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Maternal Serum Screening

Down Syndrome, Trisomy 18 and Neural Tube Defects

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Published: March 2011

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Dr. Algeciras-Schimnich provides an overview of maternal serum screening for Down syndrome, trisomy 18, and neural tube defects. She discusses the options available for maternal serum screening, describes the differences between available screening protocols, and describes what information the laboratory tests can provide.

Presenter: Alicia Algeciras-Schimnich, PhD

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Introduction

Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this program is Alicia Algeciras-Schimnich, PhD from the Division of Clinical Biochemistry & Immunology at Mayo Clinic in Rochester, Minnesota. Dr. Algeciras-Schimnich will provide an overview of maternal serum screening for Down syndrome, trisomy 18, and neural tube defects. She will discuss the options available for maternal screening, describe the differences between available screening protocols, and describe what information the laboratory tests can provide.

What is Maternal Serum Screening?

The goal of current maternal serum screening programs is to identify women at increased risk of having a baby affected with Down syndrome, trisomy 18 or neural tube defects and that will benefit from diagnostic testing. By performing diagnostic testing only in this high risk population, the likelihood of identifying an affected fetus will be higher than if a diagnostic procedure is performed in the unscreened population. The ultimate goal is to have fewer invasive procedures as well as fewer procedure related losses of normal fetuses. When a woman at high-risk or with a positive screen is identified, genetic counseling and a diagnostic procedure such a chorionic villus sampling, or CVS, or amniocentesis is offered to determine if the fetus has the genetic defect.

Maternal screening is not without disadvantages. The results provide a risk but not a diagnosis. Chorionic villus sampling or amniocentesis needs to be performed to determine whether the fetus is affect by Down syndrome, trisomy 18. Ultrasound and measurement of amniotic fluid alpha-fetoprotein (AFP) is used in the diagnosis of neural tube defects.

Although the current screening approaches have relatively high detection rate, depending on the test performed, about 5% to 20% of affected babies will not be identified. In addition, not all chromosomal conditions will be detected which is in contrast to CVS or amminocentesis where all autosomal trisomies are detected.

Who Should Be Offered Maternal Serum Screening?

Historically, maternal age 35 years or older at the time of delivery was used to identify women at high-risk and who will benefit from diagnostic procedures. However, age alone is a poor risk predictor for fetal defects. The introduction of biochemical screening in combination with the womans age has facilitated the refinement of a woman risk to carry an affected fetus and who will benefit from diagnostic procedures. In a statement published in 2007, the American College of Obstetricians and Gynecologists or (ACOG) recommended that screening and invasive diagnostic testing be offered to all women before 20 weeks of gestation, regardless of maternal age. However, it is not practical to present patients with all the options available. Instead, it is recommended that providers review the evidence available and decide which screening option or options will be best to offer to their patient population.

Maternal Serum Screening: Options

In this presentation, I will discuss 3 options for maternal serum screening. These options are first trimester, second trimester and sequential screening. Sequential screening is a type of cross-trimester screening which uses markers from the first and second trimester screening tests. Sequential screening was introduced to increase the detection rate and decrease the false-positive rate seen with the first 2 options.

It is important to keep in mind that these 3 options are screening tests. This means that a screen-negative result does not guarantee the absence of fetal defects and a screen-positive will need additional testing to determine if a defect is present.

Maternal Serum Screening: Risk Calculation

For all 3 screening options, the laboratory uses a mathematical model to calculate a woman risk of having a baby with Down syndrome, trisomy 18 or neural tube defect. This mathematical model takes into consideration the maternal age, the serum levels of various biochemical markers and, in the case of first trimester and sequential screening, the fetus ultrasound measurements.

In addition, a number of factors play a key role in the calculation of the risk as they will affect the values of the analytes. This includes gestational dating, weight, race, diabetic status of the individual, the number of fetuses present, and whether IVF treatment was used for conceiving.

For example, alpha-fetoprotein or AFP, one of the markers used in the Down syndrome and trisomy 18 risk calculation, is affected by some of these factors. Black mothers tend to have higher AFP levels but lower risk of neural tube defects and are assigned to a separate AFP median set. The AFP is adjusted upward in insulin-dependent diabetic mothers to account for lower values in diabetic pregnancies. AFP multiple of the median (MOM) values are adjusted in heavier mothers to account for the dilution effect of the analytes.

Inaccurate information can lead to significant alterations in the estimated risk. This is why it is so important that accurate information is provided when the sample is submitted for analysis.

First Trimester Serum Screening

Moving on to each type of screening, first trimester screening is performed between 10 and 14 weeks of gestation. It provides a risk for Down syndrome and trisomy 18.

