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Current Trends Rubella Vaccination during Pregnancy -- United States, 1971-1982
From January 1971 to December 1982, 959 pregnant women who received rubella vaccine either within 3 months before or 3 months after their presumed dates of conception were reported to CDC. These women were followed prospectively to determine the risk of fetal abnormalities following exposure to the vaccine.
Cendehill and HPV-77 Vaccines: Before April 1979, data were collected on 538 women vaccinated during pregnancy with either Cendehill or HPV-77 rubella vaccines (1). The outcomes of conception (live birth, stillbirth, and spontaneous or induced abortion) were known for 143 (96%) of the 149 women known to be susceptible at the time of vaccination. Ninety-four (66%) of these 143 women carried their pregnancies to term. All gave birth to infants free of defects compatible with congenital rubella syndrome (CRS)* (2), although eight infants had serologic evidence of intrauterine infection (1,3). Follow-up from 2 to 7 years of these eight infants indicates no problems compatible with CRS. An additional 196 infants born to women who either were immune (22) or of unknown immune status (174) at the time of vaccination were also free of such defects. Three other women (one susceptible, one immune, and one of unknown immune status) received unknown strains of rubella vaccine. All three delivered normal-appearing, healthy infants.
RA 27/3 Vaccine: Since licensure of the RA 27/3 rubella vaccine in 1979, 418 women who received it during pregnancy have been reported to CDC (Table 1). Outcomes of pregnancy are known for 390 (93%) women. Of the 111 women known to be susceptible at the time of vaccination, 81 (73%) carried their pregnancies to term. The dates of vaccination and estimated dates of confinement were known for all of the 81 susceptible women who had full-term pregnancies (Figure 1). Twenty-eight women (35%) were vaccinated within 1 week before to 4 weeks after conception and 57 (70%) within 6 weeks before or 6 weeks after conception. Two hundred sixty-two other women elected to carry their pregnancies to term. Three had twin births (two to susceptible women and one to a woman of unknown immune status). While none of the 346 newborns whose mothers had been vaccinated had defects compatible with CRS, 11 were born with one or more congenital defects. The mothers of two of these infants were known to be susceptible at the time of vaccination; two were known to be immune; and seven were of unknown immune status.
The two infants born to susceptible women had asymptomatic glandular hypospadias. Both had negative rubella-specific immunoglobulin (IgM) titers (less than 1:4) in cord blood at birth. A 6-month follow-up serum was available for one of the infants who had a rubella hemagglutination inhibition (HI) antibody titer of less than 1:8.
One of the two infants born to the immune women had multiple congenital anomalies; the other had a hydrocele that resolved spontaneously. Both had no detectable rubella-specific IgM antibodies at birth. Efforts to obtain follow-up sera have been unsuccessful.
Two of the seven infants born to the women whose immune status was unknown at the time of vaccination had heart murmurs that resolved spontaneously. A third infant had a spontaneously resolving hydrocele and hemangioma. Of the four remaining infants, one had asymptomatic glandular hypospadias; one had an omphalocele; one had hydrocephalus secondary to aqueductal stenosis and is being worked up for trisomy 21 mosaicism; and one had a small ventricular septal defect and an ectopic anus. Serologic data are currently available on four of these seven infants; none have any evidence of rubella infection.
Serologic evaluation (rubella HI titers and specific IgM on cord or neonatal blood specimens) was performed on 69 (83%) of the 83 infants whose mothers were susceptible. One normal-appearing infant had a rubella-specific IgM antibody titer of 1:8 in cord blood and a corresponding HI titer of 1:128. At 2 months of age, the HI titer had decreased to 1:16. The infant had no evidence of defects compatible with CRS at birth or at the 18-month follow-up examination. Blood studies were also obtained on 150 of the 241 infants born to mothers whose immune status was unknown at the time of vaccination. One such infant had a rubella-specific IgM antibody titer of 1:16 in cord blood. Both mother and infant had HI titers of 1:32 at the time of birth; the infant's HI titer was 1:32 at 4 months of age. This infant had no evidence of defects compatible with CRS at birth or at the 10-month follow-up examination. A serum specimen was not obtained at the 10-month visit.
