Rubella and pregnancy

60

Int J Gynecol Obstet,

1993, 42: 60-66

International Federation of Gynecology and Obstetrics

Rubella and pregnancy ACOG Technical Bulletin Number 171 -

August 1992

(Replaces No. 62, July 1981) Preventing maternal rubella infection and its subsequent teratogenic effects (1) on the fetus is the major objective of rubella immunization programs. The initial strategy for rubella control was to vaccinate all preschool andelementary school children. Pregnant women would be protected from rubella by reducing their risk of being exposed to infected children at home or in the community. By the mid-1970s, the incidence of rubella had been reduced considerably, but it had become evident that many pregnant women were still at risk for rubella infection. Persons 15 years of age or older, who had not been targeted in the childhood vaccination strategy, made up a greater proportion of reported cases. Outbreaks continued to occur in settings where young adults congregated. In 1977, the rubella control strategy was augmented to include recommendations that all susceptible adults, particularly postpubertal women, be vaccinated. After the implementation of this strategy, the number of reported cases of postnatal rubella and congenital rubella syndrome (CRS) steadily dropped (2,3). In 1988, an all-time low of 225 cases of rubella were reported to the National Notifiable Disease Surveillance System at the Centers for Disease Control (CDC). However, from 6-l 1% of postpubertal women may remain seronegative, according to data from premarital screening programs in selected states, and even higher rates of seronegativity were reported in special populations. These data suggested that cases of CRS might continue to occur. A moderate resurgence of rubella and a dramatic increase in CRS occurred between 1988 and 199 1(4,5). The reported incidence of rubella increased nearly fivefold during 1988-1990 to a provisional annual total of 1,093 cases, the highest total reported since 1982. In 1990, there were 17 confirmed or compatible cases and 5 provisional cases of CRS (6). While the reason for the resurgence of rubella is unclear, it appears to be associated with a failure to vaccinate susceptible persons

rather than a failure of rubella vaccine. Cases of CRS occurred primarily in infants of unvaccinated mothers.

Rubella Vaccines In 1969, three live attenuated rubella vaccines were licensed for use in the United States: the HPV-77 (DE-5 and DK- 12) vaccines and the Cendehill vaccine. RA 27/ 3 vaccine, a live attenuated vaccine produced in human diploid cells, is more immunogenic than previous vaccines and has been used exclusively in the United States since 1979. Experience with the HPV/77 strains of rubella virus vaccine showed that, a single dose of vaccine given at 12 months of age or older induced antibodies in over 95% of susceptible individuals. A number of studies have been conducted to evaluate the persistence of rubella antibody following rubella vaccination, as measured by hemagglutination inhibition or enzyme-linked immunosorbent assay (ELISA). Long-term follow-up studies conducted 16 years after immunization with the HPV/77 vaccines or the Cendehill vaccine indicated a loss of antibody detectable by ELISA in 8% of persons receiving vaccine. Other studies of long-term persistence of immunity have shown that vaccinees lacking hemagglutination inhibition antibody are often found to have antibody by other laboratory tests, such as neutralizing antibody, passive hemagglutination, or ELISA, or cell-mediated immune responses, suggesting that most, if not all, such persons are immune. RA 27/3-induced antibody levels, which are present in at least 95% of vaccinees, have been shown to persist for at least 18 years in 92% of vaccinees who had originally seroconverted (6). Further evidence for persisting immunity comes from revaccination studies of persons with low levels of antibody, who typically have an anamnestic response; viremia, when studied, has been rare. The rubella vaccine virus can be recovered from the respiratory secretions of recipients up to 28 days Int J Gynecol Obstet 42

