During the last decades, many screening markers and methods for Down syndrome have been developed. Computational procedures for combined ultrasound and serum marker testing in early and mid pregnancy have been evaluated. Moreover, the strategy of deciding whether a pregnant woman needs to undergo a screening test or an invasive diagnostic test based on the age cut-off point has been challenged. The purpose of this paper is to 1. present and evaluate the evidence that the application of ultrasound as well as serum markers in screening for selective aneuploidy during pregnancy is the most available. 2. provide practical recommendations for implementing Down syndrome screening in practice.
BACKGROUND: Mothers aged ≥35 years at delivery have long been considered to be at high risk for carrying a fetus with Down syndrome. In these pregnancies we offer genetic counseling and amniocentesis or chorionic villus sampling biopsy (CVS).Serum biochemical screening for Down syndrome in pregnant women aged <35 years was reported in 1984 and showed an association between low maternal blood levels of alpha-fetoprotein (AFP) and Down syndrome.In the 1990s, the combination of serum chorionic gonadotropin (hCG), free estriol, and AFP improved the detection rate of Down syndrome as well as trisomy 18. The median mean serum AFP level (MoM) in Down syndrome pregnancies decreased to 0.74 in whole-ploidy pregnancies. overall hCG levels were elevated in affected pregnancies with a mean MoM of 0.75, while the mean MoM for free estriol decreased to 0.75. however, the combined use of all three serologic markers (triplet test) to re-evaluate maternal age-related Down's syndrome, the detection rate of Down syndrome is approximately 70%, which corresponds to approximately one positive screening case for an average of 5% of pregnancies. In a typical fetus with trisomy 18, levels of all three serologic markers are reduced. The triplet test combined with inhibin A (quadruplet test) can increase the detection rate of Down syndrome to about 80%. The median value of inhibin A in Down syndrome pregnancies increases to 1.77 MoM, but inhibin A is not used to estimate the risk of developing trisomy 18. Increasingly, screening of all pregnant women by biochemical markers, ultrasonography, or a combination of both is being performed to provide a more accurate method of assessing the risk of occurrence of Down syndrome in individuals. Its high sensitivity or high detection rate (defined as the percentage of Down's syndrome identified as a positive result) and low false positive rate has led to the increasing use of screening tests and the decreasing clinical use of amniocentesis. In the early and mid-1990s, studies found a strong correlation between the size of fluid accumulation in the subcutaneous tissue of the dorsal neck, also known as the thickness of the fetal nuchal translucency, and the risk of trisomy 21 in early pregnancy. It is now generally accepted that nuchal translucency is an early manifestation of many chromosomal and genetic abnormalities and structural malformations in the fetus. However, early studies showed variability in the application of nuchal translucency measurements in the detection rate of Down's syndrome, which limited its practical use in clinical practice. Today, guidelines for the measurement of the nuchal translucency system have been standardized, and recommendations include specialized training in standardized measurement methods and audit of examination quality in screening programs for nuchal translucency measurement. Early in pregnancy, another ultrasound indication such as nasal bone echogenicity and tricuspid regurgitation is considered a potential screening test for Down's syndrome, but its clinical validity is still questionable. A major breakthrough in screening for Down's syndrome in early pregnancy has been achieved in large studies conducted in the United States and the United Kingdom, which demonstrated the possibility of combining two serologic tests for free beta-hCG and pregnancy-associated protein (PAPP-A) in early pregnancy to screen for Down's syndrome when the nuchal translucency value reaches the MoM value. The mean value of free β-hCG increases to 1.98 MoM in early gestation in patients carrying a fetus with Down syndrome, and the mean value of PAPP-A, an hCG-like glycoprotein secreted by trophoblast cells, decreases to almost 0.43 MoM. The test for AFP, free estriol, and inhibin A is only valid for screening in the second trimester. Table 1 shows the evaluation of several screening methods for Down's syndrome in early and midtrimester. Not all screening strategies including nuchal translucency measurements are valid in all regions, as nuchal translucency measurements require specialized training to obtain and may not be successfully completed in a given pregnancy. Table 1 Down syndrome screening tests and detection rates (5% positive screening rate)
