Periodic health examination, 1996 update:
1. Prenatal screening for and diagnosis of Down syndrome

Canadian Medical Association Journal 1996; 154: 465-479

Copies of this and the other task force reports are available from the Health Services Directorate, Health Services and Promotion Branch, Department of National Health and Welfare, Tunney's Pasture, Ottawa ON   K1A 1B4

© 1996 Canadian Medical Association

• Abstract
• Résumé
• Introduction
• Prevalence
• Burden of suffering
• Manoeuvres
• Screening for DS
• Risk factors for having a fetus with DS
• Prenatal diagnosis of DS
• Adverse effects
• Effect of prenatal diagnosis
• Recommendations
• Validation
• Research questions
• References

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Introduction

The task force assigned a high value to providing pregnant women with reproductive choice, in accordance with current societal values. Elective abortion, although still a divisive issue, is regarded by many as a matter of reproductive choice.[2] The Ethics and Public Policy Committee of the Canadian College of Medical Geneticists[3] and participants at a recent workshop on genetic testing held by the US National Institutes of Health[4] concur that prenatal diagnosis should involve allowing all women to make informed choices.

Selective abortion has been criticized for compromising the ideals of medicine by rejecting the weak and the sick,[5] and for focusing on "problematic genes" rather than on society's response to people with disabilities.[6] Society may interpret the availability of diagnosis of fetal DS, and subsequent termination, as an implicit message that having DS is undesirable. Many people are unwilling to care for children with DS. Growing societal pressure to avoid having a child with DS may create a stigma for families that include a person with DS.[7] Preventive services must therefore be carefully designed to increase patients' control; the use of these services must be voluntary, not routine or expected.

Some parents may wish to detect a fetus with DS through screening and diagnosis in order to prepare psychologically for the birth of the child rather than to decide to terminate the pregnancy. Evaluating the benefits and harms (e.g., fetal loss due to prenatal diagnosis) of diagnosis for this purpose is beyond the scope of this article. Furthermore, although cost-benefit or cost- effectiveness analysis of prenatal screening and diagnostic services may be considered relevant in designing prenatal-services programs, such analysis is complex and value laden. Cost is not currently an issue affecting physicians' provision of prenatal care or advice to women about their options. Therefore, it was not considered in this review.

The clinical options considered were "triple-marker" screening of maternal serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and unconjugated estriol (uE3), screening with the use of fetal ultrasonographic examination and prenatal diagnosis with amniocentesis or CVS. The health outcomes considered included maternal psychologic distress and physical risks to the mother and fetus from the diagnostic interventions.

These recommendations are concerned solely with the prenatal diagnosis of DS. Other chromosome anomalies (Turner's syndrome, trisomy 13 syndrome and others) are sometimes detected during prenatal diagnosis; these anomalies have not been considered independently because the diagnostic issues are similar to those involved in DS and because there are too few studies of other anomalies.

MEDLINE was searched for relevant articles published between Jan. 1, 1966, and Mar. 31, 1994, with the use of MeSH terms "Down syndrome," "prenatal diagnosis," "screening," "prevention," "amniocentesis," "chorionic villus sampling," "ultrasonography," "anxiety," "depression" and "psychological stress," in conjunction with a manual search of bibliographies, recent articles in key journals and Current Contents. Studies were evaluated using the task force's grades of evidence.[8] Graded recommendations are made on the basis of the evidence on the burden of illness, the efficacy of detection, adverse effects and overall effectiveness of the manoeuvres.

The principal author conducted the literature review and provided a written and oral report to the task force members. This report was then critically reviewed by the task force and by independent reviewers.

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Prevalence

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Burden of suffering

Literature on people with DS and their families has focused on dysfunctional outcomes.[19] Up to 10% of families with a child with DS appear unable or unprepared to cope with such a child.[20] Maternal depression and difficulty in marital and sibling relationships are often noted in these families, although other factors may play a role in these problems.[19,20] No study has shown adequately the financial burden caused by a child with DS, or the effect of having a child with DS on the careers of the parents.[21] Despite the special challenges involved with DS, many families with children with DS are intact and functional.[19-21]

Some of the manifestations of DS, such as congenital heart disease, may be amenable to specific therapies. However, there are no proven medical therapies for the cognitive deficits caused by DS.[22-25] Studies of early developmental intervention suggest that children's fine motor skills and social repertoire benefit from such intervention, but controlled trials of intervention are lacking and the evidence of long-term amelioration of developmental difficulties is poor.[26,27]

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Manoeuvres

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Screening for DS

The maternal serum level of AFP was the first widely used serum marker for DS. However, the sensitivity of this test is relatively poor; fewer than one third of fetuses with DS are detected through regular testing of AFP levels.[28-30] Tests for other maternal serum markers (levels of hCG and uE3) were also examined[31-36] but do not appear to be adequately sensitive when used individually.

