INTRODUCTION — Early detection of pregnancies at high risk for trisomy 21 (Down syndrome) is the primary target of prenatal aneuploidy screening since this syndrome is the most common autosomal trisomy among live births (1 in 500 live births in the absence of termination). Because biochemical marker screening for Down syndrome involves measuring levels of the same markers that perform well for detecting trisomy 18 (Edwards syndrome, the second most common autosomal trisomy among live births), biochemical marker screening tests provide risk assessment for both of these chromosomal abnormalities. Some biochemical marker screening tests also provide risk assessment for trisomy 13 (Patau syndrome). Testing for cell-free DNA in maternal blood is another method for screening for Down syndrome and other aneuploidies (trisomies 18 and 13, sex chromosome aneuploidy).
This topic will provide an overview of issues relating to prenatal screening for and diagnosis of Down syndrome. The clinical and genetic characteristics, medical care, and prognosis for children with these syndromes are discussed separately:
●(See "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)'.)
●(See "Down syndrome: Clinical features and diagnosis".)
●(See "Down syndrome: Management".)
RATIONALE FOR SCREENING — Protocols for prenatal screening for Down syndrome have been implemented because:
●The prevalence of trisomy 21, 18, and 13 in live births in the United States in the absence of screening, diagnosis, and termination is approximately 1 in 500, 1 in 4000, and 1 in 7000, respectively. Corresponding rates in the late first trimester are 1 in 340, 1 in 1100, and 1 in 3500, respectively. Prevalence increases with advancing maternal age (table 1). There are no strong data to suggest that these rates vary by other epidemiological factors, but available data are limited by multiple confounders .
●The burden of disease for the affected individual and their family can be significant.
●Accurate prenatal diagnostic tests are readily available.
●Prenatal diagnosis gives parents options: an opportunity to plan for the birth of an affected child or pregnancy termination.
There is little high-quality information regarding the personal and family risks of screening. Adverse psychological effects include fear of discovering an affected fetus and anxiety about possible complications from diagnostic and therapeutic interventions, particularly procedure-related loss of an unaffected fetus. Most parents are anxious when they receive a screening test result indicating increased risk of aneuploidy, even though the result is not definitive/diagnostic. Anxiety is reduced when a diagnostic procedure shows an unaffected fetus , but patients who experience a false-positive screening result (screening showed an increased risk but the fetus was unaffected) are less likely to choose screening in a subsequent pregnancy .
Patients may also have anxiety about the possibility of a falsely reassuring result (false-negative, ie, screening did not detect an increased risk for an affected fetus).
COUNSELING — The key principle when counseling patients about prenatal screening for Down syndrome is to provide easily understood, complete information that allows them to make informed screening and diagnostic testing decisions based upon their values, beliefs, and the issues that they feel most important . It should be clear that any testing is voluntary.
Counseling should be nondirective (without pressure or coercion as to what the patient's decision should be) so that patients can balance the risks, limitations, and benefits of prenatal screening and diagnosis with the issues involved in raising a child with a chromosomal abnormality versus pregnancy termination or releasing the child for adoption.
Basic information on prenatal screening and diagnosis can be given to patients individually, in a group session, or with decision aids. In a randomized trial of the three approaches, couples were most satisfied with individual counseling, but those in group sessions showed a significantly greater increase in knowledge from pre- to postintervention questionnaires than those assigned to the other two approaches . Provision of written information targeted at the eighth grade reading level is desirable to ensure that patients have a clear understanding about all of the relevant issues.
Patients weigh information provided during counseling differently and come to individual decisions regarding whether to undergo prenatal screening and which test to have. Referral to a genetic counselor or a medical geneticist can be helpful for addressing patients' concerns and facilitate their decision-making process for diagnostic testing.
The following specific information related to prenatal screening is discussed, as appropriate, during pre- and postscreening visits [6,7].
●An explanation of the difference between a screening test and a diagnostic test.
●The option of diagnostic testing instead of screening.
●The option of no testing at all.
●Potential consequences of prenatal screening and diagnosis.
●A description of the performance of available screening and diagnostic tests, including limitations and detection rates for Down syndrome and other chromosomal abnormalities. (See 'Choice of screening test in singleton pregnancies' below.)
