[ Editorials | Letters | Selected Articles | Departments and Series | Patient Handouts | Index ]

The Human Genome

Update on Prenatal Genetic Screening

Jennifer E. Lee, MS; Joann N. Bodurtha, MD, MPH; Pamela S. Board, MS, CGC; John M. Quillin, MS, CGC

When a nervous patient contemplating her first pregnancy, or an experienced mother expecting her fifth child has questions about birth defects or genetic conditions, prenatal genetic screening and genetic counseling can help to provide information. As a health care provider, supplying information about what prenatal screening is available and what the results indicate is an important role. Keeping up to date on the most current tests and interpretation of the results can be challenging in an ever-changing field.

As with any screening program, the tests are designed to provide more personalized information about a general population risk. With the results of such testing, pregnancies without known genetic conditions or birth defects should be identified as such, and some reassurance can be provided to the families. These tests are optional and some patients will choose not to have any screening tests performed. Therefore, any screening tests should be performed with consent from the patient and with respect for her regardless of the decisions made about testing or about the results. Patients with abnormal results should be informed of the results and given appropriate counseling, follow-up, and opportunities for ultrasound and diagnostic testing (eg, amniocentesis, chorionic villus sampling [CVS]). Options that might be considered when a condition is confirmed are continuation of the pregnancy with the opportunity to make plans for the birth of a child with special needs, some in utero treatments, or termination of the pregnancy.

It is important for providers and patients to understand that screening tests are typically not diagnostic, so false positive and false negative results may occur.¹ An abnormal result does not necessarily mean the pregnancy has an abnormality, and likewise, a normal test result does not guarantee a healthy child. False positive rates of 5% or less are traditionally used for general prenatal screening, while a maximum detection rate is preferred.

Some screening is possible using general information reported by the patient such as maternal age; American College of Obstetrics and Gynecology (ACOG) family history checklists; maternal medical conditions; drug and medication use; and ethnicity. For example, the American College of Medical Genetics (ACMG) and ACOG have recently recommended genetic screening for cystic fibrosis (CF) in patients with a positive family history of CF; partners of individuals with CF; couples planning a pregnancy; and couples seeking prenatal care.² These groups recommend that CF testing be offered to whites (who have the highest incidence) and patients of Ashkenazi Jewish descent (who have the highest detection rate), and that the testing be made available to other groups (where the condition is rare and the testing is not as sensitive).

Clinical screening tests primarily include biochemical and imaging methods. Other methods, including isolating fetal cells from maternal blood or cervical samples, are under investigation and may be available in the future.³

Biochemical Screening

Maternal serum a-fetoprotein (MSAFP) has been used to screen for cases of open neural tube defects (ONTD) early in the second trimester (14 to 22 gestational weeks) for more than 2 decades. As screening continued, low levels of MSAFP were also noted to be associated with an increased risk for Down syndrome.^4,5 In routine testing, total human chorionic gonadotropin (hCG) and unconjugated estriol (uE₃) are included with MSAFP in a "triple test" and can screen for not only ONTDs and Down syndrome but also for trisomy 18 and a few other conditions (Table 1). Screening does not detect all chromosome conditions, such as trisomy 13 and sex chromosome conditions. Dimeric inhibin-A (dIA) has recently been added to create a "quad" or "tetra" screen with slightly increased detection rates for Down syndrome.⁶ While both are acceptable tests, cost, availability, and detection rate may all influence the practitioner's and the patient's decision to use three or four analytes in screening.

View this table

Table 1. Detection Rates for Second Trimester Maternal Serum Screening*6,12

Based on empirical findings of increased rates of aneuploidy in older mothers, pregnant women at least 35 years old are routinely offered diagnostic prenatal testing through amniocentesis or CVS. Although biochemical screening is advocated by some to reduce overall rate of invasive testing and, therefore, procedure-related pregnancy loss, the ACMG recommends that maternal serum screening not replace the offer of diagnostic testing for women at least 35 years of age.^4,7,8 Counseling is recommended before using maternal serum screening for pregnant women at least 35 years of age, as serum screening does not look for all chromosome conditions and the false positive rate is typically increased over that for women younger than 35 years of age.

Recently, first trimester biochemical screening has demonstrated similar or better detection rates than second trimester screening for women aged 35 years and older. Beta-human chorionic gonado-tropin (b-hCG) and pregnancy-associated plasma protein A (PAPP-A) can assess a risk for Down syndrome, but not ONTD. These biochemical screens are often used in conjunction with ultrasound markers to produce a total risk estimate (Table 2). Other biochemical markers (such as isoferritin p43) as well as use of alternative samples (such as maternal urine) are under investigation for feasibility as screening tools.⁹

View this table

Table 2. Down Syndrome Detection Rates for Biochemical and Ultrasound Screening (MA ≥ 35y)*5,9,10,13

Ultrasonography

Ultrasonography is another important technique used to better determine the risk for birth defects and chromosome conditions. The identification of any major anomalies (eg, ONTDs, cardiac defects) has implications for management of the birth defect itself as well as implications for the underlying genetic cause. Counseling and invasive testing may be appropriate next steps when an anomaly is identified.
With no major anomalies identified on ultrasound examination, minor findings or "markers" can also increase the risk for aneuploidy, genetic conditions, or other complications (Table 3). Normal results from ultrasound examination for women at "high risk" for aneuploidy can decrease this risk, perhaps by 50%.^5,8 Again, ultrasonography is another screening method and is not as informative as diagnostic testing for aneuploidy.

