Prenatal screening for birth defects

Birth professionals who have been in the field a long time are well acquainted with the diagnostic tests for Down syndrome and other conditions (amniocentesis and CVS) and the challenges of explaining to clients: “Before you have the test, think about what you’ll do if you have a positive result.” Over the past 15 – 20 years, there’s been huge improvements in screening tests for these conditions, and those need to come with their own patient education and precautions about how to respond to a “screen positive” result.

Vocabulary: Before we talk about the tests, let’s talk about some terms:

• Screening test – assesses how likely it is that baby has the condition being tested for.
• Diagnostic test – determines whether the baby actually has the condition.
• False negative is the chance that a test will come up negative when the baby actually DOES have the condition being tested for. This is obviously distressing for parents if they had tests done and were told the baby was fine, and then discover at birth that it’s not as they expected. A test with a detection rate of 90% would catch 90% of the cases, and have a false negative rate of 10%.
• False positive is the chance that a test will come up positive when the baby does NOT have the condition. This could lead someone to take actions or have procedures that are not necessary. (See below.)
• Screening threshold or “cut-off” – the answer to a screening test is not really Positive or Negative / Yes or No. It’s really “If we say you’re screen positive, that means you exceed the threshold at which we think it’s a good idea for you to have diagnostic testing to determine for sure whether or not you have that condition. If we say you’re screen negative, that means we don’t think it’s worth having more testing because we don’t think it’s likely you have the problem.” For example, if a test showed you had less than 1 in 50 chance of a problem, then it doesn’t make to have a test that has a 1 in 20 chance of creating a problem.
• It is helpful to learn from a caregiver not just the screen positive or screen negative answer, but also what are your chances. For example, they might say you’re screen positive for something if the cut-off was that your risk was greater than 1 in 200. But, if your risk is estimated at 1 in 190, the recommended diagnostic test is not that likely to show you have the condition (though it’s probably still a good idea to have it.) If your risk is estimated at 1 in 10, not only will they recommend that diagnostic test, but it’s pretty likely it will turn up positive.
• Aneuplody. Chromosomal abnormalities, such as trisomy 21 – Down Syndrome and trisomy 18 – Edward syndrome.

Should anyone skip screening tests and go straight to diagnostic tests?

In the past, often the recommendation for amniocentesis was made solely on the basis of the mother’s age (typically, for those over 35). The risk of aneuplodies goes up with age, so caregivers recommended the test when her risk of having a baby with a chromosomal condition was greater than the risk of miscarriage caused by amniocentesis. (At that time 1 in 200 risk.) Age is no longer considered reason enough for diagnostic testing. Most caregivers recommend that first a pregnant person have a non-invasive screening test,and only do a diagnostic test if her risk is higher than the screening threshold.

Some women are considered high enough risk that they could go straight to the diagnostic testing. typically that’s: if the baby was conceived by IVF, if the woman or her partner has a history of a previous pregnancy with a chromosomal abnormality, or if both partners are carriers of a genetic condition that increases the risk of chromosomal birth defects.

What screening tests are available?

(Note: WordPress tables aren’t always easy to read, so here’s a PDF of the tables if you prefer to view that… )

Test	Type of test	When done	What is test screening for?	Detection rate and false positive rate for Down syndrome (DS) and neural tube defects (NFD)	Turnaround time from testing to results
First trimester blood test	Blood test	10 – 13 weeks, ideally at 10	Tests levels for PAPP-A and HcG. Down syndrome, trisomy 13 and 18	Blood test: 69% with a 5% FPR (SOGC)	Days
Nuchal translucency screening (may also assess for presence or absence of nasal bone)	Ultrasound	11 – 14 weeks, ideally at 11	Measures the thickness of a clear space at the back of a fetus’ neck. Babies with chromosomal disorders, such as Down syndrome, accumulate more fluid in this area	Ultrasound: 69 – 75%. FPR 5 – 8% (SOGC)   When combined with first trimester blood test: 82 – 87% (ACOG) 83%, 5% FPR (SOGC)	Immediate to days
Cell-free fetal DNA testing (e.g. MaterniT 21). Also known as non-invasive prenatal screening (NIPS).	Blood test	10 – 13 weeks, ACOG recommends that it be done only if blood test or nuchal translucency showed high risk (there’s a discussion of this here…)	Tests for placental DNA in mother’s blood. Screening for Down syndrome, other trisomies, and fetal sex aneuploidies. Also reveals gender and baby’s Rh factor.	99% / FPR 0.2% (Source)	7 – 10 days
Second trimester blood test (quad screen)	Blood test	16 – 20 weeks ideally at 16 – 17	Tests levels of alpha-fetoprotein (AFP), estriol, human chorionic gonadostropin (hCG) and inhibin A. Screen for Down and Edwards, plus neural tube defects.	81% (ACOG) 75-80%, FPR 3 – 5% (SOGC)   For neural tube defects: 71 – 90% with 1- 3% FPR (SOGC)	7 – 10 days
Second trimester ultrasound	Ultrasound scan	18 – 22 weeks	Screen for neural tube defects and other anatomical defects	For NTD: 68 to 86% for neural tube defects (SOGC2)	Immediate to days

Often test results are combined to increase accuracy. Here are some of the common combinations.

