First-Trimester Screening Case File

First-Trimester Screening Case File

Eugene C. Toy, MD, Konrad P. Harms, MD, Keith O. Reeves, MD, Cristo Papasakelariou, MD, FACOG

Case 2

A 36-year-old G2P1001 woman presents as a transfer of care at 10 weeks’ gestation. She was previously receiving care with another obstetrician until her insurance changed. She has no significant medical or family history. Her last pregnancy 4 years ago ended in a term delivery of a healthy female infant. She is aware of the increased likelihood of fetal chromosome disorders associated with maternal age over 35. She was advised by her previous doctor to undergo amniocentesis later in pregnancy. She is uneasy about waiting until after 16 weeks to get any information on the fetal chromosome status. Conversely, she is also uneasy about putting this pregnancy at risk by undergoing an invasive prenatal diagnostic procedure.

➤ What first-trimester screening/testing options does this patient have to address her risk for fetal aneuploidy?

➤ Would your recommendations for screening versus testing be any different if she was 26 years old instead of 36 years old?

ANSWERS TO CASE 2:

First-Trimester Screening

Summary: A G2P1001 at 10 weeks’ gestation with advanced maternal age seeks information regarding aneuploidy testing.

➤ First-trimester screening/testing options to address risk for fetal aneuploidy: This patient has the option of aneuploidy screening with serum biochemical markers in combination with nuchal translucency or invasive testing with chorionic villus sampling (CVS) if available.

➤ Recommendations for screening versus testing if patient was 26 years old instead of 36 years old: Obviously the difference for these two patients would be the a priori risk for fetal chromosome abnormalities each of these patients has. If patients truly understand the nuances and limitations of screening versus testing, there should be no important differences in the type of counseling each of these age groups should receive. All patients should be offered invasive testing for prenatal diagnosis of fetal chromosome abnormalities, and all patients should be offered noninvasive screening, if they choose to do so, before deciding about invasive testing.

ANALYSIS

Objectives

1. Become familiar with first-trimester screening and diagnostic testing options for aneuploidy.
2. Understand the biochemical and ultrasound components for aneuploidy screening in the first trimester.
3. Understand combination first- and second-trimester screening modalities and their detection rates.

Considerations

This patient should first decide about any further testing from two broad options: noninvasive screening or diagnostic invasive testing. This patient is of a maternal age that has historically been called “advanced.” There is a longrecognized increase in the risk for fetal aneuploidy with advancing maternal age, and the increased risk takes a dramatic turn upward after the mid-thirties. Historically, women who would be age 35 or older on the estimated delivery date were automatically offered invasive testing. With improvement in screening algorithms, detection rates, and improved safety profiles of invasive testing, the rationale for limiting invasive testing to this age group is no longer valid.

Currently there are no noninvasive tests commercially available that will diagnose fetal chromosome abnormalities. Available noninvasive tests can only provide refinement of a patient’s risk for carrying a fetus with a chromosome abnormality beyond that based on her age alone. This is because a series of serum analytes are found to be discrepant from the average to an extent enough to serve as a screening tool. None performs spectacularly alone, but in combination, such as the 4-marker quad test performed in the second trimester, the detection rates for fetal trisomies 21 or 18 reach suitable levels for screening purposes (see Table 2–1).

The availability of earlier first-trimester invasive testing in the form of chorionic villus sampling (CVS) allows for implementation of earlier screening modalities as well. In modern practice, first-trimester screening is typically accomplished by combining results of biochemical testing and sonographic information that includes the nuchal translucency (fluid-filled space in the posterior fetal neck) between 11 and 14 weeks gestational age. Either component can be performed independently, but overall detection rates are improved when used in combination.

Patients found to have an abnormal or positive screening test are subsequently offered invasive testing. Accordingly, there is no reason to exclude consideration of noninvasive screening for a woman who has an elevated age-related risk. Many of these women will have their risks lowered by the

Table 2–1 MEDIAN (MOM) VALUES OF SERUM MARKERS IN PREGNANCIES AFFECTED WITH FETAL TRISOMY 21
MARKER	FIRST TRIMESTERa	SECOND TRIMESTER
AFP	0.86b	0.74
uE3	0.99b	0.66
Free beta-hCG	1.70	2.66b
Total hCG	0.96b	1.93
Inhibin A	0.94b	2.28
PAPP-A	0.40	1.11b

Data derived from FASTER and SURUSS results.

