, each fetus receives their own NT measurement, so it is possible to assign a separate risk to each fetus [71]. For serum tests, serum concentrations of each marker are approximately twice as high in twin versus singleton pregnancies, with the exception of uE3, which is only 1.6 or 1.7 times higher. Since the individual contribution of each twin to the maternal serum marker levels cannot be determined, prenatal screening in dizygotic twin pregnancies is not as efficient as in singleton pregnancies. Screening monozygotic twins is likely to perform as well as in singleton pregnancies. With correction of MoM values in twin gestations, a screening result can be generated that assumes each fetus contributes equally to the marker levels. However, a precise risk estimate cannot be given because of this assumption and because the actual marker levels in twin pregnancies with a Down syndrome fetus or fetuses are not known with certainty.

Serum screening is not generally considered interpretable in higher order pregnancies (eg, triplets, quadruplets). In such cases, ultrasound evaluation of NT may be a useful screening alternative. (See "Sonographic findings associated with fetal aneuploidy" and "Triplet pregnancy".)

Previous false-positive result — Women who have a false-positive result in one pregnancy are at increased risk of a false-positive result in a subsequent pregnancy [72,73]. In a study of women who had a false-positive result in their initial pregnancy, their false-positive rate in the subsequent pregnancy was 20 percent (46/229) versus only 6.6 percent in the overall population of tested women [72]. This is caused by the correlation of serum markers between pregnancies (ie, a woman with a normal pregnancy but a higher than expected hCG MoM would be expected to have a somewhat higher hCG MoM in her next normal pregnancy). An algorithm has been developed that will minimize the problem of recurrent false-positive results by adjusting the serum markers in all women according to their values in the previous unaffected pregnancy [73]. This adjustment requires laboratories to match current patient results with their previous pregnancy results, which some may find difficult to accomplish.

IVF and other assisted reproduction techniques — Assisted reproduction techniques (ART) such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) can affect serum marker levels to mimic the pattern associated with Down syndrome: maternal hCG and InhA levels tend to be increased, uE3 and PAPP-A levels are decreased [74-76]. Without adjustment of these MoM values, the screen-positive rate for such pregnancies is approximately twice the expected rate [75,77,78]. Therefore, we recommend that clinicians inform the laboratory of IVF and ICSI conceived pregnancies so that the laboratory can adjust MoMs and thus reduce the need for follow-up invasive testing or secondary cell-free-DNA screening.

In a meta-analysis of 27 studies of NT measurement, free beta hCG, and PAPP-A concentrations in IVF/ICSI conceived pregnancies, the most pronounced effect was a decrease in serum levels of PAPP-A, which were reduced by 15 percent in IVF/ICSI pregnancies compared with spontaneously conceived pregnancies (relative risk [RR] 0.85, 95% CI 0.80-0.90) [76]. Free beta hCG was 9 percent higher in ICSI pregnancies (RR 1.09, 95% CI 1.03-1.16), but not increased with IVF alone (RR 1.03, 95% CI 0.94-1.12). Neither IVF nor ICSI resulted in changes in NT.

There are multiple forms of ART in addition to IVF and ICSI. A similar adjustment of free beta hCG and inhibin A levels may be required for pregnancies resulting from oocyte donation [75,79], ovulation induction, or intrauterine insemination [75,80]. Such adjustment is difficult to implement, mainly because of the complexities of accurately reporting these ART options to the screening laboratory. There are few reports on this issue so most, if not all, screening software programs only make adjustments for women who underwent IVF. However, as with race, adjustment of screening values for assisted reproductive technologies other than IVF will provide relatively small changes in risk.

One exception that can make a significant impact on risk calculation is the case of oocyte donation by a significantly younger woman for an older recipient mother [81]. In these cases, the a priori risk of the pregnancy is considered to be the age of the oocyte donor. The rationale for this practice is based on the concept that the risk of aneuploidy is derived from the gametes. This practice can lead to a substantially lower pregnancy-related screening risk than would otherwise occur were the mother's age used.

