Down Syndrome: Prenatal Risk Assessment and Diagnosis



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Am Fam Physician. 2000 Aug 15;62(4):825-832.

  See related patient information handout on Down syndrome, written by the author of this article.

  Related Editorial

Down syndrome (trisomy 21) is the most commonly recognized genetic cause of mental retardation. The risk of trisomy 21 is directly related to maternal age. All forms of prenatal testing for Down syndrome must be voluntary. A nondirective approach should be used when presenting patients with options for prenatal screening and diagnostic testing. Patients who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis. Women younger than 35 years should be offered maternal serum screening at 16 to 18 weeks of gestation. The maternal serum markers used to screen for trisomy 21 are alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin. The use of ultrasound to estimate gestational age improves the sensitivity and specificity of maternal serum screening.

Down syndrome is a variable combination of congenital malformations caused by trisomy 21. It is the most commonly recognized genetic cause of mental retardation, with an estimated prevalence of 9.2 cases per 10,000 live births in the United States.1,2 Because of the morbidity associated with Down syndrome, screening and diagnostic testing for this condition are offered as optional components of prenatal care. Prenatal diagnosis of trisomy 21 allows parents the choice of continuing or terminating an affected pregnancy.

Etiology and Clinical Manifestations

Down syndrome is usually identified soon after birth by a characteristic pattern of dysmorphic features (Table 1).3,4 The diagnosis is confirmed by karyotype analysis. Trisomy 21 is present in 95 percent of persons with Down syndrome. Mosaicism, a mixture of normal diploid and trisomy 21 cells, occurs in 2 percent. The remaining 3 percent have a Robertsonian translocation in which all or part of an extra chromosome 21 is fused with another chromosome. Most chromosome-21 translocations are sporadic. However, some are inherited from a parent who carries the translocation balanced by a chromosome deletion.1,3,4

TABLE 1

Frequency of Dysmorphic Signs in Neonates with Trisomy 21

Dysmorphic sign Frequency (%)

Flat facial profile

90

Poor Moro reflex

85

Hypotonia

80

Hyperflexibility of large joints

80

Loose skin on back of neck

80

Slanted palpebral fissures

80

Dysmorphic pelvis on radiographs

70

Small round ears

60

Hypoplasia of small finger, middle phalanx

60

Single palmar crease

45


Information from references 3 and 4.

TABLE 1   Frequency of Dysmorphic Signs in Neonates with Trisomy 21

View Table

TABLE 1

Frequency of Dysmorphic Signs in Neonates with Trisomy 21

Dysmorphic sign Frequency (%)

Flat facial profile

90

Poor Moro reflex

85

Hypotonia

80

Hyperflexibility of large joints

80

Loose skin on back of neck

80

Slanted palpebral fissures

80

Dysmorphic pelvis on radiographs

70

Small round ears

60

Hypoplasia of small finger, middle phalanx

60

Single palmar crease

45


Information from references 3 and 4.

Molecular genetic studies reveal that 95 percent of occurrences of trisomy 21 result from nondisjunction during meiotic division of the primary oocyte.1 The exact mechanism for this meiotic error remains unknown. Most trisomy 21 pregnancies prove to be nonviable. Only one quarter of fetuses with trisomy 21 survive to term.4

Persons with Down syndrome usually have mild to moderate mental retardation. In some, mental retardation can be severe. School-aged children with Down syndrome often have difficulty with language, communication and problem-solving skills. Adults with Down syndrome have a high prevalence of early Alzheimer's disease, further impairing cognitive function.1

A number of congenital malformations and acquired diseases occur with increased frequency in persons with Down syndrome (Table 2).1,36 Congenital heart disease and pneumonia are leading causes of mortality, especially in early childhood.

