The 11-14 Week OB Sonogram - SD

Current Concepts of the 11 to 14 Week OB Sonogram

Prenatal screening has been developed over the past 25 years, and some of the most important developments are shown in this slide, which culminate in our current concept of first trimester screening with maternal serum biochemistry and fetal nuchal translucency.

Principles of Screening

Before we discuss the data, it's important to be familiar with certain principles of screening, which may seem maddening to some, and yet if one understands it, we can see that there is method in it as seen in this quote from Hamlet.

Screening tests are evaluated using the following key measures, sensitivity, which is the proportion of people with a disease who test positive specificity, the proportion of people without the disease who test negative, positive, and negative predictive value, which are the proportions of people with positive and negative tests who do and do not have the disease that's being screened for.

Often these measures are placed into a two by two table as seen in this slide in the two by two table. The first column represents people who have the disease that's being screened for the column on the right are people who do not have the disease that's being screened for. The top row are people who test positive, and the bottom row are people who test negative. The key measures of sensitivity, specificity, positive and negative predictive value are shown with the formulas used to calculate them.

The next few slides will illustrate some basic principles of screening.

The predictive value varies with the prevalence of the disease state in the population being screened with increasing prevalence. Positive predictive value increases and negative predictive value decreases at low prevalence, which is the prevalence at which down syndrome screening is typically done. The positive predictive value will be low, and the negative predictive value will be high regardless of how good the test is. Therefore, when we're discussing down syndrome screening, the positive and negative predictive value are typically not used to compare tests.

In contrast, the sensitivity and specificity do not vary with prevalence. The sensitivity varies with the threshold value or cutoff for a positive test, and the specificity and positive predictive value vary with the sensitivity, with increasing sensitivity, specificity and positive predictive value decrease. The false positive rate varies with sensitivity. With increasing sensitivity. False positive rate increases at low prevalence. Again, the typical prevalence at which down syndrome screening is seen in the population. The false positive and screen positive rates are approximately equal, and often these terms are used interchangeably. When one hears false positive, one can think screen positive, and when one thinks screen positive, it can also mean false positive to compare different screening tests for the same population, either the false positive rate or the sensitivity must be fixed, otherwise one cannot make a valid conclusion about which test is better.

Whenever we consider screening test, the patients will be distributed as seen in this slide in some sort of a bell-shaped curve. In the next few slides, I'm going to show you the concept of a perfect test concept of a bad test and what is more realistic along this axis.

Here is the hypothetical test result. This is the normal group distributed here, and here is the abnormal group distributed here. As we can see in this perfect test, there is no overlap between the normal and abnormal groups. One can fix a cutoff at which the false positive rate is zero and the sensitivity is 100%. In real life, this never occurs.

This slide shows an example of a bad test in which there is considerable overlap between the normal and abnormal groups such that at reasonable false positive rate, the sensitivity is quite low.

This is more like the real world in which there is some, but not a lot of overlap between the normal and abnormal groups. With respect to test results in this setting, one can set a false positive rate at approximately 5%, for example, and have a reasonable sensitivity or detection rate. In this case, 66%

Changing the cutoff will change both the false positive rate and the sensitivity or detection rate. In this slide, we can see first that at a false positive rate of 0%, in other words, no normals fall above the cutoff. The sensitivity is quite low, only 20%. As we change our cutoff, we increase both the false positive rate and the sensitivity or detection rate of the test. Depending upon which test is being used and the consequences of the false positives, one can determine what false positive rate would be acceptable to maximize the sensitivity.

This is a real example using data from the second trimester triple screen. In this population, the down syndrome prevalence is one in 800. This would be considered low prevalence. What I want you to notice in this slide is that for a sensitivity of 60%, the false positive rate sensitivity here 60%, the false positive rate is 3.8%. I also would like you to notice that of the patients who test positive, almost all of them are false positives, 300 in the false positive group versus six in the true positive group. This is because of the low prevalence of down syndrome in this population and underscores my earlier comment that the false positive rate and the screen positive rate are essentially identical at a low prevalence.

