Part G. Congenital Disorders

41.  Screening for Down Syndrome

RECOMMENDATION

The offering of amniocentesis or chorionic villus sampling (CVS) for chromosome studies is

recommended for pregnant women at high risk for Down syndrome. The offering of screening for

Down syndrome by serum multiple-marker testing is recommended for all low-risk pregnant

women, and as an alternative to amniocentesis and CVS for high-risk women (see Clinical

Intervention). This testing should be offered only to women who are seen for prenatal care in

locations that have adequate counseling and follow-up services. There is currently insufficient

evidence to recommend for or against screening for Down syndrome by individual serum marker

testing or ultrasound examination, but recommendations against such screening may be made on

other grounds (see Clinical Intervention).

Burden of Suffering

Down syndrome, a congenital syndrome caused by trisomy of all or part of chromosome 21, is the

most common chromosome abnormality.1 Population-based surveillance programs have reported

a Down syndrome birth prevalence of 0.9/1,000 live births.2 The incidence of Down syndrome is

higher than the birth prevalence, however, since many fetuses are spontaneously aborted, some

are recognized in utero and electively aborted, and some cases are not recognized at birth. Affected

children are characterized by physical abnormalities that include congenital heart defects and

other dysmorphisms, and varying degrees of mental and growth retardation. Although there are

therapies for some of the specific malformations associated with Down syndrome, there are no

proven therapies available for the cognitive deficits. Life expectancy for infants born with Down

syndrome is substantially lower than that of the general population.3 Based on 1988

cross-sectional data, the lifetime economic costs of Down syndrome have been estimated to be

$410,000 per case.4

The risk for Down syndrome and certain other chromosome anomalies increases substantially with

advancing maternal age.1,5-10 Parents carrying chromosome-21 rearrangements are also at an

increased risk of Down syndrome pregnancies,11-13 with the risk being much higher if the

mother carries the rearrangement than if the father does. Also at higher risk are those who have

previously had an affected pregnancy, independent of advancing maternal age and chromosome

rearrangements.14,15

Accuracy of Screening Tests

Down syndrome is diagnosed prenatally by determining karyotype in fetal cell samples obtained by

amniocentesis or chorionic villus sampling (CVS). Because of their invasiveness, risks, and cost,

these procedures are generally reserved for women identified as high-risk either by history (i.e.,

advanced maternal age, prior affected pregnancy, known chromosome rearrangement) or by

screening maneuvers (e.g., serum markers, ultrasound). Chromosome analysis of fetal cells

obtained by second-trimester amniocentesis has been demonstrated to be accurate and reliable for

prenatal diagnosis of Down syndrome in a randomized controlled trial and several cohort

studies.16-19 CVS, a technique for obtaining trophoblastic tissue, is an alternative to

amniocentesis for detecting chromosome anomalies. The advantages of this procedure include the

ability to perform karyotyping as early as 10-12 weeks and more rapid cytogenetic analysis.

Potential disadvantages of CVS include apparent discrepancies between the karyotype of villi and

the fetus due to maternal cell contamination or placental mosaicism, and failure to obtain an

adequate specimen, resulting in a repeat procedure (usually amniocentesis) in up to 5% of tested

women.20-22 In randomized controlled trials20-22 and cohort studies23-29 comparing CVS to

amniocentesis, accurate prenatal diagnosis has been obtained in over 99% of high-risk women

when CVS is accompanied by both direct and culture methods of cytogenetic examination and when

amniocentesis is provided to clarify CVS diagnoses of mosaicism or unusual aneuploidy.

Transabdominal CVS has been reported to have comparable accuracy to transcervical CVS in

randomized controlled trials.20,30,31 First-trimester amniocentesis (at 10-13 weeks) has

been compared to CVS in one randomized controlled trial.32 Success rates were the same for the

two procedures (97.5%); early amniocentesis failures were primarily due to failed culture.

First- and second-trimester amniocentesis have not been directly compared in controlled trials.