TABLE 2

Incidence of Some Associated Medical Complications in Persons with Down Syndrome

Disorder Incidence (%)

Mental retardation

> 95

Growth retardation

> 95

Early Alzheimer's disease

Affects 75% by age 60

Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot)

40

Hearing loss (related to otitis media with effusion or sensorineural)

40 to 75

Ophthalmic disorders (congenital cataracts, glaucoma, strabismus)

60

Epilepsy

5 to 10

Gastrointestinal malformations (duodenal atresia, Hirschsprung disease)

5

Hypothyroidism

5

Leukemia

1

Atlantoaxial subluxation with spinal cord compression

< 1

Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis, periodontal disease)

Unknown

Infertility

> 99% in men; anovulation in 30% of women


Information from reference 1 and 3 through 6.

TABLE 2   Incidence of Some Associated Medical Complications in Persons with Down Syndrome

View Table

TABLE 2

Incidence of Some Associated Medical Complications in Persons with Down Syndrome

Disorder Incidence (%)

Mental retardation

> 95

Growth retardation

> 95

Early Alzheimer's disease

Affects 75% by age 60

Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot)

40

Hearing loss (related to otitis media with effusion or sensorineural)

40 to 75

Ophthalmic disorders (congenital cataracts, glaucoma, strabismus)

60

Epilepsy

5 to 10

Gastrointestinal malformations (duodenal atresia, Hirschsprung disease)

5

Hypothyroidism

5

Leukemia

1

Atlantoaxial subluxation with spinal cord compression

< 1

Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis, periodontal disease)

Unknown

Infertility

> 99% in men; anovulation in 30% of women


Information from reference 1 and 3 through 6.

Prenatal Risk Assessment

ADVANCED MATERNAL AGE

The incidence of fetal trisomies is directly related to maternal age.7 The risk of having a child with Down syndrome increases in a gradual, linear fashion until about age 30 and increases exponentially thereafter (Figure 1).8 The risk of having a child with Down syndrome is 1/1,300 for a 25-year-old woman; at age 35, the risk increases to 1/365. At age 45, the risk of a having a child with Down syndrome increases to 1/30. (By convention, maternal age refers to age at the estimated or actual delivery date.)

FIGURE 1.

Estimated risk of Down syndrome according to maternal age. Data from reference 8.

View Large


FIGURE 1.

Estimated risk of Down syndrome according to maternal age. Data from reference 8.


FIGURE 1.

Estimated risk of Down syndrome according to maternal age. Data from reference 8.

Historically, maternal age can be viewed as the first “screening test” for fetal chromosome abnormalities. In the late 1970s, about 5 percent of pregnancies in the United States occurred in women who were 35 years or older.9 At age 35, the second-trimester prevalence of trisomy 21 (1/270) approaches the estimated risk of fetal loss due to amniocentesis (1/200).10 Therefore, age 35 was chosen as the screening cutoff—the risk threshold at which diagnostic testing is offered.

MATERNAL SERUM SCREENING

If all pregnant women 35 years or older chose to have amniocentesis, about 30 percent of trisomy 21 pregnancies would be detected.11 Women younger than 35 years give birth to about 70 percent of infants with Down syndrome.12 Maternal serum screening (multiple-marker screening) can allow the detection of trisomy 21 pregnancies in women in this younger age group.

Alpha-fetoprotein (AFP), unconjugated estriol and human chorionic gonadotropin (hCG) are the serum markers most widely used to screen for Down syndrome.13 This combination is known as the “triple test” or “triple screen.” AFP is produced in the yolk sac and fetal liver. Unconjugated estriol and hCG are produced by the placenta. The maternal serum levels of each of these proteins and of steroid hormones vary with the gestational age of the pregnancy. With trisomy 21, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels and maternal serum hCG is approximately two times higher than the normal hCG level.12

The triple test is usually performed at 15 to 18 weeks of gestation. The level of each serum marker is measured and reported as a multiple of the median (MoM) for women with pregnancies of the same gestational age as that of the patient's. The likelihood of trisomy 21 is calculated on the basis of each of the serum marker results and the patient's age. A composite estimate of the risk of trisomy 21 is reported to the clinician. A standard risk cutoff is used to determine when the test is considered “positive.” Most laboratories use a risk cutoff of 1/270, which is equal to the second-trimester risk of trisomy 21 in a 35-year-old woman.13 A positive test is an indication for amniocentesis (Figure 2).

