Chances of Having Down Sydrome Baby at Age 30
Downward Syndrome: Prenatal Risk Cess and Diagnosis
A more contempo article on this topic is available.
Am Fam Physician. 2000 Aug xv;62(iv):825-832.
See related patient information handout on Down's syndrome, written past the writer of this article.
Related Editorial
Commodity 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 age. All forms of prenatal testing for Down's 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 eighteen weeks of gestation. The maternal serum markers used to screen for trisomy 21 are alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin. The employ of ultrasound to estimate gestational historic period improves the sensitivity and specificity of maternal serum screening.
Down syndrome is a variable combination of built malformations caused by trisomy 21. It is the most commonly recognized genetic crusade of mental retardation, with an estimated prevalence of 9.2 cases per 10,000 alive births in the United States.i,two Considering 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 option of continuing or terminating an affected pregnancy.
Etiology and Clinical Manifestations
- Abstruse
- Etiology and Clinical Manifestations
- Prenatal Chance Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Down's syndrome is usually identified soon after nativity past a characteristic pattern of dysmorphic features (Table 1).3,4 The diagnosis is confirmed past 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 ii percentage. The remaining 3 pct 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 counterbalanced by a chromosome deletion.1,three,four
TABLE i
Frequency of Dysmorphic Signs in Neonates with Trisomy 21
| Dysmorphic sign | Frequency (%) |
|---|---|
| Flat facial contour | 90 |
| Poor Moro reflex | 85 |
| Hypotonia | 80 |
| Hyperflexibility of large joints | lxxx |
| Loose skin on back of neck | eighty |
| Slanted palpebral fissures | 80 |
| Dysmorphic pelvis on radiographs | 70 |
| Small round ears | 60 |
| Hypoplasia of small finger, middle phalanx | 60 |
| Single palmar pucker | 45 |
Molecular genetic studies reveal that 95 percent of occurrences of trisomy 21 outcome from nondisjunction during meiotic division of the primary oocyte.i The exact machinery for this meiotic error remains unknown. Most trisomy 21 pregnancies prove to exist nonviable. Only ane quarter of fetuses with trisomy 21 survive to term.4
Persons with Down syndrome usually take mild to moderate mental retardation. In some, mental retardation can be severe. School-aged children with Down's syndrome ofttimes have difficulty with language, communication and problem-solving skills. Adults with Down's syndrome have a loftier 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).one,3–half-dozen Congenital centre disease and pneumonia are leading causes of bloodshed, 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 on Alzheimer's illness | Affects 75% by historic period 60 |
| Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot) | twoscore |
| 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 string compression | < 1 |
| Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis, periodontal disease) | Unknown |
| Infertility | > 99% in men; anovulation in 30% of women |
Prenatal Risk Assessment
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Run a risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Avant-garde MATERNAL Age
The incidence of fetal trisomies is directly related to maternal age.7 The risk of having a child with Down's syndrome increases in a gradual, linear style until virtually age 30 and increases exponentially thereafter (Figure one).eight The run a risk of having a child with Down syndrome is 1/1,300 for a 25-year-old woman; at historic period 35, the risk increases to 1/365. At age 45, the hazard of a having a child with Down's syndrome increases to ane/30. (By convention, maternal historic period refers to age at the estimated or actual delivery engagement.)
Effigy 1.
Estimated gamble of Down syndrome according to maternal historic period. Information from reference eight.
Historically, maternal age can be viewed every bit the first "screening examination" for fetal chromosome abnormalities. In the late 1970s, nigh 5 percentage of pregnancies in the United States occurred in women who were 35 years or older.9 At historic period 35, the 2nd-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 every bit the screening cutoff—the gamble threshold at which diagnostic testing is offered.
MATERNAL SERUM SCREENING
If all pregnant women 35 years or older chose to take amniocentesis, most thirty per centum of trisomy 21 pregnancies would be detected.11 Women younger than 35 years give birth to about seventy percent of infants with Down's syndrome.12 Maternal serum screening (multiple-marker screening) can allow the detection of trisomy 21 pregnancies in women in this younger age grouping.
Alpha-fetoprotein (AFP), unconjugated estriol and human chorionic gonadotropin (hCG) are the serum markers well-nigh widely used to screen for Down syndrome.xiii 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, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels and maternal serum hCG is approximately 2 times college than the normal hCG level.12
The triple exam is normally performed at fifteen to xviii 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 historic period 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'southward historic period. A blended estimate of the hazard of trisomy 21 is reported to the clinician. A standard hazard cutoff is used to determine when the test is considered "positive." Well-nigh laboratories use a risk cutoff of 1/270, which is equal to the 2nd-trimester risk of trisomy 21 in a 35-year-sometime woman.13 A positive examination is an indication for amniocentesis (Figure 2).
