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Current Trends Rubella Vaccination during Pregnancy -- United States, 1971-1988

Since licensure of live attenuated rubella vaccine in 1969, the Immunization Practices Advisory Committee (ACIP) of the Public Health Service has stated that pregnancy is a contraindication to rubella vaccination because of concerns regarding the theoretical possibility of adverse effects on the developing fetus. Because of this concern and because the Cendehill and HPV-77 vaccine virus strains (introduced in 1969) could cause intrauterine rubella infections (1), CDC established in 1971 the Vaccine in Pregnancy (VIP) registry of women who had received either of these two rubella vaccines within 3 months before or after conception (2). None of the 290 infants born to the 538 women entered into this registry through April 1979 had defects indicative of congenital rubella syndrome (CRS); this included 94 live-born infants of women who were known to be susceptible* before receiving the vaccine (3,4).

In January 1979, the RA 27/3 rubella vaccine was licensed for use in the United States. Concerns were raised that this new live attenuated-virus vaccine might have greater fetotropic and teratogenic potential than the earlier vaccines because this virus was isolated from and propagated in human tissue. Thus, women known to be susceptible to rubella who received the RA 27/3 vaccine within 3 months of their estimated date of conception have subsequently been enrolled in the VIP registry. Throughout 1979-1987, an average of 30 susceptible women were enrolled annually; for 1988, 21 women were enrolled. From 1979 through December 31, 1988, final reports have been received for 272 enrollees from physicians and health departments in 49 reporting areas (including 46 of the 50 U.S. states, the District of Columbia, Puerto Rico, and Canada); the largest numbers of enrollees have been reported from California (34 enrollees (13% of the total)) and Georgia (33 (12% of the total)).

Outcomes of pregnancy are known for 254 (93%) of the 272 susceptible women enrolled between 1979 and 1988 (Table 1). Of these 254 women, 210 (83%) delivered 212 living infants, and 13 (5%) had spontaneous abortions; 31 (12%) pregnancies were terminated. The interval between date of vaccination and estimated date of conception is known for all 210 susceptible women who had full-term pregnancies (Figure 1). The median interval for these women was -14 days (i.e., they received vaccine 14 days before conception). Of the 212 live-born infants, the average gestational age at birth was 39.5plus or minus 2.0 weeks and the average birth weight was 3384plus or minus 521 grams. For the 13 women whose pregnancies ended in spontaneous abortions, the median interval between vaccination and conception was -13 days, and five (38%) were vaccinated during the period of highest risk. Findings were comparable when the subset of 92 women who were vaccinated within 1 week before to 4 weeks after conception (the period of presumed highest risk for viremia and fetal malformations (5,6)) was analyzed. Pregnancy outcomes were known for 88 (96%) of these women: 73 (83%) delivered 74 living infants, and five (6%) had spontaneous abortions; 10 (11%) pregnancies were terminated. Of the 74 live-born infants, the average gestational age at birth was 39.5plus or minus 2.1 weeks, and the average birth weight was 3257plus or minus 535 grams.

None of the 212 live-born infants had defects indicative of CRS. Although two infants had asymptomatic glandular hypospadias (which has been anecdotally suggested to be part of the CRS constellation of symptoms (4)), including one whose mother had been vaccinated within 1 week before her estimated date of conception, both had negative rubella-specific IgM titers** (less than 1:4) in cord blood at birth. A 6-month follow-up serum specimen, available for one of the infants, showed a rubella HI antibody titer of less than 1:8 (i.e., a negative titer).

Overall, serologic evaluations were performed on 154 (73%) of the 212 live-born infants, including 43 (58%) of the 74 infants who were exposed during the period of highest risk. Three (2%) of the 154 infants, including one (1%) infant born to a mother vaccinated during the period of highest risk, were normal on physical examination but had a positive rubella-specific IgM titer in cord blood, suggesting a subclinical infection. The first (infant A), born in 1981, had a rubella-specific IgM antibody titer of 1:8 in cord blood and an initial corresponding HI titer of 1:128. The maternal HI titer was also 1:128. Simultaneous retesting of the cord blood and testing of a follow-up specimen taken when the infant was 2 months old showed a decrease in HI antibody titer from 1:64 to 1:16 over the 2-month period, suggesting that the cord blood HI titer was passively transferred maternal antibody and that subclinical infection may not have occurred. Infant A had no defects indicative of CRS at 18-month and 29-month follow-up examinations. Since 1985, two additional apparently healthy infants had positive rubella IgM titers in cord serum. Infant B had an IgM EIA index of 1.9, and infant C (whose mother had been vaccinated within 4 weeks after her estimated date of conception) had an index of 2.9. Both mothers had positive IgM indices at delivery; mother B had an index of 4.2 on a serum specimen drawn 11 months after vaccination, and mother C had an index of 2.5 on a serum specimen drawn 9 months after vaccination. No clinical or serologic follow-up was available for either of these infants. Reported by: Viral Exanthems and Herpesvirus Br, Div of Viral Diseases, Center for Infectious Diseases; Surveillance, Investigations, and Research Br, Div of Immunization, Center for Prevention Svcs, CDC.

