# 104 - 212 Rubella (German Measles)

### 212 Rubella (German Measles)

Acknowledgment
The authors acknowledge the substantial contributions of Kaitlin 
Rainwater-Lovett, who coauthored prior editions of this chapter.
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■FURTHER READING
De Swart RL, Moss WJ: The immunological basis for immunization 
series: Module 7: Measles. Update 2020. Geneva: World Health 
Organization, 2020.
Griffin DE: Measles immunity and immunosuppression. Curr Opin 
Virol 46:9, 2020.
Hübschen JM et al: Measles. Lancet 399:678, 2022.
Mina MJ et al: Measles virus infection diminishes preexisting antibod­
ies that offer protection from other pathogens. Science 366:599, 2019.
Minta AA et al: Progress toward measles elimination—Worldwide, 
2000–2022. MMWR Morb Mortal Wkly Rep 72:1262, 2023.
Moss WJ: Measles. Lancet 380:2490, 2017.
Moss WJ et al: Feasibility assessment of measles and rubella eradica­
tion. Vaccine 39:3544, 2021.
Phadke VK et al: Vaccine refusal and measles outbreaks in the US. 
JAMA 324:1344, 2020.
Strebel PM, Orenstein WA: Measles. N Engl J Med 381:349, 2019.
World Health Organization: Measles vaccines: WHO position 
paper—April 2017. Wkly Epidemiol Rec 92:205, 2017.
Alan C. Ou, Ludmila M. Perelygina, 

Laura A. Zimmerman, Susan E. Reef

Rubella (German Measles)
Rubella was historically viewed as a variant of measles or scarlet 
fever. After an epidemic of rubella in Australia in the early 1940s, the 
ophthalmologist Norman Gregg noticed the occurrence of congenital 
cataracts among infants whose mothers had reported rubella during 
early pregnancy, and congenital rubella syndrome (CRS; see “Clinical 
Manifestations,” below) was first described. Not until 1962 was a sepa­
rate viral agent for rubella isolated.
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■ETIOLOGY
Rubella virus is a member of the Matonaviridae family the genus 
Rubivirus. This single-strand RNA enveloped virus measures 40–80 nm 
in diameter. Its nucleocapsid consists of ~10-kb positive-sense RNA 
genome surrounded by a protein shell composed of a core protein and 
a single-layer lipoprotein envelope with spike-like projections contain­
ing two glycoproteins, E1 and E2. There is only one antigenic type of 
rubella virus, and humans are its only known reservoir.
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■PATHOGENESIS AND PATHOLOGY
Although the pathogenesis of postnatal (acquired) rubella has been 
well documented, data on pathology are limited because of the mild­
ness of the disease. Rubella virus is spread from person to person 
via respiratory droplets. Primary implantation and replication in the 
nasopharynx are followed by spread to the lymph nodes. Subsequent 
viremia occurs, which in pregnant women often results in infection of 
the placenta. Placental virus replication may lead to infection of fetal 
organs. The pathology of CRS in the infected fetus is well defined, with 
almost all organs found to be infected; however, the pathogenesis of 
CRS is only poorly delineated. In tissue, infections with rubella virus 
have diverse effects, ranging from no obvious impact to cell destruction. 
The hallmark of fetal infection is a chronic infection with persistence 
throughout fetal development in utero and for up to 1 year after birth.
Individuals with acquired rubella may shed virus from 7 days 
before rash onset to ~5–7 days thereafter. Both clinical and subclinical 

infections are considered contagious. Infants with CRS may shed large 
quantities of virus from bodily secretions, particularly from the throat 
and in the urine, up to 1 year of age. Outbreaks of rubella, including 
some in nosocomial settings, have originated with index cases of CRS. 
Thus, only individuals immune to rubella virus should have contact 
with infants who have CRS or who are congenitally infected with 
rubella virus but are not showing signs of CRS.

