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#19: Make SENSE of Prenatal Genetic Screening - cfDNA, First & Second Trimester, Sequential & Integrated Screen

The OB/GYN Resident Survival Guide

Sat Feb 07 2026

Summary

Podcast Summary: The OB/GYN Resident Survival Guide

Episode #19: Make SENSE of Prenatal Genetic Screening – cfDNA, First & Second Trimester, Sequential & Integrated Screen

Host: Dr. KC Miller
Date: February 7, 2026

Episode Overview

This episode, hosted by Dr. KC Miller, offers a focused, high-yield breakdown of prenatal genetic screening modalities. Dr. Miller covers the most up-to-date tests—including cell-free DNA (cfDNA), first and second trimester screening, sequential and integrated screens—clarifying indications, test timing, and clinical pearls. The content is tailored for OB/GYN residents and medical students seeking to master core knowledge for clinical practice and exam preparation.

Key Discussion Points & Insights

1. Who Should Be Offered Prenatal Genetic Screening?

Universal Offering:
- Every pregnant person should be offered prenatal genetic screening, regardless of age or risk factors.
- Screening is not mandatory; it’s opt-in with the right to decline.
Screening vs. Diagnostic Testing:
- All screenings discussed are screening tests—they cannot confirm or rule out genetic disease.
- Next Steps after Abnormal Results:
  - Abnormal screens should lead to genetic counseling, detailed anatomic ultrasound, and offer of diagnostic testing (amniocentesis or CVS), per best practice.
“Any pregnant person, regardless of their age or whether or not they have risk factors for genetic disease, should be offered prenatal genetic screening.” — Dr. KC Miller (01:17)

2. Cell-Free DNA (cfDNA) Screening

Main Takeaways:

Description: A maternal serum test evaluating fragments of fetal DNA (cfDNA) in maternal plasma—primarily placental in origin.
Timing: Can be performed as early as 9–10 weeks gestation.
Accuracy: Currently the most sensitive and specific screening for common trisomies (21, 18, 13) and sex chromosome aneuploidies.
Additional Capabilities:
- Can determine fetal sex, RH status, and screen for certain single gene disorders/microdeletions.
Notable Applications:
- Most recommended by SMFM and ACOG when available.
- Not suitable for some scenarios (e.g., vanishing twins, maternal mosaicism, organ transplants).
“Screening with cell free DNA is considered by the Society of Maternal Fetal Medicine and ACOG to be the most sensitive and specific screening modality.” — Dr. KC Miller (04:26)

3. First and Second Trimester Serum Screening

First Trimester Screen (FTS):
- Timing: 10–13 weeks gestation.
- Components:
  - Maternal serum HCG
  - Pregnancy associated plasma protein A (PAPP-A)
  - Nuchal translucency (NT) by ultrasound
- Interpretation: Normal NT is <3 mm.
- Follow-up: Positive screens → offer diagnostic testing (amnio/CVS).
“The first trimester screen should be completed between 10 and 13 weeks and includes a serum human chorionic gonadotropin or HCG, a serum pregnancy associated plasma protein A or PAPA and a nuchal translucency measurement performed by ultrasound.” — Dr. KC Miller (08:44)
Second Trimester Screen (Quad Screen):
- Timing: 15–22 weeks (AFP ideally by 20 weeks)
- Components:
  - HCG
  - Estriol
  - Inhibin
  - Maternal serum alpha-fetoprotein (AFP)
- AFP Pearls: Elevated in neural tube/abdominal wall defects
“The second trimester screen is also called the quad screen because it is a blood draw that assesses four serum analytes...” — Dr. KC Miller (11:10)
Why Still Relevant? If cfDNA is inaccessible/not desired/contraindicated (insurance, patient preference, special maternal histories), traditional screens remain important.