For low-risk women, the risks associated with prenatal diagnostic testing (see Adverse Effects of

Screening and Early Detection, below) are generally considered to outweigh the potential benefits

because of the low likelihood of diagnosing a Down syndrome gestation. If screening tests, such as

measurement of maternal serum markers or ultrasound imaging, can identify women who are at

high risk for carrying a Down syndrome fetus, the relative benefit of prenatal diagnostic testing

increases, potentially justifying the more invasive diagnostic procedures. Reduced levels of

maternal serum a-fetoprotein (MSAFP) and unconjugated estriol, and elevated levels of human

chorionic gonadotropin (hCG), have each been associated with Down syndrome gestations.

Intervention studies of screening have not been carried out with unconjugated estriol alone, while

cohort intervention studies evaluating MSAFP and hCG have found them to have relatively poor

discriminatory power as individual tests.33-36 Multiple-marker screening uses results from

two or three individual maternal serum marker tests, combined with maternal age, to calculate

the risk of Down syndrome in the current gestation.37,38 Amniocentesis and diagnostic

chromosome studies are then offered to women whose screening test results suggest a high risk of

Down syndrome, with high risk often defined as having the same or greater risk of an affected

pregnancy that a 35-year-old woman has (i.e., 1 in 270).

Six interventional cohort studies that analyzed low-risk women younger than 35 years,39-41 36

years,42 37 years,43 or 38 years,44 and six that included women of any age desiring screening

(90-95% 35 years),45-50 have evaluated the proportion of Down syndrome pregnancies

identified through double-marker (hCG and either MSAFP or estriol) or triple-marker screening

in the midtrimester compared to the total number of such pregnancies identified. Interpretation of

sensitivity is affected by incomplete ascertainment of karyotype and incomplete diagnosis at birth

in these studies, although most had active surveillance systems for Down syndrome cases born to

screened women. The reported sensitivity of multiple-marker screening for Down syndrome

ranged from 48 to 91% (median 64.5%) and the false-positive rate (after revision of dates by

ultrasound) ranged from 3% to 10%. The likelihood of Down syndrome given a positive screening

test result was 1.2-3.8%, depending on the threshold for high risk used to define a positive test

result. In these studies, the threshold chosen ranged from a 1 in 125 to a 1 in 380 chance of

having an affected pregnancy given a positive test result. A young woman with a prescreen risk of

about 1 in 1,000 who tested positive would have a postscreen risk similar to the risk in women of

advanced age who are currently offered prenatal diagnosis.

Multiple-marker screening has also been evaluated in women 35 years of age or older, for whom

prenatal diagnosis using amniocentesis or CVS is routinely recommended because of their

increased risk of Down syndrome. Studies suggest that multiple-marker screening in these women

might reduce the need for more invasive diagnostic tests. In a cohort study of 5,385 women 35

years of age with no other risk factors, all of whom were undergoing routine amniocentesis and

chromosome studies (thus allowing complete ascertainment of chromosome abnormalities),

estimates of the individual risk of Down syndrome were calculated based on maternal age in

combination with the results of multiple-marker screening using MSAFP, hCG, and unconjugated

estriol.51 If amniocentesis were performed only on older women with at least a 1 in 200 risk of

carrying a fetus with Down syndrome based on triple-marker screening, 89% of affected 

fetuses would have been detected, 25% of women with unaffected fetuses would have been identified

by screening as needing amniocentesis. A threshold of 1 in 300 (similar to risk based on age 35

years alone) did not add sensitivity but did increase the screen-positive rate to 34%. Thus,

triple-marker screening could have avoided 75% of amniocenteses in older women, with their

attendant risk of fetal loss, at a cost of missing 11% of cases of Down syndrome. In this study,

performing amniocenteses only on women with postscreen risks of at least 1 in 200 for Down

syndrome would also have detected 47% of fetuses with other autosomal trisomies, 44% of fetuses

with sex aneuploidy, and 11% with miscellaneous chromosome abnormalities. In previously cited

interventional cohort studies of double- or triple-marker screening that reported separate

results for older women, the Down syndrome detection rate was reported as 80-100% for women

35 years43,46,47,50 and 100% for women 36 years,42,45 with false-positive screening

results of 19-27%. Incomplete case ascertainment was possible, however, since screen-negative

women rarely had diagnostic chromosome studies.

