Antenatal Diagnosis

1. INTRODUCTION

• Congenital Malformations: Structural/functional anomalies that occur during intrauterine life and can be identified prenatally, at birth, or later in infancy.
• Burden: Affects 2–3% of live births; major cause of neonatal mortality and morbidity.
• Goal: Early detection to allow for parental counseling, preparation, in-utero therapy, or termination of pregnancy (secondary prevention).

2. METHODS OF DETECTION (PRENATAL DIAGNOSIS)

Detection methods are classified into Screening (non-invasive, applied to population) and Diagnostic (invasive, applied to high-risk).

A. Non-Invasive Methods (Screening)

1. Ultrasonography (USG)

• First Trimester (11–13+6 weeks):
  • Nuchal Translucency (NT): >3mm (or >95th centile) indicates risk of Down syndrome, Turner syndrome, Cardiac defects.
  • Nasal Bone: Absence is a soft marker for Trisomy 21.
  • Dating: Most accurate assessment of gestational age.
• Second Trimester (18–20 weeks) – "Target Scan" / "Level II Scan":
  • Structural Survey: Detects NTDs (anencephaly, spina bifida), renal agenesis, limb defects, cardiac anomalies.
  • Soft Markers: E.g., echogenic intracardiac focus, choroid plexus cyst, renal pyelectasis (warrants further evaluation).
• Fetal Echocardiography (20–22 weeks):
  • Indicated if maternal diabetes, SLE, previous child with CHD, or abnormal Level II scan.

2. Maternal Serum Screening (Biochemical)

• First Trimester Combined Test (11–13 wks):
  • Analytes: Free $\beta$-hCG + PAPP-A.
  • Combined with NT measurement. Detection rate for Down syndrome: ~90%.
• Quadruple Screen (15–20 wks):
  • Analytes: AFP, uE3 (Estriol), hCG, Inhibin-A.
  • High AFP: NTDs, abdominal wall defects.
  • Low AFP + High hCG: Trisomy 21.

3. Non-Invasive Prenatal Screening (NIPS/NIPT)

• Principle: Analysis of cell-free fetal DNA (cffDNA) in maternal blood.
• Timing: From 10 weeks onwards.
• Utility: Highest sensitivity (>99%) for Trisomies 13, 18, 21.
• Note: It is a screening test; positive results require confirmation via invasive testing.

B. Invasive Methods (Diagnostic)

Indicated if screening is positive, previous history of genetic disease, or advanced maternal age.

C. Laboratory Analysis Techniques

• Karyotype: Detects aneuploidy (Trisomy 21) and large structural rearrangements.
• FISH (Fluorescence In Situ Hybridization): Rapid detection (24-48 hrs) of specific trisomies (13, 18, 21, X, Y).
• Chromosomal Microarray (CMA): Gold standard for structural anomalies with normal karyotype; detects microdeletions/duplications.
• Whole Exome Sequencing (WES): Newer modality for identifying single-gene disorders when CMA is normal.

3. PREVENTION OF CONGENITAL MALFORMATIONS

Prevention strategies operate at three levels: Primary, Secondary, and Tertiary.

A. Primary Prevention (Pre-conception / Periconceptional)

Goal: Prevent the occurrence of the malformation.

1. Nutritional Supplementation:
   • Folic Acid: 400 mcg/day (low risk) or 4–5 mg/day (high risk: previous NTD, anticonvulsants) starting 1 month before conception through 1st trimester. Prevents Neural Tube Defects (NTDs) by up to 70%.
   • Iodine: Prevents congenital hypothyroidism and cretinism.
2. Maternal Disease Control:
   • Diabetes: Strict glycemic control (HbA1c <6.5%) prevents caudal regression, cardiac defects.
   • Epilepsy: Switching to safer antiepileptics (avoid Valproate) or monotherapy at lowest dose.
   • PKU: Maternal dietary restriction prevents microcephaly/ID in fetus.
3. Infection Control (TORCH):
   • Rubella Vaccination: Prior to conception (live vaccine, contraindicated in pregnancy).
   • Hygiene counseling for CMV/Toxoplasmosis.
4. Avoidance of Teratogens:
   • Alcohol (Fetal Alcohol Spectrum Disorder).
   • Smoking (IUGR, clefts).
   • Drugs (Warfarin, Retinoids, Thalidomide).
5. Genetic Counseling:
   • Consanguinity discouragement.
   • Carrier screening for recessive traits (Thalassemia, SMA).

B. Secondary Prevention (Antenatal)

Goal: Early detection and limiting the birth of affected fetuses or in-utero treatment.

1. Termination of Pregnancy:
   • Legal under MTP Act (India) up to 24 weeks for substantial fetal abnormalities (Medical Board approval required beyond 24 weeks).
2. Fetal Therapy (In-Utero):
   • Medical: Anti-arrhythmics for fetal SVT; Steroids for CAH (to prevent virilization).
   • Surgical: Laser photocoagulation for TTTS; intrauterine repair of Myelomeningocele (MOMS trial).

C. Tertiary Prevention (Postnatal)

Goal: Minimize disability in the affected newborn.

1. Newborn Screening (NBS):
   • Screening for treatable metabolic errors (Hypothyroidism, CAH, G6PD, Phenylketonuria).
2. Early Surgical Correction:
   • Timely repair of congenital heart defects, cleft lip/palate, clubfoot (Ponseti).
3. Rehabilitation:
   • Early intervention therapy for Down syndrome/CP.