4. Sequential and Integrated Screening

Sequential Screen:
- First perform first trimester screen.
- If negative, continue to second trimester (quad) screen.
- Results reported twice—after each segment.
“The sequential screen is simply a combination of the first and second trimester screens done in sequential order.” — Dr. KC Miller (10:22)
Integrated Screen:
- FTS (NT + PAPP-A) plus second trimester quad screen, but results provided only after both are complete—one comprehensive risk assessment in the second trimester.
“The integrated screen comes packaged as a single test result with the risk assessment in the second trimester.” — Dr. KC Miller (13:36)

5. Recap and Clinical Pearls

Dr. Miller offers a succinct wrap-up, reinforcing main points:

cfDNA has the highest sensitivity/specificity for aneuploidy (including sex chromosomes) and can identify additional conditions.
First Trimester Screen: HCG + PAPP-A + nuchal translucency
Second Trimester Screen: HCG + estriol + inhibin + AFP (key for neural tube defects)
Sequential Screen: First trimester screen, then second if negative
Integrated Screen: Combines above, reporting only after both are complete

“I know that's a lot to digest and sometimes these things are easier to read than to hear, so feel free to check out the transcript in the show notes along with the references for additional reading.” — Dr. KC Miller (15:30)

Notable Quotes & Memorable Moments

On Screening Necessity:

“Testing is not mandatory and should be considered opt-in only with the right to decline.” — Dr. KC Miller (01:30)
On Diagnostic Follow-Up:

“Positive or abnormal screening results should be followed up with a combination of genetic counseling, a detailed anatomic ultrasound survey, and the patients should be offered diagnostic testing...” — Dr. KC Miller (02:08)
On Clinical Relevance of Traditional Screening:

“These screening tests are still relevant and important to know, especially because not all patients will have insurance that covers cell free DNA.” — Dr. KC Miller (07:50)

Timestamps for Key Segments

00:00 – Episode Introduction; universal offering of screening
04:00 – Cell-Free DNA (cfDNA) overview
08:44 – First Trimester Screen: components and timing
10:22 – Sequential Screen: definition and workflow
11:10 – Second Trimester (Quad) Screen: analytes and timing
13:36 – Integrated Screen: definition and workflow
15:30 – Recap and additional resources

Episode Tone

Dr. Miller keeps the episode focused, clinically relevant, and encouraging, using direct and inclusive language tailored for busy residents and students.

Further Learning

Check episode show notes for transcript and reference links, including the recommended “Ethical Considerations for Genetic Testing and Counseling.”
Visit www.drkcmiller.com or follow @drkcmiller for further resources.

This episode delivers a concise yet thorough review of a topic critical for exam prep and real-world residency efficiency, staying true to Dr. Miller’s mission to distill OBGYN knowledge into high-yield, digestible pearls.