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■EPIDEMIOLOGY
The largest recent rubella epidemic in the United States took place in 
1964–1965, when an estimated 12.5 million cases occurred, resulting in 
~20,000 cases of CRS. Since the introduction of the routine rubella vac­
cination program in the United States in 1969, the number of rubella 
cases reported each year has dropped by >99%; the rate of vaccination 
coverage with rubella-containing vaccine (RCV) has been >90% among 
children 19–35 months old since 1996. In the United States, a goal for 
the elimination of rubella and CRS by 2000 was set in 1989. Interrup­
tion of endemic transmission of rubella virus was achieved by 2001. In 
2004, a panel of experts agreed unanimously that rubella was no longer 
an endemic disease in the United States. The criteria used to document 
lack of endemic transmission included low disease incidence, high 
nationwide rubella antibody seroprevalence, outbreaks that were few 
and contained (i.e., small numbers of cases), and lack of endemic virus 
transmission (as assessed by genetic sequencing). Although interrup­
tion of endemic transmission has been sustained since 2001, rubella 
virus importations continue to occur, and cases continue to develop 
among susceptible persons. During 2010−2022, 66 cases of rubella 
were reported; 71% of these cases were in persons 20−49 years old—
an age group that includes women of childbearing age. During this 
period, 13 cases of CRS were reported, all from foreign-born mothers. 
Therefore, health care providers should remain vigilant, considering 
the possibility of rubella virus infection in adults (especially those emi­
grating or returning from countries without rubella control programs) 
and recognizing the potential for CRS among their infants.
CHAPTER 212
Rubella (German Measles)
The Global Measles and Rubella Strategic Framework 2021–2030 
envisions a “world free from measles and rubella” with the goal to 
“achieve and sustain the regional measles and rubella elimination goals.” 
By 2023, five of the six World Health Organization (WHO) regions had 
rubella elimination goals (see “Prevention” below). Although rubella 
and CRS are no longer endemic in the WHO Region of the Americas, 
they remain important public health problems globally. The number 
of rubella cases reported worldwide in 2000 was ~700,000; this figure 
declined to 17,407 in 2022. However, the number of rubella cases may 
be underestimated because cases are often mild, patients may not seek 
care, cases may not be recognized or may not be reported, and, in some 
countries, cases are identified through measles surveillance systems that 
are not specific for rubella. Despite a continued increase in the number 
of countries with rubella vaccination programs, 25% of the world’s 
children remained unvaccinated against rubella in 2022. In 2010, it was 
estimated that 105,000 cases of CRS occurred annually globally.
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■CLINICAL FEATURES
Acquired Rubella 
Acquired rubella commonly presents with a 
generalized maculopapular rash that usually lasts up to 3 days 
(Fig. 212-1), although as many as 50% of cases may be subclinical or 
without rash. When the rash occurs, it is usually mild and may be dif­
ficult to detect in persons with darker skin. In younger children, rash 
is usually the first sign of illness. However, in older children and adults, 
a 1- to 5-day prodrome often precedes the rash and may include lowgrade fever, malaise, and upper respiratory symptoms. The incubation 
period is 14 days (range, 12–23 days).
Lymphadenopathy, particularly occipital and postauricular, may 
be noted during the second week after exposure. Although acquired 
rubella is usually thought of as a benign disease, arthralgia and arthritis 
are common in infected adults, particularly women. Thrombocytope­
nia and encephalitis are less common complications.
Congenital Rubella Syndrome 
The most serious consequence 
of rubella virus infection can develop when a woman becomes infected

FIGURE 212-1  Mild maculopapular rash of rubella in a child.
during pregnancy, particularly during the first trimester. The resulting 
complications may include miscarriage, fetal death, premature deliv­
ery, or live birth with congenital defects. Infants infected with rubella 
virus in utero may have myriad physical defects (Table 212-1), which 
most commonly relate to the eyes, ears, and heart. This constellation 
of severe birth defects is known as CRS. In addition to permanent 
manifestations, there are a host of transient physical manifestations, 
including thrombocytopenia with purpura/petechiae (e.g., dermal 
erythropoiesis, “blueberry muffin syndrome”). Some infants may be 
born with congenital rubella virus infection but have no apparent signs 
or symptoms of CRS and are referred to as “infants with congenital 
rubella virus infection only.”
PART 5
Infectious Diseases
■
■DIAGNOSIS
Acquired Rubella 
Clinical diagnosis of acquired rubella is difficult 
because of the mimicry of many illnesses with rashes, the varied clini­
cal presentations, and the high rates of subclinical and mild disease. 
Illnesses that may be similar to rubella in presentation include scarlet 
fever, roseola, toxoplasmosis, fifth disease, measles, Zika, and illnesses 
with suboccipital and postauricular lymphadenopathy. Thus, labora­
tory documentation of rubella virus infection is considered the only 
reliable way to confirm acute disease.
Laboratory assessment of rubella virus infection is conducted by 
serologic and virus detection methods. For acquired rubella, serologic 
diagnosis is most common and depends on the demonstration of IgM 
antibodies in an acute-phase serum specimen or a fourfold rise in IgG 
antibody titer between acute- and convalescent-phase specimens. To 
TABLE 212-1  Common Transient and Permanent Manifestations in 
Infants with Congenital Rubella Syndrome
TRANSIENT MANIFESTATIONS
PERMANENT MANIFESTATIONS
Hepatosplenomegaly
Interstitial pneumonitis
Thrombocytopenia with purpura/
petechiae (e.g., dermal erythropoiesis 
or “blueberry muffin syndrome”)
Hemolytic anemia
Bony radiolucencies
Intrauterine growth retardation
Adenopathy
Meningoencephalitis
Hearing impairment/deafness
Congenital heart defects (patent 
ductus arteriosus, pulmonary arterial 
stenosis)
Eye defects (cataracts, cloudy 
cornea, microphthalmos, pigmentary 
retinopathy, congenital glaucoma)
Microcephaly
Central nervous system sequelae 
(mental and motor delay, autism)