●The procedure-related risks of diagnostic testing. (See 'Diagnostic testing' below.)
●The potential to identify other chromosomal or subchromosomal disorders other than the common trisomies (eg, sex chromosome abnormalities, microdeletions, rare autosomal trisomies), depending on the screening test chosen.
●Information about the length of time necessary to obtain results from screening and diagnostic testing.
●The implications of having a child with Down syndrome.
•(See "Down syndrome: Clinical features and diagnosis".)
•(See "Down syndrome: Management".)
●The detection rate for common trisomies other than Down syndrome and the implications of having a child with one of these other abnormalities.
●Information about the option of continuing the pregnancy after diagnosis, including pregnancy and birth management, pediatric care, and resources and services available for families with an affected child.
●Information about the option of pregnancy termination (see "Overview of pregnancy termination") and adoption.
The occurrence of these discussions and the patient's decision to elect or to decline screening should be documented in her medical record.
A PRIORI RISK FOR DOWN SYNDROME
●A couple with no family or personal history of Down syndrome.
•Risk is based on maternal age at the expected date of delivery (table 1).
●A couple with a prior conception with Down syndrome caused by trisomy 21 (three separate chromosome 21s). Down syndrome in these cases is due to a sporadic event in the formation of egg or sperm cells termed nondisjunction. Nondisjunction accounts for 95 percent of cases of Down syndrome and occurs more frequently with advancing maternal age. Family members are not at increased risk since nondisjunction is not a heritable trait.
•When the mother is <35 years of age at the time of diagnosis of nondisjunction trisomy 21, the risk of recurrence is approximately 1 percent, which is higher than the maternal age-related risk of Down syndrome for this age group.
•When the mother is ≥35 years of age at the time of diagnosis of nondisjunction trisomy 21, the risk of recurrence is the maternal age-related risk (table 1).
●A couple with a prior conception or family member with Down syndrome caused by an unbalanced chromosomal rearrangement or translocation. Approximately 4 percent of cases of Down syndrome are due to a chromosomal rearrangement. The most common translocation that causes Down syndrome is a Robertsonian translocation involving chromosomes 14 and 21.
•The parents of an offspring with translocation Down syndrome should undergo peripheral blood chromosome analysis to evaluate for a balanced translocation. Translocations in offspring can be de novo or familial.
-When familial, the recurrence risk depends upon the sex of the carrier parent (10 to 15 percent for female carriers and 2 to 5 percent for male carriers).
-When de novo, the recurrence risk is based on the mother's age at expected delivery. If <35 years, the recurrence risk is approximately 1 percent. If ≥35 years, it is equal to the age-related risk (table 1) at expected date of delivery (EDD).
•First-degree relatives of a carrier parent should be offered peripheral blood chromosome analysis to see if they have inherited the rearrangement. If inherited, then their offspring would be at risk of having an unbalanced translocation (10 to 15 percent for female carriers and 2 to 5 percent for male carriers).
●A couple with a prior conception or family member with mosaic Down syndrome. A mosaic individual has more than one type of cell line (eg, 46XX/47XX+21). Mosaicism typically occurs as a post-zygotic error in mitotic cell division, and thus is not inherited. Family members are not at increased risk.
•The risk of recurrence is the maternal age-related risk (table 1).
CANDIDATES FOR PRENATAL SCREENING — The American College of Obstetricians and Gynecologists (ACOG) recommends that all pregnant individuals should be offered aneuploidy screening in early pregnancy . ACOG also states that all pregnant individuals should have the primary option of invasive diagnostic testing, regardless of maternal age.
CANDIDATES FOR DIAGNOSTIC TESTING — A diagnostic test is a reasonable choice for pregnant individuals of any age at high risk of having an offspring with Down syndrome or other aneuploidies, such as pregnant individuals with:
●A positive screening test for one of the common trisomies or other identified chromosomal abnormalities.
●A previous pregnancy complicated by fetal trisomy.
●At least one major or two minor fetal structural anomalies in the current pregnancy.
●A chromosomal translocation, inversion, or aneuploidy, or a partner with one of these abnormalities.
Diagnostic testing is also a reasonable choice for pregnant individuals who are not at high risk but have:
●A desire to have the most reliable information about the fetal karyotype.
