Rubella and Rubeola Cesar Rosa

Rubella and rubeola are common viral exanthems that may affect women of reproductive age. Effective vaccination programs have greatly decreased their incidence. Although Rubella is a relatively innocuous illness for the nonpregnant patient, transplacental fetal infection with rubella can result in significant and crippling fetal malformations and handicap. Because some women of reproductive age are not appropriately immunized, rubella is still a threat. The practitioner needs to be vigilant in assuring vaccination o f susceptible individuals when seen for routine health maintenance. Addition- ally, at times the obstetrician will be challenged with the evaluation and care o f a susceptible pregnant patient who is exposed to rubella. In contrast, rubeola (measles) infection during pregnancy has not been associated with congenital malformations. Affected mothers, however, experience a higher incidence of spontaneous abortions and premature delivery and are themselves at risk for serious complications such as pneumonia and encephalitis. This is a US government work. There are no restrictions on i ts use.

R ubella and rubeola are two of the most com- mon viral illnesses that affect humans. Early

in the century each of these two viral infections were included among the numbered exanthe- mata. Rubeola (measles) was "First Disease," scarlet fever, "Second" ; rubella, "Th i rd" ; Duke's disease (a mild febrile eruption probably caused by a Coxsackie-ECHO virus), "Four th" ; and exanthem subitem (erythema infectiosum, caused by Parvovirus B19) "Fifth. ''1

The availability of effective vaccines has mark- edly reduced the prevalence of both rubella and rubeola in the United States. Lack of compliance with established immunization recommenda- tions, vaccination failures, and the influx of un- vaccinated immigrants result in periodic out- breaks of these diseases, particularly in large metropoli tan centers. Consequently, these two illnesses continue to be relevant to the obstetri- cian-gynecologist because of their potential ef- fects on the pregnant patient and her fetus. The practi t ioner must be familiar with the t reatment of the patient exposed to these diseases and re- main vigilant for ensuring the vaccination of all non im mune patients.

From the Department of Obstetrics and Gynecology, Uniformed Ser- vices University of the Health Sciences, Bethesda, MD. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Address reprint requests to Cesar Rosa, MD, Department of Obstetrics and Gynecology, USUHS, 4301 Jones Bridge Rd, Bethesda, MD 20814-4799. This is a US government work. There are no restrictions on its use. O146-0005/98/2204-001050. 00/0

RubeUa

The rubella virus, a single-stranded RNA virus in the family Togaviridae, is not related to any other virus and has only one serotype. 2 Humans are the only known natural host of the virus, and the distribution is worldwide. Rubella virus is spread via respiratory droplets, and in most cases, prolonged exposure is required for trans- mission of the disease.

Clinical Manifestations

Rubella, also known as German measles, begins insidiously and is characterized by an acute exan- thematous, maculopapular eruption that lasts 3 days or less. The incubation period is approxi- mately 18 days (range, 14 to 21 days). After initial replication in the upper respiratory tract and cervical lymph nodes, viremia may be detected as early as 7 days before the exanthem. A mild prodrome, characterized by conjunctivitis, head- ache, low-grade fever, malaise, and minimal res- piratory symptoms may occur 1 to 5 days before the onset of the rash. Tender lymphadenopathy of the postauricular, suboccipital, and posterior cervical nodes is a p rominen t feature of the dis- ease and generally occurs 4 to 10 days before the onset of the rash. The adenopathy is most p ronounced during the rash and may persist for a few days afterward.

As the rash appears, prodromal symptoms di- minish. The exanthem consists of a discrete, pink, maculopapular eruption that begins on the face and within hours spreads downward over the trunk and extremities. Generally, the rash

318 Seminars in Perinatology, Vol 22, No 4 (August), 1998: pp 318-322

Rubella and Rubeola in Pregnancy 3 1 9

will fade in the same sequence, with the face clearing by the end of the second day. The erup- tion usually clears by the end of the third day but may persist 4 or 5 days. 3

The joints may be involved in up to one third of adult women. The fingers, wrists, and knees are most commonly affected. Arthralgias begin with the onset of the rash and clear without se- quelae within 2 to 30 days. Tbrombocytopenia with purpura and hemorrhage occur infre- quently. Other uncommon manifestations are encephalitis (1 in 6,000 cases), myocarditis, peri- carditis, hepatitis, hemolytic anemia, and hemo- lyric-uremic syndrome.