detect a rise in IgG antibody titer indicative of acute disease, the acutephase serum specimen should be collected within 7–10 days after onset 
of illness and the convalescent-phase specimen ~14–21 days after the 
first specimen. The enzyme-linked immunosorbent assay IgM capture 
technique is considered most accurate for serologic diagnosis, but the 
indirect IgM assays also are acceptable. After rubella virus infection, 
IgM antibody may be detectable for up to 6 weeks. In case of a negative 
result for IgM in specimens taken earlier than day 5 after rash onset, 
serologic testing should be repeated.
Although uncommon, reinfection with rubella virus is possible, and 
IgM antibodies may be present. In this instance, IgG avidity testing is 
used in conjunction with IgG testing to distinguish primary rubella 
infection from reinfection. The detection of low-avidity antibodies in 
a patient’s serum indicates recent infection. The presence of mature 
(high-avidity) IgG antibodies most likely indicates an infection occur­
ring at least 2 months previously. Avidity testing may be particularly useful 
in diagnosing rubella in pregnant women and assessing the risk of CRS.
Rubella virus is typically detected in the nasopharynx during the 
prodromal period and for as long as 2 weeks after rash onset. However, 
viral specimens (nasopharyngeal swabs are preferred but throat swabs 
or urine are also acceptable) should be collected as soon after symptom 
onset as possible, preferably 1–3 days after onset, but no later than 
7 days after onset. Rubella is usually diagnosed by viral RNA detection 
in a reverse-transcriptase polymerase chain reaction (RT-PCR) assay; 
rubella virus isolation can also be used to diagnose rubella.
Congenital Rubella Syndrome 
The classic triad of CRS—clinical 
manifestations of cataracts, hearing impairment, and heart defects—is 
seen in ~10% of infants with CRS. Infants may present with differ­
ent combinations of defects depending on when infection occurs 
during gestation. Hearing impairment is the most common single 
defect of CRS. However, as with acquired rubella, laboratory diag­
nosis of congenital infection is highly recommended, particularly 
because most features of the clinical presentation are nonspecific 
and may be associated with other intrauterine infections. Early 
diagnosis of CRS allows the prompt implementation of infection 
control measures and facilitates appropriate medical intervention 
for specific disabilities.
Diagnostic tests used to confirm CRS include serologic assays and 
virus detection. In an infant with congenital infection, serum IgM anti­
bodies are normally present for up to 6 months but may be detectable 
for up to 1 year after birth. In some instances, IgM may not be detect­
able until 1 month of age; thus, infants who have symptoms consistent 
with CRS but who test negative shortly after birth should be retested 
at 1 month. A rubella serum IgG titer persisting beyond the time 
expected after passive transfer of maternal IgG antibody (i.e., a rubella 
titer that does not decline at the expected rate of a twofold dilution per 
month) is another serologic criterion used to confirm CRS.
In congenital infection, rubella virus is detected most commonly 
from nasopharyngeal and throat swabs and urine. Infants with con­
genital rubella may excrete virus for up to 1 year, but specimens 
for RT-PCR are most likely to be positive if obtained within the first 
6 months after birth. Rubella virus in infants with CRS can also be 
detected by virus culture.
Rubella Diagnosis in Pregnant Women 
In the United States, 
screening for rubella IgG antibodies is recommended as part of routine 
prenatal care. Pregnant women with a positive IgG antibody serologic 
test are considered immune. Susceptible pregnant women should be 
vaccinated postpartum.
A susceptible pregnant woman exposed to rubella virus should be 
tested for IgM antibodies and, if positive, confirmed by testing for 
low-avidity IgG antibodies to determine whether she was infected 
during pregnancy. Pregnant women with evidence of acute infec­
tion must be clinically monitored, and gestational age at the time of 
maternal infection must be determined to assess the possibility of 
risk to the fetus. Among women infected with rubella virus during 
the first 10 weeks of gestation, the risk of delivering an infant with 
CRS is 90%. The risk of birth defects declines with infection later 
in gestation, and fetal defects are rarely associated with maternal

