Version May 2024
INTRODUCTION — Rubella, also known as German measles, was a disease of childhood that has markedly declined in incidence in the United States since the introduction of routine childhood rubella vaccination. This virus causes a self-limited infection in most hosts, but can have potentially devastating effects on the developing fetus. Screening for antibodies to rubella is routinely performed by obstetricians.
Rubella virus is a member of the Matonaviridae family, genus Rubivirus, and humans are the only reservoir for rubella infection [1]. The virus is transmitted by direct droplet contact from nasopharyngeal secretions, replicates in the lymph tissue of the upper respiratory tract, and spreads hematogenously. Congenital infection occurs when maternal viremia allows hematogenous spread of the virus across the placenta.
Rubella in pregnancy will be reviewed here. The virology, pathogenesis, clinical manifestations, diagnosis, treatment, and prevention through vaccination are discussed separately. (See "Rubella".)
EPIDEMIOLOGY — Rubella and the congenital rubella syndrome (CRS) have largely been eliminated in the United States. The incidence of rubella has declined from 0.45 per 100,000 in 1990 to 0.1 per 100,000 in 1999 [2]. However, rubella outbreaks continue to occur in other parts of the world, and CRS remains a concern.
United States — Prior to the introduction of the rubella vaccine in 1969, epidemics of rubella occurred in six to nine year cycles, usually in the late winter and early spring. In 1964, a major worldwide pandemic spread to the United States resulting in approximately 12.5 million cases of rubella, as many as 11,000 fetal deaths, and approximately 20,000 cases of CRS [3].
Since the introduction of a comprehensive vaccine program, the epidemiologic evidence in 2004 suggests that rubella is no longer endemic in the United States [4]. During 1998 to 2000, the median number of reported rubella cases was 272, whereas, during 2001 to 2004, the median number reported was 13. Since 2004, CRS has rarely been reported in the United States (figure 1). Nevertheless, some areas have declining vaccination rates, resulting in sporadic cases of rubella and a potential reservoir for transmission [5].
Other regions — The proportion of women of childbearing age who are susceptible to rubella varies greatly among nations [6]. In countries where vaccination programs are not robust, ongoing rubella infections and subsequent CRS cases occur [7]. Immigrants have been the source of CRS in resource-rich countries, such as the United Kingdom [8,9], Canada [10], and the United States [11-13]. Among women living in or emigrating from resource-limited countries, clinicians should consider the possibility that a positive rubella screening test result at the first prenatal visit may be a sign of recent active infection, rather than evidence of immunity from old infection or vaccination [14].
Even in countries where rubella vaccination programs are available, the extent of vaccination is not always optimal.
CLINICAL MANIFESTATIONS — Acquired rubella is generally a mild, self-limited disease associated with a characteristic exanthem (see "Rubella"). Symptoms appear approximately 14 to 21 days after inoculation with the virus. Though asymptomatic in 25 to 50 percent of cases, affected individuals may experience mild, prodromal symptoms consisting of low-grade fever, conjunctivitis, coryza, sore throat, cough, and occasionally headache and malaise. These symptoms usually last one to five days before the onset of the rash. Rubella may also be associated with generalized, tender lymphadenopathy, particularly involving suboccipital, postauricular, and cervical nodes, which often becomes pronounced during the rash. Just prior to the onset of the rash, approximately 20 percent of those infected will develop discrete rose spots on the soft palate (Forchheimer spots) that may later expand and coalesce.
The typical rash of rubella is an erythematous maculopapular eruption, which may be mildly pruritic and evolves into pinpoint papules similar to scarlet fever. The rash characteristically begins on the face and spreads to the trunk and extremities within hours. It lasts approximately one to three days and resolves first from the face and then from the body.
Polyarthritis and polyarthralgia are potential sequelae. Rheumatologic symptoms may develop about one week after the rash and are more commonly seen in female adolescents and adults, occurring in as many as 60 to 70 percent of adult women [15]. Classically, the hands, knees, wrists, and ankles are affected in a symmetric pattern with pain and morning stiffness for one to four weeks. Chronic arthritis rarely develops. Tenosynovitis and carpal tunnel syndrome may also be associated with rubella. Other rare complications include: thrombocytopenia associated with purpura or hemorrhage, postinfectious encephalitis, myocarditis, pericarditis, hepatitis, hemolytic anemia, and hemolytic uremic syndrome [16,17].