Screening test detection rate (%)
Early gestation NT measurement 64-70 NT measurement, PAPP-A, free or total
Midtrimester Triple screen (MSAFP, hCG, free estriol) 69 Quadruple screen (MSAFP, HCG, free estriol, inhibin A)
Early plus midtrimester Combined screening (NT, PAPP-A, quadruple screening)94-96 Serum combined screening (PAPP-A, quadruple screening)85-88 Stepwise progressive testing96 Early pregnancy test results: Positive: proposed diagnostic test Negative: proposed midtrimester test Final evaluation: sequential screening for risk assessment combining early and midtrimester screening results88-94 Pregnancy Early test results: positive: diagnostic test proposed negative: no further testing necessary intermediate status: mid-pregnancy test proposed final evaluation: risk assessment in combination with early and mid-pregnancy screening results
Abbreviation: MSAFP: maternal serum alpha-fetoprotein
Clinical considerations and recommendations Is aneuploidy screening recommended for all pregnant women?
Screening for aneuploidy before 20 weeks of gestation is certainly ideal for all pregnant women regardless of age. It is impractical for patients to choose from such a wide range of possible screening methods. Before deciding which method or methods to use for screening, review the screening methods documented in this article and determine which tests can be performed at your site before deciding which method or methods are most appropriate for your patient. For pregnant women who do not have their initial prenatal visit until mid-pregnancy, screening tests are limited to the quadruple screening test as well as ultrasonography. For pregnant women who seek prenatal testing early in their pregnancy, strategies that should be performed include screening tests in both early and mid-trimester. Regardless of the method you decide to use to screen your pregnant women, they should be provided with information about the detection rate, false-positive rate, benefits, drawbacks, and limitations of the screening protocol, as well as the risks and benefits of the diagnostic process, so that they can make an informed choice. Pregnant women may decline screening for Down syndrome because they do not use this information when deciding whether to use a diagnostic test method, or because they wish to avoid the chance of a false-positive screening result. The choice of screening method depends on many factors, including the week of gestation of the initial delivery, the number of fetuses, previous obstetric history, family history, feasibility of nuchal translucency thickness measurement, test sensitivity and limitations, risks of invasive diagnostic procedures, desire for earlier test results, and the option of earlier termination of pregnancy. Some patients, particularly pregnant women with a family history of chromosomal abnormalities, hereditary disorders, or congenital malformations, may benefit from more extensive communication with a geneticist or maternal-fetal medicine specialist.
Pros and cons of aneuploidy screening tests compared to diagnostic tests
Mothers of fetuses at high risk for Down syndrome, trisomy 18 or trisomy 13 need to be screened for aneuploidy. If her screening test is positive, further diagnostic testing such as CVS or amniocentesis is required, which improves the chances of detecting affected fetuses more than diagnostic testing in the unscreened population. In pregnant women who have been screened, there will be less need for invasive procedures to further determine if the fetus is aneuploid, and therefore the number of operation-related losses in normal fetuses is reduced. The main disadvantage of aneuploidy screening tests is that not all affected fetuses can be detected. Although effective methods are now available to obtain relatively high detection rates (sensitivity) at low screening positive rates, pregnant women should understand that screening provides an assessment of individual risk rather than a diagnosis and therefore cannot detect all chromosomal abnormalities. Physicians should counsel patients according to the specific detection rate and false positive rate of the single or multiple screening methods they are considering. The greatest benefit of invasive diagnostic testing compared to the sensitivity of screening tests is the ability to detect all autosomal trisomies. Diagnostic tests will also accurately detect sex chromosome aneuploidy, large deletions or duplications of chromosomes, and chromosome chimerism. In the unscreened population, more invasive testing will be performed for the identification of each affected fetus, which will result in more normal fetal losses compared to the screened population. In particular, those patients at increased risk for aneuploidy should be informed of the risks and then have the option of taking a diagnostic test without first applying a screening test.
