Prenatal screening for chromosomal conditions — structured SAQ (15 marks)

(a) Interpretation and next step (3 marks)

One mark for the interpretation, one for the threshold, one for the next step. ^[3]

• This is a screen-positive result. A risk of 1 in 80 for trisomy 21 is above the typical screen-positive threshold of 1 in 300 (or 1 in 150, depending on the laboratory). The result is driven by the raised nuchal translucency (3.2 mm), low PAPP-A and raised free beta-hCG.^[3]
• Most screen-positive results are false positives — the result is a probability, not a diagnosis.
• Next step: offer same-day counselling and diagnostic testing — chorionic villus sampling at 11 to 14 weeks, with rapid QF-PCR and a full karyotype or microarray. No irrevocable decision is made on a screening result.^[3]

(b) Combined screening versus cfDNA performance (4 marks)

One mark per correctly quoted performance pair. Numbers must be read from source, not approximated. ^[1][2]

• First-trimester combined screening (Malone FIRST, NEJM 2005): detection rate about 87 percent for trisomy 21 at a 5 percent false-positive rate when performed at 11 weeks (85 percent at 12 weeks, 82 percent at 13 weeks).^[2]
• cfDNA (Gil meta-analysis, UOG 2017): detection rate 99.7 percent (95% CI 99.1 to 99.9) at a false-positive rate of 0.04 percent for trisomy 21 in singleton pregnancy.^[1]
• For the other trisomies (cfDNA): trisomy 18 detection 97.9 percent at 0.04 percent FPR; trisomy 13 detection 99.0 percent at 0.04 percent FPR, though based on few cases.^[1]
• The message: cfDNA detects more and false-positives far fewer, but it is more expensive, can fail (low fetal fraction), and screens for a narrower range of conditions than a combined programme plus anomaly scan.^[1][2]

(c) Why cfDNA is a screening test and the diagnostic pathway (4 marks)

One mark for the principle, one for the biological basis, one for the diagnostic options, one for the procedural risk. ^[1][3]

• cfDNA is a screening test, not a diagnostic test. It estimates a risk from placental DNA fragments in maternal plasma; it does not sample fetal cells directly.^[3]
• Biological basis of discordance: cfDNA derives from the placenta (trophoblast), so confined placental mosaicism — where the placenta carries a chromosomal abnormality the fetus does not — produces a cfDNA result that does not match the fetal karyotype. A proportion of cfDNA positives are false positives for this reason.^[1]
• Diagnostic pathway: CVS at 11 to 14 weeks (samples trophoblast, earliest result) or amniocentesis at 15 weeks and over (samples amniotic fluid fetal cells, the gold standard); both with rapid QF-PCR and karyotype or microarray.^[3]
• Procedural risk: contemporary, ultrasound-guided sampling carries a procedure-related miscarriage risk close to zero (Akolekar: CVS 1.5 percent vs 1.2 percent control, amniocentesis 0.8 percent vs 1.2 percent, both not significant).^[5]

(d) The no-call cfDNA result (4 marks)

One mark for the meaning of no-call, one for the association with aneuploidy, one for the management options, one for the counselling principle. ^[4]

• A no-call is not a negative result. The test failed because the fetal fraction was too low to interpret (typically below about 4 percent).^[4]
• Low fetal fraction is associated with a higher background rate of fetal aneuploidy and adverse pregnancy outcome (Sarno systematic review), so reassurance alone is unsafe.^[4]
• Management options: repeat cfDNA (which may also fail, particularly with high BMI), switch to first-trimester combined screening if still in window, or offer diagnostic testing.^[4]
• Counselling principle: explain that the test did not give a result rather than a negative result, and that the next step is chosen to resolve the risk — never to file the no-call as 'normal'.^[4]