Congenital rubella syndrome — Rubella infection can have catastrophic effects on the developing fetus, resulting in spontaneous abortion, fetal infection, stillbirth, or intrauterine growth restriction. This area is discussed in detail separately. (See "Congenital rubella".)
Maternal-fetal transmission occurs via hematogenous spread and varies with gestational age. There is considerable pathologic evidence that suggests that the rubella virus spreads through the vascular system of the developing fetus after infecting the placenta. The resulting defects stem from cytopathic damage to blood vessels and ischemia in affected organs [18]. In the first trimester, fetal infection rates as high as 81 percent have been observed, dropping to 25 percent in the late second trimester and increasing again in the third trimester from 35 percent at 27 to 30 weeks to nearly 100 percent for fetuses exposed beyond 36 weeks [19].
However, the risk of congenital defects after maternal infection is essentially limited to maternal infection in the first 16 weeks of pregnancy [20]. Little, if any, risk of congenital rubella syndrome (CRS) is associated with infection after 20 weeks’ gestation, and intrauterine growth retardation may be the only sequelae of third trimester infection [19,21-23]. Similarly, there is no evidence that rubella infection immediately prior to pregnancy increases the risk of congenital infection [24].
In general, maternal immunity, either vaccine or naturally derived, is protective against intrauterine rubella infection. However, there have been CRS cases resulting from maternal reinfection [25-27]. None of these cases occurred in women infected after 12 weeks’ gestation [28].
DIAGNOSIS — Serology is widely available and may be used to screen for rubella infection [29]. Enzyme linked immunoassays (ELISAs) are sensitive, easy to perform, and measure rubella-specific immunoglobulin (Ig)G and IgM. Immunofluorescent antibody assays are also sensitive and rapid; commercial IgG and IgM assays are available. Other serologic tests include passive hemagglutination antibody, latex agglutination, complement fixation, and hemagglutination inhibition. Most laboratories use ELISA due to its convenience, sensitivity, and accuracy. The clinical diagnosis of rubella should only be made in typical cases occurring during an epidemic.
Acute rubella syndrome is best diagnosed by:
●A fourfold rise in IgG titer between acute and convalescent serum specimens
●The presence of rubella specific IgM
●A positive rubella culture
Serum should be obtained within 7 to 10 days after the onset of the rash and repeated two to three weeks later. Rubella virus may be isolated from nasal, blood, throat, urine, or cerebrospinal fluid specimens. The virus is generally isolated from the pharynx one week before to two weeks after the rash. Viral isolates can be typed to facilitate surveillance during outbreaks [30].
If rubella IgM is incidentally detected in a pregnant woman in the absence of a history of rubella-like illness or contact, further investigation is required. In persons with no or low risk of exposure to rubella, the reactive IgM is likely falsely positive due to rheumatoid factor or other antibodies to infection which can cross react with the assay. Use of rubella specific avidity assay may be useful in these situations. Because of issues of false-positivity, the Centers for Disease Control and Prevention in the United States discourages the use of rubella IgM for rubella screening in pregnancy [31].
Serologic testing to identify acute rubella in the setting of exposure during pregnancy is discussed elsewhere. (See 'Postexposure management' below.)