Although no controlled trials have directly compared double-marker to triple-marker screening,

several cohort studies of triple-marker screening have reported the detection rates for

double-marker screening with hCG and MSAFP only. Three markers appear to be somewhat more

sensitive than two for detection of Down syndrome; the net difference in sensitivity ranged from -

2 to +18% in these studies, depending on the false-positive rate and risk cut-off

used.43,48,50,51

Ultrasonography is another potential screening test for Down syndrome. Abnormalities associated

with Down syndrome (including intrauterine growth retardation, cardiac anomalies, hydrops,

duodenal and esophageal atresia) and differences in long-bone length and nuchal fold thickness

between Down syndrome and normal pregnancies observable on midtrimester ultrasound have been

reviewed.52 In prospective cohort studies of midtrimester ultrasound screening in high-risk

women who were undergoing amniocenteses for chromosome studies, nuchal fold thickening

identified 75% of Down syndrome fetuses; shortened humerus or femur length detected 31%; and

an index based on thickened nuchal fold, major structural defect, and certain other abnormalities

identified 69%.53-55 The likelihood of Down syndrome given a positive result was 7-25% in

these high-risk samples, but would be substantially lower in low-risk women. No published

cohort studies have evaluated the accuracy of ultrasound screening for detection of chromosome

abnormalities in low-risk women, nor have interventional cohort studies evaluated its efficacy as

a screening tool in high-risk women. The use of ultrasound as a screening test for Down syndrome

is limited by the technical difficulty of producing a reliable sonographic image of critical fetal

structures.56,57 Incorrect positioning of the transducer, for example, can produce artifactual

images resembling a thickened nuchal skin fold in a normal fetus.58 Sonographic indices are

therefore subject to considerable variation. Imaging techniques require further standardization

before routine screening by ultrasound for Down syndrome can be considered for the general

population.56,59,60 In addition, results obtained by well-trained and well-equipped operators in

a research context may not generalize to widespread use. In a multicenter cohort study in

high-risk women that involved a large number of ultrasonographers of varying ability, the

sensitivity of nuchal fold thickening for Down syndrome was only 38%.59 The false-psitive rate

in this study was 8.5%, many times higher than that reported in studies involving expert

ultrasonographers.55,61

Effectiveness of Early Detection

The detection of Down syndrome and other chromosome anomalies in utero provides as its

principal benefit the opportunity to inform prospective parents of the likelihood of giving birth to

an affected child. Parents may be counseled about the consequences of the abnormality and can make

more informed decisions about optimal care for their newborn or about elective abortion. No

controlled trials have been performed to assess clinical outcomes for those using screening or

prenatal diagnosis for Down syndrome compared to those who do not. Therefore, the usefulness of

this information depends to a large extent on the personal preferences and abilities of the

parents.62 Whether or not parents choose to use prenatal screening or diagnosis is related both to

their views on the acceptability of induced abortion and their perceived risk of the fetus being

abnormal.63 The perception of the harm or nature of the disability may play a greater role in the

decision than the actual probability of its occurrence.64-67

Induced abortion is currently sought by the majority of women whose prenatal diagnostic studies

(i.e., karyotyping) reveal fetuses with Down syndrome.33-35,39,40,45,48,68 Estimates of the

reduction in birth prevalence of Down syndrome associated with offering prenatal diagnosis to

women 35 years and older range from 7.3% to 29% in the U.S. and other developed

countries.2,69-73 The effect of this approach on the total number of Down syndrome births is

limited because older women have low birth rates and therefore account for a relatively small

proportion of affected pregnancies despite their exponentially increased risk for having an affected

pregnancy.74 Limited data are available to estimate the impact of serum-marker screening in

younger women on Down syndrome birth prevalence. In England and Wales, the proportion of all

cytogenetically diagnosed Down syndrome cases detected prenatally (thus potentially preventable)

increased from 31% to 46% after the introduction of screening by maternal serum analysis and

ultrasound for low-risk women.68 In cohort studies evaluating double- or triple-marker

screening, when the proportions of screen-positive women who decided not to undergo

amniocentesis or induced abortion were taken into account, the proportion of Down syndrome

births to screened women that were actually prevented ranged from 36% to 62%.39,40,45,48

