In Women Older Than 45, 1: Babies Has Trisomy 21.
Down syndrome: Prenatal Risk Assessment and Diagnosis
A more than contempo article on this topic is available.
Am Fam Doc. 2000 Aug 15;62(four):825-832.
Encounter related patient information handout on Down syndrome, written by the author of this article.
Related Editorial
Article Sections
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Down syndrome (trisomy 21) is the most commonly recognized genetic crusade of mental retardation. The risk of trisomy 21 is directly related to maternal historic period. 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 exist offered chorionic villus sampling or second-trimester amniocentesis. Women younger than 35 years should be offered maternal serum screening at sixteen to xviii 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,two Considering of the morbidity associated with Down's 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
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Down's syndrome is usually identified soon after birth past a characteristic design 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 function of an extra chromosome 21 is fused with some other chromosome. About chromosome-21 translocations are sporadic. However, some are inherited from a parent who carries the translocation balanced by a chromosome deletion.1,three,iv
Tabular array 1
Frequency of Dysmorphic Signs in Neonates with Trisomy 21
| Dysmorphic sign | Frequency (%) |
|---|---|
| Flat facial contour | xc |
| Poor Moro reflex | 85 |
| Hypotonia | 80 |
| Hyperflexibility of large joints | 80 |
| Loose skin on back of neck | eighty |
| Slanted palpebral fissures | 80 |
| Dysmorphic pelvis on radiographs | 70 |
| Minor round ears | lx |
| Hypoplasia of small finger, middle phalanx | lx |
| Single palmar crease | 45 |
Molecular genetic studies reveal that 95 pct of occurrences of trisomy 21 effect from nondisjunction during meiotic division of the primary oocyte.1 The exact machinery for this meiotic error remains unknown. Most trisomy 21 pregnancies prove to exist nonviable. Simply ane quarter of fetuses with trisomy 21 survive to term.iv
Persons with Down syndrome usually accept balmy to moderate mental retardation. In some, mental retardation tin can be severe. School-aged children with Down syndrome frequently take difficulty with language, communication and problem-solving skills. Adults with Down syndrome have a high prevalence of early on Alzheimer'due south disease, further impairing cerebral office.one
A number of congenital malformations and acquired diseases occur with increased frequency in persons with Downwardly syndrome (Table two).1,3–six Congenital middle disease and pneumonia are leading causes of bloodshed, especially in early on babyhood.
Table ii
Incidence of Some Associated Medical Complications in Persons with Down Syndrome
| Disorder | Incidence (%) |
|---|---|
| Mental retardation | > 95 |
| Growth retardation | > 95 |
| Early Alzheimer'southward illness | Affects 75% by age 60 |
| Congenital heart defects (atrioventricular culvert defect, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot) | forty |
| Hearing loss (related to otitis media with effusion or sensorineural) | 40 to 75 |
| Ophthalmic disorders (built cataracts, glaucoma, strabismus) | 60 |
| Epilepsy | 5 to 10 |
| Gastrointestinal malformations (duodenal atresia, Hirschsprung disease) | five |
| Hypothyroidism | 5 |
| Leukemia | 1 |
| Atlantoaxial subluxation with spinal string compression | < 1 |
| Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis, periodontal disease) | Unknown |
| Infertility | > 99% in men; anovulation in thirty% of women |
Prenatal Risk Assessment
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
ADVANCED MATERNAL AGE
The incidence of fetal trisomies is direct related to maternal historic period.7 The risk of having a kid with Down's syndrome increases in a gradual, linear manner until about historic period thirty and increases exponentially thereafter (Figure ane).8 The run a risk of having a child with Down syndrome is ane/1,300 for a 25-year-old adult female; at age 35, the risk increases to 1/365. At age 45, the risk of a having a child with Downwardly syndrome increases to one/xxx. (By convention, maternal age refers to age at the estimated or actual delivery date.)
Effigy 1.