Prenatal diagnosis — Polymerase chain reaction (PCR) is another option for providing presumptive diagnosis of rubella infection. This method has been used extensively in the United Kingdom for detection of rubella virus in clinical specimens [32]. There are small series reporting the usefulness of PCR for prenatal diagnosis [33,34]. A reverse transcription-nested PCR assay has been used in small studies where it detects rubella virus in chorionic villous samples (CVS) and amniotic fluid samples of affected pregnancies. The largest study to date reported 34 cases where PCR detection of rubella was better in CVS samples than amniotic fluid samples [35]. A case report of maternal primary rubella in the second trimester also showed that amniotic fluid was negative by PCR at both 19 and 23 weeks, while fetal blood was positive at 23 weeks [36]. Furthermore, rubella IgM on fetal blood was negative in eight infected cases, but PCR was positive in all eight. Although the numbers are small, it would appear that rubella specific PCR on CVS samples may be superior to standard serologic testing on fetal blood. In addition, CVS sampling ideally done at 10 to 12 weeks’ gestation would allow for earlier detection than other samples, such as fetal blood obtained at 18 to 20 weeks’ gestation.
Ultrasound diagnosis of an affected fetus would be extremely difficult given the nature of the malformations seen with congenital rubella syndrome, although, the workup of any fetus with intrauterine growth restriction should include evaluation for congenital viral infections including rubella.
TREATMENT — Treatment for acute rubella infection may include acetaminophen for symptomatic relief. Glucocorticoids, platelet transfusion, and other supportive measures are reserved for patients with complications such as thrombocytopenia or encephalopathy. The prognosis for pregnant women with rubella is generally excellent.
However, because of the potentially devastating effects on the fetus, women should be counseled about maternal-fetal transmission and offered pregnancy termination, especially prior to 16 weeks’ gestation. After 20 weeks’ gestation, management should be individualized, and parents should be counseled about the potential for delayed consequences of rubella infection (see "Congenital rubella", section on 'Late manifestations').
There is no definitively beneficial in utero treatment available for exposed or affected fetuses.
PREVENTION
Preconception vaccination — Vaccination prior to pregnancy is the primary strategy to prevent rubella during pregnancy. In the United States, where rubella vaccination is achieved with a combination measles, mumps, rubella (MMR) vaccine, efforts to control and prevent rubella rely on routine childhood vaccination as well as vaccination of susceptible, nonpregnant adolescents and adults in all clinical settings, with particular attention to persons born in countries lacking a comprehensive vaccination program. Additional details on rubella vaccination are discussed elsewhere. (See "Measles, mumps, and rubella immunization in infants, children, and adolescents" and "Measles, mumps, and rubella immunization in adults".)
Documenting immunity to rubella and vaccinating individuals who are susceptible are routine components of preconception care. Individuals are advised to avoid pregnancy for 28 days following vaccination [37]. Rubella vaccine virus may cross the placenta and infect the fetus. However, multiple studies have failed to identify cases of congenital rubella syndrome (CRS) in infants born to mothers who were vaccinated between two weeks before and six weeks after conception [38-41]. Thus, pregnancy termination is not recommended for individuals who are vaccinated during pregnancy (or become pregnant soon after vaccination) [42]. (See "Immunizations during pregnancy", section on 'Preconception immunization'.)
Postpartum vaccination — Documentation of rubella immunity is a standard component of prenatal care and should occur at the first prenatal visit. All individuals known to be susceptible should receive rubella vaccination (ie, with MMR vaccine) as soon as possible postpartum and prior to discharge [2]. For individuals who also received anti-D immunoglobulin, the ACIP in the United States suggests checking rubella immunity three months after vaccination because of a theoretic potential for blood products to interfere with vaccine response [37].
Breastfeeding is not contraindicated following vaccination. (See "Immunizations during pregnancy", section on 'Postpartum immunization'.)
Postpartum vaccination programs significantly reduce rubella susceptibility in seronegative women [43].
Postexposure management — Management of susceptible individuals (ie, with negative baseline rubella immunoglobulin [Ig]G) who are exposed to rubella involves preventing ongoing exposure, counseling on the risk of congenital rubella syndrome (CRS), and clinical monitoring for symptoms of rubella. Serologic testing is also performed to identify acute infection. The first specimen should be obtained for testing as soon as an exposure is identified and stored for future testing. A positive IgM at that time point may reflect acute infection, which is confirmed if serology repeated 5 to 10 days later demonstrates a rise in IgG titers. If the IgM and IgG are negative on initial postexposure serology, it is repeated at three to four weeks and, if negative, at six weeks following exposure [44]. The initial specimen should be retested concurrently with subsequent specimens to compare the results performed on the same assay at the same time. Acute infection with rubella is indicated by seroconversion at one of these subsequent time points. (See 'Diagnosis' above and 'Treatment' above.)