How to understand the results of aneuploidy screening tests
Laboratory reports of screening test results usually give clinicians numerical information about the patient’s age-related risk and corrected risk based on age, serum test levels and, if available, nuchal translucency measurements. Communicating the numerical risk assessment to the pregnant woman after screening allows her and her spouse to weigh the risks and consequences of both having a child with special problems and invasive diagnostic tests. Because this decision involves personal values, it is more appropriate to provide the patient with a numerical risk assessment based on the screening test rather than using arbitrary cutoffs for positive or negative screening results. It is often useful to compare the numerical risk based on the screening test with the pre-screening general population risk and age-related risk. Screening test results may be reported as positive or negative based on a fixed cut-off value. Fixed cut-off values are valuable in clinical studies because they provide a benchmark for sensitivity (detection rate) and patient acceptability and false-positive rate comparisons across study groups or across studies. The fixed cut-off values, usually derived in comparison to the risk for women of a specific age, have been artificially determined and the application of fixed cut-off values seems to provide an appropriate balance with the pregnancy loss due to invasive diagnostic tests. Fixed screening cut-off values are also useful in the development of public policy when the benefits, risks, and funding in the population are fully considered. Is measuring the nuchal translucency alone in early pregnancy a sensitive screening test for aneuploidy? Although measurement of the nuchal translucency alone has a relatively high detection rate for Down syndrome, recent studies in the United States and the United Kingdom have demonstrated that nuchal translucency measurement combined with biochemical marker screening improves Down syndrome detection by reducing the false positive rate. Cervical nuchal translucency measurement may be beneficial in the evaluation of multiple pregnancies where serologic screening is inaccurate (twin pregnancies) or not feasible (three or more pregnancies) compared to singleton pregnancies. A standardized method of measuring the nuchal translucency layer yields higher detection rates for Down syndrome, trisomy 18, and Turner syndrome. Although measurement of the nuchal translucency layer between 10+4 and 13+6 weeks is valid, the optimal period is 12-13 weeks of gestation. Training is required to learn the standardized technique of nuchal translucency measurement and specific guidelines must be followed to maintain its detection rate. In a randomized population, the positive rate of Down syndrome screening was 5%, where the detection rate was 72% (10). In addition to this, the detection rate was 74.8% for trisomy 18, 72% for trisomy 13, 87% for Na syndrome, 59% for chromosome triplication, and 55% for other significant chromosomal defects. A review analysis of the past 10 years of prospective studies on early pregnancy screening tests has been performed, which included 871 cases of Down syndrome, with a detection rate of 76.8% and a positive screening rate of 4.2% when cervical hyaline layer measurement screening alone was applied (11). Approximately one third of fetuses with increased nuchal translucency measurements in early gestation have chromosomal defects, and Down syndrome accounts for approximately 50% of these chromosomal abnormalities (10). , , and
What is the sensitivity of early pregnancy screening?
Several large multicenter trials have confirmed the effectiveness of screening for Down’s syndrome in early gestation with the combination of serologic markers (PAPP-A, free or total β-hCG,) and maternal age (Table 2). This approach is known as combined screening. For pregnant women <35 years of age at delivery, the detection rate of Down syndrome in early gestation with combined screening is comparable to that of quadruple screening in mid-gestation. For pregnant women aged ≥35 years, the detection rate is about 90%, but the screening positive rate is higher (about 16-22%) (12,13). For pregnant women of all ages, the screening positivity rate was 2%, with a 90% detection rate for 18-trisomy (13).
