Diagnostic Tests

 

Techniques available for prenatal diagnosis of Down syndrome include amniocentesis, chorionic villus sampling, chromosome analysis and fluorescent in situ hybridization Table II.

Amniocentesis looks at the babyís chromosomes from a small amount of amniotic fluid. Amniocentesis poses inherent risks such as miscarriage (.05%), injury to the fetus, and maternal infection. In general, however, the procedure is relatively safe. A complete chromosome analysis (karyotype) takes several weeks to perform.

Chorionic villus sampling (CVS) became available in the early and mid-1980s. During CVS, a piece of placental tissue is obtained either vaginally or through the abdominal wall, usually during the eighth to twelfth week of pregnancy. The cells from the placental tissue are then used for chromosome analysis. It can be performed much earlier in pregnancy, and chromosome studies can be performed immediately, yielding much quicker test results. Studies so far have shown that the miscarriage risk (1%), associated with this procedure is slightly greater than that of amniocentesis.

A technique called fluorescent in situ hybridization (FISH) allows rapid identification (48-72 hrs) of some genetic and chromosome conditions. This can be done on samples obtained by CVS, amniocentesis, or on a blood sample. Using the FISH procedure, DNA is labeled with fluorescent molecules that bind to a specific region on the target chromosome and after staining can be viewed under a fluorescence microscope. With chromosome-specific probes, a specialist quickly can determine the presence of an extra chromosome 21; instead of detecting the typical two signals (one for each chromosome 21), three signals will be observed, indicating that the fetus has Down syndrome.

 

 

TABLE I Summary of Prenatal Screening Methods

SCREENING TEST	TRIMESTER	BIOMARKERS	DETECTION RATE
Fetal sonogram	1ST	NT	65-70%
Combined screen	1ST	NT & PAPP-A or β-HCG	82-87%
Triple test	2nd	AFP, β-HCG & uE3	69%
Quadruple test	2nd	AFP, β-HCG, uE3 & Inhibin-A	81%
Integrated	1st & 2nd	NT, PAPP-A & Quadruple test	94-96%
Serum Integrated	1st & 2nd	PAPP-A & Quadruple test	85-88%
Stepwise sequential	1st & 2nd	1st Combined screen & diagnostic test (amniocentesis or CVS) OR 1st Combined screen & 2nd triple or quadruple screen	95%

From: FASTER Research Consortium, New England Journal of Medicine 353(19):2001-2011 (2005) and ACOG Practice Bulletin Number 77 Obstetrics & Gynecology 109(1):217-227 (2007)

 

 

 

 

TABLE II Summary of Prenatal Diagnostic Methods

DIAGNOSTIC TEST	TRIMESTER	BIOMARKERS	DETECTION RATE	MISCARRIAGE RISK
Chorionic villus sampling	1st (weeks 8 -12)	Chromosome analysis (karyotype) or FISH	> 99%	1%
Amniocentesis	2nd (weeks 14-18)	Chromosome analysis (karyotype) or FISH	> 99%	.05%

 

 

A SYNOPSIS OF ACOG PRACTICE BULLETIN #77

Screening for fetal chromosomal abnormalities [8]

 

ìIn the past decade, numerous markers and strategies for Down syndrome screening have been developed. Algorithims that combine ultrasound and serum markers in the 1^st and 2^nd trimesters have been evaluated. Furthermore, the practice of using age cutoffs to determine whether women should be offered screening or invasive diagnostic testing has been challenged. The purpose of this document is to 1) present and evaluate the best available evidence for the use of ultrasonographic and serum markers for selected aneuploidy screening in pregnancy and 2) offer practical recommendations for implementing Down syndrome screening in practice.î

Glossary of terms:

Aneuploidy, too many or too few chromosomes

Analytes, serum markers

Congenital anomaly, anatomical abnormality

Fetal echocardiogram, ultrasound of the fetal heart

Karyotype, chromosome analysis

Ultrasound, fetal sonogram

 

 

 

 

SUMMARY OF ACOG PRACTICE BULLETIN #77

 

Recommendations & Conclusions

based on good and consistent scientific evidence (Level A)

 

• First trimester screening using both nuchal translucency measurement and biochemical markers is an effective screening test for Down syndrome in the general population. At the same false positive rates, this screening strategy results in a higher Down syndrome detection rate than does the 2^nd-trimester maternal serum triple screen and is comparable to the quadruple screen

 

• Measurement of nuchal translucency alone is less effective for 1^st-trimester screening than is the combined test (NT measurement & biochemical markers)

 

• Women found to have increased risk of aneuploidy with 1^st-trimester screening should be offered genetic counseling and the option of CVS or 2^nd-trimester amniocentesis.