If we wanted to increase the sensitivity of this test, we can do so by changing the cutoff, and if we wanted to increase it to 80% as seen here, the false positive rate would go up considerably from 3.8% as we saw in the last slide to 10%. And as a consequence of this, 500 more individuals would test positive and they would virtually all be false positives.

Likelihood Ratio

The next screening principle I would like to discuss is the likelihood ratio. The likelihood ratio is a proportion of abnormals to normals at a given test result. This is used to calculate a patient specific risk based upon the patient's individual test result and the population distribution of the test results as seen in this slide, for example, at a test result of 21, the proportion of normals to abnormals as seen here results in a likelihood ratio of 10. As seen here at a test result of 11, the proportion of normals to abnormals results in a likelihood ratio of 0.5 as seen here. This can then be applied to the individual patient to give her a specific result for down syndrome. In this case, we can see that her result is one in 60.

The likelihood ratio is used to determine the adjusted risk compared to the background risk. And this is an example of how this is done. Here we have a patient who is 30 years of age. Her risk for down syndrome at age 30 is one in 600. If she has a test with a likelihood ratio of 0.16, this likelihood ratio is multiplied by her background risk to give her a new adjusted risk of one in 3,700. Conversely, if her test result correlates to a likelihood ratio of six, then her risk goes up to one in 100.

Current Concepts of First Trimester Screening

Now that we've covered principles of screening, let's move on to the current concepts of first trimester screening.

Reasons for First Trimester Screening

Why do we want to do screening in the first trimester? There are several reasons. First, the development of first trimester screening followed the development of first trimester invasive procedures such as chorionic villus sampling, and early amniocentesis, which is no longer performed. Advances in ultrasound have allowed us to see the fetus better in the first trimester and made it possible for us to do first trimester screening. First trimester screening provides earlier and more private results for the patient so that if her test is normal, she has earlier reassurance and if her test should be abnormal, she has more preparation time for the birth of an abnormal baby. Should she decide to terminate her pregnancy based on results, termination options are available, which are safer and cheaper for her. And finally, there's a potential, and I think now we've seen a realization of improved down syndrome screening by comparison to second trimester screening.

History and Description of Down Syndrome

Langdon down first described down syndrome in 1866, and he described babies with down syndrome in this fashion, the skin is deficient in elasticity, giving the appearance of being too large for the body. The face is flat and the nose is small, and as we can see here in this fetus with Down syndrome, this skin being deficient in elasticity causes an increase in the amount of fluid in the space below the skin in the back of the neck.

This is an ultrasound picture which shows the same thing as seen in this picture of an embryo.

Most of us are familiar with the second trimester nuchal fold as a down syndrome marker. As shown here on the right, the nuchal translucency is the first trimester correlate of the second trimester nuchal fold as seen on the left. As we can see in the second trimester, the nuchal fold is measured in the transverse plane, whereas in the first trimester, the nuchal translucency is measured in the sagittal plane.

Nuchal Translucency Measurement Technique

There is a specific measurement technique that must be utilized in order to give precise and accurate results. In nuchal translucency measurement, this requires standardized training and an ongoing quality assurance program.

This slide summarizes the technique for measurement of nuchal translucency At 11 to 14 weeks, the crown rump length must be between 45 and 84 millimeters. The measurement is done in a mid sagittal view, and the image size should include only the fetal head and thorax. The fetal neck should be in a neutral position and the fetus must be away from the amnion, such that the amnion can be identified. The maximum lucency in the nuchal region is measured with the calipers in the on to on location. The midsagittal section is crucial to making this measurement.

As we can see here on the left, although this is not magnified enough, we can see that this is a true mid sagittal section as opposed to the images on the right, which are not and would not be appropriate for this measurement.