Table 2. results of prospective studies of combined screening in early pregnancy Screening method Number of patients Number of Down syndrome cases Detection rate (%) BUN 8,216 61 79FASTER 33,557 84 83SURUSS 47,053 101 83OSCAR 15,030 82 90 Summary
FASTER: Maternal blood biochemical markers combined with fetal NT measurement FASTER: Risk assessment test in early and mid pregnancy SURUSS: Antenatal Down’s syndrome screening in early and mid pregnancy, serum and urine as well as ultrasound screening test OSCAR: One-stop screening for chromosomal abnormalities in early pregnancy combined with ultrasound and maternal serum biochemistry
What are the benefits of early pregnancy screening?
The benefit of early pregnancy screening is that information can be obtained earlier for pregnant women who come to the hospital for antenatal screening before 14 weeks of pregnancy. If she is found to be at high risk for fetal aneuploidy, she can be offered genetic counseling and, if available, CVS, or, alternatively, the patient can opt for amniocentesis in mid-pregnancy.
Can early and midtrimester screening tests be performed separately?
High detection rates for Down syndrome (94-98%) can be achieved by performing early and midterm screening tests during pregnancy and interpreting them individually; however, the cost is an increased rate of false positives and more unnecessary invasive procedures (11-17%) (12,14). For this reason, pregnant women who have undergone aneuploidy screening in early pregnancy do not need to undergo serologic screening in mid-pregnancy. However, for pregnant women who expect a high detection rate, they can undergo an integrated or sequential screening test, which combines the results of early and midtrimester screening tests.
What is integrated screening?
”Integration” means that the risk of a fetus with Down’s syndrome can be corrected for maternal age-related risk using markers from early and midterm screening (15), with final results only available after all early and midterm screening tests have been completed. The SURUSS (Serum, Urine and Ultrasound Screening Study) test yields similar results (16). Further refinement of the interpretation can lead to increased sensitivity but lower screening positivity rates. Integrated screening can also be accomplished using only serologic markers of early and mid-pregnancy without the need for a combined cervical hyaline layer assay. In the FASTER trial, the detection rate of integrated screening with serum markers was 85-8% (12). This screening method is ideal for pregnant women who do not enjoy screening with cervical hyaline layer measurements or whose measurements are unreliable. A recent prospective trial using integrated screening with serologic markers alone in a population with limited CVS testing showed that the majority of patients who participated in the survey accepted this screening protocol (17).
Pros and cons of integrating early and midtrimester screening for Down syndrome (combined analysis of early and midtrimester markers (integration), versus analysis of midtrimester results alone)
Integrated screening meets the best screening goals by providing the highest sensitivity as well as the lowest false-positive rate. The low false-positive rate leads to fewer invasive procedures, thereby reducing the loss of normal fetuses from invasive procedures (12,18). Although some patients value early screening, others are happy to wait a few weeks if it improves detection rates and reduces invasive procedures (19). For integrated screening, patients are concerned about the 3-4 week wait from start to finish of screening to produce final results, the anxiety associated with the wait, and the loss of CVS testing if the early pregnancy screening test is aneuploidy high risk (20). The departure of patients after the early series of screening tests is another potential disadvantage due to the time needed to wait for the results, resulting in the possibility that patients will not be able to complete the screening test at the midtrimester stage.
Is there a benefit to using sequential screening tests for Down’s syndrome?
Sequential screening has evolved because it eliminates some of the drawbacks of integrated screening. This strategy informs patients of the results of screening tests early in pregnancy. For those patients at high risk, an early diagnostic option is available, while those at low risk can continue to benefit from the high detection rate of additional mid-pregnancy screening tests. Two strategies are recommended: “staged sequential screening” and “discretionary sequential screening”. In the staged sequential screening model, if the early pregnancy screening test confirms that the pregnant woman is at high risk (risk of Down syndrome above a predetermined cut-off value), genetic counseling will be offered and invasive testing will be recommended. For pregnant women below the cut-off, a screening test is proposed in the middle of the pregnancy. Discretionary sequential screening has been recommended as a model, but the results of large clinical trials have not been formally published. The discretionary sequential screening model is based on the results of a screening test in early pregnancy to classify the risk of pregnancy as high, intermediate or low risk. High-risk pregnancies are screened with CVS, while low-risk pregnancies do not require further screening or testing. Only intermediate-risk pregnancies require mid-pregnancy screening. Therefore, only a small number of pregnant women continue to be screened at mid-pregnancy. Whether it is staged sequential screening or discretionary sequential screening, early diagnostic testing is required for patients who are determined to be at high risk by early gestational screening tests. The results of early and midtrimester screening are used to calculate the final risk of aneuploidy in low-risk pregnancies. The advantage of sequential screening is the high detection rate obtained by combining the results of early and mid-pregnancy screening, while its false-positive rate is only minimally increased. Theoretically, sequential screening, when appropriate, can maintain high detection rates and low false positive rates while reducing the number of patients who need to be screened at midtrimester.