 

• Specific training, standardization, use of appropriate ultrasound equipment, and ongoing quality assessment are important to achieve optimal nuchal translucency measurement and Down syndrome risk assessment, and this procedure should be limited to centers and individuals meeting these criteria.

 

• Neural tube defect screening should be offered in the 2^nd-trimester to women who elect only 1^st-trimester screening for aneuploidy.

 

Recommendations & Conclusions

based on limited or inconsistent scientific evidence (Level B)

 

• Screening and invasive diagnostic testing for aneuploidy should be available to all women who present for prenatal care before 20 weeks of gestation regardless of maternal age. Women should be counseled regarding the differences between screening and invasive diagnostic testing.

 

• Integrated 1^st- and 2^nd-trimester screening is more sensitive with lower false-positive rates than 1^st-trimester screening alone

 

• Serum integrated screening is a useful option in pregnancies where nuchal translucency measurement is not available or cannot be obtained

 

• An abnormal finding on 2^nd-trimester ultrasound examination identifying a major congenital anomaly significantly increases the risk of aneuploidy and warrants further counseling and the offer of a diagnostic procedure

 

• Patients who have a fetal nuchal translucency measurement of 3.5mm or higher, in the 1^st-trimester, despite a negative aneuploidy screen, or normal fetal chromosomes should be offered a targeted ultrasound examination, fetal echocardiogram, or both

 

• Down syndrome risk assessment in multiple gestation using 1^st- or 2^nd-trimester serum analytes is less accurate than in singleton pregnancies

 

• First-trimester nuchal translucency screening for Down syndrome is feasible in twin or triplet gestation but has lower sensitivity than 1^st-trimester screening in singleton pregnancies

 

 

 

Recommended performance measure for practicing Obstetricians

 

Percentage of patients with documentation of discussion regarding Down syndrome screening

 

 

The National down syndrome congress RESPONDS TO

THE ACOG recommendations

 

Human Principles

 

• We do not agree in principle, that ACOG, is justified in formulating Clinical Management Guidelines, on behalf of all practicing Obstetricians, which so blatantly contributes to the devaluation of life in fetuses with chromosomal anomalies including trisomy 21.

 

• In formulating the ACOG Guidelines, the mere existence of fetuses, potential persons and living individuals with trisomy 21 is more likely to be considered diminished or devalued, thereby jeopardizing the protections customarily afforded to any fetus, potential person or living individual.

 

• Unless specifically requested by a pregnant woman or expectant parents, Obstetricians are not justified in rendering any opinion regarding the ìpotential valueî of the life that has been created.

 

Discrimination

 

        The ACOG Clinical Management Guidelines, despite its title ìScreening for Fetal Chromosomal Abnormalitiesî makes only cursory mention of other detectable chromosomal conditions (such as, other autosomal or sex chromosome anomalies, large deletions or duplications, and chromosomal mosacism), and appears to single out fetuses with trisomy 21 for early diagnosis. [The reason(s) for emphasis on trisomy 21 is not entirely clear, but may reflect the relatively high frequency and increased likelihood of survival-to-term for fetuses with trisomy 21, compared to other chromosomal conditions [11]; Obstetrician concerns about wrongful life litigation [12]; and projected cost-savings to ìsocietyî when the birth-rate of babies with special healthcare and educational needs is reduced ]. Regardless of intent, the resultant Clinical Management Guidelines clearly and preferentially targets fetuses with trisomy 21 for early diagnosis.

 

• The primary reasons for 1^st-trimester screening in the general population, as a medically necessary standard-of-care procedure, are not well justified. One interpretation is that the purpose of 1^st-trimester screening is to encourage earlier diagnostic testing in screen-positive, ìhigh riskî pregnancies, in order to facilitate early termination when trisomy 21 or other chromosomal anomalies exist [13] [14]. Other reasons for prenatal diagnosis, such as parent education, hospital selection and delivery management, do not require testing during the 1st trimester.

 

Informed Consent

 

• Requirements for written, informed consent and any action resulting from refusal to consent to screening are not addressed, nor are safeguards against directive-counseling or coercion guaranteed. All medical screening and diagnostic tests need to be fully explained to patients, who should be provided the opportunity to decline or give their informed written consent prior to testing. If patients decline certain tests, physicians and medical personnel should respect the individualís wishes and not overtly or covertly pressure women to undergo prenatal screening or diagnostic testing.