●A desire to have comprehensive genetic analysis that will detect both autosomal and sex chromosome aneuploidy and pathologic copy number variants.
CHOICE OF SCREENING TEST IN SINGLETON PREGNANCIES — Choosing the most appropriate screening test can be confusing because multiple options are available (table 2). A single screening test should be chosen; multiple screening tests should not be performed simultaneously .
Serum biochemical marker-based tests — Assessment of maternal serum levels of specific biochemical markers associated with Down syndrome, with or without assessment of specific ultrasound markers, remains a widely used approach for screening. A 2020 survey of US laboratories found that over 1.3 million pregnancies were screened using biochemical markers . Although this represents an estimated 62 percent reduction in serum screening compared with a similar 2012 report , it still represents about one-third of US pregnancies. Biochemical marker screening may also provide information regarding other less common disorders (table 3).
Serum biochemical marker screening test options for Down syndrome are described below and comparative performance is shown in the table (table 4). In general, multiple marker tests with first-trimester ultrasound measurement of nuchal translucency (NT) (figure 1) perform better than tests with fewer markers, tests with multiple markers without ultrasound , or ultrasound examination alone . In 2020, first-trimester screens, second-trimester screens, and screening tests utilizing results in both trimesters accounted for 36, 48, and 16 percent of US serum screening tests, respectively .
First-trimester combined test — The combined test includes both sonographic determination of NT and determination of biochemical markers associated with aneuploidy: pregnancy-associated plasma protein A (PAPP-A) and free-beta or total hCG. In most patients, both ultrasound and biochemical marker screening are performed at 11+0 to 13+6 weeks of gestation. However, some protocols allow for earlier collection of the serum sample (beginning at 9+0 weeks) with the ultrasound performed later (10+3 to 13+6 weeks). If the combined test is offered, chorionic villus sampling (CVS) should be available for definitive prenatal diagnosis. Waiting several weeks after a screen-positive combined test result to have an amniocentesis at 15 weeks of gestation or later should be avoided. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)
●Best candidates – For patients in whom early diagnosis is the priority, the combined test is the best available biochemical marker-based screening test for Down syndrome. Since it does not include measurement of second trimester alpha-fetoprotein (AFP), maternal serum AFP or sonographic screening for open fetal neural tube defects should be offered in the second trimester. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Screening tests'.)
Second-trimester quadruple test — The quadruple test measures the level of the biochemical markers AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and dimeric inhibin A (DIA) in maternal serum. Maternal serum AFP and uE3 levels are, on average, reduced by 25 to 30 percent in pregnancies affected by Down syndrome [13-17], and hCG and DIA levels are, on average, twice as high as those in unaffected pregnancies [18-21].
The quadruple test is ideally performed at 15+0 to 18+6 weeks of gestation but can be done as late as 22+6 weeks. The quadruple test still appeared to be the most common Down syndrome screening test performed in the United States in 2020 (accounting for 48 percent of all serum screening nationwide).
●Best candidates – For patients who first present for prenatal care in the second trimester, the quadruple test is the best available biochemical marker-based screening test for Down syndrome. Since it involves measurement of AFP, it also serves as a screening test for open neural tube defects. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Alpha-fetoprotein'.)
An elevated trisomy 18 risk, when present, is also reported (table 3). The quadruple marker test can also indicate an elevated risk for Smith-Lemli-Opitz syndrome (SLOS) and other serious disorders [22-24], although very few programs report this risk. Trisomy 13 is not detected by the quadruple test. (See "Laboratory issues related to maternal serum screening for Down syndrome", section on 'Multiples of the median' and "Laboratory issues related to maternal serum screening for Down syndrome", section on 'Smith-Lemli-Opitz syndrome'.)
Tests integrated across the first and second trimesters — Integrated screening tests measure biochemical markers of Down syndrome in both the first and second trimesters and may or may not include NT measurements. Since the second-trimester portion of the integrated test includes measurement of maternal serum AFP levels, these tests also screen for open neural tube defects. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Integrated tests'.)
There are three types of integrated test:
●The full integrated test includes serum PAPP-A at 10+0 to 13+0 weeks and sonographic NT at 10+3 to 13+6 weeks as the first step. These results are then integrated with results of the quadruple test performed on a second serum sample collected ideally at 15+0 to 18+6 weeks (but can be done as late as 22+6 weeks) to determine the risk of trisomy 21. (See 'Second-trimester quadruple test' above.)