Diagnosis

A clinical diagnosis of rubella may be made only in typical cases occurring during an epidemic. Because of the variation in the manifestations of the disease, and because of the multiple condi- tions that may mimic the rubella exanthem, sero- logical tests should be obtained to establish the diagnosis.

Primary infection is diagnosed by the detec- tion of ei ther IgM-specific rubella antibodies from a single serum sample, or a fourfold in- crease between acute and convalescent-phase IgG-specific rubella antibody titers obtained 1 to 2 weeks apart. For the latter, several methods are currently available: hemagglutination-inhibition (HAI), radioimmunoassay, enzyme-linked im- munosorbent assay (ELISA), complement fix- ing, and latex agglutination. Although the HAI is considered the gold standard, the ELISA is most widely used because it is a rapid, conve- nient, highly sensitive, and accurate method.

Acute and convalescent sera should be tested simultaneously. The HIA antibody appears 12 to 14 days after exposure, peaks 12 to 14 days after the onset of the rash, and starts to decline 3 weeks after the onset of the rash. It reaches stable levels approximately 4 weeks after the rash and persists for life. A titer greater than 1:8, in associ- ation with a history of a prior infection or vacci- nation, indicates immunity. A titer less than or equal to 1:8 should be repeated in 7 days after the onset of a suspicious rash, or 14 to 28 days after exposure in asymptomatic patients.

Complement-fixing (CF) antibodies start ris- ing 7 days after the rash, peak 3 weeks after the rash, and start to decline 4 to 5 weeks after. The CF antibody may fall to undetectable levels. Inso- far as CF levels rise later than HAI, the CF anti-

body may be used to confirm a diagnosis when the patient is initially evaluated 2 to 3 weeks after the rash, when the HAl is falling.

Rubella-specific IgM antibody detection is also used to detect primary infections. The se- rum sample should be obtained 1 to 2 weeks after the onset of the rash. A false-negative test finding may result if the sample is obtained dur- ing the first week, or later than 3 weeks after the appearance of the exanthem. False-positive results may occur from difficulty in fractionating the IgM from the IgG and from cross reactivity with rheumatoid factor, Epstein-Barr virus, and cytomegalovirus. Another area of caution is the interpretation o f low-titer IgM results. In some patients, low IgM titers may persist after natural infection. In addition, in patients whose immu- nity is because of vaccination, IgM antibodies may reappear after a subclinical reinfection. 3

Therapy and Prognosis

Acetaminophen is usually sufficient to relieve the discomfort associated with symptomatic in- fections. Glucocorticoids and platelet transfu- sions have been used in patients with bleeding from thrombocytopenia, and supportive therapy is the mainstay of therapy in cases of rubella encephalopathy. Bacterial superinfection is rare, so antimicrobials are not indicated in uncompli- cated cases.

In general, the prognosis is excellent. Fatali- ties occur rarely and usually are secondary to encephalitis or cerebral hemorrhage. Immunity results after a single episode of clinical or sub- clinical infection. This protect ion is thought to be long lasting; however, reinfections have been documented.

Prevention

In 1969, three live at tenuated vaccines were li- censed: the HPV-77 (DE-5 and DK-112) vaccines and the Cendehill vaccine. Since 1979, the HPV/77, a live virus at tenuated vaccine pro- duced in human diploid cells, has been used almost exclusively in the United States. This vac- cine is more immunogenic than the Cendehill preparat ion, and a single dose given at age 12 months or older results in measurable antibod- ies in approximately 9.5% of the susceptible indi- viduals. Long-term studies to evaluate the persis- tence of antibodies after vaccination documen t lasting immunity in approximately 92% of those who initially underwent seroconversion. 4