ACOG

after subcutaneous or intranasal administration. However, studies have documented the lack of communicability of the vaccine virus in usual circumstances. Even though the vaccine virus may be excreted in the mother’s milk and seroconversion in the feeding infant may occur, there appears to be no contraindication to vaccinating a susceptible mother if she plans to breast-feed her infant. Thus, the susceptible mother should be vaccinated whether or not she plans to breast-feed. Side Effects Some recipients may develop mild and brief rubellalike signs and symptoms, such as fever, rash, and lymphadenopathy, usually 5-2 1 days after vaccination. Joint symptoms following vaccination are more common in women than in men or children. Joint complaints occur in approximately 25% of susceptible adult women vaccinated with the RA 27/3 vaccine, and frank arthritis in about 10%. Joint reactions attributable to vaccine appear to occur only in susceptible persons. Chronic or recurrent arthralgia or arthritis has been rarely reported to follow rubella vaccination of susceptible adult women, and a comparative study documented that such illnesses were substantially less frequent after vaccination than after natural rubella. Rubella Vaccine in Pregnancy Rubella vaccine virus is known to cross the placenta and may infect the fetus during the early stages of development; however, there is no evidence that it causes birth defects or illness (7). Between 1971 and 1988, the Centers for Disease Control collected data on 307 infants born to susceptible women who had received rubella vaccine up to 3 months before conception or during the first trimester of pregnancy. Ninety-four infants were born to mothers who had received the previously usedcendehill or HPV/77 vaccines, and 212 were born to mothers who had received the RA 2713 vaccine. None of the infants had defects indicative of CRS. Three of the infants born to mothers receiving the Cendehill or the HPV-77 vaccine and three born to mothers receiving the RA 27/3 vaccine had laboratory evidence of subclinical fetal infection but no illness or defects. The observed risk of congenital malformations following rubella vaccination with the RA 2713 vaccine therefore is 0; the theoretic risk may be as high as 1.7%. Although the observed risk of congenital malfor-

Technical Bulletins

61

mations following rubella vaccination is no greater than the risk of malformations occurring by chance, pregnancy remains a contraindication to rubella vaccination on theoretic grounds. Reasonable precautions should be taken to preclude vaccination of pregnant women, including asking women if they are pregnant, excluding those who say they are, and explaining the theoretic risks to the others. Because of the theoretic risk to the fetus, women who have been vaccinated should be advised to avoid conception for 3 months. If a woman who is vaccinated is discovered to be pregnant, the Immunization Practices Advisory Committee, which plays a major role in recommendations for U.S. immunization policy, has stated that “the risk of vaccineassociated defects is so small as to be negligible and should not ordinarily be a reason in itself to consider interruption of pregnancy.” The pregnant patient and her physician should make the final decision.

The risk of CRS abnormalities in infants varies according to the gestational age at which the infection occurs; therefore, counseling regarding the risk and management of pregnant women who have evidence of primary rubella infection must be individualized. Prospective studies of infection during pregnancy have demonstrated that when maternal infection occurred in the first trimester, the average incidence of abnormalities was 25%, compared with an incidence of less than 1% following infection during the second trimester. The risk was estimated to be at least 50%, 25%, and 10% during the first, second, and third month, respectively. In 1982, even higher rates overall of anomalies were reported (8). This latter study may provide a more accurate determination of risk, since all maternal cases were serologically confirmed and sensitive antibody assays were used to detect congenital infection. The risk for congenital defects in this study was 90% when maternal infection occurred before 11 weeks of gestation, 33% for infection during 11-12 weeks, 11% for 13-l 4 weeks, 24% for 15-l 6 weeks, and 0% after 16 weeks (8). Termination of pregnancy is usually considered when there is clear evidence of primary infection during the first trimester of pregnancy. Instances of rubella between 16-20 weeks of pregnancy are rare and are manifested by bilateral sensorineural deafness (ofInt J Gynacol Ohstrt 42

62

ACOG Technical Bulletins

ten severe) in the newborn. No studies have documented congenital defects following maternal infection after 20 weeks of gestation. Routine postexposure rubella prophylaxis with immunoglobulin is not recommended because it has not been shown to be effective.

An accurate diagnosis of acute primary rubella infection in the pregnant woman is imperative if appropriate management is to be undertaken. Since a large proportion of cases are subclinical and clinical diagnosis is unreliable, the diagnosis of acute rubella infection requires serologic testing. Pregnant women who present with a rubella-like illness or recent exposure to rubella but have tested positive for rubella-specific antibody during prenatal or preconception screening can be presumed to be immune. The definition of a significant rise in rubella immunoglobulin G (IgG) antibody level or a minimal IgG antibody level indicative of immunity varies by the type of assay and by the laboratory performing the testing and must be elucidated by the laboratory. A relatively sensitive assay (ie, one that is able to detect 210 IU) should be used. The serologic diagnosis of recent rubella infection requires either of the following: 1.