Cigarette smokers — Maternal cigarette smoking also appears to affect marker concentrations: AFP and InhA levels are higher and uE3, free beta hCG, and PAPP-A levels are lower in smokers than in nonsmokers [9,82-87]. Adjusting serum marker levels for smoking status, regardless of the number of cigarettes smoked per day, is becoming more common. It is especially important when using first-trimester markers and for trisomy 18 risk assessment, due to the pattern of all markers being reduced in such pregnancies [88]. Marker levels do not have to be adjusted in women who have recently quit smoking, perhaps upon learning of their pregnancy [89]. There appears to be little impact of smoking on the prevalence of Down syndrome once the maternal age of the woman is considered [90].

Diabetes mellitus — In the 1980s, second-trimester maternal serum levels of AFP were reported to be significantly decreased (by up to 20 percent) in women with pregestational (preexisting) diabetes requiring insulin treatment [91], and as a consequence, adjustment of AFP in women with diabetes was recommended and implemented in most screening laboratories. AFP values were similarly reduced (by approximately 10 percent) among women with type 1 and type 2 diabetes [92,93], regardless of management with insulin or oral antihyperglycemic agents.

More recently, adjustment of AFP in women with diabetes has been questioned on the basis that weight adjustment alone is sufficient to correct values or that the traditionally used 20 percent adjustment may be too much [93-97]. It has also been suggested that the decrease in AFP in diabetes is a function of glycemic control. A statistically significant inverse correlation between AFP and hemoglobin A1C has been shown in several studies [98-101]. Further investigation of this relationship is warranted. Currently, the decision to adjust and how much to adjust is left to the discretion of the screening software manufacturer and/or laboratory director.

Second-trimester levels of uE3 are modestly reduced (5 to 10 percent lower), while hCG and InhA levels are not significantly altered in women with pregestational diabetes [102,103].

The effect of diabetes on first-trimester serum markers is unclear. One report found decreased first-trimester PAPP-A and free beta hCG levels in women with diabetes [104], while another found that the marker levels were not significantly altered [82].

Other — Alterations in serum marker levels have also been noted in association with factors such as parity, fetal sex [32,105], and maternal systemic lupus erythematosus [106]. In these cases, the effect is small, the available data are insufficient to warrant adjustment, or the correction cannot be implemented easily.

Other factors, such as renal insufficiency/hemodialysis, adrenocorticotropic hormone insufficiency, and the use of various medications (eg, antiretroviral therapy), have also been associated with effects on maternal marker levels [107-115]. Further study is needed to confirm or exclude clinically significant associations.

PREDICTIVE VALUE FOR OTHER OUTCOMES — Abnormal maternal Down syndrome biochemical markers may also be predictive of adverse pregnancy outcomes (eg, fetal death, preeclampsia), but the predictive value is 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".)

SUMMARY AND RECOMMENDATIONS

Background – Screening markers in the late first and early second trimesters are used to estimate a pregnant woman's individualized risk of having a fetus with Down syndrome, thereby helping her to make an informed choice about whether to undergo invasive diagnostic testing. (See 'Introduction' above.)

Biochemical marker levels in affected pregnancies – Second-trimester levels of maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and first-trimester levels of pregnancy-associated plasma protein A (PAPP-A) are lower, on average, in pregnancies affected by Down syndrome than in unaffected pregnancies. Total/intact human chorionic gonadotropin (hCG), the free beta subunit of hCG (free beta hCG), and inhibin A (InhA) levels are higher, on average, in affected than unaffected pregnancies. (See 'Marker levels in selected syndromes' above.)

Select aneuploidies and genetic syndromes other than Down syndrome can also be detected by maternal marker screening (table 1). (See 'Marker levels in selected syndromes' above.)

Determination of patient-specific risk – Prenatal screening results are reported using a patient-specific risk assessment. A woman's a priori risk is determined based on her chronological age at delivery, gestational age, and history of previous Down syndrome pregnancy. This risk is then modified by comparing the woman's serum marker values against published expectations. The final result is the woman's patient-specific risk of having a fetus affected by Down syndrome in that pregnancy. (See 'Assessment of patient-specific risk' above.)

A number of factors (such as maternal weight and race) affect screening test interpretation and must be considered when calculating and interpreting results. (See 'Factors to consider for test performance and interpretation' 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 414 Version 37.0

References

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