•Best candidates – For patients who prioritize a high detection rate over first-trimester diagnosis, the full integrated test is the best biochemical marker-based screening test. When similar detection rates for Down syndrome are set, the full integrated test has a much lower false-positive rate than the combined test, the quadruple test, or the serum integrated test (table 4).
●The serum integrated test differs from the full integrated test by not including ultrasound measurement of NT.
•Best candidates – For patients in areas where expertise and accreditation in measurement of NT are not available, this test provides an option for high detection of Down syndrome with a lower false-positive rate than the quadruple screen. For an 85 percent detection rate, the false-positive rates for the serum integrated and quadruple tests are approximately 4 and 7 percent, respectively .
●Stepwise sequential testing is a modified version of the full integrated test that provides risk estimates after the first step . In most protocols, the sequential screening process involves performing the first-trimester portion of the full integrated test, reporting risks of Down syndrome to the patient, and offering CVS to patients whose results place them at very high risk of an affected fetus (eg, ≥1 in 50). Patients whose screen does not place them at very high risk go on to complete the second-trimester portion of the test.
The advantage of this approach is that patients at highest risk benefit from early detection of affected fetuses while those at lower risk benefit from the high detection rate and low false-positive rates gained by adding the second-trimester screening markers.
Cell free DNA — A screening test utilizing cell-free DNA (cfDNA) in maternal blood is also a reasonable option for screening and has become more common over time. The methods used and the disorders that can be identified vary widely. All screen for the common autosomal trisomies (21, 18, 13). Many also offer screening for fetal sex and sex chromosome abnormalities such as 45X, 47XXY, 47XYY and 47XXX. Some whole-genome methods screen for rare autosomal trisomies such as trisomy 16. Some cfDNA tests have the option of screening for specific and larger microdeletions such as 22q11.2, 1p36 deletions and microdeletions responsible for Prader-Willi, Cri-du-chat, and Angelman syndromes. As the screening targets expand, the false-positive rate will increase and the positive-predictive values will tend to decrease due to the low prevalence of these conditions.
Two prospective observational studies have provided support for offering cfDNA screening to all pregnant patients who desire screening [27,28]. In one of these studies, over 15,000 pregnant patients presenting for aneuploidy screening at 10+0 to 13+6 weeks of gestation at 35 international centers underwent both serum biochemical marker screening with measurement of NT and cfDNA screening regardless of their baseline risk of aneuploidy (mean maternal age 31 years) . cfDNA screening had higher sensitivity for detection of Down syndrome (38/38 [100 percent] versus 30/38 [78.9 percent]), a lower false-positive rate (0.06 versus 5.4 percent), and a higher positive predictive value (80.9 versus 3.4 percent). Other studies have affirmed the high sensitivity and specificity of this test in both high- and low-risk populations . The American College of Obstetricians and Gynecologists supports consideration of cfDNA for all pregnant patients as a screening test option . (See "Prenatal screening for common aneuploidies using cell-free DNA".)
CHOICE OF SCREENING TEST IN MULTIPLE GESTATIONS — cfDNA screening is suitable for patients with known twin pregnancies . The reported cfDNA test failure rate in twins is 3.8 percent (range 1.6 to 13.2). A screen-positive cfDNA result indicates that one (or both) fetuses may be affected. There are limited data regarding screening in triplet pregnancies. These pregnancies can be offered cfDNA screening, with the caveat that the test failure rate may be as high as 20 percent. However, performance when the test is successful may approach that reported in twin pregnancies . (See "Twin pregnancy: Routine prenatal care", section on 'Screening for Down syndrome'.)
Serum biochemical marker screening is not well suited for multiple gestations. Serum measurements are not fetus-specific. Although the first-trimester nuchal translucency (NT) measurements are fetus-specific, their use alone results in relatively poor test performance.
MANAGEMENT OF SCREENING RESULTS — The estimated risk of Down syndrome based on screening test results should be discussed with the patient and explained; however, communicating risk so that it is understood by patients is challenging . For example, one study found that patients who were told that their risk of Down syndrome in their offspring was 1 in 150 (1 in X format) perceived a higher risk of Down syndrome compared with 7 in 1000 (X in 1000 format) . Visual aids can help.
