Down syndrome screening

6YNEc0L06Y

&OBSTETRICS International Journal of Gynecology & Obstetrics 47 (1994) 186-190

ACOG committee opinion

Down syndrome screening Number 141 -

August 1994 (Replaces No. 76, December 1989) Committee on Obstetric Practice

Down syndrome (DS) is the most common of the serious chromosome disorders, occurring in 1 in 800 liveborns (1). Most cases of DS (95%) result from an extra chromosome 21. This type of DS, known as trisomy 21, occurs because of nondisjunction of the chromosomes in male or female meiosis. Most of these errors occur in maternal meiosis I. The first occurrence of nondisjunction in an offspring of a couple is generally considered a random event, although the empirically determined risk of recurrence of trisomy 21 is 1%. In a small percentage of cases, DS results from an unbalanced translocation. An unbalanced translocation may be inherited from a parent who is a carrier of a balanced translocation or may occur in the offspring as a new event. Balanced familial translocations and the risk of recurrent nondisjunction may be used to identify couples with a higher than usual risk for having a child with DS. RISKASSESSMENTBASED ON MATERNAL AGE The association of DS due to nondisjunction and

advanced maternal age is well known. Maternal age-specific rates of DS diagnosed at birth are available for each year of reproductive age (2). Age-specific rates for diagnosis of DS by amniocentesis are also available and are higher than those observed at birth. The difference relates to an increased rate of fetal loss even during the

second half of pregnancy when compared with chromosomally normal fetuses. Based on the association of DS due to nondisjunction with advanced maternal age, it has become standard obstetric practice to offer prenatal cytogenetic diagnosis to women who will be 35 or more years of age at delivery. Only 58% of pregnancies occur in women in this age group, but they account for 20% of DS births. Therefore, approximately 80% of children with DS are born to women who are less than 35 years old and who do not have an identifiable increased risk for delivering a child with DS (3). RISKASSESSMENT BY ULTRASONOGRAPHY

Certain clinical features of DS can be apparent on ultrasound examination (4-8). However, in addition to considerations of cost, the sensitivity of ultrasonography for detection of DS has not been established at a level of confidence that would suggest recommending a screening approach with ultrasonography alone. RISKASSESSMENT BY DETERMINATION OF MATERNAL SERUM ALPHA-FETOPROTEIN LEVELS

In 1984, an association between low levels of maternal serum alpha-fetoprotein (MSAFP) and fetal aneuploidy was reported (9). In pregnan-

ACOG

committee

opinion /ht.

ties in which the fetus has DS, MSAFP levels are about 25% lower than usual. The extensive overlap in the distributions of MSAFP in normal and DS pregnancies does not facilitate establishing an absolute MSAFP cut-off when using this serum marker to screen for DS. However, an individual patient’s DS risk based on maternal age may be adjusted with use of the results of her MSAFP test. Often, this testing is reported as positive when such a patient’s midtrimester DS risk is the same or greater than that of a 35-yearold woman (1:270). For women under the age of 35, this approach will result in the offer of amniocentesis to 5% of women and ultimately detection of approximately 25% of cases of DS (10). Increasingly, programs offering MSAFP screening for neural tube defects also provide a revised risk estimate for DS based on the same laboratory measurement.

RISK ASSESSMENT WITH OTHER BIOCHEMICAL MARKERS In 1984, it was suggested that human chorionic

gonadotropin (hCG) might also be used as a marker for fetal DS (11). Subsequently, investigators reported elevated levels of hCG in the second trimester in pregnancies in which the fetus had DS (12). This observation has been confirmed by several subsequent studies. At 16 weeks of gestation, maternal serum hCG values observed in DS pregnancies are generally 2.5 multiples of the normal median (MOM) for the gestational age. Notably, of the biochemical markers studied thus far, maternal serum hCG is the most sensitive for the detection of DS. Maternal serum levels of a number of other placental product-g, human placental lactogen, progesterone, and free beta subunit of hCG-are also higher in DS pregnancies. In 1988, researchers reported lower than usual second-trimester serum levels of unconjugated estriol in pregnancies in which the fetus had DS (13). The reduction in maternal serum unconjugated estriol is similar in magnitude to that observed in MSAFP. In 1988, a retrospective study of sera of women carrying DS fetuses compared with controls was conducted (14). The measurements of MSAFP, hCG, and unconjugated estriol were used to adjust the women’s age-related risks for

J. Gynecol.

Obstet.