320 Cesar Rosa

Vaccination is r e c o m m e n d e d for all children at 12 months using a monovalen t rubella vac- cine, or at 15 months in conjunct ion with mea- sles and mumps vaccines (MMR). Only persons with serological evidence of immunity or docu- menta t ion of immunizat ion on or after their first bir thday are considered immune . A history of a previous infection with rubella should not be considered evidence of immunity; All susceptible adolescents and adults should be vaccinated to eliminate the virus reservoir. For that reason, vaccination should be offered whenever contact with the health care system occurs (eg, postpar- tum and general outpat ient visits) and on en- trance to institutions like schools, colleges, pris- ons, and business off ices . 2 The main goal of the rubella vaccination p rog ram is to avoid the dev- astating effects of the Congenital Rubella Syn- drome. Although substantial gains have been made, there are still pockets of the populat ion that remain susceptible. 5

Contraindicat ions for vaccination include se- vere febrile illness, immunodef ic iency disorder, history of anaphylact ic react ion to neomycin, and pregnancy. Vaccinat ion should not be ad- minis tered within 2 weeks before, and 12 weeks after, adminis t ra t ion of i m m u n e globulin, be- cause seroconversion may be p reven ted by the ant ibodies present in the i m m u n e globulin. Breast feeding or adminis t ra t ion of anti- Rho (D) i m m u n e globulin is not a contraindica- tion to pos tpa r tum vaccination. The person re- ceiving the vaccine is not a transmission risk to a susceptible p r egnan t woman in the household . ~ Vaccine-related side effects occur in approxi- mately 15% of individuals. Arthralgia and ar- thrifts may last up to 11 days and are more com- m o n in adults. Rash, adenopathy , and fever also may occur.

The rubella vaccine virus crosses the placenta and may infect the fetus during the early stages of development . There is, however, no evidence that it causes birth defects. Because of the theo- retic risk to the fetus, women are advised to avoid concept ion for 3 months after vaccination. I f a woman inadvertently receives the vaccine while pregnant , the risk to the fetus is negligible and should not be a reason to consider in terrupt ing the pregnancy. 4

Congenital Rubella Syndrome

Initially described by Gregg in 1941 after an epi- demic of rubella in Australia, the Congenital Ru-

bella Syndrome (CRS) consists of congenital cat- aracts or glaucoma, deafness, and hear t disease (most commonly patent ductus arteriosus or pe- r ipheral pu lmonary artery stenosis). For the clin- ical case definition, in addition to one or more of the above findings, one of the following labo- ratory criteria should be present: isolation of ru- bella virus, demonst ra t ion of rubella-specific IgM antibody, or a rubella IgG antibody that per- sists and fails to drop at a rate of twofold dilution per month . 6

The rate of congenital infection is very high during the first tr imester (90% fetal infection, 85% of which result in sequelae). The rate of infection drops to 30% at 23 to 30 weeks' gesta- tion and then rises progressively to almost 100% at term. Congenital malformat ions are not seen after 16 weeks' gestation, but some fetuses in- fected in the later half of pregnancy may exhibit growth restriction. Fetal infection occurs during maternal viremia, and the pat tern of disease is typical o f hematogenous spread. The associated fetopathy is thought to be secondary to embolic events in the fetal circulation precipi tated by damaged desquamated endothelial cells. 7

Special Considerations

The administrat ion of i m m u n e globulin to a p regnan t pat ient who has been exposed to ru- bella is controversial. The role of this t rea tment is considered limited because of the viremia al- ready present at the t ime of administrat ion and the lack of high antirubella titer preparat ions. The i m m u n e globin may also modify the clinical manifestations in the mo the r without diminish- ing the viral replication, hence leaving the fetus unprotected. The Centers for Disease Control (CDC) recommenda t ions limit the use o f im- m u n e globin to women with known exposure to rubella who do not wish to in ter rupt the preg- nancy unde r any circumstances. 3

Maternal reinfection with rubella may occur. It is more c o m m o n in vaccinated subjects than in those whose immunity is caused by natural infection. The reinfection is usually subclinical, s There are approximately 20 cases in the litera- ture of fetuses with CRS born to mothers with documen ted immuni ty before the pregnancy. Fortunately, CRS is infrequent when the mo the r experiences a reinfection with rubella. Addition- ally, no cases have been repor ted when reinfec- tion occurs after 12 weeks' gestation. 9

The best t rea tment for patients with docu-

Rubella and Rubeola in Pregnancy 321

mented immunity who are exposed to rubella is unclear. If the exposure occurs after the first trimester, the likelihood of fetal injury appears to be very low. If exposure occurs during the first trimester, the patient should be counseled about the small risk of CRS and offered the avail- able diagnostic modalities.

