Chapter IV.3. Prenatal Genetic Screening and Diagnosis
Greigh I. Hirata, MD
June 2013

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Ms. S is a 42 yo G3P0Sab2 who presents at 12 weeks gestation seeking information regarding her prenatal screening and testing options. She is of Caucasian/Hawaiian/Chinese ethnicity and has suffered two unexplained first trimester miscarriages. She is otherwise healthy and has no medical illnesses. She also denies any history of medication, drug, alcohol, or toxin exposure. The father of the baby, Mr. W, is 50 yo of Japanese/Filipino ethnicity. He has 2 healthy children from a previous marriage and reports no history of medical illnesses.

A complete medical and family history is obtained. A review of her past obstetrical history reveals that the pregnancy losses both occurred at 11 weeks. The losses followed an otherwise normal first trimester ultrasound. The work up for these unexplained losses included negative maternal evaluations for thrombophilia, uterine structural abnormalities and medical illnesses. Karyotypes performed on she and her partner were normal. A three generation pedigree is unremarkable for birth defects, genetic conditions, and unexplained pregnancy losses. The remainder of the social history and a review of symptoms are noncontributory.

A first trimester ultrasound is performed and the fetal viability, size, and anatomy appear appropriate for her gestational age. The evaluation of the nuchal translucency was also normal. She was offered prenatal screening with a combined first and second trimester serum analyte analysis (known as sequential or integrated screening) or a newly available test for cell free fetal DNA in a maternal blood sample that can screen for several common aneuploidy conditions; a type of non-invasive prenatal screen (NIPS). Invasive diagnostic testing for aneuploidy, including chorionic villus sampling and amniocentesis, was also discussed. Based on the options available, Ms. S chose NIPS which returned 10 days later as “aneuploidy not detected” for Trisomy 21, 18, 13, and sex chromosomes. The fetus was found to be male.

Five weeks later she underwent a targeted ultrasound which was normal. She was offered maternal serum screening for neural tube defects and abdominal wall defects (measurement of serum alpha-fetoprotein) which she declined because of the normal ultrasound examination.

Ms. S ultimately delivered a 3290 g male infant at 39 weeks gestation. Both mother and baby did well and were discharged on her 2nd postpartum day.

This case illustrates many important aspects of prenatal screening and testing. Medical evaluations begin with a careful review of her medical and obstetrical history. Pertinent information to obtain includes the maternal age, past obstetrical history, family history (including the partner’s health and family history), ethnic background, medication or other potential teratogenic exposures and medical illnesses. This helps in determining the estimation of risk for birth defects (e.g., congenital heart lesions, neural tube defects), genetic diseases, and aneuploidy.

In counseling pregnant women about birth defects, it is important to note that the background risk of birth defects in the general population is 3% to 4%. Birth defects can be isolated or syndromic, and can be caused by genetic and/or teratogenic factors. Some birth defects are "sporadic" (e.g., amniotic band disruption sequence), with a negligible recurrence risk and no known genetic or teratogenic factors contributing. Multifactorial birth defects are thought to be a result of a genetic predisposition in combination with the known or unknown environmental influences. Spina bifida cystica and most congenital heart defects are examples birth defects with multifactorial inheritance. Recurrence risk for the couple for these types of disorders is typically 3% to 5%, but can be modified by primary prevention such as the use of preconceptional folic acid to reduce the risk for recurrent neural tube defect.

Autosomal aneuploidies are mostly associated with advanced maternal age. The best known and most common is trisomy 21 which results in Down syndrome. Although Down syndrome may be familial and inherited from a parent because of a Robertsonian translocation, the majority of cases of Down syndrome are a result of an extra chromosome 21 of maternal origin. Other types of autosomal aneuploidies in decreasing order of incidence include trisomy 18 (Edward syndrome) and trisomy 13 (Patau syndrome). Sex chromosomal aneuploidies (e.g., 45,X or Turner syndrome) occur sporadically and are typically not associated with maternal age.

Maternal screening for aneuploidy has evolved from simply using maternal age to estimate risk to more sophisticated algorithms in which maternal age, biochemical serum markers/analytes, and ultrasound are utilized to calculate risks. Today, the most accurate screening test for Down syndrome includes first trimester serum analytes (inhibin and beta subunit of human chorionic gonadotropin), first trimester ultrasound measurement of the fetal nuchal translucency (identifies fluid in the soft tissue of the posterior neck suggestive of Down syndrome), and second trimester serum analytes (unconjugated estriol, alpha fetoprotein, and pregnancy associated placenta protein A). Together, these are known as integrated screening tests or sequential integrated screening tests. These independent markers and the maternal age are used to calculate a risk for Down syndrome. Assuming a 5% false positive rate, the estimated sensitivity is 92% to 96%. The test also screens for fetal neural tube and ventral abdominal wall defects as well as trisomy 18.

Second trimester ultrasound is a good screening tool for major fetal structural abnormalities such as complex congenital heart lesions, abdominal wall defects (e.g., omphalocele), neural tube defects and skeletal abnormalities. This modality is greatly dependent on the sonographer and in expert hands has a sensitivity of 75% in detecting fetal anomalies. However, only 50% of pregnancies with Down syndrome are detected by ultrasound.