Detection in acute and convalescent sera of a significant rise in rubella antibody levels, either total or IgG

2.

Presence of rubella IgM antibody

In the United States, the most commonly used assays for the diagnosis of acute rubella infection are hemagglutination inhibition, ELISA, and indirect fluorescent immunoassay (9). Complement fixation tests are now used infrequently; they are less sensitive, and complement fixation antibodies appear later in the course of disease than do antibodies measured by other assays. Passive hemagglutination and passive latex agglutination tests are fast and convenient tests that are useful for detecting evidence of immunity but are not recommended for quantitating antibody or for confirming rubella illness. Neutralization tests are very sensitive but not usually available in clinical laboratories. Hemagglutination inhibition, ELISA, and indirect fluorescent immunoassays have been developed for detection of the serum rubella IgM fraction as well as for Int J Gynecol Obstet 42

measurement of IgG antibody levels. Total rubella antibodies are rarely measured now by commercial laboratories, since most ELISA and indirect fluorescent immunoassays use conjugates specific for IgG. Therefore, in this bulletin, reference will generally be made only to rubella IgG or rubella IgM antibodies. In the case that an assay for total rubella antibodies is used for immunity screening in the absence of exposure to virus, it can be assumed that the majority of the antibody is IgG class antibody. Rubella IgM antibody can be detected from early after onset of illness, reaching a peak at 7-10 days, and persisting up to 4 weeks after the appearance of rash. Some sensitive assays may detect IgM antibody longer than 4 weeks. False-positive tests for IgM antibody can occur with any indirect assay, such as ELISA or indirect fluorescent immunoassay, if the laboratory technique used does not avoid nonspecific reactions due to complexes with rheumatoid antibody. A negative IgM test, unless supported by additional laboratory or other data, cannot definitively prove lack of infection because of the potential for a false-negative result due to early waning of IgM antibody. Low levels of rubella total or IgG antibodies, while not excluding the possibility of recent rubella infection, are not characteristic of the antibody response that is seen within the first 6 months following acute rubella infection. On the other hand, high total or IgG antibody levels may be present in up to 15% of the normal population and, by themselves, do not indicate a recent infection. Thus, a single measurement of rubella total or IgG antibody is generally not helpful in making a definitive diagnosis of acute rubella infection; rubella IgM antibody testing and/or collection of a second serum specimen for evidence of seroconversion to rubella are needed. Most commercial laboratories do not routinely save serum specimens; when recent rubella infection is suspected, the clinician should specifically order that acute specimens be saved to be tested in parallel with convalescent specimens. It can be difficult to establish a diagnosis of rubella infection in a pregnant woman who is vaccinated but who has a significant rise in total or IgG antibody level after recent exposure to rubella. If IgM is present, then acute infection or reinfection has occurred. If no IgM antibody is detected, the rise in IgG level probably represents a boosting of antibody due to reinfection, rather than a primary response to infection. Boosting of

ACOG Technical Bulletins

through prior prenatal or earlier rubella testing and who presents 5 weeks or more after exposure to a rash illness or 4 weeks or more after onset of a rash. If no rubella IgG antibody is detected, the patient is clearly susceptible to rubella and has no evidence of a recent infection. If IgG antibody is detected, there is evidence of a previous rubella infection. The date of infection and the risk to the fetus are difficult to determine, although a low level of antibody suggests more remote infection, Testing for rubella IgM antibody or repeating the test for IgG antibody levels to determine whether there is a significant rise or decline may be considered.