Up to 25% of screen-positive women declined prenatal diagnosis by amniocentesis in these

studies. The effectiveness of screening in preventing Down syndrome births may be further

reduced by incomplete uptake of screening. In antenatal screening programs in which double- or

triple-marker screening was offered to all women and amniocentesis or CVS was offered to women

over 35 years of age, nearly 60% of all Down syndrome births were potentially preventable, the

remainder either being missed by screening (14-23%) or occurring in women who were not

screened (17-27%).47,49 Neither study evaluated acceptance of induced abortion, however. In

another population, offering ouble-marker screening to all women prevented 59% of all Down

syndrome births.45 This population had high rates of screening (89%), largely due to the fact

that pregnant women had to specifically ask to be excluded. There was also high acceptance of

amniocentesis in screen-positive women (89%), and of induced abortion of cytogenetically

confirmed cases (91%). The birth prevalence of Down syndrome decreased from approximately

1.1/1,000 to 0.4/1,000 after initiation of prenatal screening in this population.

Other potential effects of prenatal detection of Down syndrome have not been adequately explored.

In families at high risk of Down syndrome births, such as those with advanced maternal age, a

previous affected pregnancy, or known carriage of translocations, the availability of prenatal

diagnosis may reduce the induced abortion rate by identifying normal pregnancies that might

otherwise be electively aborted. This benefit has been reported with screening for cystic

fibrosis,75 but it has not been evaluated for Down syndrome. The diagnosis of a chromosome

abnormality may spare unsuspecting parents some of the trauma associated with delivering an

abnormal infant, and may help parents to prepare emotionally. Studies evaluating these potential

psychological benefits have not been reported, however. Prenatal diagnosis may also enable

clinicians to better prepare for the delivery and care of the baby. Studies are lacking regarding the

impact of these measures on neonatal morbidity and mortality.

An indirect benefit of testing to detect Down syndrome is the discovery during testing of

abnormalities other than the target condition. Chromosome studies on specimens obtained by

amniocentesis or CVS will detect other abnormalities besides Down syndrome. Autosomal trisomies

other than Down syndrome are usually spontaneously aborted, so the principal benefit of screening

may be avoidance of late fetal death.76 The health consequences of sex aneuploidy are less

significant than trisomies, but about half such pregnancies are nevertheless electively aborted

when discovered prenatally.77,78 Serum marker screening for Down syndrome will also identify

some patients carrying fetuses with other chromosome abnormalities (e.g., Turner syndrome,

trisomy-13 or -18); sensitivity is low,51 however, because some of these abnormalities have

different effects on serum markers than does Down syndrome, and require different risk

thresholds.50,79 Ultrasound screening for Down syndrome leads to a more accurate assessment of

gestational age in women with uncertain dates, and some studies suggest that acting on this

information may reduce the likelihood of induced labor for erroneously diagnosed postterm

pregnancy (see Chapter 36). Multiple gestations and major congenital anomalies, such as

diaphragmatic hernia, gastroschisis, nonimmune fetal hydrops, and obstructive uropathy, may

also be detected by ultrasound. These discoveries permit antenatal treatment as well as delivery

and neonatal care planning. Controlled trials proving that early detection by ultrasound of multiple

gestations or congenital anomalies improves outcome have not been published, however (see

Chapter 36). 

Adverse Effects of Screening and Early Detection.  The most important risks of early detection of