View this table

Table 3. Ultrasound Findings Associated With Aneuploidy*8,11,13

For ultrasound and biochemical screening, attention is shifting toward first trimester tests for earlier results with equivalent or better detection rates. Women tend to prefer first trimester screening to second trimester due to the earlier reassurance for most, and earlier, safer termination options for others.^9,10 The nuchal translucency (NT) can be measured from 11 to 14 weeks, and increased measurements can raise the risk for aneuploidy, especially Down syndrome, with high sensitivity.^4,5,11 However, many factors, such as operator skill, available time, gestational age, and maternal age all influence the measurement of the NT. Increased NT has not only been seen with Down syndrome but other aneuploidies as well, and in pregnancies at higher risks for spontaneous fetal demise, rare genetic syndromes, and structural anomalies (especially cardiac defects).^9,10,13 Absence of the nasal bone in the first trimester has also been associated with Down syndrome. Even with advances in first trimester screens, second trimester MSAFP and/or ultrasound is recommended to screen for ONTD. Along with new markers, new imaging techniques are being studied as prenatal screening tests; these include three- and four-dimensional ultrasound and fetal magnetic resonance imaging.¹¹

Summary

Prenatal screening is always optional, and with informed consent, patients can decide if the information is important or will benefit them personally. Prenatal screening is just that: screening. The results typically increase or decrease risk estimates without giving absolutes, so appropriate interpretation and follow-up are necessary.

Cystic fibrosis carrier testing, other ethnic screening tests, maternal serum screening, and ultrasonography are currently able to detect a number of birth defects and genetic conditions. First trimester biochemical and sonographic screens are becoming more commonly employed and better characterized.

New and experimental techniques have evolved into practical screens and certainly more techniques will be used in the future. For more information and updates, look to GeneTests (www.genetests.org), the March of Dimes (www.modimes.org), ACOG (www.acog.net) and the National Society of Genetic Counselors (www.nsgc.org).

Jennifer E. Lee, MS, is genetic counselor; Joann N. Bodurtha, MD, MPH, is professor of human genetics, pediatrics, and obstetrics and gynecology; Pamela S. Board, MS, CGC, is genetic counselor; and John M. Quillin, MS, CGC, is genetic counselor; all are at the Department of Genetics, Virginia Commonwealth University, Richmond.

References

1. American College of Medical Genetics. Principles of Screening: Report of the Subcommittee on Screening of the ACMG Clinical Practice Committee. Bethesda, Md:ACMG;1997:a997.
2. Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG. American College of Medical Genetics. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. 2001;3(2):149-154.
3. Miny P, Tercanli S, Holzgreve W. Developments in laboratory techniques for prenatal diagnosis. Curr Opin Obstet Gynecol. 2002;14(2):161-168.
4. Benn P. Improved antenatal screening for Down's syndrome. Lancet. 2003; 361(9360):794-795.
5. Benn PA. Advances in prenatal screening for Down syndrome: I. General principles and second trimester testing. Clin Chim Acta. 2002;323(1-2):1-16.
6. Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening for Down's syndrome with the quadruple test. Lancet. 2003; 361(9360):835-836..
7. American College of Medical Genetics. ACMG position statement on multiple marker screening in women 35 and older. Bethesda, Md: ACMG Newsletter;1994.
8. Nyberg DA, Souter VL, El-Bastawissi A, Young S, Luthhardt F, Luthy DA. Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. J Ultrasound Med. 2001;20(10):1053-1063.
9. Benn PA. Advances in prenatal screening for Down syndrome: II First trimester testing, integrated testing, and future directions. Clin Chim Acta. 2002;324(1-2):1-11.
10. Cuckle H. Time for total shift to first-trimester screening for Down's syndrome. Lancet. 2001;358(9294): 1658- 1659.
11. Snijders R, Smith E. The role of fetal nuchal translucency in prenatal screening. Curr Opin Obstet Gynecol. 2002; 14(6):577-585.
12. Yankowitz J, Fulton A, Williamson R, Grant SS, Budelier W. Prospective evaluation of prenatal maternal serum screening for trisomy 18. Am J Obstet Gynecol. 1998;178(3):446-450.
13. Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW, Macri JN. First-trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstet Gynecol. 2000;96(2):207-213.

Written in memory of Lorna Phelps, friend and genetic counselor.

back to top