Triple Screen and Quadruple Screen

PART 1: ANTENATAL SCREENING FOR DOWN SYNDROME

1. Introduction

• Goal: To identify pregnancies at “High Risk” (>1:250) for Trisomy 21, warranting invasive diagnostic testing (Amniocentesis/CVS).
• Strategy: Multimodal approach using Ultrasound markers and Maternal Serum Biochemistry.

2. First Trimester Screening (11 – 13+6 Weeks)

The Combined Test (Gold Standard for 1st Trimester)

• Components:
  1. Ultrasound: Nuchal Translucency (NT) measurement.
  2. Biochemistry: Maternal serum Free $\beta$-hCG + PAPP-A (Pregnancy Associated Plasma Protein-A).
• Down Syndrome Pattern:
  • NT: Increased (>95th percentile or >3mm).
  • Free $\beta$-hCG: Increased (~2.0 MoM).
  • PAPP-A: Decreased (~0.4 MoM).
• Sensitivity: 87–90% (False positive rate 5%).
• Additional USG Markers: Absence of Nasal Bone, Tricuspid Regurgitation, abnormal Ductus Venosus flow (improves detection to 95%).

3. Second Trimester Screening (15 – 20 Weeks)

Indicated for women presenting late or where NT scan was not available.

A. Triple Test

• Analytes: AFP + uE3 (Unconjugated Estriol) + hCG.
• Down Syndrome Pattern:
  • AFP: Low (~0.7 MoM).
  • uE3: Low (~0.7 MoM).
  • hCG: High (~2.0 MoM).
• Sensitivity: 60–70%.

B. Quadruple (Quad) Test

• Analytes: Triple Test components + Inhibin A.
• Down Syndrome Pattern: High Inhibin A (~1.8 MoM) + Pattern of Triple test.
• Sensitivity: 80% (Preferred over Triple test).

4. Cell-Free Fetal DNA (NIPS/NIPT)

• Technique: Analysis of cffDNA in maternal blood (from 10 weeks).
• Performance: >99% detection rate for Down Syndrome; False positive <0.1%.
• Role: Screening test (not diagnostic). High-risk results require confirmation via Karyotype.

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PART 2: UTILITY OF TESTS IN OTHER DISORDERS

Beyond Down Syndrome, these screening modalities detect other chromosomal, structural, and metabolic anomalies.

1. Utility of The Combined Test (1st Trimester)

Disorder	PAPP-A	Free $\beta$-hCG	Nuchal Translucency (NT)
Trisomy 18 (Edwards)	Very Low	Very Low	Increased
Trisomy 13 (Patau)	Low	Low	Increased
Triploidy	Very Low	Low	Normal/Inc
Turner Syndrome (45,X)	Low	Normal	Very High (Cystic Hygroma)
Preeclampsia Risk	Low PAPP-A is a marker for poor placentation and future preeclampsia/IUGR.

2. Utility of Triple & Quadruple Tests (2nd Trimester)

A. Neural Tube Defects (NTDs)

• Marker: Alpha-Fetoprotein (AFP).
• Pattern: Significantly Raised (>2.5 MoM).
• Conditions: Anencephaly (highest levels), Open Spina Bifida, Encephalocele.
• Note: Combined with Acetylcholinesterase (AChE) in amniotic fluid for diagnosis.

B. Abdominal Wall Defects

• Marker: Raised AFP.
• Conditions: Omphalocele, Gastroschisis.

C. Trisomy 18 (Edwards Syndrome)

• Pattern: “All markers are Low”.
  • AFP: Low
  • uE3: Low
  • hCG: Low
  • Inhibin A: Normal/Low.

D. Smith-Lemli-Opitz Syndrome (SLOS)

• Defect: Defect in cholesterol synthesis (7-dehydrocholesterol reductase).
• Pattern: Very Low uE3 (Estriol requires fetal adrenal precursors derived from cholesterol).

E. Steroid Sulfatase Deficiency (X-Linked Ichthyosis)

• Pattern: Undetectable uE3.

F. Adverse Obstetric Outcomes

• Unexplained High AFP: Risk of placental abruption, IUGR, fetal death, or oligohydramnios.
• High Inhibin A: Associated with increased risk of Preeclampsia.

Summary Table of Patterns

Condition	AFP	uE3	hCG	Inhibin A
Down Syndrome	$\downarrow$	$\downarrow$	$\uparrow \uparrow$	$\uparrow \uparrow$
Trisomy 18	$\downarrow$	$\downarrow$	$\downarrow$	N / $\downarrow$
NTDs / Wall Defects	$\uparrow \uparrow$	N	N	N
SLOS	N	$\downarrow \downarrow$	N	N
Fetal Demise	$\uparrow \uparrow$ (Initial)	$\downarrow$	$\downarrow$	-