Screening for Down Syndrome

FIGURE 2.

Algorithm for Down syndrome screening using the triple test results and a risk of 1/270 or higher. (LMP = last menstrual period)

View Large

Screening for Down Syndrome


FIGURE 2.

Algorithm for Down syndrome screening using the triple test results and a risk of 1/270 or higher. (LMP = last menstrual period)

Screening for Down Syndrome


FIGURE 2.

Algorithm for Down syndrome screening using the triple test results and a risk of 1/270 or higher. (LMP = last menstrual period)

The triple test can detect 60 percent of trisomy 21 pregnancies; it has a false-positive rate of 5 percent.11,14 The likelihood of a fetus having trisomy 21 in a patient with a positive test is about 2 percent. A normal result reduces the likelihood of trisomy 21 but does not exclude it. Test performance can be slightly improved by adjusting for maternal weight, ethnic group and insulin-dependent diabetes mellitus.12 In 1995 in the United States, maternal serum screening for Down syndrome was ordered in 60 percent of pregnancies.13

For women 35 years or older, maternal serum screening can provide an individual estimate of the likelihood of fetal trisomy 21.15 However, the triple test fails to detect 10 to 15 percent of trisomy 21 pregnancies in women in this older age group.16 Therefore, current U.S. practice standards indicate that for women 35 years or older, maternal serum screening should not be offered as an equivalent alternative to amniocentesis or chorionic villus sampling.1618 Guidelines published by the American College of Obstetricians and Gynecologists state that maternal serum screening may be offered “as an option for those women who do not accept the risk of amniocentesis or chorionic villus sampling or who wish to have this additional information prior to making a decision about having amniocentesis.”18

ULTRASOUND ASSESSMENT

An estimate of gestational age by ultrasound examination improves the performance of the triple test. In one study,19 the use of ultrasound was found to raise the sensitivity of the triple test from 60 percent to 74 percent and to decrease the initial false-positive rate from 9 percent to 5 percent. When available, an ultrasound estimate of gestational age should be provided to the laboratory instead of the due date based on the patient's last menstrual period. The biparietal diameter provides the best gestational age estimate for this purpose. Femur length and composite estimates derived from it should not be used, because this parameter underestimates the gestational age of fetuses with trisomy 21.19

Second-trimester ultrasound assessment may be helpful for predicting the likelihood of trisomy 21 in pregnancies at increased risk.20,21  This method of evaluation may be useful when amniocentesis is being considered in a patient with advanced maternal age or positive findings on the triple test. The most common ultrasonographic finding associated with trisomy 21 is increased nuchal fold thickness (nuchal translucency), which is caused by subcutaneous edema at the base of the occiput (Table 3).2022

TABLE 3

Ultrasonographic Findings Associated with Fetal Down Syndrome

Intrauterine growth restriction

Mild cerebral ventriculomegaly

Choroid plexus cysts

Increased nuchal fold thickness

Cystic hygromas

Echogenic intracardiac foci

Congenital heart defects

Increased intestinal echogenicity

Duodenal atresia (“double-bubble sign”)

Renal pelvis dilation

Shortened humerus and femur

Increased iliac wing angle

Incurving (clinodactyly) and hypoplasia of the fifth finger

Increased space between first and second toes

Two-vessel umbilical cord


Information from references 20, 21 and 22.

TABLE 3   Ultrasonographic Findings Associated with Fetal Down Syndrome

View Table

TABLE 3

Ultrasonographic Findings Associated with Fetal Down Syndrome

Intrauterine growth restriction

Mild cerebral ventriculomegaly

Choroid plexus cysts

Increased nuchal fold thickness

Cystic hygromas

Echogenic intracardiac foci

Congenital heart defects

Increased intestinal echogenicity

Duodenal atresia (“double-bubble sign”)

Renal pelvis dilation

Shortened humerus and femur

Increased iliac wing angle

Incurving (clinodactyly) and hypoplasia of the fifth finger

Increased space between first and second toes

Two-vessel umbilical cord


Information from references 20, 21 and 22.