However, the simultaneous measurement of the three maternal serum markers (levels of AFP, hCG and uE3) during the second trimester has gained attention recently. In "triple-marker" screening, the probabilities of a fetus with DS derived from the individual tests of the three markers are combined with the maternal age-specific risk to produce a summary probability that the fetus has DS.[37-39] Women with a calculated probability exceeding a predetermined cut-off (e.g., a 1-in-250 risk of DS in the fetus) undergo a fetal ultrasonographic examination to verify the estimated dating of the pregnancy. If, on the basis of the accurate dating, the risk still exceeds the cut-off, the woman is offered amniocentesis. Many experts advocate routine ultrasonographic examination to establish accurate dating before screening. However, the value of this manoeuvre is contested.[40-42]

Four cohort studies (Table 1) have compared the number of fetuses with DS identified through triple-marker screening with the total number of fetuses with DS and infants born with DS detected through follow-up by the regional cytogenetics laboratory[44-46] or with the total number of infants expected to be born with DS on the basis of age-specific rates (in agreement with the actual number of infants born with DS, as detected through follow-up).[43] With the exception of one,43 these studies involved low-risk pregnancies (mainly among women less than 35 or 37 years of age, depending on the study).

The rate of detection of DS through triple-marker screening ranged from 48% to 91%, with a median rate of 58% (95% confidence interval [CI] 44% to 72%). In one of the studies, of the women screened, 3.8% were offered amniocentesis.[43] In this study, the risk cut-off at which women were offered amniocentesis was 1 in 190. The positive predictive value (PPV) achieved among women at a low risk of having a fetus with DS (1.5% when the age-related risk is 1 in 1000) is well within the range of risk at which prenatal diagnosis is now offered on the basis of maternal age or a previous child with DS. A recent report[47] on implementation of a triple-marker screening program shows results consistent with those of this study.

Two studies reported that the sensitivity of the test was lower among younger women than among older women (39% among women younger than 37 years v. 71% among those 37 and older,[45] and 67% among women younger than 30 years v. 100% among those 30 to 39[46]). In addition, the studies showed, without an explanation, that a significant proportion of women (21% to 31%) with a positive result of the screening tests did not undergo prenatal diagnosis (Table 1). The reason for this is not made apparent. The more limited sensitivity and the lack of diagnostic follow-up of positive results reduce the manoeuvre's effectiveness in preventing the birth of children with DS in young women with a low prior risk.

Ultrasonographic screening

Abnormalities associated with DS (intrauterine growth retardation, hydrops and some cardiac anomalies) can be observed in an ultrasonographic examination of a fetus during the second trimester.[48,49] Attention has focused on differences in long-bone length and nuchal skinfold thickness between fetuses with and without DS. One prospective clinical trial of ultrasonographic screening for DS has been reported. In a sample of 3338 pregnancies, 47 fetuses (1.4%) had nuchal skinfold measurements of 6 mm or more, found by ultrasonographic examination.50 The sensitivity of this manoeuvre was 75% and the PPV was 25%; 12 of the 16 fetuses with DS were detected by ultrasonography. This sample consisted mainly of pregnant women at a high risk of having a fetus with DS because of their age or other factors. Hence, although the results seem promising, the PPV of ultrasonographic screening is expected to be significantly lower among pregnant women at a low risk of having a fetus with DS.

Interobserver and intraobserver reliability in ultrasonographic screening have not been adequately addressed. Differences in technique among those performing ultrasonography may have a substantial effect on screening performance, and the results obtained from a select group of ultrasonographers are not necessarily generalizable. This may explain some of the variation in the reported results and indicate a need for evaluation of the manoeuvre in large, community-based trials.[51-53]

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Risk factors for having a fetus with DS

Birth of a previous child with nondisjunction trisomy 21, one form of DS, is a risk factor for subsequent births of children with DS.[74,75] The observed recurrence rate of pregnancy involving a fetus with DS is approximately 0.5%, and this rate is apparently independent of age among women younger than 35 years of age.[76]

Parents who have previous children with DS caused by chromosome rearrangements, and who are carriers of certain chromosome rearrangements, have an increased risk of having subsequent fetuses with DS. The estimated risk of having a fetus with DS caused by chromosome rearrangements involving chromosome 21 is specific to the type of rearrangement; the risk ranges up to 15%.[77-79]