The magnification should be such that only the head and upper chest of the fetus is included the equipment must be of sufficient quality such that each movement of the caliper on the ultrasound machine changes the measurement by 0.1 millimeters.

This slide reviews the image size requirements. As we can see, we have only the fetal head and the upper part of the chest in the picture. Approximately 75% of the image should include the head and neck, and the remaining 25 can include the chest region. The nuchal translucency should be measured with the neck in the neutral position. If the neck is extended or flexed, it will cause an error in the measurement as seen in this slide. And here is an example of a neutral head position on the left and a hyperextended head position on the right, which should not be used for the measurement.

It is crucial to identify the amnion as separate from the skin as seen in this slide. The measurement would be taken below the skin line here, but if one thought that this line, which is the amnion were the skin, we can see that the measurement taken would be larger than it should be and provide an inaccurate result for the patient.

The calipers are placed in what's called the on to on position, which is to say that the calipers are placed on the skin line and on the subcutaneous tissues below the nuchal fold as seen here.

This slide illustrates the importance of proper technique. As we can see on this fetus on the left, if the measurement is taken here, it produces a decrease in the risk result, and if the measurement is taken here, it produces an increase in the risk result. It's important to understand that this is the correct measurement in this case of 2.9 millimeters, because otherwise we would not be giving the correct result to the patient. We would tell her her risk is decreased, whereas in fact her risk is increased.

In this study published in 1997, we can see how important training in this area is. The detection rate before training in this study was only 30% for chromosome abnormalities, whereas after training, depending on what cutoff was used to determine the increased risk, the detection rate for chromosomal abnormalities was 76 to 84%.

Quality assurance, which is ongoing, is also very important as we can see, if only images of good quality are considered. The detection rate at a fixed false positive rate increases at a fixed detection rate. The false positive rate decreases Training courses are available from a variety of sources, both land-based and online. This slide provides the websites where one can go to get this training.

Using NT to Assess Down Syndrome Risk

Now that we've reviewed the technique for nuchal translucency measurement, I'll review how this is used to assess down syndrome risk by comparison to the background risk.

As the nuchal translucency increases, the risk for chromosome abnormalities increases, and as the nuchal translucency decreases, the risk goes down. The background risk is determined based upon the patient's age, the gestational age at the time of the measurement, and whether or not she's had a previous trisomy.

The cutoff value for nuchal translucency is based upon the crown rump length. The reason for this is because normally the nuchal translucency increases with increasing gestational age approximately 17% per week, such that if a single cutoff were used for the entire 11 to 14 week range, the false positive rate would be unacceptably high at larger or greater gestational ages as seen in this slide, this is the normal crown rump length. This is the normal nuchal translucency for each crown rump length, and as we can see on the right, The percentage of fetuses that will have a nuchal translucency greater than a particular cutoff. In this case, 2.5 millimeters increases as the gestation increases from 10 to 13 weeks.

Once the measurement has been obtained, the likelihood ratio is generated by comparing the NT measurement that we have obtained to the expected normal median value for the crown rump length or gestational age can be used, but normally the crown rump length is used to determine the expected value. Then the deviation or the difference in our measured nuchal translucency from the expected value is converted by one of these two methods, the delta value or the multiple of the median value into a likelihood ratio. That likelihood ratio is used to modify the patient's background risk and give her an adjusted risk for, in this case, trisomy 21.

We've already seen this slide, but this just emphasizes how the likelihood ratio is used to modify the risk. Again, by review, a 30-year-old patient would have a background risk for down syndrome of one in 600. If on the basis of her NT translucency measurement, her likelihood ratio is 0.16, then her adjusted risk would be one in 3,700. On the other hand, if her likelihood ratio is six, then her adjusted risk would be one in 100.