Screening for Downward Syndrome
FIGURE 2.
Algorithm for Down's syndrome screening using the triple test results and a gamble of 1/270 or higher. (LMP = last menstrual period)
The triple test tin can discover 60 percentage of trisomy 21 pregnancies; it has a simulated-positive rate of 5 percent.xi,14 The likelihood of a fetus having trisomy 21 in a patient with a positive exam is about 2 per centum. A normal outcome reduces the likelihood of trisomy 21 but does not exclude information technology. Test operation tin exist slightly improved by adjusting for maternal weight, ethnic group and insulin-dependent diabetes mellitus.12 In 1995 in the Usa, 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 Nevertheless, the triple examination fails to detect x to 15 percentage of trisomy 21 pregnancies in women in this older age group.16 Therefore, current U.S. do standards indicate that for women 35 years or older, maternal serum screening should non be offered as an equivalent culling to amniocentesis or chorionic villus sampling.xvi–18 Guidelines published past the American College of Obstetricians and Gynecologists state that maternal serum screening may be offered "as an option for those women who practise not accept the risk of amniocentesis or chorionic villus sampling or who wish to have this additional information prior to making a conclusion nearly having amniocentesis."18
ULTRASOUND Cess
An gauge of gestational age by ultrasound examination improves the functioning of the triple exam. In ane study,19 the utilise of ultrasound was establish to raise the sensitivity of the triple test from 60 percent to 74 percent and to subtract the initial simulated-positive rate from nine percent to v per centum. When available, an ultrasound estimate of gestational historic period should be provided to the laboratory instead of the due appointment based on the patient'due south last menstrual period. The biparietal bore provides the best gestational age guess 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.xix
Second-trimester ultrasound assessment may be helpful for predicting the likelihood of trisomy 21 in pregnancies at increased risk.xx,21 This method of evaluation may be useful when amniocentesis is existence considered in a patient with advanced maternal historic period or positive findings on the triple exam. The well-nigh mutual ultrasonographic finding associated with trisomy 21 is increased nuchal fold thickness (nuchal translucency), which is acquired past subcutaneous edema at the base of the occiput (Tabular array iii).20–22
TABLE three
Ultrasonographic Findings Associated with Fetal Down syndrome
| Intrauterine growth restriction |
| Balmy cerebral ventriculomegaly |
| Choroid plexus cysts |
| Increased nuchal fold thickness |
| Cystic hygromas |
| Echogenic intracardiac foci |
| Congenital center 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 betwixt first and second toes |
| 2-vessel umbilical string |
Starting time-TRIMESTER SCREENING
Ultrasound measurement of nuchal translucency has been studied alone and in combination with new biochemical markers every bit a potentially useful first-trimester screening test for trisomy 21. Estimates are that outset-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 percentage false-positive rate.23 Combining this procedure with measurement of maternal serum complimentary beta-hCG subunit and pregnancy-associated protein A (PAP A) could increase the detection rate to lxxx percentage, at the same imitation-positive rate.23 Further study of the clinical utility and reliability of starting time-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 ane percent in a higher place the baseline hazard 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 take normal karyotypes, the recurrence chance is ii to 3 percent. If one parent carries a counterbalanced translocation, the recurrence risk depends on the sex of the carrier parent and the specific chromosomes that are fused.four
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
- Abstract
- Etiology and Clinical Manifestations
- Prenatal Risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Definitive prenatal diagnosis of trisomy 21 requires cytogenetic assay of cells obtained by one of iii invasive procedures (Table four).10 Second-trimester amniocentesis has been used the virtually extensively, and the safety of this technique continues to improve equally technical advances have occurred.24 Chorionic villus sampling offers the opportunity for first-trimester diagnosis, when elective pregnancy termination carries the lowest hazard of maternal morbidity, every bit 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.ten
Karyotype analysis ordinarily 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 historic period 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 xx | 0.5 to 1.0 |
Counseling Aspects
- Abstruse
- Etiology and Clinical Manifestations
- Prenatal Risk Assessment
- Prenatal Diagnosis
- Counseling Aspects
- References
Assessment of the hazard of Down syndrome begins with the beginning prenatal visit. All forms of prenatal testing for Downwards syndrome must be voluntary. A nondirective arroyo 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 abnormality or if either parent is known to carry a balanced translocation.
