Rubella and pregnancy

Introduction

Rubella, often called German measles, is a generally mild viral disease that usually occurs in childhood. In 1941, researchers first demonstrated the link between rubella infection during pregnancy and congenital defects, highlighting its teratogenic potential. The virus can easily cross the placenta, and infection during the first trimester may result in miscarriage, fetal death, or the development of congenital rubella syndrome (CRS). CRS can include hearing impairment, cardiac defects, and ocular abnormalities.

While prenatal diagnosis of fetal infection is possible when infection occurs within the first four months of pregnancy, it remains challenging in some cases. Vaccination campaigns have significantly reduced rubella incidence worldwide, though the virus still persists in certain regions, posing a risk of preventable disabilities.

Pathogenicity and Epidemiology

Before widespread vaccination, rubella typically occurred in spring, with sporadic cases year-round in temperate climates. Humans are the only known reservoir, and the virus spreads primarily through aerosolized droplets. After inhalation, RV replicates in the respiratory mucosa and cervical lymph nodes before reaching systemic circulation.

The infectious period ranges from about 8 days before to 8 days after rash onset, and while rubella is less contagious than measles or influenza, asymptomatic cases make true infection rates difficult to determine.

  • Global Distribution: Rubella occurs worldwide, with incidence varying by age and region. Epidemics in industrialized countries occurred every 5–9 years prior to vaccination. Infection predominantly affected children aged 5–9 years.

  • Developed Countries: Widespread vaccination has drastically reduced cases. In the United States, rubella is largely eliminated, with most sporadic cases linked to travelers or immigrant populations.

  • Developing Countries: Limited vaccine coverage increases susceptibility among women of childbearing age, as the virus continues to circulate in children. Surveillance programs are gradually improving detection and vaccination coverage.

Vaccination

Rubella vaccines, introduced in 1969, are live attenuated vaccines based on the RA 27/3 strain, with alternative strains used in Japan (TO-336) and China (BRD-2). Vaccines are available as monovalent or combined formulations with measles, mumps, and varicella vaccines.

  • Efficacy: A single dose induces protective antibodies in >95% of recipients; two doses approach 100% efficacy. Immunity typically persists for decades.

  • Schedule: Most countries follow a two-dose schedule in early childhood, often alongside measles vaccination. Adults without immunity may receive booster doses.

  • Safety: Vaccination is generally well-tolerated, with mild side effects such as fever, rash, or transient lymphadenopathy. Severe adverse events are rare. Vaccination is not recommended during pregnancy due to theoretical teratogenic risks, though studies have shown no evidence of CRS following inadvertent vaccination.

  • Strategies: Vaccination can target young girls/women of childbearing age or the broader population to halt viral circulation. Global initiatives aim to eliminate rubella and CRS through ≥95% vaccination coverage with two doses.

Rubella Re-Infection

Re-infection can occur in individuals with pre-existing immunity from natural infection or vaccination. Typically, these infections are subclinical, with detectable rises in antibody levels (IgG and/or IgM). The risk of fetal transmission is low (<5%), and antigenic variation does not appear to drive re-infection.

Diagnosis of Rubella Infection

Natural Immunity

Diagnosis relies on antibody kinetics:

  • RV-IgM: Appears 3 days after rash onset, disappears in 4–12 weeks.

  • RV-IgG: Appears slightly later (5–8 days post-rash) and persists lifelong.

Determining Immunity

Women of childbearing age are routinely screened for RV-IgG to identify susceptibility. Seronegative women are vaccinated postpartum. Immunity is measured in international units (IU/mL), though results may vary depending on the assay.

Maternal Infection Diagnosis

Clinical diagnosis is unreliable due to non-specific symptoms. Laboratory confirmation involves:

  • Seroconversion detection

  • RV-IgM and IgG kinetics

  • IgG avidity testing

  • Detection of viral RNA via RT-PCR in nasopharyngeal secretions

Early testing is critical following exposure to suspected cases. IgG avidity helps date primary infections, while RT-PCR on amniotic fluid is highly reliable for prenatal diagnosis.

Congenital Rubella Syndrome (CRS)

Pathogenesis

CRS results from chronic, non-lytic fetal infection affecting multiple organs. Mechanisms include:

  • Non-inflammatory necrosis in chorionic and endothelial cells, leading to thrombosis and ischemia in fetal tissues

  • Disruption of actin assembly, inhibiting cell mitosis and organ development

  • Cytokine-mediated interference with fetal cell differentiation

Fetal Infection Risk

The risk of congenital infection depends on gestational age:

  • <11 weeks: Infection rate ~90%; major defects ~85%; spontaneous abortion ~20%

  • 12–18 weeks: Rapid decline in risk

  • >18 weeks: Very low risk of congenital infection

Fetal Manifestations

Classic CRS manifestations include:

  • Triad: Cataracts, cardiac defects, sensorineural deafness

  • Permanent defects: Ophthalmic abnormalities, hearing loss, CNS deficits, cardiac malformations

  • Transient defects: Low birth weight, thrombocytopenia, hepatosplenomegaly

  • Late-onset: Endocrine, cardiovascular, and neurological abnormalities

  • CRS may also increase the risk of autoimmune disorders, including diabetes and thyroid disease

Diagnosis of Congenital Infection

Prenatal

Prenatal diagnosis is recommended after maternal infection and involves:

  • Detection of RV-IgM in fetal blood

  • Detection of viral RNA in amniotic fluid, fetal blood, or chorionic villus samples via RT-PCR

Postnatal

Postnatal diagnosis uses immunocapture ELISA to detect RV-IgM in infants (<3 months old), supplemented by viral RNA detection in saliva, urine, or nasopharyngeal swabs. Early diagnosis is critical to ensure appropriate follow-up including neurological and hearing assessments.

Management of Rubella in Pregnancy

Management depends on gestational age at infection:

  • <18 weeks: High fetal risk; termination may be considered where legally permitted. Detailed ultrasound and amniotic fluid testing are recommended.

  • >18 weeks: Pregnancy can continue with monitoring; neonatal examination and RV-IgM testing are advised.

Ultrasound Findings: Cardiac septal defects and ocular abnormalities are most common. Microcephaly, hepatosplenomegaly, and intrauterine growth restriction may also occur.

Conclusion

Significant progress has been made in preventing CRS since the teratogenic potential of rubella was first recognized in 1941. Nonetheless, rubella infection in pregnancy continues to occur, especially in developing countries.

Key points:

  • Understanding rubella virus pathogenesis and its interactions with the immune system remains critical.

  • RV-IgG avidity and prenatal RT-PCR provide reliable tools for infection diagnosis.

  • Vaccination coverage must increase globally to eliminate rubella and CRS.

  • Ongoing research is needed on the long-term autoimmune effects of congenital rubella.

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