Congenital Rubella Syndrome

Introduction

Congenital Rubella Syndrome (CRS) is a devastating constellation of fetal malformations resulting from maternal infection with the rubella virus during pregnancy. Historically known as "German Measles," rubella is typically a mild, self-limiting exanthematous illness in children and adults. Its immense public health significance lies almost entirely in its teratogenic potential.

The syndrome was first described in 1941 by the Australian ophthalmologist Norman Gregg, who noted a triad of congenital cataracts, heart defects, and deafness in infants born to mothers infected during the 1940 epidemic. The "classic triad" has since been expanded to include a wide spectrum of transient, permanent, and late-onset abnormalities affecting virtually every organ system.

Etiology and Virology

• Agent: Rubella virus.
• Classification: It is the sole member of the genus Rubivirus within the family Togaviridae.
• Structure: It is a spherical, enveloped, positive-sense, single-stranded RNA virus. It contains three structural proteins: a nucleocapsid protein (C) and two envelope glycoproteins (E1 and E2). E1 is the major antigenic determinant targeted by neutralizing antibodies.
• Host: Humans are the only natural host.
• Stability: The virus is heat-labile and inactivated by lipid solvents, extremes of pH, and ultraviolet light.

Epidemiology

• Transmission: Rubella spreads via nasopharyngeal secretions (droplets). The virus is shed from 7 days before to 7 days after the onset of the rash.
• Burden: While widespread vaccination has eliminated endemic rubella in many developed nations (e.g., the USA), it remains a significant cause of preventable congenital defects in developing countries. The World Health Organization (WHO) estimates that over 100,000 cases of CRS occur annually worldwide.
• Indian Scenario: Serological surveys in India indicate that 10–30% of adolescent girls and women of childbearing age remain susceptible to rubella, posing a continued risk for CRS.

Pathogenesis

1. Maternal-Fetal Transmission

Maternal viremia is a prerequisite for fetal infection. The virus infects the placenta (placentitis) and then spreads hematogenously to the fetus.

• Chronicity: A hallmark of congenital rubella is chronic, persistent infection. The virus can persist in fetal tissues (such as the eye, brain, and lymphoreticular system) throughout gestation and for months to years after birth.

2. Mechanism of Teratogenicity

Rubella virus is non-cytolytic in many cell lines but causes damage through:

• Mitotic Arrest: The virus produces a protein that inhibits mitosis, leading to reduced cellular multiplication time. This results in hypoplastic organs and intrauterine growth restriction (IUGR).
• Vascular Damage: Infection causes endothelial necrosis and vasculitis in developing organs, leading to ischemia and tissue damage.
• Apoptosis and Chromosomal Breaks: Direct cytopathic effects and chromosomal damage also contribute to anomalies.

3. Timing of Infection (The Critical Factor)

The risk of fetal infection and the severity of defects are inversely related to the gestational age at the time of maternal infection.

• First Trimester (<11 weeks): Highest risk. Infection results in defects in ~90% of fetuses. This period coincides with organogenesis, leading to multiple severe malformations (heart, eyes, ears).
• 11–16 Weeks: Risk reduces to ~10–20%. Deafness and retinopathy are the primary concerns.
• >16–20 Weeks: Fetal infection may occur, but structural defects are rare.
• >20 Weeks: Risk of fetal damage is negligible.

Clinical Manifestations

The clinical spectrum of CRS is broad and can be categorized into transient manifestations (due to active infection), permanent structural defects (teratogenesis), and late-onset manifestations.

1. Classical Triad (Gregg’s Triad)

1. Cataracts (Ocular)
2. Sensorineural Hearing Loss (Auditory)
3. Congenital Heart Defects (Cardiac)

2. Transient Manifestations (Active Infection at Birth)

These are due to ongoing viral replication and tissue damage in the neonate. They often resolve spontaneously over weeks but can be fatal.

• Intrauterine Growth Restriction (IUGR): Seen in 50–85% of cases; often symmetric.
• Thrombocytopenic Purpura: The classic "Blueberry Muffin" rash represents dermal erythropoiesis.
• Hepatospenomegaly and Jaundice: Hepatitis is common; usually resolves but can be severe.
• Meningoencephalitis: Occurs in 10–20%. Manifests as a bulging fontanelle, irritability, lethargy, and CSF pleocytosis. It can persist for up to 12 months.
• Radiolucent Bone Disease: Characteristic "celery stalk" appearance (linear radiolucencies) in the metaphyses of long bones.
• Interstitial Pneumonitis.

3. Permanent Structural Defects

• Auditory (Most Common): Sensorineural hearing loss is the single most common defect (60–90%). It may be unilateral or bilateral and can be profound. It is often the only manifestation of infection occurring after the first 8 weeks of gestation.
• Ocular:
  • Cataracts: Occur in ~30% of cases. Typically nuclear and pearly white. Can be unilateral or bilateral.
  • Salt-and-Pepper Retinopathy: Pigmentary changes in the retina. It is the most common ocular finding but usually does not significantly affect vision.
  • Microphthalmia and Congenital Glaucoma.
• Cardiac:
  • Patent Ductus Arteriosus (PDA): The most common cardiac lesion.
  • Peripheral Pulmonary Artery Stenosis (PAS): Highly characteristic of CRS.
  • Ventricular Septal Defect (VSD) and Atrial Septal Defect (ASD) may also occur.
• Neurologic:
  • Microcephaly.
  • Intellectual disability (Mental retardation).
  • Behavioral disorders (Autism spectrum).

4. Late-Onset Manifestations

These conditions appear months to years after birth, likely due to autoimmune mechanisms or persistent viral replication.