How good is this method at detecting down syndrome? If NT is used by itself without considering maternal age, the detection rate for down syndrome as seen in this study from 1997 is approximately 57% If maternal age is included. So based upon nuchal translucency and maternal age, the detection rate is approximately 77% for a 5% false positive rate as seen in this slide.

First Trimester Serum Analytes

In order to improve our detection rate, we add maternal serum biochemistry to the nuchal translucency measurement. The PAPP-A free beta hCG total hCG and inhibin A can be used in the first trimester to assess down syndrome risk. And I will discuss each of these in detail. I'd like to mention that the data on inhibin A is a bit conflicting. There are some reports that suggest that inhibin A is not useful in the first trimester, whereas more recent reports have shown that inhibin A is in fact useful in the first trimester.

As we will discuss, most of this data that we will be discussing come from four large scale population studies, two in the United States, the BUN or biochemistry, ultrasound and nuchal translucency study, and the FASTER or first and second trimester evaluation of risk study. Both of these were sponsored by the NICHD. There were also two studies in the United Kingdom, the serum urine and ultrasound screening study, and an ongoing clinic called the OSCAR Clinic, which stands for one stop clinic for assessment of risk. This is Professor Nicolaides clinic in London, England, and it is sponsored by the Fetal Medicine Foundation.

And this slide summarizes the number of patients down syndrome cases and detection rate for a 5% false positive rate amongst these large scale population studies. As we can see, the detection rates are in the mid to high 80% range.

Now, I'll discuss the first trimester serum analytes in more detail free beta human chorionic gonadotropin or free beta hCG is higher in Trisomy 21 pregnancies. If used alone, the detection rate for Trisomy 21 would be approximately 31% at a 5% screen positive rate.

Total human chorionic gonadotropin is also higher in Trisomy 21 pregnancies and has a slightly lower detection rate for Trisomy 21 when used by itself by comparison to the free beta hCG.

These next few slides summarize the difference between free beta hCG and total hCG. As you know, the hCG molecule is a dimer with alpha and beta subunits. The figure on the left represents the intact hCG molecule, and the figure on the right represents the free beta subunit. The assay that detects hCG actually detects both the intact molecule and the free beta molecule. However, in maternal serum intact hCG is present in a much greater amount than free beta hCG. Therefore, this assay effectively reflects intact hCG concentration. In contrast, the free beta hCG assay measures specifically the free beta subunit of hCG and does not measure the intact molecule as seen in this slide.

The terminology for these assays is a bit confusing. As we can see, beta hCG is sometimes used to describe both measurement of the intact hCG molecule and the free beta hCG molecule. In the United States, the free beta hCG assay is patented. The free beta hCG has been shown to be a better single marker than total hCG in the first trimester. And more studies have been published using free beta hCG than total hCG. However, as we will see, free beta hCG and total hCG are similarly effective as a third marker when combined with NT translucency and PAPP-A. And this is the way that either of these assays are typically used in first trimester screening. Therefore, it really doesn't matter whether free beta hCG or intact hCG is used.

Pregnancy associated plasma protein A or PAPP-A is produced by the syncytiotrophoblast. It is detected in maternal circulation starting at 28 days and increases throughout pregnancy as opposed to hCG. PAPP-A is lower in Trisomy 21 pregnancies, and it is the best of the analytes when taken by itself for down syndrome screening with a 44% detection rate at a 5% screen positive rate. Inhibin A is a dimeric glycoprotein, and it acts as indirect negative feedback on pituitary production of follicle stimulating hormone or FSH. It is higher in Trisomy 21 pregnancies, and it has a detection rate similar to hCG at a 5% screen positive rate.

This slide summarizes the changes from normal for PAPP-A beta hCG and inhibin A in Trisomy 21 and trisomy 18. Note that inhibin A is not informative for trisomy 18.

These analytes can be measured using dried blood technology such that the patient can prick her finger or have her finger pricked for her, and the dried blood is placed on a card and sent to the laboratory.