Screen-negative test result — A screen-negative result means the fetus is at low risk of Down syndrome and trisomy 18 as defined by the specific laboratory cutoff (eg, <1 in 250 is commonly used as a second-trimester risk cutoff for Down syndrome). It does not exclude the possibility of Down syndrome or trisomy 18 or the possibility of a fetus with a chromosomal abnormality not targeted by the screening test but detectable with diagnostic testing . It is not appropriate to tell patients with a screen-negative result that their test was "normal" as they may interpret the term to mean the fetus definitely has a normal karyotype.
The patient's pre- and posttest risks of Down syndrome and trisomy 18 may be provided in the laboratory report (eg, pretest risk of Down syndrome: 1 in 290; posttest risk of Down syndrome: 1 in 1900). These numbers should be shared with the patient and explained. After a low risk result, further testing for Down syndrome and trisomy 18 is not recommended.
Screen-positive test result — A screen-positive test result means the fetus is at increased risk of Down syndrome as defined by the specific laboratory cutoff (eg, ≥1 in 250). The patient's pre- and posttest risks of Down syndrome should be provided in the laboratory report (eg, pre-test risk of Down syndrome: 1 in 390, posttest risk of Down syndrome: 1 in 75). These numbers should be shared with the patient and explained.
Screen-positive biochemical marker-based tests — Patients who screen positive on a biochemical marker-based test may undergo secondary screening or a diagnostic procedure. A secondary screening test aims to collect additional information about risk that screen-positive patients can use in deciding whether to proceed to diagnostic testing or forgo further testing because the additional information of the secondary test has greatly reduced the risk reported by the initial screening test.
For patients who have not undergone a cell-free DNA (cfDNA) test for initial screening, secondary screening is best performed with this test. Because of the high sensitivity and very low false-positive rate of cfDNA tests, many patients with false-positive biochemical marker tests will be reclassified as screen-negative with minimal risk of misclassification of true positives. Patients who choose secondary screening with a cfDNA test and are secondary screen-positive should be offered an invasive test for definitive diagnosis because false-positive results are still possible (<0.1 percent ).
Alternatively, a patient who screens positive on a biochemical marker-based test may decide that they want a definitive diagnosis as quickly as possible, which can be provided by invasive testing (chorionic villus sampling, or amniocentesis) and a karyotype or chromosomal microarray analysis. Each approach has advantages and disadvantages (table 5). After a positive screening test, it is helpful for parents to meet with a genetic counselor to inform them of their diagnostic and management options and answer questions.
Biochemical marker screening tests should not be repeated . Repeat testing of the entire population would result in only a small increase in detection rates but is not justified because of the expense and risk of false reassurance or confusion. Repeat biochemical marker testing limited to only screen-positive patients can reduce the false-positive rate, but a small percentage of affected pregnancies will be incorrectly reclassified as screen-negative. However, it is prudent to double-check the laboratory form to make sure the patient's age, weight, gestational age, and other important factors, such as family history, were recorded correctly, as these can affect the risk calculation. If an ultrasound examination has not been done, it should be performed to confirm gestational age and exclude other causes of a screen-positive test (eg, multiple gestation, some congenital anomalies). (See "Laboratory issues related to maternal serum screening for Down syndrome".)
Screen-positive cell-free DNA-based test — Patients who undergo cfDNA screening as their initial screening test should be offered invasive testing for definitive diagnosis. In general obstetric populations, the reported positive predictive value of a positive cfDNA test result for Down syndrome ranged from 46 to 81 percent in three studies [27,28,35]. False positives can be due to factors such as confined placental mosaicism, an unrecognized demised co-twin, large maternal copy-number variants, or maternal malignancy. (See "Prenatal screening for common aneuploidies using cell-free DNA", section on 'False-positive cfDNA test results'.)