Down syndrome include those to the fetus from amniocentesis and CVS performed as a primary or

follow-up diagnostic test, the psychological effects of a positive test on the parents, and the

complications resulting from induced abortion. The risks of amniocentesis include rare puncture

of the fetus, bleeding, infection, and possibly isosensitization.80,81 The procedure-related rate of

fetal loss with current technique appears to be about 0.5-0.8%.16,17,29 The best evidence on

amniocentesis risks comes from a randomized controlled trial of screening,16 which reported a

procedure-related risk of fetal loss of 0.8% of pregnancies. This may nevertheless overestimate

current rates of loss as techniques have improved. In a more recent series of patients undergoing

amniocentesis as part of a clinical trial, the risk of fetal loss was 0.04%.22 In a randomized

controlled trial, neonatal respiratory distress syndrome and neonatal pneumonia were more

frequent after amniocentesis, independent of birth weight and gestational age; the additional risk

was about 1%.16 A similar trend was seen in the Medical Research Council study,18 but has not

been confirmed in other studies. Infection has not been identified as a significant problem in any

large studies. No clinically important effects on development, behavior, or physical status were

identified in 4-year-old children whose mothers had undergone midtrimester amniocentesis.83

Case series of women undergoing first-trimester amniocentesis suggest a procedure-related fetal

loss rate of 3-7%.84-87 In a randomized controlled trial, the total fetal loss rate with early

amniocentesis was significantly higher than with CVS (5.9 vs. 1.2%).32

Several randomized controlled trials comparing amniocentesis and CVS have reported significantly

higher fetal loss rates with CVS (1.0-1.5%) when compared with second-trimester

amniocentesis.20-22 Inexperience and the use of transcervical CVS appear related to a greater

risk of fetal loss, although at least one trial found no significant difference in fetal loss rates

between transcervical and transabdominal CVS (2.5% vs. 2.3%).31 An increased risk of

transverse limb reduction anomalies in infants born after CVS has been reported in case-control

and case-series studies.88-93b Conflicting evidence from cohort studies may relate to varying

methods of case ascertainment or classification.94-99a Decreasing risk and a trend from

proximal to distal limb damage with increasing gestational age at CVS provide biologic plausibility

for a true association with limb reduction defects.93,99b Current estimates for the overall risk

of transverse limb deficiency from CVS range from 0.03% to 0.10% of procedures.99a Severe

maternal complications from CVS are rarely reported, but the Canadian Collaborative Study

suggested a higher risk of bleeding requiring intervention for women undergoing CVS compared to

amniocentesis.22 None of the CVS trials has reported increased risks of birth defects or major

infant health problems, but sample size is inadequate in these trials to rule out rare adverse

effects.

A positive screening test result can produce a harmful psychological effect on parents. This is

especially important because the large majority of positive screening tests occur in normal

pregnancies. Adverse psychological  effects of screening tests include the fear of discovering an

abnormal pregnancy as well as anxiety over possible complications from diagnostic and

therapeutic procedures. Women who have been identified as being at high risk because of a positive

serum-marker screening test may have greater distress than women who are identified as high

risk because of advanced age.100,101 Distress is reduced following a diagnostic procedure

confirming a normal pregnancy, but some anxiety related to the false-positive screening test may

persist.102,103 Most women screened will have normal results, however, and this may have

psychological benefits for the reassured parents.

The potential complications of induced abortion must also be considered, since this is the outcome

of the majority of positive diagnostic test results. Morbidity from first-trimester induced

abortion, including infection, hemorrhage, and injury, occurs in 2-3% of procedures, but serious

complications are rare; in one series of 170,000 cases, 0.07% required hospitalization and none

resulted in death.104-107 Complication rates, including maternal case-fatality rates, are higher

with second-trimester abortions, but remain uncommon.108-110 The case-fatality rate from

legally induced abortion, 0.4/100,000 procedures, is substantially lower than the risk of

pregnancy-related death, which is 8-9/100,000 live births.108,109,111,112 The most

serious consequence of false-positive test results, the induced abortion of a normal pregnancy,

was not reported in any of the trials, and appears to be rare with current techniques. The

likelihood of diagnostic error is slightly higher with CVS than with amniocentesis, but the risk of

induced abortion as a consequence has not been fully evaluated.