In 1997, it was reported that cell free fragments of fetal DNA (cffDNA) circulate in the maternal blood as early as 6 weeks gestation. These DNA fragments represent the entire fetal genome and appear to originate from the placental cytotrophoblast. The cffDNA rapidly disappears after delivery. A new test analyzing these fragments of cffDNA has the promise of greatly improving screening for the common fetal autosomal aneuploidies. It has many of the desired attributes of a good screening test including high sensitivity, high specificity, low false positive rate, low false negative rate, and low risk to the pregnancy at a relatively low cost (see Table). Studies on high risk patient populations show that NIPS (non-invasive prenatal screen) has 99.9% sensitivity and 99.9% specificity for Down syndrome detection with a false positive rate of less than 1%. It is currently being tested on a low risk population and, although the positive and negative predictive values may be altered, the sensitivity and specificity of the test in this low risk population are not expected to be significantly changed.

Disease positive
Disease negative
Test positive
A (true positive)
B (false positive)
Test negative
C (false negative)
D (true negative)

Sensitivity = A / (A + C)
Positive predictive value = A / (A + B)

Specificity = D / (B + D)
Negative predictive value = C / (C + D)

Screening tests are designed to identify a population of patients at a high risk for the screened condition. Diagnostic tests are designed to be definitive for that condition. In the setting of pregnancy testing for chromosomal abnormalities, chorionic villus sampling and amniocentesis are diagnostic tests.

Chorionic villus sampling is typically performed in the first trimester of pregnancy. This involves a biopsy of the placenta either transabdominally with a needle or transcervically with a catheter. The placental cells typically reflect the chromosomes of the fetus. The tissue then may be analyzed for a karyotype or DNA can be extracted and analyzed for genetic diseases or traits. This invasive test has an estimated fetal loss rate of 1%.

Amniocentesis is a procedure where amniotic fluid is removed from the uterus through a transabdominal percutaneous approach. The fetal cells suspended in the amniotic fluid originate from the fetus (skin, bladder, and lung) and placenta. It accurately reflects the fetal genetic information and thus can be analyzed for a karyotype or genetic disease much like that of a chorionic villus sample. In addition, the amniotic fluid supernatant contains fetal alpha-fetoprotein (AFP). This protein is elevated in fetal conditions such as spina bifida and ventral abdominal wall defects. Analysis of the level of this protein allows for the diagnosis of these fetal conditions. The estimated risk for a genetic amniocentesis is 0.25% (1:400).

We have seen how screening and testing for birth defects begin with a careful solicitation of the history of both mother and father. Significant information includes medical illnesses, exposures, and family history. This information then directs the options for screening and diagnostic testing.


1. Which of the following fetal conditions are NOT associated with maternal age?
. . . . . a. Down syndrome/Trisomy 21
. . . . . b. Edward syndrome/Trisomy 18
. . . . . c. Patau syndrome/Trisomy 13
. . . . . d. Spina bifida cystica

2. True/False: Chorionic villus sampling would determine if the fetus has an omphalocele.

3. Non-invasive prenatal testing is able to detect all of the following conditions except:
. . . . . a. Down syndrome/Trisomy 21
. . . . . b. Edward syndrome/Trisomy 18
. . . . . c. Turner syndrome
. . . . . d. Tetralogy of Fallot

4. The advent of non-invasive prenatal testing is based on cell free fetal DNA thought to originate from the following source(s):
. . . . . a. Placenta
. . . . . b. Fetal skin
. . . . . c. Fetal blood
. . . . . d. Fetal bladder

5. The most common aneuploidies in descending order in a live born are:
. . . . . a. Down syndrome, Edward syndrome, Patau syndrome
. . . . . b. Edward syndrome, Down syndrome, Patau syndrome
. . . . . c. Down syndrome, Patau syndrome, Edward syndrome
. . . . . d. Patau syndrome, Edward syndrome, Down syndrome

6. True/False: The sensitivity and specificity of a laboratory test is significantly influenced by the incidence of the disease in the population.

7. True/False: The positive and negative predictive value of a laboratory test is significantly influenced by the incidence of the disease in the population.

8. Attributes of a good screening test include:
. . . . . a. High sensitivity and specificity
. . . . . b. Low cost
. . . . . c. Low risk
. . . . . d. All of the above

9. True/False: Non-invasive prenatal screening (NIPS) with cell free DNA has the ability to detect over 99% of pregnancies affected with Down syndrome.

10. True/False: Invasive testing with chorionic villus sampling and amniocentesis are both designed to detect chromosomal abnormalities.


1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 77: screening for fetal chromosome abnormalities. Obstet Gynecol 2007;109(1):217-227.

2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88: Invasive prenatal testing for aneuploidy. Obstet Gynecol 2007;110(6):1459-67.

3. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No 545. Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012;120(6):1532-1534.

Answers to questions

1. d. Spina bifida cystica

2. False

3. d. Tetralogy of Fallot

4. a. Placenta

5. a. Down syndrome, Edward syndrome, Patau syndrome

6. False

7. True

8. d. All of the above

9. True

10. True

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