Type	Combines results from	Detection rate and FPR for Down syndrome	When are results reported to parents
Integrated screening	First trimester blood test, nuchal translucency ultrasound, and second trimester quad screen	94 – 96% (ACOG) 85 – 87% with FPR of 0.8% to 1.5% (SOGC) 92% with 3% FPR (Quest)	Results not reported until after the second trimester results are in
Serum integrated screening	First trimester blood test and second trimester quad screen	85 – 88% (ACOG) 88, with 6% FPR (Quest)	Same as above
Sequential integrated screening	First trimester blood test and nuchal translucency scan are done. Then second trimester screening or diagnostic testing, depending on risk level.	95% (ACOG) 92%, with 4% FPR (Quest)	After first trimester tests, if risk is high, diagnostic testing is recommended. Otherwise, second trimester screening is done before results are reported
Stepwise sequential	First trimester blood test and nuchal translucency scan. Then no further testing, second trimester screening, or diagnostic testing, depending on risk level.	95% (ACOG) 92%, with 4% FPR (Quest)	After first trimester tests, results are reported. If high risk, diagnostic testing is recommended. If moderate risk, second trimester screening is recommended as a follow-up. If low risk, no further testing.

Explaining Test Results to Clients

It’s very important for expectant parents to understand the difference between a screening test and a diagnostic test, and important to understand what false positives are.

If a screening test comes up positive, one of the first questions an expectant parent should ask their caregiver is: how certain are we that this test is correct? Are there other tests I could have to confirm this?

They can ask their caregiver to explain the false positive rate – the chance that although they screened positive, the baby does not actually have that defect.There’s two sides to that… 1) what’s the false positive rate for all people tested and 2) amongst people who test positive, what percent of those are false positives and what percent actually have the condition. (This latter number is called the positive predictive value of a test.)

For example, all the advertising for cell-free fetal DNA testing will talk about how it will detect 99% of cases, and has a false positive rate of 0.2%. This is true, and MUCH more accurate than other screening methods. But it’s still not perfect. One study showed that of 1909 patients screened, most people screened negative. 11 screened positive. After diagnostic testing, it turned out that 5 of the 11 babies had Down syndrome and 6 did not. So, for the whole population screened, only 0.3% were false positives. But of those who screened positive, 55% of those were false positives. (Source)

In another study of cell-free fetal DNA testing, of 41 patients who screened positive, 38 were true positives. 3 were false- positives. (Source) Better… but still 7% of the people who screened positive were not.

A parent who has heard the 99% accuracy advertising may not be aware of the subtleties of all this, and may not fully understand what a screen-positive result means.

The rates of false positives with other testing are much higher than that, and even more important for expectant parents to understand in order to interpret what a “screen positive” result means. (Note: screening results should not just be given as “positive” or “negative.” They should also be given in terms of probability. For example,  “you have a 1 in 150 chance of this condition.” The expectant parents can ask for this information if it was not given to them clearly.)

Responses to a False Positive Test

In the case of Down syndrome, some parents might use a positive screening test result as a reason to spend the rest of their pregnancy learning about Down syndrome and lining up resources to help them care for their child. If they found out at birth that the test was a false positive and the baby did not have Down syndrome, it is likely they would be relieved not to need to use those resources.

However, a majority of expectant parents choose to terminate a pregnancy if the baby is diagnosed with Down syndrome.

The Society for Maternal-Fetal Medicine states

all positive cell free DNA screening results require confirmatory diagnosis before an irreversible action, such as pregnancy termination, is undertaken.   (Source)

However, 6 – 17% of those who screen positive with cell-free fetal DNA testing are choosing to terminate the pregnancy based on those results alone without any further testing.

Before getting testing, and definitely before getting results, it is very helpful for expectant parents to understand that a screening test is not absolute, and what their options will be. If they screen positive, they could choose diagnostic testing to confirm the diagnosis – CVS can be done at week 10 – 12, in time for a first trimester termination decision. If for some reason, CVS is not an option for the parents, another option could be additional screening tests. The cell-free fetal DNA testing, first trimester blood tests, and nuchal translucency look at separate factors, and having results from more than one test could be illuminating information to have before making an irreversible decision.

Learn more

An interesting article on this topic is Oversold and Misunderstood.

Or click on any of the links above…