Women who will exist 35 years or older on their due date should be offered chorionic villus sampling or 2nd-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 well-nigh the imperfect sensitivity of maternal serum screening and the possibility that a false-positive result could atomic number 82 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 exist reassured by the knowledge that the likelihood of Downward syndrome is modest, fifty-fifty after a positive triple test.28 Ultrasound and amniocentesis should be offered. The risk of fetal loss from amniocentesis should exist 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, standing the pregnancy and seeking adoption placement for the child or terminating the pregnancy. Consultation with a genetic advisor, a medical geneticist or a developmental pediatrician can be helpful to address the parents' concerns and facilitate their controlling process.29
Parents who decide to continue the pregnancy should be advised that there is an increased run a risk of fetal demise in trisomy 21 pregnancies. A fetal echocardiogram should be performed at xx weeks of gestation to discover serious cardiac malformations. An ultrasound test 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 Downward syndrome and their families.five A positive outlook should be encouraged, recognizing that improvements in medical intendance, early on intervention, special pedagogy and vocational counseling accept enabled persons with Down's syndrome to live more normal lives.29
SOURCES OF INFORMATION FOR PATIENTS AND PHYSICIANS
In add-on to the patient information handout that accompanies this article, a more detailed brochure, "Facts About Downwardly Syndrome," has been produced past the National Found of Kid Health and Man Development (NIH Publication No. 97–3402). This brochure is available in English and Castilian from NICHD Clearinghouse, PO Box 3006, Rockville, Dr. 20847; telephone: 800-370-2943. In addition, the Genetic Counseling and Primary Care Spider web site (http://stork.cellb.bcm.tmc.edu/~genetics/) provides links to sources of boosted information nigh Down's syndrome and case-oriented tutorials on topics in genetics and genetic counseling.
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This work was supported in part past a Faculty Development Grant from the Bureau of Health Professions, Health Resource and Services Administration.
REFERENCES
show all references
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2. Down's 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–five.
4. Tolmie JL. Down syndrome and other autosomal trisomies. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin'south Principles and do of medical genetics. 3rd ed. New York: Churchill Livingstone, 1996:925–71.
five. Saenz RB. Main care of infants and young children with Down syndrome. Am Fam Md. 1999;59:381–90392395–6.
half-dozen. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Atlantoaxial instability in Down's syndrome: bailiwick review. Pediatrics. 1995;96:151–iv.
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'due south 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 clan 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 G, Royston P, Chard T, et al. Maternal serum screening for Downward'southward 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.
xiii. Palomaki GE, Knight GJ, McCarthy JE, Haddow JE, Donhowe JM. Maternal serum screening for Down's syndrome in the Usa: 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 Downwardly'due south syndrome with use of maternal serum markers. Due north Engl J Med. 1992;327:588–93.
15. Haddow JE, Palomaki GE, Knight GJ, Cunningham GC, Lustig LS, Boyd PA. Reducing the demand for amniocentesis in women 35 years of age or older with serum markers for screening. Northward Engl J Med. 1994;330:1114–8.
sixteen. American Higher of Medical Genetics Clinical Practice Commission. ACMG position statement on multiple marker screening in women 35 and older. American Higher of Medical Genetics Higher Newsletter, January 1994;2.
17. American Higher of Medical Genetics Clinical Do Committee. Argument on multiple marker screening in pregnant women. American College of Medical Genetics College Newsletter, Jan 1996;6.
xviii. 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 historic period 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 direction of patients at increased hazard for fetal trisomy 21. Obstet Gynecol. 1996;87:948–52.
22. Gross SJ, Bombard AT. Screening for the aneuploid fetus. Obstet Gynecol Clin Due north Am. 1998;25:573–95.
23. Chitty LS. Antenatal screening for aneuploidy. Curr Opin Obstet Gynecol. 1998;10:91–half dozen.
24. U.S. Preventive Services Task Force. Guide to clinical preventive services: written report of the U.S. Preventive Services Chore Force. 2nd ed. Baltimore: Williams & Wilkins, 1996:449–65.
25. Jalal SM, Police force 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 50. Counseling prior to prenatal testing. In: Abramsky Fifty, Chapple J, eds. Prenatal diagnosis: the human side. New York: Chapman & Hall, 1994:70–85.
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29. Stein MT, Scioscia A, Jones KL, Cohen WI, Glass CK, Glass RF. Responding to parental concerns afterwards a prenatal diagnosis of trisomy 21. J Dev Behav Pediatr. 1997;18:42–half dozen.
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