Estimated risk of Down syndrome according to maternal historic period. Data from reference 8.
Historically, maternal age can be viewed as the offset "screening test" for fetal chromosome abnormalities. In the late 1970s, about five percent of pregnancies in the United States occurred in women who were 35 years or older.9 At historic period 35, the 2d-trimester prevalence of trisomy 21 (ane/270) approaches the estimated risk of fetal loss due to amniocentesis (1/200).ten Therefore, age 35 was chosen as the screening cutoff—the take a chance threshold at which diagnostic testing is offered.
MATERNAL SERUM SCREENING
If all pregnant women 35 years or older chose to accept amniocentesis, about thirty per centum of trisomy 21 pregnancies would be detected.11 Women younger than 35 years give nativity to about 70 percent of infants with Down syndrome.12 Maternal serum screening (multiple-marker screening) can permit the detection of trisomy 21 pregnancies in women in this younger age group.
Alpha-fetoprotein (AFP), unconjugated estriol and human being chorionic gonadotropin (hCG) are the serum markers most widely used to screen for Down syndrome.thirteen 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 historic period of the pregnancy. With trisomy 21, 2nd-trimester maternal serum levels of AFP and unconjugated estriol are about 25 pct lower than normal levels and maternal serum hCG is approximately two times higher than the normal hCG level.12
The triple examination is usually performed at 15 to 18 weeks of gestation. The level of each serum marking 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 mark results and the patient'due south age. A composite judge of the risk of trisomy 21 is reported to the clinician. A standard risk cutoff is used to determine when the examination is considered "positive." Most laboratories utilize a risk cutoff of one/270, which is equal to the second-trimester risk of trisomy 21 in a 35-twelvemonth-quondam woman.13 A positive test is an indication for amniocentesis (Figure 2).
Screening for Down syndrome
FIGURE ii.
Algorithm for Downwardly syndrome screening using the triple exam results and a run a risk of 1/270 or higher. (LMP = last menstrual period)
The triple test can detect 60 percent of trisomy 21 pregnancies; information technology has a faux-positive rate of 5 per centum.11,14 The likelihood of a fetus having trisomy 21 in a patient with a positive test is virtually 2 percent. A normal result reduces the likelihood of trisomy 21 but does not exclude information technology. Test functioning tin can be slightly improved past adjusting for maternal weight, ethnic group and insulin-dependent diabetes mellitus.12 In 1995 in the United States, maternal serum screening for Down's syndrome was ordered in 60 percent of pregnancies.13
For women 35 years or older, maternal serum screening tin provide an individual guess of the likelihood of fetal trisomy 21.15 However, the triple test fails to notice 10 to 15 percentage of trisomy 21 pregnancies in women in this older age group.16 Therefore, electric current U.Due south. exercise standards signal that for women 35 years or older, maternal serum screening should not exist offered equally an equivalent alternative to amniocentesis or chorionic villus sampling.16–18 Guidelines published by the American College of Obstetricians and Gynecologists state that maternal serum screening may be offered "every bit an option for those women who practice not take the gamble of amniocentesis or chorionic villus sampling or who wish to have this boosted data prior to making a decision about having amniocentesis."xviii
ULTRASOUND ASSESSMENT
An estimate of gestational age by ultrasound examination improves the performance of the triple test. In one report,19 the apply of ultrasound was establish to heighten the sensitivity of the triple examination from 60 percent to 74 percentage and to decrease the initial fake-positive rate from ix percentage to 5 percent. When available, an ultrasound estimate of gestational historic period should be provided to the laboratory instead of the due date based on the patient'southward last menstrual period. The biparietal bore provides the all-time gestational historic period estimate for this purpose. Femur length and composite estimates derived from it should not be used, because this parameter underestimates the gestational historic period of fetuses with trisomy 21.19
Second-trimester ultrasound cess may exist 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 mutual 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 iii).twenty–22
TABLE three
Ultrasonographic Findings Associated with Fetal Downwardly Syndrome
| Intrauterine growth restriction |
| Balmy cognitive ventriculomegaly |
| Choroid plexus cysts |
| Increased nuchal fold thickness |
| Cystic hygromas |
| Echogenic intracardiac foci |
| Built heart defects |
| Increased intestinal echogenicity |
| Duodenal atresia ("double-chimera sign") |
| Renal pelvis dilation |
| Shortened humerus and femur |
| Increased iliac fly bending |
| Incurving (clinodactyly) and hypoplasia of the fifth finger |
| Increased infinite between kickoff and second toes |
