QUESTION 1
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Q1(a). Interpretation of first and second trimester serum screening methods. (20 Marks)
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Long Answer Q1(a) — 20 MARKS
1. Overview & Purpose
Key Concept
Serum screening tests estimate an individualised risk of fetal aneuploidy (principally trisomy 21, 18, and 13) and open neural tube defects by combining maternal serum biochemical marker concentrations (expressed as multiples of the median, MoM, to correct for gestational age and maternal weight) with maternal age and, where applicable, ultrasound findings — producing a numerical risk estimate rather than a definitive diagnosis.
Fig 1. Timeline of Aneuploidy Screening Methods in Pregnancy
Sketch — first-trimester, second-trimester, and cfDNA screening windows
Sketch — first-trimester, second-trimester, and cfDNA screening windows
2. First Trimester Screening — The Combined Test (11–14 weeks)
| Component | Pattern in Trisomy 21 |
|---|---|
| Nuchal translucency (NT) | Increased (>95th centile for crown-rump length) |
| Free beta-hCG | Increased (>1 MoM) |
| PAPP-A (pregnancy-associated plasma protein-A) | Decreased (<1 MoM) |
Combined with maternal age-related background risk, these three parameters generate an individualised risk estimate with a detection rate of approximately 85–90% for trisomy 21 at a ~5% false-positive rate. In trisomy 18/13, NT is increased but both PAPP-A and free beta-hCG are characteristically decreased, helping differentiate the specific aneuploidy risk pattern.
Additional First-Trimester Ultrasound Markers
- Nasal bone — absent or hypoplastic in a significant proportion of trisomy 21 fetuses, used to refine risk in some protocols.
- Ductus venosus Doppler — reversed “a-wave” flow associated with increased aneuploidy and cardiac defect risk.
- Tricuspid regurgitation — additional soft marker increasing aneuploidy risk when present.
3. Second Trimester Screening — The Quadruple Test (15–20 weeks)
| Marker | Trisomy 21 Pattern | Trisomy 18 Pattern |
|---|---|---|
| Alpha-fetoprotein (AFP) | Decreased | Decreased |
| Human chorionic gonadotrophin (hCG) | Increased | Decreased |
| Unconjugated oestriol (uE3) | Decreased | Decreased |
| Inhibin A | Increased | Normal/unchanged |
Detection rate for trisomy 21 is approximately 80% at a 5% false-positive rate — used when a woman presents beyond the first-trimester window, or as part of an integrated/sequential protocol. Isolated markedly elevated AFP (with the other three markers normal) instead suggests an open neural tube defect, abdominal wall defect, or multiple pregnancy rather than aneuploidy.
4. Integrated & Sequential Screening Strategies
| Strategy | Details |
|---|---|
| Integrated test | Combines first-trimester (NT + PAPP-A) and second-trimester (quadruple test) results into a single risk report only released after both are complete — highest detection rate (~94–96%) but delays result disclosure |
| Sequential (stepwise) screening | Discloses an interim first-trimester result; high-risk women are offered immediate diagnostic testing, while intermediate/low-risk women proceed to second-trimester testing for a revised combined risk — balances early reassurance/action with improved overall detection |
| Cell-free DNA (NIPT) | Increasingly used as a highly sensitive secondary screening step after an intermediate-risk combined/quadruple test result, reducing unnecessary invasive testing, though it remains a screening (not diagnostic) test |
Evidence-Based Guidelines
FIGO and ACOG guidelines endorse first-trimester combined screening as the preferred initial approach where available (given the earlier result and additional structural information from the NT scan), with the quadruple test as an appropriate alternative for women presenting later. Both bodies now support cfDNA/NIPT as a highly effective screening option, particularly for women at increased background risk or with a positive conventional screen, while emphasising it must be followed by diagnostic testing (CVS/amniocentesis) before irreversible clinical decisions.
Quick Viva Voce
Q. Why are marker levels expressed as multiples of the median (MoM) rather than absolute concentrations?
Serum marker concentrations vary substantially with gestational age, maternal weight, ethnicity, and assay-specific factors; expressing each woman’s result as a ratio to the population median for her exact gestational age (MoM) allows meaningful, standardised comparison and risk calculation across different laboratories and patient characteristics.
Q. Why does trisomy 18 show a different biochemical pattern from trisomy 21 despite both being autosomal trisomies?
Trisomy 18 is associated with severe placental dysfunction and growth restriction from early pregnancy, causing broadly reduced placental protein/hormone output (low PAPP-A, low free beta-hCG, low AFP, low uE3), whereas trisomy 21 placentas typically show relatively preserved or even increased hCG/inhibin A production alongside reduced PAPP-A — this distinct combined pattern helps differentiate the specific trisomy risk.
Q. Why is sequential screening sometimes preferred over the fully integrated test despite a lower overall detection rate?
Sequential screening discloses a risk result after the first-trimester component alone, allowing women at high risk to proceed immediately to diagnostic testing without waiting for second-trimester results — this earlier actionable information and reduced anxiety for high-risk women is considered by many programmes to outweigh the small reduction in overall population detection rate compared with the fully integrated test.