FIRST-TRIMESTER SCREENING

Ultrasound measurement of nuchal translucency has been studied alone and in combination with new biochemical markers as a potentially useful first-trimester screening test for trisomy 21. Estimates are that first-trimester screening by means of maternal age and measurement of nuchal translucency could provide a trisomy 21 detection rate of 63 percent, with a 5 percent false-positive rate.23 Combining this procedure with measurement of maternal serum free beta-hCG subunit and pregnancy-associated protein A (PAP A) could increase the detection rate to 80 percent, at the same false-positive rate.23 Further study of the clinical utility and reliability of first-trimester screening is ongoing.

RECURRENCE RISK AND FAMILY HISTORY

If a patient has had a trisomy 21 pregnancy in the past, the risk of recurrence in a subsequent pregnancy increases to approximately 1 percent above the baseline risk determined by maternal age. Diagnosis of a chromosome-21 translocation in the fetus or newborn is an indication for karyotype analysis of both parents. If both parents have normal karyotypes, the recurrence risk is 2 to 3 percent. If one parent carries a balanced translocation, the recurrence risk depends on the sex of the carrier parent and the specific chromosomes that are fused.4

The significance of a family history of Down syndrome depends on the karyotype of the affected person (proband). If the proband has trisomy 21, the likelihood of a trisomy 21 pregnancy is minimally increased for family members other than the parents. If the proband has a chromosome-21 translocation or if the karyotype is unknown, family members should be offered genetic counseling and karyotype analysis.4

Prenatal Diagnosis

Definitive prenatal diagnosis of trisomy 21 requires cytogenetic analysis of cells obtained by one of three invasive procedures (Table 4).10 Second-trimester amniocentesis has been used the most extensively, and the safety of this technique continues to improve as technical advances have occurred.24 Chorionic villus sampling offers the opportunity for first-trimester diagnosis, when elective pregnancy termination carries the lowest risk of maternal morbidity, as compared with the risk in the second and third trimesters. Early amniocentesis offers a similar advantage, but the fetal loss rate associated with this technique is higher than that of chorionic villus sampling.10

Karyotype analysis usually requires seven to 10 days. A recently developed assay that uses fluorescent in situ hybridization (FISH) can allow rapid diagnosis of trisomy 21 after amniocentesis.25

TABLE 4

Procedures for Prenatal Genetic Diagnosis

Diagnostic procedure Gestational age when test is done (weeks) Risk of fetal loss (%)

Chorionic villus sampling

10 to 12

0.5 to 1.5

Early amniocentesis

12 to 15

1.0 to 2.0

Second-trimester amniocentesis

15 to 20

0.5 to 1.0


Adapted from Kuller JA, Laifer SA. Contemporary approaches to prenatal diagnosis. Am Fam Physician 1995;52:2277–83.

TABLE 4   Procedures for Prenatal Genetic Diagnosis

View Table

TABLE 4

Procedures for Prenatal Genetic Diagnosis

Diagnostic procedure Gestational age when test is done (weeks) Risk of fetal loss (%)

Chorionic villus sampling

10 to 12

0.5 to 1.5

Early amniocentesis

12 to 15

1.0 to 2.0

Second-trimester amniocentesis

15 to 20

0.5 to 1.0


Adapted from Kuller JA, Laifer SA. Contemporary approaches to prenatal diagnosis. Am Fam Physician 1995;52:2277–83.

Counseling Aspects

Assessment of the risk of Down syndrome begins with the first prenatal visit. All forms of prenatal testing for Down syndrome must be voluntary. A nondirective approach should be used when discussing the methods of prenatal screening and diagnostic testing.26 Informed consent to testing should be documented in the patient's chart.

Consultation with a medical geneticist or a genetic counselor should be sought if there has been a previous pregnancy complicated by a chromosome abnormality or if either parent is known to carry a balanced translocation.

