A 28-week pregnant woman undergoes second-trimester screening and has an elevated maternal serum alpha-fetoprotein (AFP) and low unconjugated estriol (uE3) with normal human chorionic gonadotropin (hCG). The risk calculation suggests increased risk for trisomy 21. What is the most appropriate next investigation to confirm or exclude the diagnosis?

Explanation

## Confirmatory Investigation for Abnormal Prenatal Screening ### Clinical Context: Abnormal Triple/Quad Screen The maternal serum marker profile (↑ AFP, ↓ uE3, normal hCG) is consistent with **trisomy 21 risk**. After abnormal screening, the next step is **diagnostic confirmation**, not further screening. ### Diagnostic vs. Screening Tests | Test | Type | Invasive? | Risk of Miscarriage | Diagnostic? | Timing | |---|---|---|---|---|---| | **Amniocentesis + Karyotyping** | **Diagnostic** | **Yes** | 0.1–0.3% | **YES** | 15–20 weeks | | NIPT (cell-free DNA) | Screening | No | 0% | No | 10+ weeks | | Cordocentesis | Diagnostic | Yes | 0.5–1% | Yes | 18+ weeks | | Repeat serum screening | Screening | No | 0% | No | N/A | ### Why Amniocentesis Is Correct **Key Point:** Amniocentesis with karyotyping is the gold standard **diagnostic test** for suspected aneuploidy in the second trimester. It provides a definitive chromosomal diagnosis and can detect all forms of trisomy 21 (regular, translocation, mosaic). **High-Yield:** At 28 weeks, amniocentesis is safe and appropriate. Karyotyping from amniotic fluid cells takes 7–14 days but is definitive. ### Why Other Options Are Incorrect **NIPT (Cell-Free Fetal DNA):** - Is a **screening test**, not diagnostic - Has high sensitivity (>99%) and specificity (>99%) but is not definitive - Used for initial risk assessment, not confirmation after abnormal screening - Requires diagnostic confirmation (amniocentesis or CVS) if abnormal **Cordocentesis:** - Reserved for **specific indications** (suspected congenital infection, severe anemia, isoimmunization) - Higher miscarriage risk (0.5–1%) than amniocentesis - Not first-line for aneuploidy diagnosis - Performed after 18 weeks **Repeat Serum Screening:** - Does not provide diagnostic confirmation - Delays definitive diagnosis - Not indicated after abnormal first screening ### Clinical Pearl **Mnemonic: "SCAN before AMNIO"** — **S**creening tests (triple, quad, NIPT) come first; if abnormal, proceed to **A**mniocentesis (or **C**VS in first trimester) for diagnostic **N**uclei **I**nformation (**O**btain karyotype). [cite:Park 26e Ch 11; Harrison 21e Ch 466]