Editorial Note

Editorial Note: Data collected by CDC in the VIP registry since 1979 show no evidence that the RA 27/3 rubella vaccine administered in pregnancy can cause defects indicative of CRS. These data include information for 379 women whose immune status were not known, 32 immune women, and 272 women known to be susceptible at vaccination (7). Previous reviews of data collected before April 1979 on 538 women vaccinated during pregnancy with either Cendehill or HPV-77 rubella vaccines have shown no CRS-indicative outcomes (2,3,8). Therefore, the observed risk for CRS following rubella vaccination continues to be zero. These results are consistent with the experiences in the Federal Republic of Germany and the United Kingdom (9,10), where rubella vaccine has not been associated with CRS among infants born to susceptible mothers who were vaccinated around the time of conception. Based on the 95% confidence limits of the binomial distribution, the theoretical maximal risk for CRS in the group of 212 live-born infants of susceptible women who received RA 27/3 vaccine is 1.7%; the overall maximal risk for all known susceptible women vaccinated during pregnancy with any of the three types of vaccine since 1971 is 1.2% (Table 2). If the analysis is limited to the 74 infants born to mothers vaccinated with RA 27/3 within 1 week before to 4 weeks after conception, the corresponding maximal theoretical risk is 4.9%. These estimates are less than the 20% or greater risk of CRS associated with maternal infection with wild rubella virus during the first trimester (2,11) and are comparable with the 2%-3% rate of major birth defects observed in the absence of exposure to rubella vaccine (12). A sample of approximately 375 susceptible women would be required to lower the overall maximal theoretical risk below 1% for receipt of the RA 27/3 vaccine, assuming that no CRS-like anomalies are observed. At the observed average rate of annual enrollment into the VIP registry, this sample size might be attained by 1992 for all women vaccinated within 3 months of conception; however, at this same rate of enrollment, a similar number of women vaccinated in the highest-risk period would not be enrolled until 2023. In either case, the maximal risk can never be lowered to zero.

Although no CRS-like defects have been noted, rubella vaccine viruses can cross the placenta and infect the fetus. The rubella virus isolation rate from the products of conception for the RA 27/3 vaccine was 3% (1/35), and the rate of virus isolation for Cendehill and HPV-77 vaccines was 20% (17/85) (2). Thus, because of this evidence and because the theoretical risk to the fetus, however small, cannot be absolutely ruled out, the ACIP continues to state: 1) pregnancy remains a contraindication to rubella vaccination because of the theoretical, albeit small, risk of CRS; 2) 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 theoretical risks to the others; and 3) if vaccination occurs within 3 months before or after conception, the risk of CRS is so small as to be negligible; thus, inadvertent vaccination of a pregnant woman should not be a reason in itself to consider interruption of pregnancy. The patient and her physician, however, should make the final decision (13).

The results obtained from the VIP registry data also provide adequate support for the recommendations that routine laboratory screening for both pregnancy and rubella antibody is not necessary before administration of vaccine and that physicians and other health-care personnel should offer rubella vaccine whenever they encounter a potentially susceptible*** woman lacking contraindications for vaccination. Thus, the essential purposes for which the VIP registry was initiated have been accomplished. Therefore, as of April 30, 1989, CDC discontinued accepting new enrollees into the VIP registry. All women enrolled before that date will be followed to completion of their pregnancy, and the final data will be analyzed for a summary report. However, all suspected cases of CRS, whether presumed to be due to wild-virus or vaccine-virus infection, should continue to be reported through state and local health departments.

References

1.Phillips CA, Maeck JV, Rogers WA, Savel H. Intrauterine rubella infection following immunization with rubella vaccine. JAMA 1970;213:624-5. 2.Preblud SR, Stetler HC, Frank JA Jr, Greaves WL, Hinman AR, Herrmann KL. Fetal risk associated with rubella vaccine. JAMA 1981;246:1413-7. 3.CDC. Rubella vaccination during pregnancy--United States, 1971-1981. MMWR 1982;31: 477-81. 4.Bart SW, Stetler HC, Preblud SR, et al. Fetal risk associated with rubella vaccine: an update. Rev Infect Dis 1985;7(suppl 1):S95-S102. 5.O'Shea S, Parsons G, Best JM, Banatvala JE, Balfour HH Jr. How well do low levels of rubella antibody protect? (Letter). Lancet 1981;2:1284. 6.Balfour HH Jr, Groth KE, Edelman CK, Amren DP, Best JM, Banatvala JE. Rubella viraemia and antibody responses after rubella vaccination and reimmunisation. Lancet 1981;1: 1078-80. 7.CDC. Rubella vaccination during pregnancy--United States, 1971-1986. MMWR 1987;36: 457-61. 8.CDC. Rubella vaccination during pregnancy--United States, 1971-1985. MMWR 1986;35: 275-6,281-4,315. 9.Sheppard S, Smithells RW, Dickson A, Holzel H. Rubella vaccination and pregnancy: preliminary report of a national survey. Br Med J (Clin Res) 1986;292:727. 10.Enders G. Rubella antibody titers in vaccinated and nonvaccinated women and results of vaccination during pregnancy. Rev Infect Dis 1985;7(suppl 1):S103-S107. 11.Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;2:781-4. 12.CDC. Congenital malformations surveillance report: January 1981-December 1983. Atlanta: US Department of Health and Human Services, Public Health Service, 1985. 13.ACIP. Rubella prevention. MMWR 1984;33:301-10,315-8. *Women who had had negative serologic tests for rubella within 1 year before vaccination were considered susceptible at vaccination. **Since July 1985, the CDC laboratory has tested for rubella-specific IgM antibody using an indirect enzyme immunosorbent assay (EIA) with an enzyme-conjugated antihuman IgM serum. An IgM index is calculated for each serum specimen using a known low-positive IgM serum specimen as a reference standard. An IgM index greater than or equal to 1.0 is considered positive, with increasing values indicating increasing antibody levels. Before July 1985, the CDC laboratory performed sucrose density gradient centrifugation and hemagglutination-inhibition (HI) tests for rubella- specific IgM. ***Persons are considered susceptible unless they can present documentation of laboratory evidence of immunity and/or documentation of adequate immunization with rubella vaccine on or after their first birthday (13).

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