Combining Nuchal Translucency and Biochemistry

We'll now discuss combining the nuchal translucency and biochemistry in first trimester screening. Multiple studies have shown us that the NT measurement is independent of maternal age and serum markers, therefore, they can be used together for screening. Mathematical modeling suggests an 80% detection rate for Trisomy 21 at a 5% screen positive rate.

This slide summarizes a number of studies that have been done looking at combined screening for Trisomy 21 in the first trimester. As we can see, the sensitivity when looking at all of the studies taken together is approximately 82% for a false positive rate of 5%.

Combined screening can also be used to detect trisomy 18, trisomy 13 Turner Syndrome and triploidy as seen on this slide.

The nuchal translucency and biochemistry changed their effectiveness during the 11 to 14 week window. And as we can see in this slide, which is taken from one of the FASTER trial papers, the NT translucency detection rate decreases from 11 to 13 weeks. PAPP-A detection rate also decreases from 11 to 13 weeks, whereas free beta inhibin A and total hCG increase their effectiveness over this period of time.

This is the basis for combining one of the three analytes free beta hCG inhibin A or total hCG with NT and PAPP-A in order to improve the detection rate for Trisomy 21 at the later part of this gestational age window.

And as seen here again, data from the FASTER trial, it really doesn't matter which of these analytes are used to combine with PAPP-A and nuchal translucency because the free beta hCG total hCG and inhibin A are all similarly effective at improving the detection rate in later parts of the gestational age window around 13 weeks.

To summarize then, our current method of first trimester screening will detect approximately 85% of down syndrome cases at a false positive rate of 5%. This compares very favorably to nuchal translucency alone, triple screen at 16 weeks and is much better than maternal age.

Other Advantages and Uses of 11 to 14 Week Screening

Other potential advantages of screening at 11 to 14 weeks, besides a higher Trisomy 21 detection rate than the second trimester is an opportunity to detect structural defects and other chromosomal abnormalities. As we can see, NT can be used to detect abnormalities other than Trisomy 21, including trisomy 18, trisomy 13 Turner Syndrome, and triploid.

A number of markers have been used to assess the risk for chromosomal defects at 11 to 14 weeks, some of which are listed on this slide.

This slide summarizes how some of these markers are used to assess the risk for trisomy 18 13 Turner Syndrome and triploidy.

The next few slides will summarize some ultrasound findings that can be seen at 11 to 14 weeks, which are correlated with chromosome abnormalities.

Megacystis, which is an enlarged bladder defined as at least seven millimeters in diameter, has a likelihood ratio of six for trisomy 13 and trisomy 18. Omphalocele can also be seen in the first trimester as long as the crown rump length is at least 45 millimeters at crown rump. Lengths of less than 45 millimeters, physiologic bowel herniation can be seen, which is a normal finding. If you think that there is an abdominal wall defect such as in omphalocele, it's important that you make sure the crown rump length is more than 45 millimeters As seen in this slide. The likelihood ratio for trisomy 18 and 13 is five.

If an omphalocele is detected holoprosencephaly can also be seen in the first trimester, and is correlated with an increased risk for Trisomy 13.

This slide summarizes some guidelines for performance of the 11 to 14 week sonogram and is the protocol that we follow in our unit.

These next few slides are examples of images that we obtained in our unit during the 11 to 14 week window to show you some of the anatomy that can be seen.

As you can see in this transverse images of the fetal head, we can see the midline, and we can also see the choroid plexus. The fetal face palate and maxilla can also be seen at this time. The nuchal translucency can be measured. As we have already discussed, the fetal heart can be visualized in the first trimester, though as you can see in these slides it is not as good as in the second trimester. The outflow tracts can also be seen. The fetal stomach seen here and the fetal bladder seen here can also be identified in the first trimester as well as a three vessel cord as seen using power doppler in this image. The fetal kidneys can be identified as seen here in this transverse image and here in this coronal image, notice how hypoechoic and prominent the adrenal glands are at this gestational age. And notice also that we can identify the renal arteries using power doppler. The fetal spine and the abdominal cord insertion can also be evaluated as well as the fetal extremities, hands and feet. Doppler studies can be done when indicated. And here we see a doppler of the ductus venosus.