Is a subsequent evaluation required after early pregnancy screening?
Pregnant women found to be at high risk for aneuploidy at early gestational screening should receive genetic counseling and diagnostic testing such as CVS or amniocentesis at mid-gestation. Pregnant women who are screened for aneuploidy only in early pregnancy or who have normal CVS results need to be screened for neural tube defects in mid-gestation. Screening for neural tube defects includes mid-gestation serum alpha-fetoprotein (AFP) screening or ultrasonography. Fetuses of pregnant women with nuchal translucency measurements ≥3.5 mm in early gestation should undergo targeted ultrasound and/or fetal heart ultrasound even if they have negative aneuploidy results and/or normal fetal chromosomal results because these fetuses are at significant risk for nonchromosomal abnormalities including congenital heart defects, abdominal wall defects, diaphragmatic hernia, and genetic syndromes (21-25). Patients with abnormal serum marker screening results or thickened fetal nuchal translucency measurements in early pregnancy may also be at high risk for adverse pregnancy outcomes such as spontaneous abortion, stillbirth, low birth weight, or preterm delivery before 24 weeks of gestation (26,27). At this time, there are no data to suggest whether fetal monitoring in late pregnancy would be helpful in the care of these pregnancies. The importance of ultrasound indicators in pregnant women with negative early gestational screening results who undergo ultrasound in the second trimester is unclear. Down syndrome has been associated with a wide variety of ultrasound findings. Major malformations such as heart defects should undergo further evaluation. More subtle findings (“soft indicators”) such as dilated renal pelvis alone, shortened femur or humerus, or strong echogenicity of the intestinal canal do not significantly increase the risk of Down’s syndrome. However, these findings should be considered in the context of the screening results, the patient’s age and medical history.
Are other ultrasound indicators in early pregnancy beneficial for Down syndrome screening?
Several other ultrasound indicators in early pregnancy including nasal bone echogenicity, tricuspid regurgitation, head-rump length, femur and humerus length, head and trunk volume, and umbilical cord diameter have been used as potential markers for the evaluation of aneuploidy screening in early pregnancy. Studies of high-risk groups in early pregnancy have found a high incidence of nasal bone echo defects on ultrasound detection in Down syndrome fetuses. Three European trials reported a detection rate of 66.7-80% for Down syndrome and a false positive rate of 0.2-1.4% (28-30). The value of ultrasound for nasal bone assessment in screening tests for Down’s syndrome in the general population is controversial. A study conducted in the United States in early pregnancy did not find a usefulness of this test (12). In addition, there are ethnic differences in areas where nasal bone defects are prevalent, with a 2.8% prevalence of nasal bone defects in Caucasian haploid fetuses compared to 6.8% in Asians and 10.4% in Afro-Caribbeans (31). This suggests that nasal bone assessment should be standardized (32) and that extensive training as well as quality control procedures should be developed before this technique is applied to the general population (33). A restrictive strategy of developing nasal bone assessment for a subset of women with high-risk pregnancies after a combined screening test in early pregnancy rather than for the entire population seems more feasible and is also under investigation.
What are the benefits and limitations of midtrimester ultrasonography as a screening tool for Down syndrome?