Women who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis. These patients may be offered maternal serum screening and ultrasound evaluation before they make a decision about having amniocentesis, provided that they are informed of the limited sensitivity of noninvasive testing.18

Women younger than 35 years should be offered maternal serum screening at 15 to 18 weeks' gestation. They should be counseled about the imperfect sensitivity of maternal serum screening and the possibility that a false-positive result could lead to invasive testing. Test results should be reported to the patient promptly. Patients who receive news of abnormal results often experience considerable anxiety.27 These patients can be reassured by the knowledge that the likelihood of Down syndrome is small, even after a positive triple test.28 Ultrasound and amniocentesis should be offered. The risk of fetal loss from amniocentesis should be discussed.

If diagnostic testing reveals fetal trisomy 21, the parents should be provided with current, accurate information about Down syndrome and assistance in deciding on a course of action. Their options include continuing the pregnancy and raising the child, continuing the pregnancy and seeking adoption placement for the child or terminating the pregnancy. Consultation with a genetic counselor, a medical geneticist or a developmental pediatrician can be helpful to address the parents' concerns and facilitate their decision-making process.29

Parents who decide to continue the pregnancy should be advised that there is an increased risk of fetal demise in trisomy 21 pregnancies. A fetal echocardiogram should be performed at 20 weeks of gestation to detect serious cardiac malformations. An ultrasound examination should be performed at 28 to 32 weeks of gestation to monitor growth and detect duodenal atresia.29 The parents should be provided with referrals to support groups and organizations that advocate for persons with Down syndrome and their families.5 A positive outlook should be encouraged, recognizing that improvements in medical care, early intervention, special education and vocational counseling have enabled persons with Down syndrome to live more normal lives.29

SOURCES OF INFORMATION FOR PATIENTS AND PHYSICIANS

In addition to the patient information handout that accompanies this article, a more detailed brochure, “Facts About Down Syndrome,” has been produced by the National Institute of Child Health and Human Development (NIH Publication No. 97–3402). This brochure is available in English and Spanish from NICHD Clearinghouse, PO Box 3006, Rockville, MD 20847; telephone: 800-370-2943. In addition, the Genetic Counseling and Primary Care Web site (http://stork.cellb.bcm.tmc.edu/~genetics/) provides links to sources of additional information about Down syndrome and case-oriented tutorials on topics in genetics and genetic counseling.

The Author

DAVID S. NEWBERGER, M.D., is clinical assistant professor in the Department of Family Medicine, State University of New York at Buffalo, where he also completed a faculty development fellowship. Dr. Newberger graduated from the University of Miami School of Medicine, and completed a residency at the Tacoma (Wash.) family medicine residency program, an affiliate in the University of Washington Residency Network.

Address correspondence to David S. Newberger, M.D., Louis Lazar Family Medicine Center, 1542 Maple Rd., Suite 31, Williamsville, NY 14221 (e-mail: dsn@acsu.buffalo.edu). Reprints are not available from the author.

The author thanks Raymond Bissonette, Ph.D., Andrew Danzo, Carlos Jaén, M.D., Marion Koenigsberg, Ph.D., David Morelli, M.D., and Judith Shipengrover, M.D., Department of Family Medicine at the State University of New York at Buffalo, for review of the first draft of the manuscript. The author also thanks Timothy Cowan, M.S.P.H., for creating the graph in Figure 1 and Thomas C. Rosenthal, M.D., for providing suggestions on the manuscript. Mr. Cowan and Dr. Rosenthal are also with the Department of Family Medicine at SUNY.


This work was supported in part by a Faculty Development Grant from the Bureau of Health Professions, Health Resources and Services Administration.

REFERENCES

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2. Down syndrome prevalence at birth—United States, 1983–1990. MMWR Morb Mortal Wkly Rep. 1994;43:617–22.

3. Smith DW, Jones KL. Smith's Recognizable patterns of human malformation. 4th ed. Philadelphia: Saunders, 1988:10–5.

4. Tolmie JL. Down syndrome and other autosomal trisomies. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin's Principles and practice of medical genetics. 3rd ed. New York: Churchill Livingstone, 1996:925–71.