| 2-vessel umbilical cord |
Offset-TRIMESTER SCREENING
Ultrasound measurement of nuchal translucency has been studied alone and in combination with new biochemical markers as a potentially useful starting time-trimester screening examination for trisomy 21. Estimates are that first-trimester screening by ways of maternal age and measurement of nuchal translucency could provide a trisomy 21 detection rate of 63 percent, with a v percentage simulated-positive rate.23 Combining this process with measurement of maternal serum free beta-hCG subunit and pregnancy-associated protein A (PAP A) could increase the detection rate to fourscore percent, at the same false-positive rate.23 Further study of the clinical utility and reliability of commencement-trimester screening is ongoing.
RECURRENCE Take a chance AND Family HISTORY
If a patient has had a trisomy 21 pregnancy in the past, the gamble of recurrence in a subsequent pregnancy increases to approximately 1 percent higher up the baseline risk determined past 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 accept normal karyotypes, the recurrence adventure is 2 to three percentage. If ane 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 assay.iv
Prenatal Diagnosis
- Abstruse
- Etiology and Clinical Manifestations
- Prenatal Take a chance Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Definitive prenatal diagnosis of trisomy 21 requires cytogenetic analysis of cells obtained by one of three invasive procedures (Tabular array 4).10 Second-trimester amniocentesis has been used the nearly 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 chance of maternal morbidity, as compared with the risk in the second and tertiary trimesters. Early on amniocentesis offers a like advantage, but the fetal loss rate associated with this technique is higher than that of chorionic villus sampling.ten
Karyotype assay ordinarily requires seven to 10 days. A recently developed assay that uses fluorescent in situ hybridization (FISH) tin can allow rapid diagnosis of trisomy 21 after amniocentesis.25
Table 4
Procedures for Prenatal Genetic Diagnosis
| Diagnostic procedure | Gestational historic period when test is done (weeks) | Hazard of fetal loss (%) |
|---|---|---|
| Chorionic villus sampling | 10 to 12 | 0.5 to 1.5 |
| Early amniocentesis | 12 to 15 | 1.0 to 2.0 |
| 2nd-trimester amniocentesis | 15 to xx | 0.5 to 1.0 |
Counseling Aspects
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Gamble Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Assessment of the take a chance 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'south chart.
Consultation with a medical geneticist or a genetic advisor should be sought if there has been a previous pregnancy complicated by a chromosome aberration 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 earlier they make a decision near having amniocentesis, provided that they are informed of the limited sensitivity of noninvasive testing.eighteen
Women younger than 35 years should be offered maternal serum screening at 15 to 18 weeks' gestation. They should be counseled virtually the imperfect sensitivity of maternal serum screening and the possibility that a faux-positive result could lead to invasive testing. Test results should be reported to the patient promptly. Patients who receive news of aberrant results often experience considerable anxiety.27 These patients can be reassured past the noesis that the likelihood of Down's syndrome is small-scale, even subsequently 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, authentic information near 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 kid or terminating the pregnancy. Consultation with a genetic counselor, a medical geneticist or a developmental pediatrician can exist helpful to accost the parents' concerns and facilitate their decision-making process.29
Parents who decide to continue the pregnancy should exist advised that there is an increased gamble of fetal demise in trisomy 21 pregnancies. A fetal echocardiogram should exist performed at 20 weeks of gestation to detect serious cardiac malformations. An ultrasound examination should exist 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's syndrome and their families.5 A positive outlook should be encouraged, recognizing that improvements in medical care, early intervention, special didactics and vocational counseling have enabled persons with Down syndrome to live more normal lives.29
SOURCES OF INFORMATION FOR PATIENTS AND PHYSICIANS
In improver to the patient data handout that accompanies this article, a more detailed brochure, "Facts Well-nigh Down's syndrome," has been produced by the National Constitute of Child Wellness and Human being Development (NIH Publication No. 97–3402). This brochure is bachelor in English and Spanish from NICHD Clearinghouse, PO Box 3006, Rockville, MD 20847; telephone: 800-370-2943. In addition, the Genetic Counseling and Main Care Web site (http://stork.cellb.bcm.tmc.edu/~genetics/) provides links to sources of additional information nigh Down syndrome and case-oriented tutorials on topics in genetics and genetic counseling.