When a susceptible pregnant patient is ex- posed to rubella, seroconversion should be de- termined using rubella-specific antibody tests. If the mother is deemed to have acquired the dis- ease during the first trimester, the parents should be counseled about the risk of CRS and made aware of the option of pregnancy termina- tion. A more precise ascertainment of the risk of CRS may be possible via chorionic villous sam- pling or amniocentesis using reverse transcrip- tion and nested polymerase chain reaction for determinat ion of fetal infect ionJ ~

Rubeola

The rubeola virus is a single-stranded RNA virus of the family Paramyxoviridae. Humans and monkeys are the only known hosts. There are no carrier states. The disease is endemic throughout the year in heavily populated areas, and it is not affected by age or gender. It is one of the most highly contagious of infectious diseases and is spread via respiratory droplets. 11

Clinical Manifestations

Rubeola, more commonly known as measles, is largely a disease of children. The incubation period is 10 to 14 days. After a 2- to 4-day prodro- mal phase characterized by malaise and fever, coryza, conjunctivitis, and cough develop, which increase in severity and peak with the onset of the exanthem on the fourth to fifth day. The total duration is 7 to 10 days. The respiratory symptoms are similar to those of a severe cold. The pa thognomonic Koplik's spots--faint , white, 1- to 2-mm elevated lesions on an erythem- atous background that occur on the inner lip or opposite the lower mo la r s - - appea r at the end of the prodrome. The exanthem usually begins on the head and neck as faintly pink macules, progressing to a maculopapular eruption that spreads downward over the next 3 days.

Measles is a generalized infection associated with inflammatory changes that can be intense. The most f requent complications are related to

involvement of the respiratory tract, manifested as coryza, odds media, laryngotracheobronchitis, and pneumonia. The frequency of pneumonia ranges from 3.5% to 50% and is more f requent in pregnant patientsJ 2

Measles encephalitis occurs in approximately 0.2% of patients and has a mortality rate ap- proaching 10%. Odds media develops in approx- imately 10% of children with measles. Keratitis and conjunctivitis are f requent during the pro- dromal phase. The keratitis is symptomatic in 50% of cases and is usually self limited. Abdomi- nal pain may occur because of general lymphoid hyperplasia. Hepatitis is another recognized late complication. Hepatic enzyme elevation may oc- cur in 50% to 75% of young adults. 11a2

Unlike rubella, there is no consistent pattern of congenital malformations associated with transplacentally acquired measles. The clinical course of the disease during pregnancy usually is similar to that in nonpregnan t women. How- ever, in one early report , the maternal mortality rate was strikingly increased during an epidemic in the unexposed population of Greenland in 1951. Even in recent years, maternal deaths have occurred from encephalitis, hepatitis, and severe pneumonia . There is a recognized increase in fetal loss rate and premature births related to measles. 13

Diagnosis

The diagnosis is commonly made on the basis of clinical presentation, particularly during an epidemic. Laboratory confirmation may be of value in diagnosing sporadic cases. The hemag- glutination-inhibition assay is the most fre- quently used test but is now being replaced by the ELISA. Serum antibodies appear 1 to 3 days after the onset of the rash and peak 3 to 4 weeks later. Paired samples document ing a fourfold in- crease in titer confirm the diagnosis. An assay for IgM measles-specific antibody is also avail- able. For confirmation of the diagnosis, the CDC recommends a laboratory criterion along with the clinical case definition. The laboratory crite- ria are positive IgM antibodies, a significant rise in IgG measles antibody levels, a n d / o r isolation of the virusJ 4

Therapy and Prognosis

The treatment of uncomplicated measles is symptomatic. There is no specific antiviral agent

322 Cesar Rosa

shown to be effective. Antibiotics are indicated only for the treatment of secondary bacterial in- fections such as otitis media and pneumonia. Most patients will recover without sequelae. Im- munity after measles seems to be lifelong, and second attacks are exceedingly rare) 2