These next couple of slides show some anomalies that we've detected in our unit at 11 to 14 weeks. This is a case of Gastroschisis. As mentioned previously, abdominal wall defects should not be diagnosed unless the crown rump length is at least 45 millimeters. Here is a case of anencephaly in the first trimester, and it's very obvious here that there is no skull covering this brain.

How good are we at detecting fetal anomalies At 11 to 14 weeks? In this study that was published in 2002, it was shown that the overall detection rate, this is combining the first and second trimester scans was 71.5%. 22.3% of anomalies were detected at 11 to 14 weeks, and this represented 37.8 of the major anomalies. So it's probably not as good as the second trimester for anomaly detection, but as seen here, about a third of major anomalies can be detected at this gestational age.

If the nuchal translucency is increased, but the fetus has a normal karyotype, this correlates with an increased risk for certain birth defects and syndromes. In addition, the risk for fetal death increases as the nuchal translucency increases. Cardiac defects in particular are associated with increased NT translucency in the first trimester when the karyotype is normal. And this slide shows a list of abnormalities and syndromes that have been seen with increased NT translucency and a normal karyotype at 11 to 14 weeks.

Strategies to Improve Test Performance

Now, I'd like to discuss some strategies to potentially improve our test performance, specifically to try to decrease the false positive rate. The strategies that have been proposed include first trimester contingent screening using additional sonographic markers and combining the first and second trimester screening tests.

Three additional sonographic markers have been shown to correlate with chromosomal abnormalities at 11 to 14 weeks. Those are absence of the fetal nasal bone, abnormal ductus venosus waveform, and fetal tricuspid regurgitation. I will be discussing the absent nasal bone in more detail.

Absent Nasal Bone

As mentioned previously, Langdon down noted in 1866 that in babies and children with down syndrome, the face is flat and the nose is small. Subsequent studies have shown that there is a 50 to 65% incidence of absent or short nasal bone in babies with down syndrome and also in fetuses with down syndrome.

This slide summarizes the technique that's used to assess the fetal nasal bone in the first trimester at 11 to 14 weeks. The crown rump length is the same as for nuchal translucency, and the image size and caliper movement are also the same. The beam must be vertical to the nose in order to assess the nasal bone as we'll see in the next slide.

This slide shows why it is very important to have adequate magnification. As we can see, this magnification is much too little and we're unable to identify whether the nasal bone is present or not. With appropriate magnification, we're able to identify the nasal skin and the cartilage and the nasal bone, which is present in this fetus.

This slide shows the importance of the ultrasound beam being perpendicular to the nasal bone in order to see it. This is the same fetus with an improper technique on the left in which the nasal bone cannot be visualized. And with proper technique on the right, we can see that the nasal bone can be visualized again. The beam must be perpendicular to the nose in order to assess the nasal bone.

This technique is somewhat difficult to learn and it requires at least 120 scans in order to have adequate visualization of the nasal bone. As seen in this study from 2003,

It is not helpful to measure the length of the nasal bone at 11 to 14 weeks as seen in this slide. There is no correlation between the length of the nasal bone and the incidence of trisomy 21. So we only look to see if it is present or absent. We do not measure the length at 11 to 14 weeks.

In this slide, which summarizes work done by Simone Cicero, we can see that the risk of chromosome abnormalities when the nasal bone is absent varies with the ethnicity of the patient. It is much more significant to have an absent nasal bone in a Caucasian than it is in an Afro-Caribbean or Asian mother.