DIAGNOSTIC TESTING — In the first trimester, chorionic villus sampling (CVS) is performed and a conventional karyotype is generally obtained. Preliminary results can be available within two days if a direct preparation is performed; final results from cultured cells take 7 to 10 days. If the cfDNA result suggests the possibility of a confined placental mosaicism, CVS may not be the preferred option. In the second trimester, amniocentesis is performed to obtain fetal cells (amniocytes) and a conventional karyotype analysis is generally obtained. A rapid targeted result may be available within two days, but complete karyotype results from cultured cells take approximately 8 to 14 days. When performed at a high-volume, experienced center, the procedure-related pregnancy loss rate for amniocentesis and CVS is estimated to range from approximately 1 in 300 to 1 in 1000 (0.1 to 0.3 percent) . The observed pregnancy loss rate after CVS is higher than after amniocentesis because CVS is performed at an earlier gestational age when the background risk for spontaneous loss is higher. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)
Some clinicians advocate chromosomal microarray analysis (CMA) as a first-line diagnostic test whenever fetal chromosomal analysis is indicated . It provides more genetic information (eg, microdeletions, microduplications) than a conventional karyotype but is not more effective for diagnosis of Down syndrome and trisomy 18. It may be more costly than a conventional karyotype. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)
Rapid tests — Fluorescent in situ hybridization (FISH) targets chromosomes 13, 18, 21, X, and Y. It can be used for rapid diagnostic testing for common aneuploidies because it can be performed on interphase cells. Analysis of the full conventional karyotype/CMA is generally also performed if FISH is normal to enable detection of other aneuploidies, as well as detection of major structural chromosomal abnormalities (eg, translocations, inversions, marker chromosomes) or microdeletions/duplications.
A quantitative fluorescence polymerase chain reaction (QF-PCR)-based approach is a more recent rapid technique that can be used for rapid diagnostic testing detection of trisomies 13, 18, 21, X, and Y [38-40]. An advantage of this technique is that it can be automated to allow high throughput of samples. As with FISH, analysis of the full karyotype/CMA needs to be performed if QF-PCR is normal and further information about fetal chromosomes is desired. It is not yet commonly offered by laboratories in the United States.
COMMUNICATING THE DIAGNOSIS TO PATIENTS WITH AFFECTED PREGNANCIES — The National Society of Genetic Counselors has published a guideline for communicating a prenatal or postnatal diagnosis of Down syndrome to parents . The following is a synopsis of their recommendations:
●Inform patients as soon as possible.
●The diagnosis should be delivered in person to both the pregnant patient and their partner by a health care professional with sufficient knowledge of the condition. A professional medical interpreter should be present, when appropriate.
●Avoid using value judgments, such as "I'm sorry" or "Unfortunately, I have bad news," when starting the conversation. Use active listening and empathic responses to support the patient and partner. Allow time for silence and time for tears and offer them time alone. Answer their questions and make plans for a follow-up conversation.
●Provide up-to-date, accurate verbal and written information with a balanced perspective and tailored to the patient's knowledge base and emotional needs. Include the range of cognitive and health concerns of individuals with the syndrome and both the positive aspects and challenges related to the syndrome. (See "Down syndrome: Management".)
●Provide informational resources, including national and local support groups and local medical and educational resources. The National Down Syndrome Society website is https://www.ndss.org/ (toll-free telephone number 1-800-221-4602). The SOFT (Support Organization for Trisomy 18, 13, and related disorders) website is https://trisomy.org/. The Spina Bifida Association website is https://www.spinabifidaassociation.org/ (toll-free telephone number 1-800-621-3141).
●When appropriate, provide referrals to other specialists (eg, medical geneticists, genetic counselors, cardiologists, neonatologists, pediatricians, pediatric surgeons).
●Discuss possible pregnancy outcomes, such as the increased risk of miscarriage and fetal demise. Medical and surgical issues that may require prompt attention after the birth should be addressed. (See 'Risk of spontaneous fetal demise' below.)
●Patients with an affected pregnancy have several options (continuing the pregnancy, pregnancy termination, releasing the child for adoption), which should be discussed with sensitivity to their beliefs, needs, and values. Offer an opportunity to meet with families who are raising a child with Down syndrome, those who have chosen to create an adoption plan, and/or those who have terminated a pregnancy.
For patients who elect to continue a pregnancy with a life-limiting diagnosis (eg, trisomy 13 or 18), perinatal palliative care is an option . (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers", section on 'Posttest counseling'.)
RISK OF SPONTANEOUS FETAL DEMISE — Fetal demise before delivery is common in trisomic pregnancies and increases with maternal age [43,44]. Trisomy 18 has the highest risk for intrauterine demise, trisomy 13 has an intermediate risk, and trisomy 21 has a lower risk (table 1).