IgG antibody has been seen in persons whose immunity was documented prior to exposure. Maternal reinfections usually pose no risk to the fetus. Figure 1 shows a guide to assessing the risk of CRS in a fetus of a woman who is exposed to rubella or who has a rubella-like illness during pregnancy. Figure 2 shows a schematic representation of the rubella antibody responses following exposure and infection. The following guidelines amplify the evaluation suggested in the figures: All women not known to be immune to rubella who have exposure to rubella or a rubella-like illness during pregnancy should be evaluated serologitally for evidence of recent infection. If testing indicates that recent infection is likely to have occurred, then the woman should receive appropriate counseling, including the information that there is a high risk of CRS for the fetus if the primary infection occurred during the first trimester of pregnancy. Women who have documented positive tests for rubella-specific antibody at some point prior to pregnancy can be presumed to be immune. Should these women have a significant rise in rubella IgG antibody titer without detection of IgM antibody, they should be counseled that asymptomatic reinfection is most likely to have occurred. Serologic testing for diagnosis of recent rubella infection should include testing of acute sera for both IgG and IgM antibody. The presence of rubella-specific IgM antibody indicates acute infection. If tests for IgM are negative or unavailable, testing of paired acute and convalescent sera for IgG antibody should be carried out. In the setting of rubella-like illness during pregnancy, the acute specimen should be drawn as soon after rash onset as possible, followed by a convalescent specimen 2-3 weeks later if the initial test for IgM is negative. When suspected exposure to rubella has occurred, the acute specimen should be drawn immediately, followed by a convalescent specimen 4-5 weeks later. A relatively sensitive assay, such as ELISA, hemagglutination inhibition, or indirect fluorescent immunoassay, should be used. 4.

Another difficult diagnostic the patient whose immune

dilemma is posed by status is not known

63

5. When the risk of CRS for the fetus is unclear because maternal serologic tests are not diagnostic, other information may be useful. This includes historical and epidemiologic information, such as recent maternal exposure to rubella, rash illness, vaccination history, stage of pregnancy in which infection is thought to have occurred, and timing of laboratory specimens (10). These patients need to be counseled about the uncertainties involved in assessing their degree of risk.

Recommendations to Prevent Rubella Exposure In order to decrease both the number of pregnant women who are susceptible to rubella and the incidence of CRS, the following practices are encouraged: 1. Rubella vaccination of all children 12-15 months of age or older should be routine. All prepubertal school children without a record of previous rubella immunization shouldbe vaccinated. Mothers should be given a copy of the vaccination records. Since there is conclusive evidence that the vaccine virus is not transmitted from person to person, children may be vaccinated even when there is a pregnant woman in the household. 2.

All adolescents and adults not known to be immune to rubella, especially women of childbearing age, should be vaccinated unless they are pregnant or have other contraindications to vaccination. Only persons with detectable antibodies or a physiciansigned record of rubella immunization should be considered immune. A history of rubella disease is not sufficient evidence of prior immunity. Any

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ACOG Technical Bulletins

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Days after onset

Onset

FIG. 2. Schema of immune response in acute rubella infection. EWRIA. enzyme immunoassay/radioimmunoassay; HI, hemagglutination inhibition; WFIAX, indirect flourescence immunoassay; Nt, neutralization test; CF, complement fixation; IgM, immunoglobulin M: PHA. massive hemaaalutination. Adaoted with oermission from: Herrmann KL. Available rubella serologic tests. Rev Infect Dis 1985; 7 &ppl 1 :S108-S’ii 2.

woman with no history of vaccination and no contraindications for vaccination can be vaccinated without prior serologic testing. Immunization of adult women of childbearing age is particularly important, as is immunization of health care personnel who may transmit rubella to pregnant women or who might themselves contract rubella while pregnant. Because of the theoretic risk to the fetus, women of childbearing age should not receive rubella vaccine if they are pregnant, and they should understand that they should not become pregnant for 3 months after vaccination. 3.

All prenatal patients should be screened for susceptibility to rubella as early in pregnancy as practical. Seronegative women, including those who are breast-feeding, should be vaccinated in the postpartum period, prior to discharge from the hospital. Since the vaccine is usually effective in immunizing the seronegative woman, postvaccination antibody testing is not necessary until a subsequent pregnancy. Although antenatal or postpartum ad-

ministration of D immune globulin (human) or other blood products is not a contraindication for postpartum vaccination, in this situation, antibody testing should be done 6-8 weeks following vaccination to ensure seroconversion. If seroconversion does not occur, a second vaccination is necessary. 4.

All suspected cases of rubella should be reported immediately to the local or state health department. While the clinical evaluation is being completed, the health department can determine what exposures may have occurred and initiate appropriate rubella control measures. Suspected cases of CRS should also be reported.