rubella after the 16th week of gestation, although sensorineural hear­
ing deficit may occur with infection as late as 20 weeks. Because of 
the potential for false-positive results, rubella IgM antibody testing is 
not recommended for pregnant women with no history of illness or 
contact with a rubella-like illness.
TREATMENT
Rubella
No specific therapy is available for rubella virus infection. Symptombased treatment for various manifestations, such as fever and arthral­
gia, is appropriate. Immunoglobulin does not prevent rubella virus 
infection after exposure and therefore is not recommended as routine 
postexposure prophylaxis. Although immunoglobulin may modify 
or suppress symptoms, it can create an unwarranted sense of secu­
rity: infants with congenital rubella have been born to women who 
received immunoglobulin shortly after exposure. Administration of 
immunoglobulin should be considered only if a pregnant woman who 
has been exposed to a person with rubella will not consider termina­
tion of the pregnancy under any circumstances. In such cases, IM 
administration of 20 mL of immunoglobulin within 72 h of rubella 
exposure may reduce—but does not eliminate—the risk of rubella.
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■PREVENTION
After the isolation of rubella virus in the early 1960s and the occur­
rence of a devastating rubella pandemic in 1964–1965, a vaccine for 
rubella was developed and licensed in 1969. The majority of rubellacontaining vaccines (RCVs) used worldwide are combined measles and 
rubella (MR) or measles, mumps, and rubella (MMR) formulations. A 
tetravalent measles, mumps, rubella, and varicella (MMRV) vaccine is 
available but is not widely used. Available rubella-containing vaccines 
are live attenuated vaccine virus.
The public health burden of rubella virus infection is measured 
primarily through the occurrence of CRS cases among women who 
were infected during pregnancy. The 1964–1965 rubella epidemic in 
Vaccine intro - Rubella vaccine by Country - 2022
Yes
Yes (Partial)
No
Not applicable
4000 km
FIGURE 212-2  Countries using rubella vaccine in national childhood immunization schedules, 2022. Disclaimer—The boundaries and names shown and the designations 
used on this map do not imply the expression or any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, 
city, or area nor of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted or dashed lines on maps represent approximate border lines for which 
there may not be full agreement. (Reproduced with permission from the World Health Organization; 2024.)

the United States resulted in >30,000 infections during pregnancy. 
CRS occurred in ~20,000 infants born alive, including >11,000 infants 
who were deaf, >3500 infants who were blind, and almost 2000 infants 
with intellectual disability. The medical cost of this epidemic exceeded 
$1.5 billion. It has been estimated that the lifetime medical costs for 
children with CRS range from $11,255 in low-income countries to 
$934,000 in high-income countries.

In most countries, there are few data to document the epidemiology 
of CRS, but clusters of CRS cases have been reported in developing coun­
tries. Before the introduction of routine immunization against rubella in 
the United States, the incidence of CRS was 0.1–0.2 case per 1000 live 
births during endemic periods and 1–4 cases per 1000 live births dur­
ing epidemic periods. Where rubella virus is circulating and women of 
childbearing age are susceptible, CRS cases will continue to occur.
The most effective method of preventing acquired rubella and CRS 
is through vaccination with an RCV. One dose induces seroconversion 
in ≥95% of persons ≥1 year of age. Immunity is considered long-term 
and is probably lifelong. The most commonly used vaccine globally is 
the RA27/3 virus strain. The recommendation for routine rubella vac­
cination schedules in the United States is a first dose of MMR vaccine 
at 12–15 months of age and a second dose at 4–6 years. Other persons 
recommended to receive a dose of a rubella-containing vaccine include 
adolescents and adults without documented evidence of immunity, 
individuals in congregate settings (e.g., college students, military per­
sonnel, childcare and health care workers), international travelers, and 
susceptible women before and after pregnancy.
Because of the theoretical risk of transmission of live attenuated 
rubella vaccine virus to the developing fetus, women known to be 
pregnant should not receive RCV. In addition, pregnancy should be 
avoided for 28 days after receipt of RCV. In follow-up studies of ~3000 
unknowingly pregnant women who received rubella vaccine, no infant 
was born with CRS. Receipt of RCV during pregnancy is not ordinarily 
a reason to consider termination of the pregnancy.
CHAPTER 212
In 2022, 175 (90%) of the 194 member countries of the WHO rec­
ommended inclusion of RCV in the routine childhood vaccination 
schedule (Fig. 212-2). Goals for the elimination of rubella and CRS 
Rubella (German Measles)