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Prenatal diagnosis of DS

Women who are at high risk of having a fetus with DS are usually offered prenatal diagnosis through amniocentesis or CVS. The usual age threshold at which amniocentesis or CVS is offered is 35 years, if there are no other risk factors.[80] Triple-marker screening may lead to more efficient use of amniocentesis among women of advanced age, with little loss of detection ability.[43,80] Among 5385 women 35 years of age and older who underwent amniocentesis, 89% of the fetuses with DS were borne by the 25% of women who had had a positive result of a triple-marker screening test.[80] In a study of the implementation of antenatal screening, 64% of women 36 years of age and older participating chose serum-marker screening over amniocentesis.[47] It is unclear whether this choice would be significantly influenced by the availability of CVS, which may be used to diagnose DS earlier in the pregnancy.

Amniocentesis

In one randomized controlled trial of amniocentesis, DS was detected in 0.17% of pregnancies among 2239 women at low risk of having a fetus with DS.[81] No fetus with DS was missed, nor were any fetuses without DS misdiagnosed as a result of amniocentesis. Among 2268 controls, 0.13% delivered an infant with DS.[81] Apart from some increase in reports of abdominal pain and amniotic-fluid leakage, the rate of pregnancy complications in the group receiving amniocentesis was no higher than in the control group. Other studies that are not randomized controlled trials have shown a similar accuracy rate for amniocentesis.[82-84]

In a randomized controlled trial by Tabor and associates[81] involving women 25 to 34 years of age, there was a statistically significant higher rate of fetal loss after 16 weeks' gestation in the group receiving amniocentesis (1.7%) than in the control group (0.7%), for a difference of 1.0% (95% confidence interval [CI] 0.3% to 1.5%). The difference between groups in the rate of fetal loss during the entire pregnancy was 0.8%. Neonatal respiratory distress syndrome and neonatal pneumonia were more frequent among the infants of mothers who had undergone amniocentesis than among infants in the control group, regardless of the infants' birth weight and gestational age (1.8% v. 0.8%, p < 0.05).[81]

The increased neonatal morbidity and fetal loss observed in Tabor and associates' study has been attributed to their reported use of 18-gauge needles to perform amniocentesis.[84-87] Others have given lower estimates of fetal loss (approximately 0.5%) with the use of smaller-bore needles.[88] Tabor and associates subsequently published a correction in which they stated that, among most of the women who participated in their trial, amniocentesis was performed with a 20-gauge needle, and that the rate of fetal loss was not increased in the small group among whom amniocentesis was performed with an 18-gauge needle.[89]

In a trial of amniocentesis conducted by the Medical Research Council in Britain, the investigators noted increased rates of fetal loss, neonatal morbidity and orthopedic anomalies among the infants of the mothers who had undergone amniocentesis.[83] However, this study had a cohort design with inadequately matched controls; therefore, the strength of this evidence is poor. Other studies have shown that the risk of spontaneous abortion appears to be increased if there is a bloody tap or placental perforation.[81,82,90] Among children followed up for 4 years after amniocentesis, no clinically significant effects on development or physical status were evident.[91]

CVS

CVS is an alternative to amniocentesis for obtaining tissue for karyotype analysis and, hence, diagnosis of DS in a fetus. CVS has the advantage of being performed late in the first trimester, several weeks before amniocentesis or triple-marker screening can be undertaken. Like amniocentesis, it may be offered to women who are at a high risk of having a fetus with DS (as a result of advanced age or of having had a previous infant with DS). Six uncontrolled studies have shown that transcervical CVS provides accurate prenatal diagnosis in more than 99% of women at a high risk of having a fetus with DS.[92-97] Subsequent amniocentesis was necessary among up to 5% of women, to clarify the diagnosis or to obtain a karyotype, because CVS failed to provide a definitive diagnosis.

The rates of fetal loss following CVS (2.4% to 6.2%) were similar to rates after a routine first-trimester ultrasonographic examination[98-101] (except in one centre[95]), but this evidence is of poor quality. Better estimates of risk were obtained from comparative studies of amniocentesis and CVS (see the next section). No increases or unusual patterns in neonatal morbidity or congenital anomalies as a result of CVS were noted in these uncontrolled trials.

