What is the recommended protocol for Enhanced First Trimester Screening (EFTS) using the First Trimester Quadruple Test (FTQT)?

Enhanced First Trimester Screening Protocol

Enhanced First Trimester Screening (EFTS) combines nuchal translucency (NT) measurement with two maternal serum biochemical markers—pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG (or intact hCG)—performed between 11 weeks 0 days and 13 weeks 6 days of gestation, achieving approximately 90% detection of Down syndrome with a 5% false-positive rate. 1, 2

Core Components of the Quadruple First Trimester Test

The term "quadruple" in first trimester screening refers to the four risk parameters assessed:

• Maternal age - incorporated into baseline risk calculation 2
• Nuchal translucency (NT) measurement - fluid-filled space behind fetal neck measured via ultrasound, with increased NT defined as ≥3 mm or ≥99th percentile for crown-rump length 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 more commonly used in the United States due to limited access 1, 2

Optimal Timing and Technical Requirements

The ideal gestational age for combined testing in a single visit is 12 weeks, as fetal anatomy visualization is superior at 12-13 weeks compared to 11 weeks, allowing detection of structural malformations in addition to aneuploidy screening. 3

Timing specifications:

• Gestational age window: 11 weeks 0 days to 13 weeks 6 days 2
• Crown-rump length: 45-84 mm for accurate NT measurement 2
• Alternative two-stage approach: Blood draw at 10 weeks with NT measurement at 12 weeks achieves 94-96% detection rates at 3-5% false-positive rates, though this increases cost and potential non-compliance 3

Performance by gestational age (single-visit strategy):

• At 11 weeks: 92-94% detection at 3-5% false-positive rates 3
• At 12 weeks: 85-90% detection at 3-5% false-positive rates 3
• At 13 weeks: 79-83% detection at 3-5% false-positive rates 3

Quality Assurance Requirements

Sonographers must be appropriately trained in proper NT measurement technique and maintain certification through available organizations, as considerable inter- and intra-observer variability exists. 1, 2

• Operators must participate in external quality assurance programs such as the Fetal Medicine Foundation or Nuchal Translucency Quality Review 1
• Strict laboratory standards must be maintained for biochemical marker assays 1
• PAPP-A and intact hCG are stable at 4-8°C for at least 6 days, but free beta-hCG is sensitive to high temperatures 4

Ultrasound Approach

Transabdominal ultrasound obtains adequate NT measurements in approximately 95% of patients. 1

• Transvaginal ultrasound should be utilized when optimal transabdominal views cannot be obtained, particularly helpful for women with high body mass index 1
• NT measurement alone detects only 70% of trisomy 21 fetuses and should never be used in isolation 1
• Doppler imaging is not advised when NT is normal or <3 mm due to theoretical risk of thermal damage to the developing fetus 1

Optional Enhanced Markers

Nasal bone assessment can be incorporated but should be limited to clinicians with specific training and ongoing quality assurance participation. 1, 2

• Absence of the nasal bone at 11-14 weeks is a powerful marker of aneuploidy and improves screening algorithms when added to standard markers 1, 2
• This enhancement is optional and not universally recommended due to technical requirements 1

Risk Calculation and Reporting

The laboratory calculates patient-specific risk by:

• Starting with maternal age-related baseline risk for trisomy 21 at term 3
• Adjusting for gestational age at screening 3
• Converting measured NT into a likelihood ratio using mixture model distributions 3
• Converting PAPP-A and free β-hCG/intact hCG into multiples of the median (MoM), adjusted for maternal weight, ethnicity, smoking status, method of conception, and parity 1, 3
• Multiplying likelihood ratios by baseline risk to derive final patient-specific risk 3

Risk estimates are provided for trisomy 21,18, and 13 after adjusting for crown-rump length and maternal factors. 1, 2

Critical Action Thresholds

When NT measures ≥3.5 mm, even with low-risk screen results or normal karyotype, detailed anatomic ultrasound and echocardiogram must be performed. 1, 4

• Approximately one-third of fetuses with NT ≥3.5 mm will have chromosomal abnormality, with half being trisomy 21 2
• Increased NT is associated with congenital heart defects, diaphragmatic hernias, skeletal dysplasias, and genetic syndromes 1, 2

Additional high-risk parameters requiring action:

• Low PAPP-A (<0.4 MoM): Major risk factor for fetal growth restriction; implement increased ultrasound surveillance and consider low-dose aspirin (75-100 mg daily) starting before 16 weeks 4
• Free β-hCG <0.2 MoM or ≥5.0 MoM: Should be classified as high-risk 5
• Maternal age ≥45 years: Automatic high-risk classification 5

Multiple Gestations

First trimester screening can be used in twin pregnancies, but women must be informed of limitations. 1

• Combined ultrasound and serum screening for multifetal gestations is less sensitive than singleton pregnancies 1, 2
• NT measurement alone is useful but associated with higher positive screening rates 1
• Serum marker levels reflect both pregnancies and are averaged, reducing accuracy 1

Follow-up Requirements

Women who undergo first trimester screening must be offered maternal serum AFP screening and/or anatomic survey between 16-20 weeks for neural tube defect detection. 1, 4

• First trimester ultrasound should not replace the standard second trimester anatomic fetal survey 1
• Only 50% of major fetal anomalies can be detected before 14 weeks with 3-4% false-positive rate 1
• Less than 25% of major heart defects are detected using NT cutoff at 99th percentile in euploid fetuses 1

Patient Counseling Framework

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 should be informed of adjusted risk for Down syndrome and allowed to make decisions based on this number, as individuals weigh risk/benefits differently 1
• Age is no longer used as a cutoff to offer invasive testing, making predetermined age-based cutoffs for screening programs illogical 1
• Women who do not want any information regarding fetal chromosomal status should not be required to undergo testing after appropriate documentation 1, 2

Common Pitfalls to Avoid

• Never use NT measurement alone - detection rate drops to 70% versus 90% with combined approach 1, 2
• Do not perform first trimester screening outside 11-14 week window - accuracy depends on proper gestational age 2
• Avoid assuming normal NT excludes all anomalies - most congenital heart disease occurs with normal NT 1
• Do not skip second trimester follow-up - neural tube defects and many structural anomalies require later detection 1, 4