Recommendations of Other Groups

Most organizations recommend offering amniocentesis or CVS for prenatal diagnosis to all pregnant

women who are aged 35 years and older or otherwise at high risk for chromosome

abnormalities.113-115 The Canadian Task Force on the Periodic Health Examination concluded

that there is fair evidence to offer second-trimester triple-marker screening to all pregnant

women less than 35 years of age, and as an alternative to prenatal diagnosis by karyotyping in

women 35 years and older; such offering should be accompanied by education on its limited

efficacy, as well as on the risks of second-trimester diagnosis and abortion, and on the

psychological implications of screening and of a Down syndrome birth.114 Offering

multiple-marker screening between 15 and 18 weeks of gestation to low-risk women under 35

years of age to assess Down syndrome risk is also recommended by the American College of

Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG);

neither group recommends a specific multiple-marker protocol.115,116 Neither ACOG nor ACMG

recommends prenatal cytogenic screening by multiple-marker testing in women 35 years and

older; ACOG recommends that multiple-marker testing may be offered as an option for those

women who do not accept the risk of amniocentesis or who wish to have this additional information

prior to making a decision. No organizations currently recommend routine screening for Down

syndrome by ultrasound. ACOG117 and a National Institutes of Health consensus development

conference118 have recommended that ultrasound imaging be performed during pregnancy only in

response to a specific medical indication.

Discussion

Prenatal diagnostic testing is accurate and reliable for detecting Down syndrome, but it is

associated with a procedure-related fetal loss risk of about 0.5% for second-trimester

amniocentesis and 1-1.5% for CVS, and a measurable risk of transverse fetal limb deficiency

after CVS. The currently accepted medical practice of routinely offering amniocentesis or CVS for

prenatal diagnosis to pregnant women aged 35 years and older or otherwise at high risk is based on

the mother's increased risk of having a fetus with a chromosome abnormality balanced against the

risk of fetal loss associated with these procedures, and therefore includes an element of judgment.

It can be predicted from available data (odds of Down syndrome during the second trimester) that a

program offering amniocentesis to all pregnant women at age 35 has the potential of exposing

200-300 normal fetuses to this procedure for every case detected.10 With an estimated

procedure-related fetal loss rate of 0.5%, one normal fetus would be lost by amniocentesis for

every one to two chromosome anomalies detected in such women. For CVS, the number of normal

fetuses lost per case detected would be higher, and for first-trimester amniocentesis, it may be

higher still. The older the maternal age, the more favorable the ratio of affected fetuses to fetal

loss. Most women who request such testing and receive a diagnosis of a Down syndrome pregnancy

choose to abort the pregnancy, resulting in a measurable reduction in Down syndrome births.

There is little good evidence of the effect on personal and family outcomes, however, or on the

balance of risks and benefits for the group as a whole. Nevertheless, those women at high risk who

desire prenatal diagnosis of Down syndrome may benefit substantially from it. Thus, there is fair

evidence to support offering prenatal diagnosis to high-risk pregnant women who are identified by

age, history, or screening tests when a comprehensive prenatal diagnosis program that includes

education, interpretation, and follow-up is avaiable.

In low-risk pregnant women, maternal serum multiple-marker screening in the second trimester

can detect nearly two thirds of Down syndrome fetuses, but it will result in a large number of

young women being offered amniocentesis who would not otherwise be subjected to its risks. The

ratio of affected fetuses detected to procedure-related fetal loss in women with positive

multiple-marker screening would be similar to or more favorable than that of women 35 years

and older. The risk of fetal loss may be acceptable to parents with strong fears of having an affected

child.64,119-121 There is also evidence that multiple-marker screening in women 35 years and

older can detect 80% or more of Down syndrome pregnancies while allowing the majority of such

women to avoid the risks associated with invasive diagnostic testing. Multiple-marker screening

is not supported by the same strength of evidence as is amniocentesis or CVS, however. Potential

problems include the reduced sensitivity for Down syndrome and other chromosome

abnormalities, the large proportion of false-positive tests, and the substantial number of women

who refuse or do not receive follow-up amniocentesis and chromosome studies. This is of

particular concern if such screening is offered to women 35 years and older who might otherwise

receive amniocentesis or CVS. Nevertheless, in some older women, particularly those who may

have had difficulty conceiving or carrying a pregnancy, the reduced likelihood of amniocentesis or

CVS and consequent risk of fetal loss or injury may outweigh the reduced sensitivity of

multiple-marker screening. There is therefore fair evidence to support offering

multiple-marker screening to pregnant women of all ages when a comprehensive prenatal

diagnosis program is available that includes education, interpretation, and follow-up.