Three large registry-based case-control studies have evaluated a possible link between CVS and fetal limb defects.[102-104] Results from one of these supports an association between CVS and increased risk of transverse limb deficiency,[102] and another supports an association with transverse digital deficiency.[103] The estimated absolute risk of such a deficiency is 0.03%,[103] lower than the risk of DS or of fetal loss among women undergoing CVS. The risk may be limited by performing CVS after 70 days' gestation, since the strength of the association and the severity of the deficiency appear to decrease as the gestational age of the fetus increases.[102,103]

Transabdominal CVS is a new alternative to transcervical CVS with comparable accuracy.[105-107] Transabdominal CVS appears to be associated with a lower risk of fetal loss. The ease with which the sample is obtained, and the choice of sampling technique, may depend on uterine and placental position.

CVS versus amniocentesis

Three randomized controlled trials have compared CVS with amniocentesis.[61,105,108] Interpretation of karyo-types was more difficult in samples obtained through CVS than in those obtained through amniocentesis because contamination of the sample with maternal cells is more common in CVS and because karyotypic abnormalities confined to the placenta are sampled by CVS but not by amniocentesis. Although accurate diagnosis was ultimately obtained in more than 99% of the pregnancies in the group undergoing CVS, the rate of repeat procedures was up to 4.7%, whereas it was 1.0% in the group undergoing amniocentesis. The Association of Cytogenetic Technologists has published guidelines for the use of direct and culture methods to aid in the interpretation of maternal cell contamination and placental mosaicism.[109]

These studies have shown that CVS results in higher rates of all fetal loss (including pregnancy termination and perinatal death),[105,108] and of fetal loss before 28 weeks' gestation (excluding terminations)[108] compared with amniocentesis (these results are statistically significant). More bleeding and spotting[61,105,108] and a greater trend toward maternal complications requiring inpatient treatment (e.g., sepsis or bleeding necessitating a transfusion)61 have been observed after CVS than after amniocentesis. However, in the study of these complications, the rate in both groups was low (less than 1%).[61]

Another study showed that, among women 38 years of age, on average, CVS appears to entail a greater risk of fetal loss than amniocentesis.[110] The best estimates of risk come from two recent Canadian and European trials of CVS and amniocentesis.[61,108] Both studies involved pregnant women with an increased risk of having a fetus with DS as a result of age (mean 38 years), previous birth of an infant with DS or chromosomal-abnormality carrier status. The European trial reported a rate of spontaneous fetal loss before 28 weeks' gestation of 9% in the CVS group and of 6% in the amniocentesis group (statistically significant difference of 2.9%, 95% CI 0.6 to 5.3).[108] The Canadian trial reported a rate of total fetal loss (including induced abortions) of 16.9% in the CVS group and of 15.2% in the amniocentesis group (difference of 1.7%, 95% CI-1.4 to 4.4).[61] For these two trials, the combined odds ratio for fetal loss before 28 weeks' gestation after CVS, compared with amniocentesis, is 1.32 (95% CI 1.11 to 1.57).[110]

The sample sizes in these trials were inadequate for statistical testing of the frequencies of rare maternal or fetal adverse effects. To test for a difference in an outcome that occurs among 0.2% to 0.4% of fetuses (with Type I error of 5% and Type II error of 20%) requires a trial with approximately 13 000 pregnancies in each group -- a much larger sample than those in existing studies.[111]

Intervention

First-trimester abortion following CVS is the safest form of intervention; it has extremely few complications.[112] The complication rate in second-trimester abortion, which would be required following amniocentesis, is substantially higher (the main complication being retention of the products of conception).[113,114] Maternal death due to abortion in either the first or second trimester is extremely rare (occurring in less than 1 in 300 000 abortions).[115]

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Adverse effects

Some studies have suggested that women with a positive result of a screening test involving the AFP serum marker may experience greater distress than women of an advanced age, despite the equivalent risk. However, these studies report a reduction in distress after amniocentesis.[127,128] Counselling and information may not reduce anxiety experienced after a false-positive result of a screening test.[129,130] However, in a randomized controlled trial, detailed written information about the AFP serum marker screening test given to those undergoing the test resulted in more knowledge about the test and greater satisfaction with it.[129] This effect may be generalizable to triple-marker screening; therefore, physicians offering this screening should consider the value of giving patients detailed information on the efficacy of the screening test, the implications of false-positive results and the subsequent procedures after positive results.

Women with positive results of AFP tests who do not undergo amniocentesis appear to experience more anxiety than those who undergo amniocentesis that confirms that the fetus does not have DS.[128] No study has adequately addressed possible psychologic harm to women with a positive result of a screening test who do not subsequently undergo amniocentesis.

