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).

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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.

Procedure	Gestation	Tissue Sampled	Risk of Loss	Common Indications
Chorionic Villus Sampling (CVS)	10–13 wks	Trophoblasts	0.5–1%	Karyotype, DNA analysis (Thalassemia), Enzyme assay.
Amniocentesis	15–20 wks	Amniocytes	0.3–0.5%	Karyotype, infections (CMV), biochemical errors.
Cordocentesis (FBS)	>18 wks	Fetal Blood	1–2%	Rapid karyotype, fetal anemia/hydrops workup.
Fetoscopy	2nd Trim	Direct Visualization	High	Rare. Used for fetal skin biopsy or laser surgery (TTTS).

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.

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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.