In a pregnant woman with a singleton gestation, when and how should first‑trimester screening for aneuploidy be offered, and what follow‑up steps are recommended if the calculated risk is elevated?

First-Trimester Screening for Aneuploidy

All pregnant women, regardless of maternal age, should be offered first-trimester combined screening between 11 weeks 0 days and 13 weeks 6 days of gestation, consisting of nuchal translucency (NT) measurement by ultrasound plus two maternal serum biochemical markers: pregnancy-associated plasma protein A (PAPP-A) and free β-hCG or intact hCG. 1, 2

Core Screening Components and Timing

The optimal gestational window is critical: First-trimester screening must be performed between 11 weeks 0 days and 13 weeks 6 days (crown-rump length 45-84 mm) for valid results. 2, 3 NT measurements performed outside this window are not valid for aneuploidy risk assessment and should be repeated within the appropriate gestational age range. 3

The three essential components are:

• Nuchal translucency (NT): A fluid-filled space behind the fetal neck measured via ultrasound, with increased NT (≥3 mm or ≥99th percentile for crown-rump length) significantly associated with Down syndrome and other aneuploidies. 1, 2

• PAPP-A: Typically reduced in Down syndrome pregnancies. 1, 2

• 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

Performance Characteristics

This combined approach detects approximately 85-92% of Down syndrome cases with a false-positive rate of 1-5%, substantially superior to maternal age alone (30% detection) or NT measurement alone (70% detection). 1, 2, 3 The screening also provides risk assessment for trisomy 18 and 13. 1, 2

Mandatory Quality Assurance Requirements

NT measurement has considerable inter- and intra-observer variability, making operator training absolutely essential. 1, 2 Sonographers must be appropriately trained in the proper technique of NT measurement and have appropriate certification through available organizations with ongoing quality assurance participation. 1 Programs not meeting these standards should not offer NT screening. 1

Patient Counseling Framework

All women should have the option of invasive diagnostic testing (CVS or amniocentesis) regardless of maternal age to definitively identify all major fetal aneuploidies. 1, 2 Counseling must be non-directive and respect a woman's right to accept or decline any testing. 4

Women who do not want any information regarding fetal chromosomal status should not be required to undergo testing after appropriate documentation. 1, 2

Follow-Up Steps for Elevated Risk Results

When Screening Indicates Elevated Risk:

Women should be informed of their adjusted risk for Down syndrome and allowed to make decisions based on this number, because individuals weigh risk/benefits differently and are capable of such decision-making. 1 Because age is no longer used as a cutoff to offer invasive testing, it is no longer logical to use predetermined cutoffs based on age risk for screening programs. 1

• Genetic counseling should be offered promptly to discuss the meaning of the risk assessment and options for diagnostic testing. 2

• Invasive diagnostic testing (CVS or amniocentesis) should be offered to provide definitive chromosomal diagnosis. 1

Critical Action Threshold for NT Measurement:

An NT measurement of ≥3.5 mm, even in the setting of a low-risk aneuploidy screen result or normal fetal karyotype, should prompt a detailed anatomic ultrasound, echocardiogram, or both. 1 Increased NT is associated with congenital heart defects, diaphragmatic hernias, skeletal dysplasias, and a variety of genetic syndromes. 1, 2

Essential Second-Trimester Follow-Up

Women who have elected first-trimester screening and/or CVS should be offered maternal serum alpha-fetoprotein (MSAFP) screening and/or an anatomic survey, optimally between 16 and 20 weeks' gestation for the detection of neural tube defects. 1, 3, 5 First-trimester screening does not assess for open neural tube defects. 1

Optional Additional Markers

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, 2 Absence of the nasal bone is associated with Down syndrome but its value as a screening test in the general population is controversial. 1

Special Considerations for Multiple Gestations

First-trimester screening can be used in multifetal pregnancies; however, women should be made aware of the limitations of screening in this setting. 1 NT measurement alone is useful for screening twins but is associated with a higher positive screening rate. 1, 2 Combined ultrasound and serum screening for multifetal gestations remains less sensitive than in singleton pregnancies because serum marker levels reflective of both pregnancies are actually averaged. 1, 2

Common Pitfalls to Avoid

• Performing NT measurements without proper training and quality assurance produces unreliable results and should not be offered. 1, 2

• Using NT measurement alone without biochemical markers in singleton pregnancies reduces detection rates from 85-92% to only 70%. 1, 2

• Failing to confirm gestational age with ultrasound when menstrual dating is unreliable can lead to incorrect risk calculations. 4

• Not providing MSAFP screening or anatomic survey in the second trimester to women who had first-trimester screening leaves neural tube defects undetected. 1, 3

• Using maternal age alone as an indication for invasive testing when non-invasive screening is available is a poor standard of care. 4