αFor data from FASTER trial, median levels at 12 weeks gestation were used in calculating the medians

for this table.

bData from SURUSS only.

screening algorithm, to a point where they may choose to forego invasive testing. As such, this particular patient who will be 35 years or more at delivery can benefit from aneuploidy screening. All patients regardless of age should be offered the opportunity to have either noninvasive screening or invasive testing for prenatal diagnosis of fetal chromosomal abnormalities.

APPROACH TO

First-Trimester Screening

1. Obtain nuchal translucency measurement (NT) by sonography.
2. Obtain maternal serum for PAPP-A and beta-hCG (free or total).

These data are then combined with the mother’s a priori age-related risk to calculate a new risk for fetal DS (and trisomy 18). If the level reaches a predetermined cutoff, the lab interprets this as “screen positive.” Alternatively, the patient may opt to proceed with invasive testing based on her impression of the degree of fetal aneuploidy risk determined by the screening process.

Measurement of Nuchal Translucency

In order to obtain reliable and reproducible screening performance, strict adherence to careful measurement of the nuchal translucency is paramount. Sonography units/practitioners adhere to the standards set forth by various certifying bodies to maintain high-quality images and measurements (eg, the Nuchal Translucency Quality Review or NTQR program). The fetus must be of sufficient size to perform NT measurement, and this can generally be accomplished when the crown to rump length (CRL) is between 45 and 84 mm (approximately 11 wk-14 wk). Other criteria for proper NT measurement are as follows: margins of NT edges need to be clearly defined; fetus needs to be in mid-sagittal plane; fetus occupies majority of image; fetal head must be in neutral position; fetus must be away from amnion; measurement should be at widest NT space; proper caliper alignment. Figure 2–1 depicts proper alignment of fetus and location of calipers when measuring NT. This fetus has an increased NT measurement and was found to have trisomy 21 by CVS.

There is no single NT measurement that serves as the cut off between normal and abnormal. All NT measurements obtained for screening purposes are considered in the context of the patients’ gestational age. However, NT greater than 3.5 mm is not only a risk factor for fetal trisomy 21 or trisomy 18, but may also indicate presence of congenital heart disease. Such patients should be offered later assessment of fetal heart anatomy, such as can be accomplished with fetal echocardiography even in those with negative aneuploidy screen results or normal chromosomes by invasive testing (1; level II-3).

Figure 2–1. Nuchal translucency as demonstrated by the clear area between the two cursors. (Courtesy of Dr. Jeff Dungan).

Biochemical Screening in First Trimester

Levels of PAPP-A (pregnancy-associated plasma protein A produced by trophoblasts) in fetal trisomy 21 tend to be significantly lower than from pregnancies with chromosomally normal fetuses. Additionally, hCG levels are typically elevated. See Table 2–2 for PAPP-A and hCG values in pregnancy. Analogous to the use of serum analytes in second trimester screening algorithms, these first trimester analytes are converted into multiples of the median (MoM), and used to calculate relative likelihood ratios for fetal trisomy 21. When multiplied by the patients existing age-related risk, a new risk is then calculated.

Table 2–2 PAPP-A AND hCG VALUES IN PREGNANCY
	PAPP-A (MoM)	FREE BETA-hCG (MoM)
Median value in euploid	1.0	1.0
Median value in fetal trisomy 21	0.47 ↓	1.94 ↑
Median value in fetal trisomy 18	0.24	0.19

(Gestational age 12 weeks—Data from FASTER trial)

If NT screening is not available at one’s center, biochemical screening is still valid with detection rates of fetal aneuploidy comparable to that obtainable with traditional second-trimester serum screening.

Detection Rates

The combined use of NT measurement with levels of PAPP-A and hCG are reported to be able to detect about 85% of fetuses with trisomy 21 with a 5% false-positive rate (FPR) when all maternal ages are screened. Given the underlying higher prevalence of trisomy 21 in women of advanced maternal age, the positive predictive value of any abnormal screen in women over age 35 will be higher than in women under age 35.