For screening for Down syndrome, especially for screening of low-risk individuals, ultrasound indicators such as strong echoes in the intestines, focal echoes in the heart, and dilated renal pelvis in mid-pregnancy individuals are hypersensitive and low specificity (34). Studies have confirmed that the highest detection rates are obtained with systematic combined ultrasound indices and gross abnormalities such as thickened dorsal neck folds or cardiac defects (35,36). Studies in high-risk populations have shown detection rates of about 50-75% in mid-pregnancy, but with a high rate of false positives (e.g., 100% detection rate for Down syndrome, with a false positive rate of 21.9%) (37). Studies have reported an 82-88% reduction in the risk of patients originally classified as high risk for Down syndrome (increased maternal age and abnormal serologic screening) if the absence of abnormal ultrasound markers is determined after careful scanning by skilled ultrasound examiners at a specialized screening center (38). Since the RADIUS (Routine Antenatal Diagnostic Ultrasound Imaging) test (39) and other tests show that even some major fetal anomalies are frequently missed on ultrasound, the drawbacks of relying on ultrasound alone for screening for Down syndrome should be carefully considered. The combination of midtrimester ultrasonography with biochemical markers is a relatively new approach and has been shown to be a feasible way to improve the performance of screening for Down syndrome compared to either ultrasonography alone or only midtrimester serum markers (40). A major limitation of screening with midtrimester ultrasound indicators is the lack of standardization of measurements and the definition of which are abnormal markers. This can cause variability in the representation of diagnostic reports across different study groups. A recent prospective study of large randomly selected cases in the United States applied specific criteria to define abnormal ultrasound indicators and confirmed a statistically significant increase in the frequency of various ultrasound markers in individuals with Down syndrome compared with normal cases in midtrimester (41,42). At this point, adjustment of risk assessment based on various markers of midtrimester ultrasound should be limited to centers with dedicated ultrasound specialists and medical centers engaged in clinical studies to develop standardized methods to assess markers. However, there is a significantly increased risk of fetal aneuploidy in pregnancies with congenital anomalies of major organs confirmed by midtrimester ultrasound, and these pregnancies require further genetic counseling as well as diagnostic testing.
What are the differences in aneuploidy screening in multiple pregnancies?
Serum screening tests are not sensitive in twins or triplets, partly because data on multiple pregnancies including aneuploid fetuses are scarce and experts need to judge the criteria for markers by mathematical models. In addition, substances from both normal and abnormal fetuses enter the maternal serum and are mixed together, thus masking abnormal levels in the affected fetus. In monochorionic twin pregnancies, 38% eventually develop a severe twin transfusion syndrome and the median nuchal translucency value is greater in these fetuses (43). Moreover, genetic counseling is further complicated by the fact that in cases where only one fetus is affected, the pregnant woman must consider a set of different management options. Early gestational nuchal translucency screening offers the possibility that whether further CVS or earlier elective reduction is worthwhile for some pregnant women. There is limited experience with triplet pregnancies, but some studies suggest that nuchal translucency measurements are practical. However, risk assessment for multiple pregnancies should be cautious at least until further findings are available, and patients at increased risk for aneuploidy should be counseled about diagnostic testing.
Should invasive diagnostic tests be used in all pregnant women for screening for aneuploidy?
All pregnant women, excluding age, should have the option of invasive testing. The decision to perform amniocentesis or CVS is based on a number of factors, including the risk of fetal chromosomal abnormalities, the risk of fetal loss due to the invasive procedure, and the consequences of having a child with abnormalities if a diagnostic test is not performed. Studies evaluating maternal preference have shown that pregnant women differ in weighing the potential consequences. The decision to perform an invasive test should take into account the wishes of these individuals, not just age, and the differences between screening and diagnostic tests should be communicated to all pregnant women. Therefore, maternal age alone of 35 years should no longer be used as a cut-off value to determine who performs screening tests versus who performs invasive tests.