5. Saenz RB. Primary care of infants and young children with Down syndrome. Am Fam Physician. 1999;59:381–90392395–6.

6. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Atlantoaxial instability in Down syndrome: subject review. Pediatrics. 1995;96:151–4.

7. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol. 1981;58:282–5.

8. Cuckle HS, Wald NJ, Thompson SG. Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol. 1987;94:387–402.

9. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosome abnormalities. Am J Obstet Gynecol. 1984;148:886–94.

10. Kuller JA, Laifer SA. Contemporary approaches to prenatal diagnosis. Am Fam Physician. 1995;52:2277–83.

11. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ. 1988;297:883–7 [Published erratum appears in BMJ 1988;297:1029]

12. Saller DN, Canick JA. Maternal serum screening for Down syndrome: clinical aspects. Clin Obstet Gynecol. 1996;39:783–92.

13. Palomaki GE, Knight GJ, McCarthy JE, Haddow JE, Donhowe JM. Maternal serum screening for Down syndrome in the United States: a 1995 survey. Am J Obstet Gynecol. 1997;176:1046–51.

14. 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;327:588–93.

15. Haddow JE, Palomaki GE, Knight GJ, Cunningham GC, Lustig LS, Boyd PA. Reducing the need for amniocentesis in women 35 years of age or older with serum markers for screening. N Engl J Med. 1994;330:1114–8.

16. American College of Medical Genetics Clinical Practice Committee. ACMG position statement on multiple marker screening in women 35 and older. American College of Medical Genetics College Newsletter, January 1994;2.

17. American College of Medical Genetics Clinical Practice Committee. Statement on multiple marker screening in pregnant women. American College of Medical Genetics College Newsletter, January 1996;6.

18. American College of Obstetricians and Gynecologists. Maternal serum screening. ACOG Educational Bulletin, 1996; no. 228.

19. Benn PA, Borgida A, Horne D, Briganti S, Collins R, Rodis J. Down syndrome and neural tube defect screening: the value of using gestational age by ultrasonography. Am J Obstet Gynecol. 1997;176:1056–61.

20. Benacerraf BR. Ultrasound of fetal syndromes. New York: Churchill Livingstone, 1998:328–38.

21. Vintzileos AM, Campbell WA, Rodis JF, Guzman ER, Smulian JC, Knuppel RA. The use of second-trimester genetic sonogram in guiding clinical management of patients at increased risk for fetal trisomy 21. Obstet Gynecol. 1996;87:948–52.

22. Gross SJ, Bombard AT. Screening for the aneuploid fetus. Obstet Gynecol Clin North Am. 1998;25:573–95.

23. Chitty LS. Antenatal screening for aneuploidy. Curr Opin Obstet Gynecol. 1998;10:91–6.

24. U.S. Preventive Services Task Force. Guide to clinical preventive services: report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore: Williams & Wilkins, 1996:449–65.

25. Jalal SM, Law ME, Carlson RO, Dewald GW. Prenatal detection of aneuploidy by directly labeled multicolored probes and interphase fluorescence in situ hybridization. Mayo Clin Proc. 1998;73:132–7.

26. Abramsky L. Counseling prior to prenatal testing. In: Abramsky L, Chapple J, eds. Prenatal diagnosis: the human side. New York: Chapman & Hall, 1994:70–85.

27. Green JM. Women's experiences of prenatal screening and diagnosis. In: Abramsky L, Chapple J, eds. Prenatal diagnosis: the human side. New York: Chapman & Hall, 1994:37–53.

28. Reynolds TM, Nix AB, Dunstan FD, Dawson AJ. Age-specific detection and false-positive rates: an aid to counseling in Down syndrome risk screening. Obstet Gynecol. 1993;81:447–50.

29. Stein MT, Scioscia A, Jones KL, Cohen WI, Glass CK, Glass RF. Responding to parental concerns after a prenatal diagnosis of trisomy 21. J Dev Behav Pediatr. 1997;18:42–6.


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