Prenatal genetic screening is a routine but often confusing part of obstetric care. With multiple screening options available—each with different timing, methods, and limitations—it’s important for clinicians to understand what each test evaluates and how to counsel patients appropriately.

In this episode of the OB/GYN Resident Survival Guide, we break down the most commonly used prenatal genetic screening tests, including first- and second-trimester screening, sequential and integrated screening, and cell-free DNA testing.

Who Should Be Offered Prenatal Genetic Screening?

All pregnant patients, regardless of age or risk factors, should be offered prenatal genetic screening. Screening is optional and should always be presented as an opt-in choice, with patients retaining the right to decline testing.

It’s critical to emphasize that all tests discussed here are screening tests, not diagnostic tests. An abnormal or positive screening result does not confirm a genetic diagnosis. Instead, it should prompt further evaluation, including genetic counseling, detailed anatomic ultrasound, and the option of diagnostic testing with chorionic villus sampling (CVS) or amniocentesis.

Cell-Free DNA Screening

Cell-free DNA (cfDNA) screening was introduced in 2011 and has become one of the most widely used prenatal screening modalities. It is a maternal serum test that can be performed as early as 9–10 weeks of gestation.

This test analyzes fragments of fetal DNA circulating in the maternal plasma, which primarily originate from placental cell turnover. Evidence suggests that cfDNA screening is the most sensitive and specific screening test for common aneuploidies, including trisomy 21, 18, and 13, as well as sex chromosome aneuploidies.

In addition to aneuploidy screening, cfDNA can also be used to determine fetal sex, Rh status, and screen for certain single-gene conditions, duplications, and microdeletions (see the SMFM recommendation regarding microdeletion screening here).

First- and Second-Trimester Screening

Before the availability of cfDNA testing, prenatal genetic screening relied primarily on maternal serum analytes and ultrasound findings. These methods remain clinically relevant today.

First-Trimester Screening

Performed between 10 and 13 weeks, first-trimester screening includes:

Maternal serum human chorionic gonadotropin (hCG)
Pregnancy-associated plasma protein A (PAPP-A)
Fetal nuchal translucency measurement by ultrasound

A normal nuchal translucency measurement is less than 3 mm. If first-trimester screening is positive, diagnostic testing should be offered. If negative, patients may proceed to second-trimester screening.

Second-Trimester Screening (Quad Screen)

The second-trimester screen is performed between 15 and 22 weeks, with alpha-fetoprotein (AFP) ideally drawn by 20 weeks. This serum test evaluates:

hCG
Estriol
Inhibin
Maternal serum AFP

Elevated AFP levels may indicate an increased risk of neural tube defects or abdominal wall defects.

Sequential and Integrated Screening

The sequential screen consists of a first-trimester screen followed by a second-trimester quad screen, with results reported in stages. If the first-trimester screen is abnormal, patients can be offered diagnostic testing without waiting for second-trimester results.

The integrated screen combines first-trimester PAPP-A and nuchal translucency measurement with a second-trimester quad screen. Unlike sequential screening, results are reported all at once in the second trimester, after all testing has been completed.

Key Takeaways

Prenatal genetic screening uses a combination of maternal serum testing and ultrasound to assess the risk of chromosomal abnormalities and select fetal anomalies. Cell-free DNA offers the highest sensitivity and specificity for common aneuploidies, while first- and second-trimester screening methods remain important alternatives when cfDNA is not available, appropriate, or desired.

Understanding the timing, components, and limitations of each screening option is essential for providing clear, ethical, and patient-centered counseling during prenatal care.