First Trimester Contingent Screening

The first trimester contingent screen is done as shown in this slide. The patients are divided into three risk groups. A high risk group, which correlates to a risk of one in a hundred or greater and intermediate risk group, which is a risk of one in a hundred to one in a thousand and a low risk group in which the risk is less than one in a thousand.

The principle of contingent screening is that those in the high risk group are offered a diagnostic tests such as chorionic villus sampling. Those in the low risk group are finished with their screening, and those in the intermediate risk group are offered further screening with either the nasal bone, the doppler of the tricuspid valve or the doppler of the ductus venosus as seen in this slide.

The first trimester contingent screening does improve the detection rate and also decreases the false positive rate as seen here for a fixed false positive rate of 2.5%. Using the nasal bone produces a 90% detection rate.

Combining First and Second Trimester Screening

The second strategy that's used to improve screening is combining first and second trimester screening. This can be done in several ways. One is the integrated screen in which the first and second trimester screening are done and combined to give a single risk. So there's a two step screen, one in the first trimester, one in the second trimester, and afterwards one result is given to the patient. This can be done as a serum integrated screen in which the nuchal translucency is not included, resulting in a down syndrome detection rate of 85 to 88%, or fully integrated in which the NT translucency is used. And this has been shown to have a detection rate of about 95% at a 5% false positive rate. The disadvantage of this is that it does not allow the patient to have an early diagnosis in the first trimester because she does not get her result until the second trimester.

Other methods of combining first and second trimester markers include the sequential screen, in which there is a two step screen, but two risk results are given. So screening is done at 11 to 14 weeks with nuchal translucency and biochemistry, and the results are given to the patient and she's offered a diagnostic test if she wants later. In the second trimester, a quadruple screen is done and the results are provided using the first trimester screen result as the new background risk.

The next three slides summarize strategies for sequential screening.

In this slide, this shows a strategy that is not recommended, in which the first trimester screen is done, followed by the second trimester screen without any adjustment of the risk based on the first trimester screen. While this does result in a down syndrome detection rate of 92%, it does so at the expense of the false positive rate, which is additive. So the false positive rate from the first trimester screen is added to the false positive rate from the second trimester screen. Therefore, the false positive rate for this strategy is 10 to 20%, which is unacceptably high. With a stepwise sequential screen. The first trimester screen is done using a cutoff in this case of one in 60, and the patient is offered invasive testing if she wants this results in a detection rate of 70% with a false positive rate of one to 2%. All patients are then offered an integrated screen, and this is used. The adjusted cutoff is used at one in 190 to produce a down syndrome detection rate of 70% at a false positive rate of one to 2%. Remember that the false positive rate is additive. Therefore, this strategy results in a false positive rate of only two to 4% for a down syndrome detection rate of 93%.

The contingent sequential screen is similar, however, in this scenario, patients who are at low risk are not tested in the second trimester. So if the risk is less than one in 1200, the patient does not have any further testing, and only patients at an intermediate risk between one in 60 and one in 1200 are offered the second trimester screen. This results in similar detection rates and false positive rates to the other sequential screening.

Summary

To summarize what we've discussed, first trimester nuchal translucency and serum biochemistry is a very effective screen for down syndrome and other aneuploidies in the general population. The down syndrome detection rate by this strategy is approximately 85% at a false positive rate of 5%. Training in the nuchal translucency measurement technique and a quality assurance program are necessary for effective screening. Down syndrome screening in singleton pregnancies based upon NT alone is not as effective as NT combined with biochemistry, NT and PAPP-A performance deteriorate from 11 to 13 weeks. This suggests that first trimester component of integrated screening is optimally performed at 11 weeks of gestation. A third marker, either free beta hCG total hCG, or inhibin A may be added to improve test performance in the later part of this gestational age window. First trimester contingent screening and combining first and second trimester tests improve the down syndrome screening performance. Increased nuchal translucency with a normal fetal karyotype is associated with an increased risk for structural anomalies, syndromes, and fetal infection, such as parvovirus.