Of women undergoing second-trimester abortion because of a fetal abnormality, 80% reported an acute grief reaction, and in some cases the grief was prolonged.[131] The grief experienced by women who have terminated a pregnancy because of genetic indications may be as intense as that felt by those who lose a fetus spontaneously.[132]

Use of prenatal diagnosis is related to views on the acceptability of pregnancy termination and to the perceived risk of abnormality in the fetus.[133] The role played by health care professionals in shaping beliefs may be important. Although most women feel that they are autonomous in their decision making, many feel there is a risk that they will be persuaded.[134] There is some evidence that individuals' perceptions of the risk of procedures and of DS may be inconsistent.[135] Some couples may accept the risk of amniocentesis even when the chance of having a fetus with DS is very low. The perception of the nature of the disability may play a greater role in the decision than its probability of occurrence.[136-138]

The psychologic implications of having no access to prenatal diagnosis or of giving birth to an infant with DS must be weighed against those of receiving false-positive results of screening tests, of undergoing the procedures and of making decisions concerning diagnosis and termination. No study has contrasted these benefits and harms directly. Although a randomized controlled trial of screening versus no screening, in which psychologic as well as physical outcomes were compared, would address these issues directly, the challenge of conducting such a trial may be onerous given the values and preferences involved. It remains to be shown whether decision analysis (such as that used to study the decisions concerning amniocentesis versus CVS[126]) or other approaches would clarify the balance of harms and benefits.

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Effect of prenatal diagnosis

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Recommendations

There is fair evidence (grade B recommendation) to offer triple-marker screening to women under 35 years of age within a comprehensive screening and prenatal-diagnosis program including education, interpretation and follow-up. However, there is concern about the limited sensitivity of the screening test, the number of women who receive false-positive results and the number of women who receive positive results but do not subsequently undergo amniocentesis. These limitations may place a heavy burden on family physicians and obstetricians to inform fully all parents interested in screening. Screening of maternal serum markers outside of a comprehensive program is not recommended.

Women provided with detailed information on serum-marker screening may demonstrate more knowledge of the procedure and more satisfaction with it. Relevant information about triple-marker screening may include (1) the limited sensitivity and specificity of screening, (2) the time sequence, nature and risks of prenatal diagnosis and second-trimester abortion, and (3) the psychologic implications of screening and diagnosis as well as the implications of having a child with DS.

There is fair evidence (grade B recommendation) to offer prenatal diagnosis with CVS or amniocentesis, accompanied by information on the limitations and advantages of each procedure, to women who are 35 years of age or over, who have had a previous fetus with DS or who are carriers of chromosome 21 rearrangements. The quality of evidence concerning the balancing of all risks with benefits among these women is limited; therefore, a grade A recommendation has not been made. However, the potential benefit in reducing distress among women who are at a high risk of having a fetus with DS is clearly substantial. Although triple-marker screening has been advocated as a more efficient method of diagnosing DS among fetuses of women at a high risk (older than 35 years of age), its value as a replacement for CVS or amniocentesis in high-risk groups has not been assessed. However, some women in this age group may see triple-marker screening as an attractive alternative that provides a chance of avoiding prenatal diagnostic procedures. Accordingly, it may be offered as an alternative to prenatal diagnosis for women 35 years or older.

There is insufficient evidence to offer testing of single maternal-serum markers (such as AFP alone) specifically for screening of DS. However, maternal serum AFP measurement may be offered to screen for neural tube defects. An abnormal AFP result, which suggests a risk of DS in the fetus, necessitates subsequent counselling and offering of prenatal diagnosis.

Ultrasonographic screening with the use of long-bone and nuchal skinfold measurements is not currently recommended as a method of screening for DS because there is insufficient evaluation of its effectiveness, insufficient comparison with triple-marker screening and concern about the reliability and generalizability of these techniques.

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Validation

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Research questions

• Are tests of other maternal serum markers or other combinations of markers (e.g., AFP and hCG) more effective than triple-marker screening, or effective earlier in pregnancy?
• Is routine ultrasonographic examination to determine gestational age a necessary step in conducting triple-marker screening?
• How effective is ultrasonographic screening, in comparison with serum-marker screening, in a community setting?
• What are the outcomes among women with a positive result of a screening test who decline prenatal diagnosis?
• Are there safer, effective alternatives to CVS and to second-trimester amniocentesis (e.g., first-trimester amniocentesis)?
• What effect do prenatal screening and diagnosis have on societal perceptions of people with disabilities?
• What are the financial, emotional and social implications of having a child with DS? How effective and how widely available are interventions and community resources to improve outcomes among families with children with DS?
• Can further development and evaluation of early interventions and therapies for children with DS improve their cognitive and functional outcomes?

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