With so many Down syndrome screening tests available, how do we choose?
Screening tests are chosen for their high detection rate, low false positive rate, and to give patients the options they need to consider a diagnosis. Ideally, patients should be screened for aneuploidy in early pregnancy and later combined with screening tests in early and mid-pregnancy (integrated or sequential). The choice of screening protocol will depend on the availability of trained professionals in the area for CVS and nuchal translucency measurements. If CVS is not available, integrated screening will be offered to pregnant women who come to the hospital in early gestation and mid-gestation screening will be offered to pregnant women who come to the hospital at 13+6 weeks in order to take advantage of the higher detection rate and the low false positive rate. If nuchal translucency measurements are not available or are not available for an individual woman, it is reasonable to propose integrated serologic screening for those who come early for delivery and midtrimester screening for those who come late for delivery. In areas where each screening strategy is feasible, it is reasonable to choose two screening methods in practice, such as sequential screening for pregnant women who have their first delivery before 14 weeks of gestation (because they are offered an early gestational risk assessment and a wait until mid-gestation including mid-gestation serologic screening results for corrected risk assessment) and mid-gestation serologic screening for pregnant women who have their first delivery after 13+6 weeks. In some cases, patients considering early rather than midtrimester termination may only want to undergo screening in early pregnancy.
Summary of Recommendations and Conclusions The following recommendations are based on good and consistent scientific evidence (Level A evidence).
In the general population, the application of nuchal translucency measurements and biochemical markers in early gestation is a valid screening test for Down syndrome. This screening protocol yields a higher detection rate of Down syndrome than maternal serum triple screening in mid-gestation and is comparable to quadruple screening, with the same false-positive rate. Measurement of the nuchal translucency alone in early pregnancy is less effective than the combined test (nuchal translucency measurement and biochemical marker testing). Pregnant women at high risk for aneuploidy detected by early gestational screening should be offered genetic counseling and the option of CVS testing or amniocentesis at mid-gestation. Specialized training, standardization, applicable ultrasound equipment, and continuous quality assessment are important in the assessment of risk for Down syndrome to be able to obtain optimal values for cervical hyaline layer measurements. This operation should be limited to medical centers that meet these criteria and to individuals. For pregnant women who opt for aneuploidy screening only in early gestation, screening for neural tube defects should be offered in mid-gestation.
The following recommendations are based on limited or inconsistent scientific evidence (Level B evidence).
Aneuploidy screening tests, as well as invasive diagnostic tests, are feasible for all pregnant women who participate in maternity testing before 20 weeks of gestation, regardless of age. Pregnant women should be counseled about the differences between screening tests and invasive diagnostic tests. Integrated screening in early and midtrimester has higher sensitivity and lower false-positive rates than screening in early pregnancy alone. The option of serum integration screening tests for pregnant women in those areas where nuchal translucency measurements are not available or accessible is beneficial. If an abnormal finding of a major congenital anomaly is confirmed by ultrasound in mid-pregnancy, the risk of aneuploidy is significantly increased, ensuring that further counseling is given and diagnostic testing is offered. Patients with fetal nuchal translucency measurements ≥3.5 mm in early gestation should receive targeted ultrasound and/or fetal cardiac ultrasound even if the aneuploidy screen is negative or the fetus is chromosomally normal. The application of early or midtrimester serologic testing in multiple pregnancies is not as accurate as in singleton pregnancies for risk assessment of Down’s syndrome. Early gestational nuchal translucency screening for Down syndrome is desirable in twin or triplet pregnancies, but the test is less sensitive relative to early gestational screening in singleton pregnancies.
The following recommendations are based on major consensus and expert opinion (level C evidence).
After early gestational screening, a subsequent midtrimester Down syndrome screening test is not necessary unless it is a component of integrated screening, stage-sequential or discretionary sequential screening. Fine ultrasound markers at midtrimester should be interpreted to the patient in the context of the patient’s age, medical history, and serum screening results.