REFERENCES I. Dudgeon JA. Congenital rubella: Pathogenesis and immunology. Am J Dis Child 1969; 118:354 2. Centers for Disease Control. Rubella and congenital rubella syndrome-United States, 1985-1988. MMWR 1989;38:173-182 Int J Gynecol Obstet 42

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3. Cochi SL, Edmonds LE, Dyer K, Greaves WL, Marks JS, Rovira EZ, et al. Congenital rubella syndrome in the United States, 1970-1985. On the verge of elimination. Am J Epidemiol 1989; 129:349-36 1 4. Centers for Disease Control, Immunization Practices Advisory Committee. Increase in rubella and congenital rubella syndrome-United States, 1988-1990. MMWR 199 1;40:93-99 5. Centers for Disease Control, Immunization Practices Advisory Committee. Outbreaks of rubella among the Amish-United States, 1991. MMWR 1991; 40:264265 6. O’Shea S, Best JM, Banatvala JE, Marshall WC, Dudgeon JA. Persistence of rubella antibody 8-l 8 years after vaccination. BMJ 1984;288:1043 7. Centers for Disease Control. Rubella vaccination during pregnancy-United States, 1971-1988. MMWR 198938: 289-293 8. Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;2:781-784 9. Herrmann KL. Available rubella serologic tests. Rev Infect Dis 1985;7 Suppl l:S108-S112 10. Mann JM, Preblud SR, Hoffman RE, Brandling-Bennett AD, Hinman AR, Hemnann KL. Assessing risks of rubella infection during pregnancy. A standardized approach. JAMA 1981;245:1647-1652

RECOMMENDEDREADlNG Centers for Disease Control, Immunization Practices Advisory Committee. Rubella prevention. MMWR 1990;39 (RR-15):1-18 Enders G, Knotek F. Rubella IgG total antibody avidity and IgG subclass-specific antibody avidity assay and their role in the differentiation between primaly rubella and rubella reinfection. Infection 1989; 17:2 18-226 Hedman K, Hietala J, Tiilikainen A, Hartikainen-Sorri AL, Raiha K, Suni J, et al. Maturation of immunoglobulin G avidity after rubella vaccination studied by an enzyme linked immunosorbent assay (avidity-ELISA) and by haemolysis typing. J Med Virol 1989;27:293-298 Herrmann KL. Rubella virus. In: Lennette EH, Schmidt NJ. eds. Diagnostic procedures for viral,. rickettsial and chlamydial infections. 5th ed. Washington: American Public Health Association, 1979 Orenstein WA, Bart KJ, Hinman AR, Preblud SR, Greaves WL, Doster SW, et al. The opportunity and obligation to eliminate rubella from the United States. JAMA 1984;251:1988-1994 Preblud SR, Serdula MK, Frank JA Jr, Brandling-Bennett AD, Hinman AR. Rubella vaccination in the United States: a ten-year review. Epidemiol Rev 1980;2:171194 Schom TR, Nelson DB, Duma MA, Sedmak GV. Increasing rubella seronegativity despite a compulsory school law. Am J Public Health 1990;80:66-69 Stehr-Green PA, Cochi SL, Preblud SR, Orenstein WA. Evidence against increasing rubella seronegativity among adolescent girls. Am J Public Health 1990;80:88

This Technical Bulletin was developed under the direction of the Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists as an educational aid to obstetricians and gynecologists. The committee wishes to thank Laura J. Fehrs, MD; Walter W. Williams, MD; Stephen L. Cochi, MD; Walter A. Grenstein, MD; and Carl W. Tyler, MD, for their assistance in the development of this bulletin. This Technical Bulletin de not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognized methods and techniques of clinical practice for consideration by obstetrician-gynecologists for incorporation into their practices. Variations of practice taking into account the needs of the individual patient, resources, and limitations unique to the institution or type of practice may be appropriate. Copyright 0 August 1992 THE AMERICAN COUE6E OF OBSYEYNICIANS AND GYNECOUIGISTS 4lM12thStrMSW Washington, DC 20024-2188 Int J Gynecol Obstet 42