• Endocrinopathies:
  • Diabetes Mellitus: Insulin-dependent diabetes occurs in ~20% of CRS survivors, often in the 2nd or 3rd decade.
  • Thyroid dysfunction (Hypothyroidism/Hyperthyroidism).
• Progressive Rubella Panencephalitis (PRP): A rare, fatal neurodegenerative disorder similar to SSPE, presenting in the second decade with deterioration of motor and mental functions.
• Vascular: Renovascular hypertension.

Diagnosis

1. Clinical Diagnosis (WHO Case Definition)

• Suspected Case: Any infant <1 year with heart disease, cataracts, glaucoma, hearing loss, or pigmentary retinopathy.
• Clinically Confirmed: Presence of two from Group A OR one from Group A and one from Group B.
  • Group A: Cataracts/Glaucoma, Congenital Heart Disease, Hearing Loss, Pigmentary Retinopathy.
  • Group B: Purpura, Splenomegaly, Microcephaly, Mental Retardation, Meningoencephalitis, Radiolucent bone disease, Jaundice (onset <24 hours).

2. Laboratory Diagnosis

Laboratory confirmation is essential as clinical signs are not pathognomonic.

• Serology:
  • Rubella IgM: The diagnostic test of choice in the newborn. Detection of rubella-specific IgM in cord blood or serum indicates intrauterine infection. Sensitivity is high in the first 3–6 months.
  • Rubella IgG: Persistence of IgG antibodies beyond 6–12 months (when maternal antibodies should have disappeared) confirms congenital infection.
  • IgG Avidity: Low avidity IgG indicates recent primary infection; high avidity suggests past infection/reinfection. This is useful for maternal diagnosis.
• Viral Isolation/PCR:
  • The virus can be isolated from nasopharyngeal secretions, urine, CSF, or blood.
  • Infants with CRS shed high quantities of virus for prolonged periods (up to 1 year or more).
  • RT-PCR is highly sensitive and can detect viral RNA in amniotic fluid (prenatal diagnosis) or neonatal specimens.

Differential Diagnosis

• Cytomegalovirus (CMV): Periventricular calcifications, chorioretinitis is more common; no cataracts usually.
• Toxoplasmosis: Intracranial calcifications (diffuse), hydrocephalus, chorioretinitis.
• Syphilis: Skeletal lesions (periostitis), snuffles, rash (palms/soles).
• Zika Virus: Severe microcephaly, arthrogryposis.

Management

There is no specific antiviral therapy for CRS. Management is supportive and multidisciplinary.

1. Neonatal Care

• Isolation: Infants with CRS are highly contagious. They shed virus in urine and nasopharyngeal secretions for up to 12 months.
  • Contact isolation is required.
  • Pregnant women must not care for or be exposed to these infants.
  • Isolation can be discontinued only after two negative cultures/PCRs obtained 1 month apart after 3 months of age.
• Supportive: Management of thrombocytopenia, hepatitis, and respiratory distress.

2. Management of Defects

• Ophthalmology:
  • Cataracts: Surgical removal is indicated but may be delayed until inflammation subsides to prevent complications.
  • Glaucoma: Requires immediate management to preserve vision.
• Cardiology: Surgical or catheter-based correction of PDA and stenosis.
• Audiology: Early hearing screening (BERA/OAE). Hearing aids and cochlear implants for sensorineural hearing loss. Early speech therapy is crucial.
• Neurology: Physical therapy and special education for developmental delay and cerebral palsy.

3. Long-term Follow-up

• Regular monitoring for late-onset diabetes, thyroid disorders, and hearing deterioration.

Prevention

CRS is a vaccine-preventable disease. The goal of rubella vaccination is specifically to prevent CRS.

1. Vaccination

• Vaccine: Live attenuated RA 27/3 strain. Usually given as MR (Measles-Rubella) or MMR (Measles-Mumps-Rubella).
• Schedule (IAP/Universal Immunization Program):
  • Dose 1: 9–12 months.
  • Dose 2: 15–18 months (or 16-24 months in UIP).
• Strategy: Vaccinating all children reduces the reservoir of the virus. Vaccinating adolescent girls and women of childbearing age provides individual protection.
• Pregnancy: Vaccination is contraindicated during pregnancy (live vaccine). However, inadvertent vaccination during pregnancy has not been shown to cause CRS, and termination of pregnancy is not warranted in such cases. Women should avoid pregnancy for 4 weeks (28 days) after vaccination.

2. Management of Exposed Pregnant Women

If a pregnant woman is exposed to a suspected case of rubella:

1. Check IgG Status immediately.
   • IgG Positive: Immune. No risk to fetus. Reassure.
   • IgG Negative: Susceptible.
2. If Susceptible:
   • Monitor for symptoms.
   • Repeat serology (IgM and IgG) in 2–3 weeks and again at 6 weeks.
   • Seroconversion (Negative to Positive IgG) or Positive IgM: Indicates acute infection.
3. Counseling:
   • If infection is confirmed in the first trimester, the risk of severe CRS is very high (up to 90%). Therapeutic termination of pregnancy should be discussed.
   • Immunoglobulin (IG): Usage is controversial. It may be considered (0.55 mL/kg IM) if termination is not an option, but it does not guarantee prevention of fetal infection.

Prognosis

• Mortality: High in early life for infants with severe multi-organ involvement (sepsis-like picture, heart failure).
• Morbidity: Prognosis for psychomotor development depends on the severity of CNS involvement. Children with only hearing loss or cardiac defects (corrected) may have a normal lifespan and intelligence. However, those with microcephaly and meningoencephalitis often have poor neurodevelopmental outcomes.

Summary Table: Key Features of CRS