The markers used on the risk calculation are 2 serum markers: Pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin or hCG. Decreased levels of PAPP-A before the 14th week of gestation are associated with an increased risk for Down syndrome and trisomy 18. Whereas increased levels of hCG are associated with an increased risk of Down syndrome. The third marker is the fetal nuchal translucency which is performed by ultrasound.

Nuchal Translucency (NT)

The nuchal translucency is a fluid-containing area behind the fetal neck as shown by the red arrow in the picture. The nuchal translucency measurement needs to be performed by experienced sonographers and should be obtained between 10 weeks and 13 weeks 6 days of gestation which is equivalent to a crown-rump length between 31 and 80 millimeters. The majority of fetuses with Down syndrome have an increase NT measurement when compared to normal fetuses of the same gestational age.

NT measurement is a technically difficult measurement to obtain, therefore can only be performed by certified sonographers. This certification could be obtained by either the Fetal Medicine Foundation or the Nuchal Translucency Quality Review Program.

Mayo Medical Laboratories require that sonographers submit proof of certification prior to submitting measurements for risk estimation. In addition, we request that sonographers submit paired NT and crown-rump length measurements from as many pregnancies as possible in order to determine the NT median to apply to each sonographer when future risk calculations are performed. Selection of the right NT median based on sonographer performance it is important as this will greatly influence the risk calculation.

Once sonographers are approved a code is assigned. This code is used to monitor sonographers' quality performance over time. The laboratory will provide sonographers with a quality report based on a minimum of 50 data points to determine if sonagraphers measurements continue to be within the target ranges.

First Trimester Serum Screening

For first trimester serum screening, a screen-positive or screen-negative result is based on the laboratory-specific cutoffs. For the first trimester, Down syndrome risk calculation is based on a cutoff of 1 in 230. A screen-positive interpretation is provided if the calculated risk is equal to or higher than 1 in 230. Using this cutoff, the Down syndrome detection rate is 85% and the false-positive rate is 5%.

Keep in mind that in practice, both the detection rate and false-positive rate increase with age, thus detection and positive rates will vary depending on the age distribution of the screening population. If the screened population is older, the detection rate and the false-positive rate will be higher.

For trisomy 18, risk estimates of 1 in 100 or higher are reported as screen positives. In the first trimester, the detection rate for trisomy 18 is approximately 80% and the false-positive rate is less than 1.0%.

First Trimester Screening

All the screening approaches have benefits and limitations that need to be taken into consideration. In first trimester screening, the woman learns early in the pregnancy if they are at high risk, and earlier genetic counseling and diagnostic procedures such as CVS could be offered. In addition if the woman decides to terminate the pregnancy the risk of complications is less during early pregnancy compared to the second trimester.

The limitations of first trimester screening include the fact the NT measurements need to be performed by trained and certified sonographers, which might not be available in all areas or hospitals. In addition, in the first trimester, a risk for neural tube defect could not be provided. Therefore, another sample needs to be sent during the second trimester for measuring maternal alpha-fetoprotein and determine the risk for neural tube defect.

Second Trimester Screening

Second trimester screening is performed between 15 and 22 weeks of gestation.

The biochemical markers used to derive a risk estimate are: alpha-fetoprotein or AFP, unconjugated estriol or ue3, hCG and inhibin A. AFP is used on the risk calculation of the all 3 conditions. Low levels of AFP are seen in Down syndrome and trisomy18 pregnancies, whereas increases are seen in neural tube defects. Unconjugated estriol, an estrogen produced by the placenta, is decreased in the majority of Down syndrome or trisomy 18 pregnancies. hCG is normally increased in Down syndrome pregnancies and decreased in trisomy 18 pregnancies. Inhibin A is only used to calculate the risk for Down syndrome, as in these cases it tends to be elevated.

In contrast to first trimester screening, second trimester screening provides risk estimates for Down syndrome, trisomy 18 and also neural tube defects. For Down syndrome, a screen-positive or negative interpretation and a numeric risk is provided based on the cut-off of equal or higher than 1 in 270. Using this cutoff, the detection rate for Down syndrome is approximately 81% and the false-positive rate is approximately 5%. For trisomy 18, risk estimates of 1 in 100 or higher are reported as screen positives. The detection rate for trisomy 18 is 80% with a false-positive rate of less than 1% for the second trimester screening. For neural tube defects, only alpha-fetoprotein is used for the risk assessment. An AFP multiple of the median (or MOM) equal to or higher than 2.5 is reported as screen positive. Second trimester screening has a detection rate for neural tube defect of approximately 80% with a false-positive rate of 1% to 3%.