The role for other postexposure interventions is limited. Specifically, Ig is not routinely recommended for postexposure prophylaxis [37]. Although some evidence suggests that intramuscular or intravenous Ig may reduce the risk of clinically evident rubella after exposure [45], it has not been demonstrated to prevent asymptomatic infection, viremia, or CRS. Cases of CRS have been identified in infants of individuals who received Ig shortly following an exposure during pregnancy [46]. Furthermore, Ig administration makes the subsequent diagnosis of rubella more challenging; since virus-specific IgG seroconversion would reflect receipt of exogenous Ig, the diagnosis would have to rely only on virus-specific IgM testing, which may be associated with false-positive results.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Rubella (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Since the introduction of a comprehensive vaccine program, rubella and congenital rubella syndrome (CRS) have largely been eliminated in the United States. However, in other parts of the world, particularly resource-limited settings, a considerable proportion of women of childbearing age remain susceptible to rubella, and thus CRS remains a concern. (See 'Epidemiology' above.)
●Clinical features – Acquired rubella in the pregnant woman is generally a mild, self-limited disease characterized by an erythematous maculopapular eruption that is sometimes preceded by prodromal symptoms of low-grade fever, conjunctivitis, coryza, sore throat, and cough. Rheumatologic symptoms, including polyarthritis and arthralgias of the hands, wrists, knees, and ankles, commonly occur in women about a week following the rash. (See 'Clinical manifestations' above and "Rubella", section on 'Clinical manifestations'.)
●Risk of congenital rubella syndrome – Rubella infection of the fetus can be catastrophic, resulting in spontaneous abortion, stillbirth, congenital defects, and intrauterine growth retardation. Maternal-fetal transmission occurs via hematogenous spread and is highest in the first trimester and after 36 weeks’ gestation. However, the risk of congenital defects after maternal infection is essentially limited to maternal infection in the first 16 weeks of pregnancy. (See 'Congenital rubella syndrome' above and "Congenital rubella".)
●Diagnosis – Immunity to rubella in pregnant women should be documented as part of initial prenatal care. In susceptible pregnant women with suggestive clinical features, acute rubella syndrome can be diagnosed by one of the following (see "Prenatal care: Initial assessment", section on 'Documentation of rubella immunity' and 'Diagnosis' above):
•A fourfold rise in immunoglobulin (Ig)G titer between acute (within 7 to 10 days of rash onset) and convalescent (two to three weeks later) serum specimens
•The presence of rubella-specific IgM
•A positive rubella culture (from nasal, blood, throat, urine, or cerebrospinal fluid samples)
●Fetal testing – In women with documented acute rubella infection during pregnancy, fetal infection is diagnosed by testing chorionic villous samples and amniotic fluid samples with a rubella-specific polymerase chain reaction assay. Ultrasound findings are not specific for the prenatal diagnosis of CRS, but finding intrauterine growth restriction should prompt evaluation for congenital viral infections, including rubella. (See 'Prenatal diagnosis' above.)
●Management – Women should be counseled about maternal-fetal transmission and offered pregnancy termination, especially when infection is diagnosed prior to 16 weeks’ gestation, due to the high risk for CRS. Otherwise, there is no definitively beneficial in utero treatment available for exposed or affected fetuses. (See 'Treatment' above.)
●Prevention – Rubella vaccination can effectively protect against subsequent infection and is the best strategy to eliminate cases of CRS. Vaccination is contraindicated during pregnancy because of the theoretical risk of fetal infection with the rubella vaccine virus, and women are advised to avoid pregnancy for one month following vaccination. However, CRS associated with the rubella vaccine has not been reported, and thus, pregnancy termination is not indicated for women who are inadvertently vaccinated during pregnancy. Vaccination should be given to all postpartum individuals who are susceptible. (See 'Prevention' above.)
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