●For trisomy 21 (Down syndrome), it is estimated that the risk of fetal demise between chorionic villus sampling and delivery is 30 to 50 percent, between diagnostic amniocentesis and delivery it is up to 30 percent, and between 24 weeks and delivery it is 7.4 percent, excluding electively terminated pregnancies [45-47]. Presumably, many of these losses are related to severe structural anomalies  but also to the adverse effect of trisomy 21 on placental function [49-51]. In comparison, the risk of fetal demise was 0.4 percent in a reference population of singleton pregnancies without anomalies or Down syndrome.
●For trisomy 18 (Edwards syndrome), spontaneous loss is estimated to occur before birth in 70 percent of fetuses alive at 12 weeks of gestation and 65 percent of those alive at 18 weeks . A high proportion (33 percent) are stillborn.
●For trisomy 13 (Patau syndrome), spontaneous loss before birth is estimated to occur in 50 percent of fetuses alive at 12 weeks and 43 percent of those alive at 18 weeks . A lower proportion (16 percent) are stillborn.
PREGNANCY MANAGEMENT — Prenatal, intrapartum, and postpartum care are provided according to usual obstetric standards. As discussed above, patients should be referred to national and local support groups and local medical and educational resources for information about the wide variability in manifestations and prognosis. (See "Down syndrome: Clinical features and diagnosis" and "Down syndrome: Management".)
There are few studies on use of nonstress testing, the biophysical profile, or other antepartum tests for fetal assessment to monitor the fetus with Down syndrome. It is reasonable to use these tests for the usual obstetric indications (eg, fetal growth restriction, oligohydramnios, preeclampsia, decreased fetal movement, abruption). A retrospective review of 64 pregnancies with a Down syndrome fetus reported delivery for new-onset nonreassuring antepartum fetal surveillance in 35.9 percent of the pregnancies and the average gestational age at delivery was 37 weeks . There was no difference in the rate of growth restriction, major anomalies, or maternal complications between Down syndrome pregnancies with and without nonreassuring fetal surveillance. However, 52 percent of those with nonreassuring fetal surveillance results had evidence of placental insufficiency on pathological examination. (See "Overview of antepartum fetal assessment".)
Ultrasound examination at 18 to 22 weeks is the optimum time to evaluate the fetus for congenital anomalies associated with Down syndrome. These fetuses are at increased risk for congenital heart defects and duodenal atresia. (See "Sonographic findings associated with fetal aneuploidy", section on 'Trisomy 21 (Down syndrome)' and "Down syndrome: Clinical features and diagnosis".)
IMPACT OF OFFERING PRENATAL SCREENING — The widespread implementation of prenatal screening programs combined with prenatal diagnosis and pregnancy termination has substantially reduced the number of Down syndrome births . In a systematic review of 24 United States studies (1995 to 2011) that reported data for pregnancies with definitive prenatal diagnosis of Down syndrome and subsequent pregnancy termination, the weighted mean termination rate was 67 percent (range 61 to 93 percent) .
Overall, the rate of Down syndrome live births has remained relatively constant or increased over time in some areas (eg, England and Wales , United States ) and has dropped in others (eg, China , Western Australia ). In some countries, the expected Down syndrome birth rate would have risen by 50 to 100 percent without screening, diagnosis, and termination due to the continuing trend of patients delaying pregnancy until they are older [56,59].
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.)
●Basics topics (see "Patient education: Testing for Down syndrome during pregnancy (The Basics)")
●Beyond the Basics topics (see "Patient education: Should I have a screening test for Down syndrome during pregnancy? (Beyond the Basics)")
The following table can also be helpful in deciding on which test might be most suitable for a given patient (table 6).
SUMMARY AND RECOMMENDATIONS
●Candidates – Relevant professional societies recommend offering prenatal screening for Down syndrome as early as 10 or 11 weeks of gestation to all pregnant individuals. In addition, patients should have the option of invasive diagnostic testing, regardless of maternal age. A diagnostic test is a reasonable choice for those at high risk of Down syndrome. Patients can also choose to decline screening and diagnostic testing. (See 'Candidates for prenatal screening' above.)
