What are the recommended first trimester screening markers for chromosomal abnormalities?

First Trimester Screening Markers for Chromosomal Abnormalities

The recommended first trimester screening markers are nuchal translucency (NT) measurement by ultrasound combined with two maternal serum biochemical markers: pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (free β-hCG) or intact hCG, performed between 11-14 weeks of gestation. 1, 2

Core Screening Components

The three essential markers that comprise first trimester combined screening are:

• Nuchal translucency (NT) measurement: A fluid-filled space behind the fetal neck measured via ultrasound between 11-14 weeks, with increased NT (≥3 mm or ≥99th percentile) significantly associated with Down syndrome and other aneuploidies 1
• PAPP-A (pregnancy-associated plasma protein A): Typically reduced in Down syndrome pregnancies 1, 2, 3
• Free β-hCG or intact hCG: Elevated in Down syndrome, with free beta-hCG considered superior though intact hCG is more commonly used in the United States due to limited access 1, 2, 3

Performance Characteristics

This combined approach detects approximately 90% of Down syndrome cases with a 5% false-positive rate, which is substantially superior to maternal age alone (30% detection) or second-trimester serum screening (65% detection) 1, 2, 4. The detection rate specifically for trisomy 21 using combined first trimester screening is approximately 70% when NT is used alone, but increases to 85-90% when combined with both biochemical markers 1, 5.

Timing and Technical Requirements

• Optimal gestational age window: 11 weeks 0 days to 13 weeks 6 days for NT measurement 1
• Crown-rump length: Should be 45-84 mm for accurate NT measurement 1
• Early biochemistry advantage: Recent data indicate improved performance when blood samples are obtained at 8-10 weeks gestational age, though the standard window remains 11-14 weeks 6

Additional Markers (Optional)

Nasal bone assessment can be incorporated into first trimester screening protocols but should be limited to clinicians with specific training and ongoing quality assurance participation 1. Absence of the nasal bone is a powerful marker of aneuploidy and improves screening algorithms when added to the standard three markers 1. However, this remains optional and requires standardization of technique 1.

Quality Assurance Requirements

NT measurement has considerable inter- and intra-observer variability, making ongoing quality assessment essential 1. Operators must be appropriately trained and participate in external quality assurance programs, as established by organizations like the Fetal Medicine Foundation 4. The NT measurement can be obtained transabdominally in approximately 95% of patients, with transvaginal ultrasound available when needed 1.

Screening Beyond Trisomy 21

The combined first trimester screening also provides risk assessment for:

• Trisomy 18 and 13: Combined algorithms are available 1
• Other chromosomal abnormalities: Large databases show efficiency for rare autosomal trisomies, marker chromosomes, and other chromosomal aberrations 6
• Structural anomalies: Increased NT is associated with congenital heart defects, diaphragmatic hernias, skeletal dysplasias, and genetic syndromes 1

Multiple Gestations

For twin pregnancies, NT measurement alone is useful for screening but is associated with a higher positive screening rate 1. Combined ultrasound and serum screening for multifetal gestations remains less sensitive than in singleton pregnancies, as serum marker levels reflective of both pregnancies are averaged 1, 2.

Critical Action Thresholds

When NT measures ≥3 mm, genetic counseling and invasive diagnostic testing should be promptly offered 1. Approximately one-third of fetuses with NT thickness above this threshold will have a chromosomal abnormality, with half being trisomy 21 1. There is minimal benefit in waiting for maternal serum results when NT is ≥3 mm 1.

Common Pitfalls to Avoid

• Do not use NT measurement in isolation: NT alone detects only 70% of trisomy 21 fetuses; it must be combined with biochemical markers for optimal performance 1
• Do not replace second trimester anatomy scan: First trimester ultrasound detects only 50% of major fetal anomalies compared to 75% at 18-22 weeks 1
• Do not use NT as a screening test for congenital heart disease: Less than 25% of major heart defects are detected using NT at the 99th percentile cutoff 1
• Ensure proper sample handling: PAPP-A and intact hCG are stable at 4-8°C for at least 6 days, but free β-hCG is sensitive to high temperatures 3

Patient Counseling Requirements

All women regardless of maternal age should be offered the option of invasive diagnostic testing (CVS or amniocentesis) to definitively identify all major fetal aneuploidies 1, 2. Women who do not want any information regarding fetal chromosomal status should not be required to undergo testing after appropriate documentation 1. For women choosing screening over diagnostic testing, first trimester combined screening provides early reassurance, maternal privacy, and timely detection with options for earlier and safer pregnancy termination if desired 1.