To date, 11 women have had spontaneous abortions or stillbirths. Thirty-six others elected to have induced abortions (Table 1). Rubella virus has now been isolated from the products of conception in one (4%) of 28 cases involving susceptible women (15 cases reported to CDC and 13 from the literature) (4-6). Reported by Birth Defects Br, Chronic Diseases Div, Center for Environmental Health; Surveillance and Investigations Section, Surveillance, Investigations, and Research Br, Div of Immunization, Center for Prevention Svcs, CDC.
Editorial Note: Since 1971, CDC has maintained a register to monitor and quantitate the risks to the fetus following exposure to attenuated rubella vaccine virus. Data are obtained through reports from physicians and from state and local health departments, as well as directly from women vaccinated either within 3 months before or 3 months after conception. The patients are followed prospectively to determine the outcome of pregnancy. In 1979, when RA 27/3 rubella vaccine replaced the other rubella vaccines, concern was raised that it might have greater potential for teratogenicity than earlier vaccines. As with the other vaccines, data collected so far show no evidence that the RA 27/3 rubella vaccine can cause defects compatible with CRS. While hypospadias has been noted in CRS cases (7,8), there are no data to suggest that glandular hypospadias should be considered a CRS-associated defect.
Twenty-eight (35%) of the 81 susceptible mothers were vaccinated with the RA 27/3 vaccine during the highest risk period for viremia and fetal defects (1 week before to 4 weeks after conception) (9,10). Neither those infants nor any others were born with CRS; therefore, the observed risk of CRS following rubella vaccination continues to be zero. The theoretical maximum risk for the occurrence of CRS in this group of 83 children, however, based on the 95% confidence limits of the binomial distribution, may be as high as 5%. (If the 95 infants exposed to the other rubella vaccines are included, the maximum theoretical risk is 2%.) This overall maximum risk remains far less than the 20% or greater risk of CRS associated with maternal infection with wild rubella virus during the first trimester of pregnancy (3).
The occurrence of any congenital defect following maternal vaccination deserves careful analysis and follow-up. If only susceptibles are considered, the overall birth-defect rate is approximately 2% (2/83), which is less than the reported 4%-5% rate of birth defects in the absence of exposure to rubella vaccine recently noted by CDC (11,12). Neither of the two infants with congenital deformities born to women known to be susceptible at the time of vaccination had any evidence of rubella infection. The absence of rubella-specific IgM antibodies at birth was confirmed by the absence of HI antibodies after 6 months of age in the one infant tested.
While no CRS-like defects have been noted, it is clear that rubella vaccine viruses, including the RA 27/3 strain, can cross the placenta and infect the fetus. Approximately 2% of infants born to susceptible vaccinees had serologic evidence of subclinical infection, regardless of vaccine strain (3). On the other hand, while the rubella virus isolation rate from the products of conception for the RA 27/3 vaccine is only 4% (1/28), the rate for Cendehill and HPV-77 vaccines is 20% (17/85) (3). These data indicate that the risk of placental or fetal infection from RA 27/3 vaccine is minimal.
Following an earlier review of these data, the Immunization Practices Advisory Committee (ACIP) stated in 1981 that (13): (1) pregnancy remains a contraindication to rubella vaccination because of the theoretical, albeit small, risks of CRS; (2) reasonable precautions 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 does occur within 3 months of conception, the risk of CRS is so small as to be negligible; thus, rubella vaccination of a pregnant woman should not in itself indicate interruption of pregnancy. The patient and her physician, however, should make the final decision. Data collected through 1982 continue to support these recommendations.
Since the inception of its vaccine-in-pregnancy register, CDC has encouraged reporting of all such cases. Because of the increasing number of cases reported to CDC, the experience with known susceptibles is becoming well defined. Therefore, CDC now encourages reporting only cases involving women known to have been susceptible at
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