Posted in Pre-Parenting

First Trimester Prenatal Screening: Science and False Positives

Around weeks 9-12 in your first trimester, people commonly screen the fetus for extra chromosomes via 1) the standard first trimester screen for maternal blood markers (HCG, PAPP-A), or 2) the relatively new more sensitive NIPT (Non-Invasive Prenatal Test) fetal DNA sample from maternal blood (cell-free DNA). There is a fabulous review of both options by a scientifically minded chemist mom at Infertilechemist.com

Note: These are all screening tests- meaning most patients will have a negative result (and thus low risk of abnormality); however, false positive rates can be 5% or more—so if you test positive, it doesn’t necessarily mean your baby has the abnormality, but that more testing may be needed.  If you happen to get a positive result, there is more information for you at the end of the article.  

(As always, this article does not constitute medical advice, and you should discuss all questions, risks and benefits to make a decision with your personal medical care provider.)

Standard First Trimester Screen (HCG/PAPP-A):

Basically the HCG/PAPP-A maternal blood test will risk stratify you for Down Syndrome (and to a limited degree, Trisomy 18), and is typically drawn around 9-10 weeks gestation (but up to 13weeks 6days).  This blood test may be part of a “combined test”, including an ultrasound of nuchal translucency (around 10.5 to 13.9 weeks) to assess for increased thickness behind the neck (>3-4mm in some studies) which can be associated with Down Syndrome or other birth defects.  ”The combined test detects approximately 85 percent of Down syndrome (ie, detection rate [DR] = sensitivity = 85 percent) with a false positive rate (FPR) of 5 percent” (UptoDate.com)–however this rate of detection varies upon pre-test risks like patient age.  Babies with Down Syndrome have high Beta-HCG (Human Chorionic Gonadotrophin, a common pregnancy marker) and low PAPP-A (Pregnancy-Associated Plasma Protein-A).   Babies with Trisomy 18 (an often fatal defect of three copies of chromosome 18) have very low beta-HCG and very low PAPP-A.  Studies of screening efficacy for Trisomy 18 via first trimester screening are more limited as the condition is more rare (1 in 6,000 births, with many spontaneously dying in utero), suggesting somewhere between 60-91% detection in small studies (NEJM 2003, Lambert-Messerlian et al, 2004).

The ACA: Affordable Care Act (Obamacare) currently requires coverage of most prenatal care (often with no copay- but check with your insurance).  In California, I was told the benefit of doing this test alone is that if it is abnormal there is a state fund to cover your amniocentesis or related prenatal care for free (which might save you money in that case based on your specific insurance).  This test also tends to cost less than NIPT–however, HCG/PAPP-A alone is much less accurate.  If your insurance only covers HCG/PAPP-A, you can see if a nuchal translucency ultrasound (the “combined test”) might be part of your coverage to increase sensitivity.  Those who are higher risk (older moms etc.) might consider any extra cost of the NIPT to be worth it (and insurance may also cover the NIPT for higher risk patients).  Again, check with your current insurance as you might not pay much more for the more sensitive NIPT test.

NIPT (Non-Invasive Prenatal Test) of a fetal DNA sample from maternal blood (cell-free DNA):

NIPT (cell free DNA, cfDNA) is much more sensitive and specific than the traditional first trimester blood screen (cfDNA detects 98-99% of Down Syndrome versus just ~85% with the traditional “combined test”).  Furthermore, cfDNA screens for a wider set of conditions: Trisomy 21 (Down Syndrome), Trisomy 18, Trisomy 13 and Sex Chromosome duplication/deletions.  cfDNA screening works by detecting the small amounts of fetal DNA present in maternal blood, and is typically done via maternal blood draw anytime after weeks 9-10 (with no end date).  Test results come back in about 2 weeks or possibly less depending on your lab.  (Some people enjoy the extra benefit that it tells you fetal sex earlier than ultrasound as well.)

UptoDate Reprint of: Performance of cell-free DNA screening for trisomy 21,18,&13

Disorder Studies Cases DetectionRate (%) False Negative Rate (%) Controls False Positive Rate(%)
Trisomy 21 31 1587 99.4 0.6 146,757 0.1
Trisomy 18 24 444 97.7 2.3 146,496 0.1
Trisomy 13 16 85 90.6 9.4 134,606 0.1
All three* 98.5* 1.5 0.3

DR: detection rate (or sensitivity); FNR: false-negative rate (1-sensitivity); FPR: false-positive rate (or 1-specificity).

* Weighting is by the disorder’s prevalence in the late first trimester of pregnancy (approximately 10:2:1).

Data from the article: Mackie FL, Hemming K, Allen S, et al. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG 2017; 124:32.

The only downside for this more sensitive NIPT test is that the list price for cfDNA testing is often higher than HCG/PAPP-A–however, do check your specific insurance for coverage and out of pocket costs for this test.  Obamacare requirements might make it covered for you, and especially being 35 or over (AMA: advanced maternal age) might help get this test done for free or little cost.  In my case, my OB/Gyn recommended to the NIPT test alone (without the HCG/PAPP-A test) and added the nuchal translucency ultrasound for more accuracy.  I am 35, but had no co-pays for either test.

If you get an Abnormal cfDNA Screening Test:

Most people will have negative results, thus putting you at low risk for any trisomy or abnormality.  However if you do get a positive result I does not mean your fetus definitely has it. OB/Gyns see positive results rarely, so they may not realize the exact statistics for a positive finding in your case.  If you’re one of the rare people who gets a call with an abnormal results:

  • Ask what brand the cfDNA test was and go to this website for more information of your actual risk: http://www.med.unc.edu/obgyn/Patient_Care/specialty-services/maternal-fetal-medicine/nips_calc.html
    • The relevant calculation for you on this website is the PPV: Positive Predictive Value, which tells you the percent chance your positive result is a “true positive”, aka the fetus actually has the chromosomal abnormality. This can be somewhat reassuring especially for chromosome 18 or 13, where a positive results have just a 11 to 35% chance of actually having the abnormality.   Please note that if your results are negative, this chart is not relevant to you, except to show you your background risk for abnormality based on your age.
  • In addition to that, if you do get a positive result screening from either test:
    • Ask for both a nuchal translucency ultrasound and perinatology consult referral, if this has not been ordered already.  The nuchal translucency ultrasound for a chromosomal or other abnormality is typically done around weeks 10.5-13.9 of the pregnancy and helps further stratify risk. Perinatologists are extra fellowship trained Ob/Gyns who interpret ultrasound results and also tend to get involved if there is a chromosomal abnormality.
    • Ask for a referral to a genetic counselor, who should have more specific information on your specific risks and testing options as well.
    • Talk with your provider about whether a CVS: Chorionic Villus Sampling (~10 to 13 weeks) or Amniocentesis (typically after 14 weeks gestation) can confirm the finding as needed.  Often they can begin the referral process for that now to help minimize the delay of insurance processing for what can be time sensitive procedures.  The cell samples from these invasive procedures can be confirmatory for fetal genetic testing via FISH (a rapid fluorescent probe on chromosomes in ~48hrs-72hrs) and full karyotype analysis (which images and counts all fetal chromosomes, typically taking 2 weeks).  Risks of miscarriage or other complications of these invasive procedures should be discussed by your Ob/Gyn.
    • Based on the results of the follow up testing, your provider can further counsel on the likelihood of the screening test being a true positive and further treatment options.

Screening tests have reached new advances in recent years, particularly with the NIPT cell-free DNA screens.  Sometimes screening can be stressful, but hopefully this helps calm and inform during this process.

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