 

Training

 

        The competency and training of medical personnel and guidelines for non-directive counseling, regarding the diagnosis of fetuses with trisomy 21 are not discussed. Obstetricians often lack the training and clinical experience to convey the meaning of Down syndrome to expectant mothers or couples. Studies by Skotko [4] note that many Obstetricians are inadequately prepared to explain a diagnosis of trisomy 21, often using overtly negative language or out-of-date information. Training standards to insure the provision of accurate, balanced information and the source of that information have not been established.

 

Performance Measures

 

        The proposed ACOG performance measure percentage of patients with documentation of discussion regarding Down syndrome screening should already be at 100%, as a part of standard medical practice, and is not an appropriate measure given the intensity of service being recommended. A more appropriate performance measure would be the impact of implementing the ACOG recommendations on the termination rate of trisomy 21 and non-affected fetuses.

 

NDSC Recommendations

 

• Improve the regulation of informed consent and disclosure of information regarding prenatal screening and diagnostic testing for all pregnant women.
• Improve training about Down syndrome for Genetic counselors, Obstetricians, Pediatricians and students in training.
• Educate and support pregnant women or couples with a positive screen or diagnosis for trisomy 21.
• Monitor statistics regarding termination and non-termination rates for all fetuses with chromosomal anomalies, including trisomy 21.

 

References

 

1. Pueschel, S., Ethical issues pertaining to prenatal diagnosis of Down syndrome, in Down syndrome: A review of current knowledge, J. Rondal and L. Nadel, Editors. 1999, Whorr Publishers Ltd: London. p. 170-177.

2. Chervenak, F., L. McCullough, and S. Chassen, Clinical implications of the ethics of informed consent for the first-trimester risk assessment for trisomy 21. Seminars in Perinatology, 2005. 29: p. 277-279.

3. Glover, N.M. and S.J. Glover, Ethical and legal issues regarding selective abortion of fetuses with Down syndrome. Mental Retardation, 1996. 34(4): p. 207-214.

4. Skotko, B., Prenatally diagnosed Down syndrome: Mothers who continue their pregnancies evaluate their health care providers. American Journal of Obstetrics & Gynecology, 2005. 192: p. 670-677.

5. Vassy, C., From a genetic innovation to mass health programmes: The diffusion of Down's Syndrome prenatal screening and diagnostic techniques in France. Social Science & Medicine, 2006. 63: p. 2041-2051.

6. Reddy, U.M. and M.T. Mennuti, Incorporating first-trimester Down syndrome studies into prenatal screening. Obstetrics & Gynecology, 2006. 107(1): p. 167-173.

7. Malone, F.D., N.J. Wald, and M.E. D'Alton, First-trimester or second-trimester screening, or both, for Down's syndrome. The New England Journal of Medicine, 2005. 353(19): p. 2001-2011.

8. Bahado-Singh, R. and D. Driscoll, ACOG Practice Bulletin 77, Clinical Management Guidelines for Obstetrician-Gynecologists: Screening for fetal chromosomal abnormalities. Obstetrics & Gynecology, 2007. 109(1): p. 217-227.

9. Odibo, A.O., D.M. Stamilio, and D.B. Nelson, A cost-effectiveness analysis of prenatal screening strategies for Down syndrome. Obstetrics & Gynecology, 2005. 106(3): p. 562-568.

10. Macones, G.A. and A. Odibo, First trimester screening: Economic implications. Seminars In Perinatology, 2005. 29: p. 263-266.

11. Canfield, M.A., M.A. Honein, and N. Yuskiv, National estimates and race/ethnic-specific variation of selected birth defects in the united states, 1999-2001. Birth Defects Research (Part A): Clinical and Molecular Teratology, 2006. 76: p. 747-756.

12. ACOG Survey on professional liability results. 2007, ACOG website http://www.acog.org/departments/dept_notice.cfm?recno=4&bulletin=3963.

13. Mansfield, C., S. Hopfer, and T. Marteau, Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: A systematic literature review. Prenatal Diagnosis, 1999. 19: p. 808-812.

14. Siffel, C., A. Correa, and J. Cragan, Prenatal diagnosis, pregnancy terminations and prevalence of Down syndrome in Atlanta. Birth Defects Research (Part A): Clinical and Molecular Teratology, 2004. 70: p. 565-571.