Prevention

Measles vaccines, both killed and live attenuated, have been available since 1963, resulting in a 99% reduction in the incidence of measles in the United States. The killed virus vaccine was withdrawn in 1967 because of its short-term pro- tection and association with atypical measles. The initial live-attenuated virus vaccine (Edmond- ston B-strain) was immunogenic but was associ- ated with high rates of adverse reactions. The attenuated Moraten vaccine, introduced in 1968, is still in use, is highly immunogenic, and has a favorable side-effect profile. 12

The present recommendation is for initial vacci- nation between 12 and 15 months of age, with a second dose at 4 to 6 or 11 to 12 years of age. The second dose may be administered at any time, but not sooner than I month from the first dose. Other candidates for vaccination include recipients of the killed virus vaccine, those who received the live virus vaccine before their first birthday, individuals born after 1957 who have no history of measles or vacci- nation, and susceptible individuals within 72 hours of exposure. There is no harm in revaccinating per- sons already immune to any of the components of the MMR vaccine. Contraindicafions to vaccination include anaphylaxis with egg ingestion, allergy to neomycin, administration of IgG within the previ- ous 3 months, immunodeficiency disorder, and ac- tual or planned pregnancy, tl'a2

Passive immunization is indicated to prevent or modify measles after exposure of children un- der 1 year of age, chronically ill patients, immu- nosuppressed patients, and pregnant patients. The recommendat ion is to administer immune human globulin intramuscularly within 6 days of exposure. The dose is 0.25 m L / k g as a single injection. If there is no contraindication, the pa- tient should then receive the live virus vaccine no sooner than 3 months after) 1

Pregnancy-Related Considerations

Measles does not cause congenital malforma- tions but has been associated with an increased risk of spontaneous abortion, preterm birth, and maternal complications. Vaccination is not rec- o m m e n d e d during the 3 months before preg- nancy as well as during pregnancy, the same as with other live-attenuated viral vaccines. 13 If ma- ternal infection occurs near delivery, the fetus may acquire the disease at birth, and should re- ceive intravenous IgG immediately after delivery.

References

1. Shapiro L: The numbered diseases: First through sixth. JAMA 194:210, 1965

2. Marcy SM, Jordan MC: Rubella, in Hoeprich PD, Jordan MC, Ronald AR (eds): Infectious Diseases (ed 5). Phila- delphia, PA, Lippincott, 1994, pp 903-911

3. Leissa B, Sever JL: Rubella (German measles), in Gor- bach SL, BartlettJG, Blacklow NR (eds): Infectious Dis- eases. Philadelphia, PA, Saunders, 1992, pp 1093-1101

4. American College of Obstetricians and Gynecologists Technical Bulletin, Number 171, August 1992

5. McGregor JA: Prevention of rubella: Missed opportuni- ties. Infect Control Hosp Epidemiol 14:511-512, 1993

6. Centers for Disease Control: Case definitions for infec- tious conditions under public health surveillance. MMWR 46:30, 1997

7. Kaplan C: The placenta and viral infections. Semin Diag Radiol 10:232-250, 1993

8. Burgess MA: Rubella reinfection--What risk to the fe- tus? MedJ Aust 156:824-825, 1992

9. Robinson J, Lemay M, Vaudry WL: Congenital rubella after anticipated maternal immunity: Two cases and a review of the literature. Pediatr Infect Dis J 13:812-815, 1994

10. Tanemura M, Suzumori K, Yagami Y, et ah Diagnosis of fetal rubella infection with reverse transcription and nested polymerase chain reaction: A study of 34 cases diagnosed in fetuses. Am J Obstet Gynecol 174:578-582, 1996

11. Bernstein DI, Schiff GM: Measles, in Gorbach SL, Bart- lettJG, Blacklow NR (eds): Infectious Diseases. Philadel- phia, PA, Saunders, 1992, pp 1088-1092

12. Sullivan cJ,Jordan MC: Measles, in Hoeprich PD,Jordan MC, Ronald AR (eds): Infectious Diseases (ed 5). Phila- delphia, PA, Lippincott, 1994, pp 892-902

13. Eberhart-PhillipsJE, Frederick PD, Baron RC, et ah Mea- sles in pregnancy: A descriptive study of 58 cases. Obstet Gynecol 82:79%801, 1993

14. Centers for Disease Control: Case definitions for Infec- tious Conditions Under Public Health Surveillance. MMWR 46:23-24, 1997