The Serum, Urine, and Ultrasound Screening Study (SURUSS) trial was designed to compare screening performance of first trimester, second trimester, and integrated screening algorithms. This trial contained over 40,000 women from multiple centers. Use of maternal age, NT assessment, and levels of free beta-hCG plus PAPP-A resulted in 83% detection rate with a FPR of 5% (2; level II-2). In the United States, the results of the Biochemistry, Urine, Nuchal Translucency (BUN) study were reported in 2003. This multicenter, prospective trial investigated the combined use of NT, PAPP-A, and free beta-hCG collected during first trimester (74-97 days, gestation) from over 8500 patients. When using a risk cutoff of 1 in 270 for trisomy 21, they identified 85.2% of trisomy 21 fetuses, with a FPR of 9.4%. If the FPR had been fixed at 5%, then 78.7% of trisomy 21 fetuses were detected. When stratified by maternal age, screening performance was not quite as favorable for those women under age 35, as expected. When maternal age was less than 35 years, then this screening regimen detected 66.7%, and in those more than 35 years, detection rate was 89.8% (3; level II-3). The First- and Second-Trimester Evaluation of Risk (FASTER) trial also examined screening performance in the first trimester. The first-trimester algorithm utilized by this multicenter trial was able to detect 86% of trisomy 21 fetuses at a false positive rate of 5.6% (utilized risk cut off of 1 in 300) (4; level II-2). When considering women of all ages, 90% of trisomy 18 cases are detected with first trimester screening with a FPR of 2% (3; level II-3). Risk assessment for trisomy 21 with serum analytes in multiple gestations is less accurate than in singleton gestations.

First-trimester screening performance, however, is maintained only by a rigorous training and QA implementation. The NT measurement is best performed between 11 and 136/7 weeks; however, the highest detection rates occur with scans done at 12 to 13 weeks as shown by Wald et al. in the SURUSS trial. Visualization at earlier gestational age can be technically difficult. On the other hand, performance of PAPP-A as a serum marker is highest at the earlier end of the screening window (10 wk), and so overall, earlier screening results improve detection rates at lowest false-positive rates. Resolution of the increased NT over time is not a contraindication to invasive testing, as the NT is known to resolve in many aneuploid fetuses.

Combination First- and Second-Trimester Screening

Screening tests performed in both the first and second trimester should not be evaluated independently, but rather as part of an established integrated or sequential screening algorithm. The false-positive rate using independently calculated second-trimester quad screening is unacceptably high for women who have already undergone a first-trimester evaluation. (This is because the majority of the true positives will not be rescreened in the second trimester, and thus the underlying prevalence of trisomy 21 will be much lower in this “prescreened” group than that used by the risk calculation software.) On the other hand, additional fetuses with trisomy 21 missed by the first-trimester screen will be detected by means of a second-trimester risk assessment, and therefore the highest detection rates are found with screening algorithms that incorporate information from the first and the second trimester.

In the large FASTER trial, the researchers sought to determine the optimalcombination of first- and second-trimester serum screening with firsttrimester NT assessment. Optimal test performance was achieved by the so-called “integrated” approach. In this method, the screening results from the first-trimester assessment are withheld until the second-trimester serum analysis is performed. In other words, there is no option for invasive testing if the first-trimester screen shows an elevated risk for fetal trisomy 21. After the second-trimester screen is performed, the two calculated risks are “integrated” into a single calculated risk. By using this approach, these investigators were able to identify 96% (87/92) of the fetuses with trisomy 21 from the group of over 33,000 women who underwent both first and second-trimester assessments. Several authorities have voiced concern over the withholding of firsttrimester screening information from women found to have elevated risks. A compromise approach is sequential screening, in which women are informed of the first-trimester screening results, and offered invasive testing if the calculated risk is deemed “sufficiently” elevated. Those women who have a normal, or negative, first-trimester screen then go on to have serum screening drawn at 16 to 18 weeks, with a final risk calculation provided that incorporates information from both serum specimens and the first-trimester ultrasound. If the second (final) risk calculation is elevated, the patient is offered amniocentesis. Sequential screening was shown in the FASTER trial to have comparable test performance to integrated screening, that is, 95% detection of Down syndrome with an overall false-positive rate of about 5%.