Second trimester screening using these 4 markers is the best option for women presenting for prenatal care later in the pregnancy.

Second trimester screening tends to have a slightly lower detection rate for Down syndrome compared to first trimester. In addition, since risk information is not available until the second trimester, the time for counseling and follow-up testing is limited.

Sequential Screening

Sequential screening is a type of cross trimester screening that has been introduced as a mean to increase the detection rate and provide the lowest false-positive rate. The markers used in the risk calculation include: NT and PAPP-A which are measured during the first trimester and AFP, unconjugated estriol, hCG and inhibin A which are measured in the second trimester.

In sequential screening, once NT and PAPP-A information is available, a risk calculation is performed. If the screen is positive, results are reported and this is considered the end of the screening test. In contrast, if the screen is negative, a second sample is collected in the second trimester and new risk estimate is generated.

In this schematic representation of the sequential screening test, the first measurements are performed at 11 to 13 weeks of gestation and include an NT measurement by ultrasound and a PAPP-A measurement in serum. Based on the laboratory’s predetermined cutoffs, a screen-positive or screen-negative result is generated. If the screen is positive, meaning that the woman is considered to be at high risk of carrying an affected fetus, the results will be reported immediately to give the woman the option to undergo early genetic counseling and diagnostic testing. If the woman had a negative screen in the first trimester, the results are not provided. A second sample needs to be sent to the lab between 15 and 22 gestational weeks for measurement of AFP, estriol, hCG and inhibin A. A risk calculation using 6 markers is provided on the second trimester test. Based on the set of cutoffs used for sequential screening, the majority of women will complete the second part of the test providing a higher detection rate and a lower false-positive rate.

Calculation of the risk estimate for Down syndrome is based on 2 cutoffs. In the first trimester, risk estimate values of greater than or equal to 1 in 50 are interpreted as positive and a report will be issued. If the risk is below 1 in 50, a report will not be issued until the second sample is received in the second trimester. In the second trimester, the cutoff used for Down syndrome is equal to or higher than 1 in 270. Using this approach, the overall detection rate for Down syndrome is approximately 90% with a false-positive rate of approximately 4%.

Trisomy 18 risk estimates greater than or equal to 1 in 100 are reported as positive in the first part of the screening when the Down syndrome risk is also increased. If the risk is below 1 in100, the woman will continue to the second part of the screening. In the second trimester, the cutoff used for trisomy 18 is also 1 in 100. Using this approach, the overall detection rate for trisomy 18 is approximately 90% with a false-positive rate of less than 0.5%.

Neural tube defect calculation is the same as the second trimester screening. A multiple of the median (or MOM) equal or higher than 2.5 is reported as screen positive. The detection rate in second trimester screening for neural tube defect is approximately 80% with a false-positive rate of approximately 1 to 3%.

One of the benefits of sequential screening is that if the woman is at high risk of having an affected child, the risk information is provided right away in the first trimester so genetic counseling and diagnostic testing is provided early in the pregnancy. In addition, if the decision of pregnancy termination is made, this could be performed earlier and with fewer risks. If the woman is consider low risk after the first risk calculation, continuation to the second part of the test provides a higher detection rate.

The limitations of sequential screening include the fact that 2 samples are required for the majority of women. This could be an issue for providers that have a noncompliant population. If the patient does not return for a second blood draw, the patient will be left with no screening results. In addition, for those women that are considered to be at high risk in the first trimester, a neural tube defect calculation is not provided.

Mayo Medical Laboratories Maternal Serum Screening Options

To summarize this presentation, it is recommended that regardless of which test is offered for prenatal screening, information about the detection rate, false-positive rate, and the benefits and limitations of the test should be available to patients so they could make an informed decision. This table summarizes the options available for maternal screening through Mayo Medical Laboratories. A number of factors could influence which test is chosen including the woman’s preference. For example, if a woman wants to know her risk of having an affected child early in pregnancy, the best option will be first trimester screening which has a detection rate slightly higher than second trimester and results will be available early in the pregnancy. This option will also be best for patients that might not return to have the second blood draw necessary to complete the sequential screening.

 In contrast, for those women that present later in the pregnancy, second trimester screening using the 4 biochemical marker also know as QUAD screening is the best available maternal serum screening option.

If a patient wants to have a test with the highest detection rate, then sequential screening should be the test of choice as it provides a higher detection rate of all the screening options.

References

Finally, I have included in this presentation a list of references that might be useful. Thank you.

 


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