Antenatal Diagnosis of Congenital Malformations

PART 1: ANTENATAL DIAGNOSIS OF NEURAL TUBE DEFECTS (NTDs)

Neural Tube Defects (e.g., Anencephaly, Spina Bifida, Encephalocele) are among the most common congenital anomalies, resulting from failure of neural tube closure by the 4th week of gestation.

1. Screening Methods (Biochemical)

Maternal Serum Alpha-Fetoprotein (MSAFP)

• Timing: 15–20 weeks gestation.
• Physiology: AFP is produced by the fetal liver, excreted into amniotic fluid, and crosses to maternal blood. Open NTDs allow massive leakage of AFP.
• Threshold: Levels >2.5 MoM (Multiples of Median) indicate high risk.
• Sensitivity: Detects ~85–90% of Anencephaly and ~80% of Open Spina Bifida.
• False Positives: Wrong dates (most common), Twins, Abdominal wall defects, Fetal demise.

2. Diagnostic Methods (Ultrasound - Gold Standard)

High-resolution ultrasound (Level II) is diagnostic in >95% of cases.

A. Cranial Signs (The "Arnold-Chiari II" Malformation markers)
Reliable indirect signs of open spina bifida seen in the 2nd trimester:

• Lemon Sign: Scalloping of frontal bones (due to hypotension in the subarachnoid space).
• Banana Sign: Herniation of the cerebellum through the foramen magnum, curving it around the brainstem; obliteration of the Cisterna Magna.
• Ventriculomegaly: Associated hydrocephalus (often >10mm).

B. Spinal Signs

• Transverse view: Splaying of posterior ossification centers ("U" shape instead of normal circle).
• Sagittal view: Disruption of skin continuity or cystic sac (meningocele).
• Anencephaly: Absence of calvarium and brain tissue ("Frog eye" appearance).

3. Confirmatory Invasive Testing

Indicated if USG is equivocal or in obese patients where visualization is poor.

• Amniocentesis:
  • Amniotic Fluid AFP (AFAFP): Significantly elevated.
  • Acetylcholinesterase (AChE): Qualitative assay. diagnostic for open NTDs (highly specific, rules out other causes of high AFP).

4. Prevention & Management

• Primary Prevention: Folic Acid 4 mg/day (pre-conceptional) for high-risk mothers reduces recurrence by 70%.
• Management:
  • Termination: Option up to 24 weeks (India MTP Act 2021) for severe defects.
  • Fetal Surgery: in-utero repair (MOMS Trial) for Myelomeningocele (reduces shunt dependence).
  • Delivery: Caesarean section recommended for large cysts to prevent sac rupture.

PART 2: ANTENATAL DIAGNOSIS OF CONGENITAL MALFORMATIONS (GENERAL)

1. Classification of Diagnostic Modalities

Diagnosis follows a tiered approach: Screening (Population-based) $\to$ Diagnostic (High risk).

A. Non-Invasive Visualization (Ultrasound)

1. First Trimester Scan (11–13+6 Weeks)

• Dating: Crown-Rump Length (CRL) is accurate for age (vital for interpretation of biomarkers).
• Nuchal Translucency (NT): >3mm or >95th centile. Associated with Trisomy 21, Turner syndrome, Cardiac defects, Diaphragmatic hernia.
• Nasal Bone: Absence is a strong marker for Down syndrome.
• Early Anatomy: Acrania (early Anencephaly), Megacystis, Limb reduction defects.

2. Second Trimester "Anomaly Scan" (18–20 Weeks)

• The Standard of Care: Systematic survey of fetal anatomy.
• Central Nervous System: Ventriculomegaly, Holoprosencephaly, Agenesis of Corpus Callosum.
• Cardiac: Four-chamber view + Outflow tracts (detects ~60–80% of major CHDs).
• Renal: Renal agenesis (absent bladder/liquor), Hydronephrosis, Multicystic dysplastic kidney.
• Gastrointestinal: Duodenal atresia ("Double Bubble"), Echogenic bowel.
• Skeletal: Club foot, skeletal dysplasias (femur length).

3. Fetal Echocardiography (20–22 Weeks)

• Indicated for: Maternal diabetes, IVF pregnancy, family history of CHD, or abnormal cardiac view on Level II scan.

4. Fetal MRI (Ultrafast)

• Adjunct to USG: Used when USG is limited by oligohydramnios or maternal obesity.
• Best for: CNS anomalies (cortical migration defects, posterior fossa cysts) and lung masses (CDH lung volume calculation).

B. Maternal Serum Screening (Biochemical)

• First Trimester Combined Test: PAPP-A + Free $\beta$-hCG + NT (Detection ~90% for Trisomy 21).
• Quadruple Test (15–20 Weeks): AFP, hCG, Estriol, Inhibin-A.
  • High AFP: NTDs, Gastroschisis.
  • Low AFP/Estriol + High hCG/Inhibin: Down Syndrome.

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

• Screens for Aneuploidy (T21, T18, T13) and Sex Chromosome Abnormalities.

• 99% sensitivity for Down syndrome.

• Note: It detects chromosomal anomalies, not structural malformations (unlike USG).

D. Invasive Diagnostic Testing

Used to obtain fetal tissue for genetic/genomic analysis when screening is abnormal.

Laboratory Advances:

• Chromosomal Microarray (CMA): First-line test for structural anomalies (detects microdeletions missed by karyotype).
• Whole Exome Sequencing (WES): For syndromic fetuses with normal CMA.

5. Summary of Diagnostic Flow

1. Risk Assessment: Age, Family History, Teratogen exposure.
2. Universal Screening: NT Scan + Dual Marker (11–13w) + Anomaly Scan (18–20w).
3. High Risk Identified: $\to$ Genetic Counseling $\to$ Invasive Test (Amnio/CVS) $\to$ CMA/Exome.
4. Action: Continuation with Therapy vs. Termination (MTP).