With so many different options for aneuploidy testing, a patient can easily feel confused and overwhelmed. The differences between screening and diagnostic testing should be discussed with the patient. The patient who presents early enough in the first trimester should be offered combined first and second- trimester screening or diagnostic testing (either CVS or amniocentesis). Sequential screening provides a high detection rate with low false-positive rates. It also provides the patient the option of knowing her first-trimester screening results and the option of waiting until the second trimester for an adjusted risk assessment that combines the results of the second-trimester screen. If there is a lack of personnel to perform nuchal translucency, serum integrated screening (combined first- and second-trimester serum biochemical markers) can be a reasonable approach. If CVS is not available, either sequential or integrated screening can be performed depending on the patient’s desire. If a patient desires diagnostic testing and CVS is not available, then a secondtrimester amniocentesis is a reasonable alternative.

Comprehension Questions

2.1 A 29-year-old G1 at 8 weeks’ gestation with triplet gestation presents for prenatal care. She is sure she does not desire to have invasive testing as a first step but desires “to have some information” regarding her risk for fetal Down syndrome. What option do you recommend?

A. Integrated screen

B. Sequential screen

C. Quad screen

D. Nuchal translucency only

2.2 A 22-year-old woman is being seen at 11 weeks’ gestation for an ultrasound examination. Besides the nuchal translucency, which other sonographic finding is associated with fetal aneuploidy?

A. Fetal biparietal diameter

B. Fetal cerebellar diameter

C. Fetal nasal bone

D. Fetal crown rump length

ANSWERS

2.1 D. Serum screening tests are less sensitive in multiple gestations compared to singletons given that analytes from both fetuses (normal and abnormal) enter maternal circulation and are averaged together. Although data is limited, it is reasonable to offer nuchal translucency measurement to those with triplets as long as the patient is informed that the sensitivity is lower compared to firsttrimester screening in singleton gestations.

2.2 C. The fetal nasal bone should be visualized by 11 weeks’ gestation, and should be noted in the fetus in mid sagittal plane. An absent or shortened nasal bone is associated with fetal Down syndrome.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ All women, regardless of age, should be counseled regarding screening and diagnostic testing options for aneuploidy (Level III).

➤ Integrated or sequential first- and second-trimester screening have the highest detection rates for Down syndrome with lower false-positive rates than first-trimester screening alone (Level II-2).

➤ Nuchal translucency measurement ≥ 3.5 mm is associated with an increased risk of congenital heart defect (Level II-2).

REFERENCES

1. Bahado-Singh RO, Wapner R, Thom E, et al. Elevated first-trimester nuchal translucency increases the risk of congenital heart defects. First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Study. Am J Obstet Gynecol. 2005;192:1357-1361. Increased nuchal translucency was associated with a higher risk of major congenital hearing defects in chromosomally normal pregnancies. At ≥ 3.5 mm, the incidence was 1 in 43 pregnancies (level II-3). 

2. Malone F, Vonick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortum. N Eng J Med. 2005;353:2001-2011. This multicenter prospective study of over 38,000 participants showed that stepwise sequential screening and integrated screening had the highest detection rates (95% and 96%, respectively) with low FPR (level II-2). 

3. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS) [published erratum appears in J Med Screening Study. 2006;13:51-21]. J Med Screen. 2003;10:56-104. A prospective multicenter European trial of approximately 47,000 participants that showed the use of maternal age, NT assessment, and levels of free beta-hCG plus PAPP-A resulted in 83% detection rate with a FPR of 5% (level II-2). 

4. Wapner R, Thome E, Simpson JL, et al. First trimester screening for trisomies 21 and 18. First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. N Eng J Med. 2003;349:1405-1413. A large multicenter prospective study of 8872 participants in whom serum beta-hCG, PAPP-A, and nuchal translucency was measured. The detection rate for trisomy 21 was 85% with a 9% FPR (1:270 risk cutoff rate). For trisomy 18, the detection rate was 91% with a 2% FPR. This study provided data supporting that first-trimester screening is superior to maternal age alone, maternal age and biochemistry, and maternal age and nuchal translucency (level II-3).

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