47 (1994)

186-190

187

DS. Using a term risk cut-off of 1:250 for the birth of a child with DS, which is comparable to that of a 37-year-old woman, the study estimated a detection rate of 60% of fetal DS with an amniocentesis rate of 5%. Other similar retrospective investigations confirmed these findings. It should be noted that the rate of identification of DS and the rate of amniocentesis with this approach are expected to vary based on the cut-off used and the maternal age distribution in the population screened. Since these initial reports, several groups of investigators in the United States have reported their experience with prospective screening for DS using all three serum markers. One group screened 9,530 women who were less than 35 years of age and used a cut-off of a midtrimester risk of 1:270 (15). Another screened 25,207 consecutive patients including women who were over 35 years of age and used a cut-off of a midtrimester risk of 1:190 (16). In these studies 57% and 58% of DS pregnancies were identified, respectively. The rates of patients with risks above the cut-offs were 7.2% and 4.6% but were reduced to 3.2 and 3.8%, respectively, after sonographic correction of gestational age. The results of these two studies are consistent with the expectations projected by the retrospective observations. Another group also reported its experience with screening 7,718 women including women over 35 (17). Using a cut-off of a midtrimester risk of 1:195,91% of DS cases were identified. Six percent of these patients had a positive screening test. However, the positive screening rate after ultrasonography was reduced to 4.1%. The reason for the higher than expected rate of detection of DS in this latter study is not entirely apparent. It is important to emphasize that the interpretation of screening using these three markers is influenced by errors in gestational dating. A 2-week error in gestational dating can significantly change the estimate of DS risk. Falsepositive results were reduced significantly in the prospective studies when results of positive screening tests were adjusted for gestational age as corrected by ultrasound measurements. Therefore, all patients with a positive screening test should be offered gestational dating by ultrasound measurement of the biparietal diameter to verify their risk prior to considering prenatal cytogenetic diagnosis. For patient conve-

188

ACOG committee opinion/Int. J. Gynecol. Obstet. 47 (1994) 186-190

nience, this is often scheduled at a time when amniocentesis may also be performed. If a discrepancy is found between the menstrual age and the biparietal diameter, it is important to readjust the patient’s risk of DS prior to proceeding with amniocentesis. There are insufficient data to allow interpretation of these tests in multifetal pregnancies or pregnancies in women with insulin-dependent diabetes mellitus. Screening programs may establish different cut-offs. Some programs establish cut-offs to maintain a specified low amniocentesis rat-g, less than 5%. Other programs establish cut-offs based on the relative risk for DS (eg, risk equivalent to that of a 35 year old). The relative value of the use of two markers (MSAFP and hCG) versus three markers (MSAFP, hCG, and unconjugated estriol), free P_ hCG compared with the other markers, and additional markers such as pregnancy-specific beta-1-glycoprotein and leukocyte alkaline phosphatase have been discussed by other investigators (18-22). Well-conducted analyses of costbenefit and risk-benefit ratios are needed to determine the best combination of tests for screening and the optimal cut-off to use.

RISK ASSESSMENT FOR WOMEN

OVER 35

The preliminary prospective experience with this screening in patients over age 35 appears to provide a revised risk that is reliable. However, the number of patients in this age group who have been screened prospectively is a relatively small proportion of the patients studied to date. Furthermore, DS is not the only disorder associated with nondisjunction and advanced maternal age. Other disorders that result from maternal nondisjunction, such as trisomy 18, trisomy 13,47,XxX, and 47,XXY, are also increased in fetuses of women in this age group (2). Prospective studies reported to date have not included complete chromosome ascertainment. Therefore, the failure to detect other abnormalities, particularly those that do not have distinct phenotypic features in the newborn, can be estimated only indirectly. Furthermore, patients in this age group should be informed that the frequency of a positive serum screening test is relatively high and that DS is considerably less likely to be detected than with prenatal cytoge-

netic diagnosis by chorionic villus sampling or amniocentesis.