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This work was supported in part by a Faculty Evolution Grant from the Bureau of Health Professions, Health Resources and Services Administration.
REFERENCES
prove all references
ane. Epstein CJ. Down syndrome (Trisomy 21). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995:749–94. ...
2. Down's syndrome prevalence at birth—U.s., 1983–1990. MMWR Morb Mortal Wkly Rep. 1994;43:617–22.
three. Smith DW, Jones KL. Smith'due south Recognizable patterns of human being malformation. 4th ed. Philadelphia: Saunders, 1988:10–five.
iv. 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. Chief care of infants and immature children with Downward syndrome. Am Fam Physician. 1999;59:381–90392395–six.
six. American Academy of Pediatrics Commission 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 adult female'due south risk of having a pregnancy associated with Down'due south syndrome using her historic period and serum alpha-fetoprotein level. Br J Obstet Gynaecol. 1987;94:387–402.
ix. 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 Doc. 1995;52:2277–83.
11. Wald NJ, Cuckle HS, Densem JW, Nanchahal Yard, 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's 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. North Engl J Med. 1994;330:1114–viii.
16. American College of Medical Genetics Clinical Practice Committee. ACMG position argument on multiple marker screening in women 35 and older. American College of Medical Genetics College Newsletter, Jan 1994;2.
17. American College of Medical Genetics Clinical Practice Committee. Argument on multiple mark screening in pregnant women. American College of Medical Genetics Higher Newsletter, Jan 1996;6.
18. American Higher of Obstetricians and Gynecologists. Maternal serum screening. ACOG Educational Bulletin, 1996; no. 228.
19. Benn PA, Borgida A, Horne D, Briganti Southward, Collins R, Rodis J. Downwards 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 gamble 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;x:91–half dozen.
24. U.S. Preventive Services Task Force. Guide to clinical preventive services: study of the U.Southward. Preventive Services Task Force. 2d ed. Baltimore: Williams & Wilkins, 1996:449–65.
25. Jalal SM, Police ME, Carlson RO, Dewald GW. Prenatal detection of aneuploidy by direct labeled multicolored probes and interphase fluorescence in situ hybridization. Mayo Clin Proc. 1998;73:132–vii.
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. Light-green JM. Women's experiences of prenatal screening and diagnosis. In: Abramsky Fifty, Chapple J, eds. Prenatal diagnosis: the human being side. New York: Chapman & Hall, 1994:37–53.
28. Reynolds TM, Goose egg AB, Dunstan FD, Dawson AJ. Age-specific detection and false-positive rates: an assist to counseling in Down syndrome risk screening. Obstet Gynecol. 1993;81:447–l.
29. Stein MT, Scioscia A, Jones KL, Cohen WI, Drinking glass CK, Glass RF. Responding to parental concerns after a prenatal diagnosis of trisomy 21. J Dev Behav Pediatr. 1997;eighteen:42–6.
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In Women Older Than 45, 1: Babies Has Trisomy 21.
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