●Pretest counseling – Pretest counseling should provide clear, easily understood, nondirective, and complete information that allows patients to make informed, preference-based screening and diagnostic testing decisions. It should be clear that testing is voluntary. (See 'Counseling' above.)
●Choice of screening test – Prenatal screening programs based on maternal serum and ultrasound testing can detect up to 95 percent of pregnancies affected by Down syndrome at a false-positive rate of 5 percent. Several tests are available (table 2). (See 'Choice of screening test in singleton pregnancies' above.)
•Cell-free DNA – Maternal plasma cell-free DNA (cfDNA) testing is a screening test not a diagnostic test. It has higher sensitivity for detection of Down syndrome and a much lower false-positive rate than serum-based screening tests, which leads to more cases detected with far fewer invasive procedures. cfDNA testing does not screen for open neural tube defects and sometimes fails to obtain a result. (See 'Cell free DNA' above.)
•First-trimester combined test – The first-trimester combined test is the best serum screening option for patients whose most important goal is to obtain their estimate of risk of Down syndrome early in pregnancy. Diagnostic testing by chorionic villus sampling (CVS) or secondary screening by cfDNA must be available to follow-up screen-positive results. An additional measurement of alpha-fetoprotein or ultrasound screening is recommended in the second trimester for detection of open neural tube defects. (See 'First-trimester combined test' above.)
•Quadruple test – The quadruple test was the most commonly used serum-based Down syndrome screening test in the United States in 2020. It is the best screening test for patients who present for prenatal care in the second trimester. It provides screening for both Down syndrome and open neural tube defects. (See 'Second-trimester quadruple test' above.)
•Full integrated test – Among serum-based screening tests, the full integrated has the highest detection rate for Down syndrome, the lowest rate of procedure-related losses per patient screened (table 4), and includes screening for open neural tube defects. The serum integrated test has the highest detection rate for any serum screening test in which nuchal translucency measurement is not used. (See 'Tests integrated across the first and second trimesters' above.)
•Stepwise sequential screening – Stepwise sequential screening offers the advantages of the integrated test but allows those patients at very high risk (<2 percent) to receive an early diagnosis. (See 'Tests integrated across the first and second trimesters' above.)
●Management of screening results
•Screen-positive result – A screen-positive result means the fetus is at increased risk of Down syndrome (or some other condition). After a positive screening test, it is helpful to have the parents meet with a genetic counselor to inform them of their diagnostic and management options, including information about the natural history of the specific condition.
After a positive biochemical or ultrasound marker screening test, cfDNA testing may be offered as a secondary screening test. Because of the high specificity and sensitivity of the cfDNA test, many patients with false-positive biochemical marker tests will be reclassified as screen-negative with minimal risk of misclassification of true positives. Alternatively, patients may choose to have a diagnostic test. (See 'Screen-positive test result' above.)
Patients who undergo cfDNA screening as their initial screening test and are screen positive should be offered invasive testing for definitive diagnosis.
•Screen-negative result – A screen-negative result means the fetus is at low risk of Down syndrome as defined by a specific laboratory cutoff. No further testing is indicated, although a negative screen cannot completely exclude the possibility of Down syndrome. A negative screen also does not exclude the possibility of a fetus with a chromosomal abnormality other than Down syndrome but detectable with diagnostic testing. cfDNA and first-trimester screening tests do not provide a risk assessment for open neural tube defects. (See 'Screen-negative test result' above.)
●Prenatal care and course of pregnancy in cases of Down syndrome – Ongoing pregnancies with fetal trisomy are at increased risk for fetal demise. For Down syndrome, it is estimated that the risk of fetal demise between chorionic villus sampling and delivery is 30 to 50 percent, between diagnostic amniocentesis and delivery is up to 30 percent, and between 24 weeks and delivery is 7.4 percent, excluding planned pregnancy terminations. (See 'Risk of spontaneous fetal demise' above.)
Prenatal, intrapartum, and postpartum care are provided according to usual obstetric standards. Ultrasound examination at 18 to 22 weeks is the optimum time to evaluate the fetus for congenital anomalies (particularly cardiac abnormalities) associated with Down syndrome. (See 'Pregnancy management' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jacob A Canick, PhD, who contributed to an earlier version of this topic review.
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