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Transcript

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Hello and welcome back for another episode of the OB GYN Resident Survival Guide. I'm your host, Dr. Casey Miller and this is a podcast that contains bite sized, straight to the point clinical pearls that you can consume on the run. Today we are going to be breaking down prenatal genetic screening via the first and second trimester screen, the sequential and integrated screen and screening with cell free DNA. So, so buckle up. First and foremost, which patients should be offered prenatal genetic screening? Well, that's a trick question. Any pregnant person, regardless of their age or whether or not they have risk factors for genetic disease, should be offered prenatal genetic screening. Testing is not mandatory and should be considered opt in only with the right to decline. It's important to remember that all of the studies I'm reviewing today are screened screening tests alone and are not diagnostic, meaning they do not confirm the presence or absence of genetic disease. Positive or abnormal screening results should be followed up with a combination of genetic counseling, a detailed anatomic ultrasound survey, and the patients should be offered diagnostic testing or confirmatory testing with amniocentesis or chorionic villus sampling. And when offering these screening tests, it's important that the patients are aware of this and the implications of a positive or abnormal screening value. Because I'm just going to be focusing on the basics this episode. I've attached a great journal article in the references called Ethical Considerations for Genetic Testing and Counseling and it's worth a read for a deeper dive on some of the potential incidental or secondary findings that might arise as a result of these screening studies. All right, so let's jump in and start with the first and probably the most common, at least recently, screening modality, and that is cell free DNA. This is a serum study that was introduced fairly recently, back in 2011. It can be performed as early as 9 to 10 weeks gestation. And it works by evaluating fragments of fetal DNA, also called cell free DNA, that circulate in the maternal plasma. These fragments are a result of cell breakdown primarily arising from the placenta. Screening with cell free DNA is considered by the Society of Maternal Fetal Medicine and ACOG to be the most sensitive and specific screening modality for some of the common aneuploidies, including trisomies 21, 18 and 13, as well as sex chromosome aneuploidies. That being said, it can also be utilized to identify fetal sex, RH status and even to screen for single gene conditions, duplications, microdeletions and more. So that's cell free DNA. Now let's jump into the longer standing screening modalities. The first and second trimester screen and sequential and integrated screen were introduced in the 80s-90s and assess serum analytes as opposed to cell free DNA in combination with the fetal nuchal translucency measurement by ultrasound. These studies screen for aneuploidy and other chromosomal abnormalities in addition to neural tube and abdominal wall defects. They do not assess for fetal sex or sex chromosome aneuploidies. These screening tests are still relevant and important to know, especially because not all patients will have insurance that covers cell free DNA. Some patients may not desire cell free DNA testing and some patients are generally not candidates for cell free DNA screening, for example those experiencing vanishing twin syndrome, maternal mosaicism, or with a personal history of organ transplant. The first trimester screen should be completed between 10 and 13 weeks and includes a serum human chorionic gonadotropin or HCG, a serum pregnancy associated plasma protein A or PAPA and a nuchal translucency measurement performed by ultrasound. And as a reminder, a normal nuchal translucency measurement is less than 3 millimeters. If the first trimester screen is positive, the patient should be offered diagnostic testing such as with an amniocentesis or chorionic villus sampling. If the screen is negative, we then perform the second trimester screen and this sequence of performing the first and then the second trimester screen is what the sequential screen is. The sequential screen is simply a combination of the first and second trimester screens done in sequential order. So that's pretty straightforward. The second trimester screen is also called the quad screen because it is a blood draw that assesses four serum analytes, hcg, estriol inhibin and maternal serum alpha fetoprotein or afp. AFP is the one we would expect to be elevated in neural tube defects or abdominal wall defects. The second trimester screen should be performed between 15 and 22 weeks. However, the AFP should ideally be drawn by 20 weeks. Some labs might go as far to let you draw it at 21 weeks. All right, so we've talked about the first trimester screen, the second trimester screen and the sequential screen. Lastly, the integrated screen is a combination of the first trimester nuchal translucency measurement and a first trimester serum Pap A followed by a second trimester quad screen. Unlike the sequential screen where you receive the result of the first trimester screen and then the second trimester screen, the integrated screen comes packaged as a single test results with the risk assessment in the second trimester. All right, let's review Prenatal genetic screening utilizes a combination of maternal serum studies and ultrasound evaluation. Cell free DNA tests assess fragments of fetal DNA that circulate within the maternal bloodstream and have the highest sensitivity and specificity for detecting common aneuploidies such as Trisomy 13, 18 and 21. They can also screen for sex chromosome aneuploidies and a variety of other genetic conditions. The first trimester screen includes a maternal serum HCG papa and a fetal mucotranslucency measurement by ultrasound. The second trimester screen or quad screen includes the hcg, estriol inhibin and maternal serum alpha fetoprotein. The sequential screen is simply the first trimester screen followed by the second trimester screen. The integrated screen includes a first trimester papa and nuchal translucency measurement followed by a second trimester quad screen and the patient receives the results all at once in the second trimester after all studies have been completed. I know that's a lot to digest and sometimes these things are easier to read than to hear, so feel free to check out the transcript in the show notes along with the references for additional reading. That's it for today and I will see you next week for another episode.