RISK ASSESSMENT FOR TRISOMY

18

All three markers are reduced in patients carrying a fetus with trisomy 18 (23). Thus, in contrast to DS, in which hCG is elevated, hCG is reduced in trisomy 18. In one study that used a specific low MOM cut-off for each marker, a high proportion of trisomy 18 pregnancies was detected (23). A very small number of patients had laboratory results of all three markers lower than the specific MOM cut-offs, and thus the rate at which amniocentesis was offered for trisomy 18 with this approach was very low. The use of absolute or fixed MOM cut-offs for trisomy 18 screening differs from DS screening, in which the cut-off is based on maternal age and a combination of the results of all three tests.

RECOMMENDATIONS Based on the experience with the prospective application of maternal serum screening methods for DS, the Committee on Obstetric Practice makes the following recommendations: ??

??

??

??

Women who are less than 35 years of age and who are between 15 and 18 weeks of gestation by menstrual dating should be offered serum screening to assess DS risk. Screening should be voluntary and based on informed consent. The various options for screening that are available, including the detection rates expected, should be discussed with the patient. Prior to screening, patients should be provided with information regarding the nature and purpose of the tests, the predictive value of the tests, and the limitations of screening tests in contrast to a diagnostic test. Based on the data available, a specific multiple biochemical marker protocol cannot be exclusively recommended at this time. The laboratory selected should be able to confirm that the specific combination of tests and the particular assays that are performed will yield a DS detection rate comparable to that of the prospective reports (ie, 20-25% with

ACOG committee opinion / ht. J. Gynecol. Obstet. 47 (1994) 186-M

MSAFP alone and at least 55-60% with MSAFP, hCG, and unconjugated estriol) with a positive rate of screening after ultrasound correction of gestational age that is less than 5%. The laboratory should be able to provide information regarding actual rates of positive screening and may be able to provide rates of positive screening after ultrasound correction. For many programs, the estimate of the detection rate of DS is initially based on measurements of samples obtained retrospectively. Programs with a large prospective screening experience may provide actual rates of DS detection. The laboratory or screening program should request the information needed to interpret the test result. This may include the date of the patient’s last menstrual period and her age, weight, race, and relevant obstetric and family history. The obstetrician should be familiar with the reporting method of the laboratory. Reporting should include information about 1) the patient’s age-related risk, 2) the patient’s risk as adjusted by the laboratory result, and 3) an indication of the patient’s adjusted risk relative to a specific cutoff level (eg, greater or less than that of a 35-year-old woman). The cut-off selected for counseling the patient should be consistent with the DS risk at which the obstetrician routinely offers prenatal cytogenetic diagnosis based on maternal age alone. All patients who have a DS risk higher than the selected cut-off should have ultrasonography performed to confirm gestational age and to revise the risk estimate when dating errors are detected prior to performing amniocentesis. Revision of gestational age should be based on biparietal diameter and not femur length measurement because femurs are shortened in some fetuses with DS (5). At this time, multiple marker testing in women over the age of 35 cannot be recommended for routine DS screening as an equivalent alternative to offering prenatal cytogenic diagnosis. However, it may be offered as an option for those women who do not accept the risk of amniocentesis or who

189

wish to have this additional information prior to making a decision about having amniocentesis. If serum screening for DS is requested by a patient over the age of 35, the patient should be informed of the higher rate of a positive screening test in this age group. The patient should also be informed of the diminished ability of screening to detect DS and certain other chromosome abnormalities, such as 47,XxX and 47,XXY, when screening with this approach is compared with diagnostic testing by chorionic villus sampling or amniocentesis.

REFERENCES 1. Jones KL. Recognizable patterns of human malformation. 4th ed. Philadelphia: WB Saunders, 1988:1&12 2. Hook EB, Cross PK, Schreinemachers

DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:20342038 3. Adams MM, Erickson JD, Layde PM, Oakley GP. Down’s syndrome. Recent trends in the United States. JAMA 1981;246:758-760 4. Benacerraf BR, Gelman R, Frigoletto FD Jr.

