Prenatal Genetic Screening and Diagnosis (Shaffer, 1/20/2021)

Many thanks to Dr. Brian Shaffer, Sutter West Bay Medical Group Perinatologist, who gave an informative Grand Rounds this week on Prenatal Genetic Screening and Diagnosis. Prenatal Screening is a BIG topic that is ever evolving with improving gene sequencing technology and innovation, necessitating important (and potentially challenging) decision-making conversations with women early in their prenatal care.

Just a reminder that there are important differences between genetic screening tests (e.g. first and second trimester blood screens, nuchal translucency ultrasound, and even our standard fetal survey) and prenatal diagnostic tests (e.g. chorionic villous sampling, amniocentesis and cord blood in terms of their positive predictive values as well as their risks. The new-ish kid on the block is non-invasive prenatal testing/screening (aka NIPT, NIPS), which is a screening test and NOT diagnostic. 

Of note, ACOG and other guiding bodies  recommend that a discussion of the risks, benefits, and alternatives of ALL prenatal screening and diagnostic testing should occur with ALL patients, ideally at first visit, regardless of maternal age, including non-invasive prenatal screening (NIPS) and diagnostic testing "even in low risk pregnancy" (e.g. CVS, amniocentesis)

Dr. Shaffer gifted us with a set of probing questions to conduct these conversations about prenatal screening with patients. This can be a really challenging conversation, and it is helpful to consider the language we use to frame the conversation. Consider starting with:

If your pregnancy was affected with a genetic disorder or chromosome abnormality, would you want to know?

• What would the information mean to you?
• Would an abnormal result or prenatal diagnosis ruin the experience of the pregnancy or provide valuable guidance?
• Some people want more information to help them (and healthcare providers) prepare for the birth of a child with special needs
• Some might choose to terminate a pregnancy with a diagnosed condition
• Some couples do not want this information during pregnancy

There is a spectrum of congenital disease that can affect a pregnancy (as depicted in image below), and no ONE screening test can provide results about the entirety of this spectrum. Really, in fact, a combination of screening tests aims to cover this range (e.g. ultrasound is best to evaluate structural malformation vs. a quad screen designed to detect some autosomal disease, NIPT is excellent for down syndrome but gives no information regarding spina bifida). 

The menu of screening tests we currently offer includes: 

1. Nuchal translucency ultrasound (NT),
2. First Trimester screening (serum),
3. Integrated/sequential screening (first and second trimester), 
4. Quad screen, and 
5. Cell free DNA (often referred to as NIPS or NIPT).  

Each of these tests has benefits and limitations as well as variable sensitivities for different conditions. See table below for some of these stats. For example, for Down Syndrome (DS), the NT alone has a 70% sensitivity as compared to the NT plus serum markers which brings that to 90-95%. 

However, also note that because these conditions are quite rare, the positive predictive value (PPV) is only 5-10%. That is only 5-10% of positive screens will actually correlate with a abnormality in the fetus. And the impact of false positives is real.

What are the implications of this 5% PPV?

Well, let's take an example: with the prevalence of DS in the US, 1/16 women with a positive screen will have a child with DS. 15/16 will have a normal fetus. And if the abnormal screen leads to more invasive diagnostic testing (CVS, amnio)--> that equates to 570 losses of normal fetuses. Is this an acceptable tradeoff? Up to each woman to decide. And up to us to counsel those women.

What should we know about NIPS?

NIPS is a pretty awesome technology that is able to identify cell-free DNA segments (from the placenta) in maternal serum. It can be done from 10-30 weeks EGA and has a a very high positive predictive value in "high risk pregnancies" (defined as women with advanced maternal age/AMA). In younger women-- lower risk women-- while the sensitivity and specificity remain the same, the PPV is decreased because the prevalence of these chromosomal abnormalities are just so much rarer. 

NIPS screens for Trisomy 21 (Downs), Trisomy 18, and Trisomy 13, as well as sex chromosome abnormalities (XXX, XXY, XY) and some other microdeletion and microduplication disorders.

Results return as:

LOW risk

INCREASED risk (including borderline)

Other (including no call, maternal chromosomal conditions, and inconclusive/atypical)

A "No call" (aka test failure) occurs in 1-8% of patients, often due to low fetal fraction. Low fetal fraction may be due to too young gestational age, as well as maternal conditions (e.g. SLE) and women on lovenox. Can also be low in obese women (<1% in women <60kg, >50% in women >160mg). Can also be low in placentas with certain aneuploidies (particularly Trisomy 18 and triploidy). NIPS cannot be used for paternity or single gene deletions.

This table from Society Maternal and Fetal Medicine summarizes NIPS key points nicely

Dr. Shaffer cautioned us that there is no "best test"-- up to 2% of of pregnancies with a conventional positive screen had a detectable chromosomal abnormality not detectable on NIPS.

What about ultrasound (including NT and 2nd trimester screening ultrasound)?

• Between 11 through 13+6 EGA
• NT<3.5mm is considered normal
• If  an abnormal NT is detected, recommendation include 1) formal genetic counseling 2) invasive testing (CVS) as well as 3) fetal echocardiogram

What about advanced paternal age (APA)?

• in men >40, associated with small increased risk for de novo autosomal dominant disorders
• possible increase in behavioral issues including schizophrenia and autism
• structural malformation
• fetal growth restriction and preterm birth

Expanded carrier screening vs. Ethnicity Based Screening

Over the last decade, we have been offering women "ethnicity based screening'-- e.g. offering CF, Tay Sachs, hemoglobinopathies based on a maternal report of heritage. There is evolving argument in the literature that we are very unaware of our genetic heritage AND that there may be benefit to offering all women expanded carrier screening for conditions that might impact pregnancies and pregnancy outcomes. As expanded carrier screening cost come down, and as our capacity to test for a large number of conditions simultaneously, the argument is that more information in the hands of the mother can be helpfu. However, the risk is that we currently have no uniform or standard best practices on these ECS panel, and such testing may give us information on late onset genotypes (e.g. BRCA1) that parents don't really want to be thinking about.

In summary,

All screening and diagnostic testing are optional in pregnancy and women should ALWAYS have the right to decline.

Remember that a screening/anatomy ultrasound is still a screening test (and women should know this)

If a patient wants screening, they should have the most accurate screening tests available

Providers should be able to explain what conditions we are screening for, explain false positives and detection rates, and have a plan for results if they are anything other than "normal"

Any questions: contact Dr. Shaffer at shaffebl@sutterhealth.org