There is a lack of sound evidence to support the use of individual maternal serum markers to

screen for Down syndrome, and currently available evidence suggests that sensitivity is

substantially lower than with multiple-marker screening. Similarly, ultrasonography has not

been adequately evaluated as a routine screening test for Down syndrome, and there are important

concerns about the measurement reliability and generalizability of this technology to widespread

use. Since there is evidence supporting the effectiveness of other screening and diagnostic methods,

neither individual serum markers nor ultrasonography can be recommended as screening tests for

Down syndrome outside clinical trials.

Identification and selective abortion of Down syndrome pregnancies raises important ethical

concerns, a full discussion of which is beyond the scope of this chapter. These concerns include the

implicit message that Down syndrome is an undesirable state, the interpretation of induced

abortion in eugenic terms by some persons, and societal and economic pressures that may

stigmatize families with a Down syndrome member. Attitudes held by both physicians and by

society toward individuals with Down syndrome have changed over time, and various Down

syndrome associations now offer support for families and individuals with Down syndrome,

promote their participation in society, and seek respect for them.122,123 These issues highlight

the importance of offering screening and prenatal diagnosis of Down syndrome in a value-sensitive

fashion with emphasis on reliable information about Down syndrome itself as well as about the

potential risks and benefits of screening procedures.

In these recommendations, primary consideration has been given to the prenatal detection of Down

syndrome. Other chromosome anomalies (e.g., Turner syndrome, trisomy-18) are often detected

during prenatal screening and diagnosis and many may consider their detection important. There

are few studies directly addressing screening for these conditions, however, and screening

protocols have not been sufficiently evaluated to warrant review at this point.

CLINICAL INTERVENTION

The offering of amniocentesis or CVS for chromosome studies to pregnant women aged 35 years and

older and to those at high risk of Down syndrome for other reasons (e.g., previous affected

pregnancy, known carriage of a chromosome rearrangement associated with Down syndrome) is

recommended ("B" recommendation). In some circumstances, depending on resources,

preferences, and other factors, the selection of a different age threshold for offering prenatal

diagnosis may be considered. Counseling before the procedure should include a comparison of the

risks to the fetus from the procedure and the probability of a chromosome defect given the

patient's age or other risk factors, as well as a full discussion of the potential outcomes associated

with delivering a child with Down syndrome and of aborting a Down syndrome fetus.

The offering of screening for Down syndrome by maternal serum multiple-marker testing at 15-

18 weeks of gestation is recommended for all pregnant women who have access to counseling and

follow-up services, skilled high-resolution ultrasound and amniocentesis capabilities, and

reliable, standardized laboratories ("B" recommendation). There is currently insufficient

evidence to recommend a specific multiple-marker screening protocol. Counseling regarding

screening should include information on the procedure itself, the likelihood of follow-up testing

with amniocentesis and its associated risks, as well as a full discussion of the potential outcomes

associated with delivering a child with Down syndrome and of aborting a Down syndrome fetus.

Women with a positive screen should receive detailed information comparing the increased risk of

trisomy and the risks of fetal loss from amniocentesis. For women aged 35 years and older, the

choice of serum multiple-marker screening versus amniocentesis or CVS for chromosome studies

depends on patient preferences and therefore requires a detailed discussion of the potential risks

and benefits of each procedure. In particular, the patient should understand the reduced sensitivity

of multiple-marker screening for Down syndrome and for other chromosome abnormalities

compared to prenatal diagnosis by chromosome studies, and the increased risk of fetal loss or

injury with amniocentesis and CVS.

There is currently insufficient evidence to recommend for or against routine ultrasound

examination or the use of individual maternal serum markers in pregnant women as screening

tests for Down syndrome ("C" recommendation). Recommendations against these tests may be

made on other grounds, however, including the availability of other screening tests of proven

effectiveness.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by

Carolyn DiGuiseppi, MD, MPH, based in part on material prepared for the Canadian Task Force on

the Periodic Health Examination by Paul Dick, MDCM, FRCPC.

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