Sonographic identification of second-trimester fetuses with Down’s syndrome. N Engl J Med 1987;317:1371-1376

5. Nyberg DA, Resta RG, Luthy DA, Hickok DE, Williams MA. Humerus and femur length shortening in the detection of Down’s syndrome. Am J Obstet Gynecol 1993;168:534-538 6. Lockwood

C, Benacerraf B, Krinsky A, Blakemore K, Belanger K, Mahoney M, et al. A sonographic screening method for Down syndrome. Am J Obstet Gynecol1987;157:803-808

7. Nicolaides KH, Snijders RJ, Gosden CM, Berry C,

Campbell S. Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet 1992;340:704-707 8. Lettieri L, Rodis JF, Vintzileos AM, Feeny L,

Ciarleglio L. Craffey A. Ear length in secondtrimester aneuploid fetuses. Obstet Gynecol 1993;81:57-60

9. Merkatz I, Nitowsky HM, Macri JN, Johnson WE.

An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol1984;148:88&894 10. Combining maternal serum alpha-fetoprotein measurements and age to screen for Down

190

ACOG committee opinion /ht.

J. Gynecol. Obstet. 47 (1994) 186-190

syndrome in pregnant women under age 35. New England Regional Genetics Group Prenatal Collaborative Study on Down Syndrome Screening. Am J Obstet Gynecol1989;160:575-581 11. Chard T, Lowings C, Kitau MJ. Alphafetoprotein and chorionic gonadotropin levels in relation to Down’s syndrome. Lancet 1984;2:750 12. Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn 1987;7:623-630 13. Canick JA, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down’s syndrome. Br J Obstet Gynaecol 1988;95:330-333 14. Wald NJ, Cuckle HS, Densem JW, Nachahal K, Royston I’, Chard T, et al. Maternal serum screening for Down’s syndrome in early pregnancy. BMJ 1988;297:883-887 15. Phillips OP, Elias S, Shulman LP, Andersen RN, Morgan CS, Simpson JL. Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hCG and unconjugated estriol: a prospective 2-year study. Obstet Gynecol 1992;80:353-358 16. Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down’s syndrome with use of maternal serum markers. N Engl J Med 1992;327:588-593 17. Cheng EY, Luthy DA, Zebelman AM, Williams MA, Lieppman RE, Hickok DE. A prospective

evaluation of a second-trimester screening test for fetal Down syndrome using maternal serum alpha-fetoprotein, hCG, and unconjugated estriol. Obstet Gynecol1993;81:72-77 18. Spencer K, Coombes EJ, Mallard AS, Ward AM. Free beta human choriogonadotropin in Down’s syndrome screening: a multicentre study of its role compared with other biochemical markers. Ann Clin Biochem 1992;29:506-518 19. Macri JN, Kasturi RV, Krantz DA, Cook EJ, Sunderji SG, Larsen JW. Maternal serum Down syndrome screening: unconjugated estriol is not useful. Am J Obstet Gynecol1990;162:672-673 20. Knight GJ, Cole LA. Measurement of choriogonadotropin free B-subunit: an alternative to choriogonadotropin in screening for fetal Down’s syndrome? Clin Chem 1991;37:779-782 21. Cuckle HS, Wald NJ, Goodbum SF, Sneddon J, Amess JA, Dunn SC. Measurement of activity of urea resistant neutrophil alkaline phosphatase as an antenatal screening test for Down’s syndrome. BMJ 1990;301:1024-1026 22. Knight GJ, Palomaki GE, Haddow JE, Johnson AM, Osathanondh R, Car-rick JA. Maternal serum levels of the placental products hCG, hPL, SPI and progesterone are all elevated in cases of fetal Down syndrome. Am J Hum Genet 1989;45 (suppl):A263 23. Canick JA, Palomaki GE, Osathanondh R. Prenatal screening for trisomy 18 in the second trimester. Prenat Diagn 1990;10:546-548

Copyright 0 August 1994 ISSN 1074-861 X This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Requests for photocopies should be directed to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923. The American College of Obstetricians and Gynecologists 409 12th Street, SW ??Washington, DC 20024-2188