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Current Trends Rubella Vaccination during Pregnancy -- United States, 1971-1983

From January 1971 to December 1983, 1,096 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, or 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 infants 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). These eight children were all followed for at least 2 years, at which time all were growing and developing normally. The longest follow-up is for a child who is now 8H years old who had both an elevated rubella-specific immunoglobulin M (IgM) titer at birth and persistence of hemagglutination inhibition (HI) antibodies. Although he is still HI-antibody positive (he has not been vaccinated), he continues to grow and develop normally.

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 CRS-associated 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, 555 women who received this vaccine during pregnancy have been reported to CDC (Table 1). One hundred fifty-seven of these 555 women were known to be susceptible at the time of vaccination. Outcomes of pregnancy are known for 147 (94%) of these women. Of the 147 women, 119 (81%) delivered 121 living infants. An additional 28 immune women and 309 women of unknown immune status delivered 338 living infants. All of these 459 infants were free of defects compatible with CRS.

The dates of vaccination and estimated dates of confinement were known for all of the 119 susceptible women who had full-term pregnancies (Figure 1). Forty-four women (37%) were vaccinated within 1 week before to 4 weeks after conception, the period of presumed highest risk.

Serologic evaluations (rubella HI titers and specific IgM on cord or neonatal blood specimens) were performed on 104 (86%) of the 121 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. The maternal titer was also 1:128. Retesting of cord blood and testing of a 2-month follow-up specimen run simultaneously showed an expected decrease in maternally derived HI antibody over the 2-month period from a titer of 1:64 to 1:16, suggesting that subclinical infection may not have occurred. The infant had no evidence of defects compatible with CRS at birth or at the 18-month and 29-month follow-up examinations. Further follow-up sera could not be obtained to document persistence or disappearance of HI antibodies.

Blood studies were also obtained on 150 of the 241 infants born to mothers whose immune statuses were unknown at the time of vaccination. Subclinical infection was documented in two infants. One 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 had a persistent HI titer of 1:32 at 4 months of age. This infant had no evidence of defects compatible with CRS at birth or at the 10-month and 17-month examinations. A serum specimen was not obtained at the follow-up visits. The second infant had a persistent HI titer of 1:8 at 3 months of age, suggesting that there had been subclinical infection. This infant was diagnosed as normal at the 3-month follow-up visit.

While none of the 121 infants born to susceptible women had defects compatible with CRS, two infants did have asymptomatic glandular hypospadias. However, both had negative rubella-specific IgM titers (less than 1:4) in cord blood at birth. A 6-month follow-up serum was available for one of the infants; he had a rubella HI antibody titer of less than 1:8.

Twenty-five susceptible women elected to have induced abortions (Table 1). Thus, rubella virus has now been isolated from the products of conception in one (3%) of 32 cases involving susceptible women (19 cases reported to CDC and 13 from the literature) (4-6). Reported by Surveillance and Investigations Section, Surveillance, Investigations, and Research Br, Div of Immunization, Center for Prevention Svcs, CDC.

Editorial Note

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 fetotropic and teratogenic potential 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.

Forty-four (37%) of the 119 susceptible mothers were vaccinated with RA 27/3 vaccine during the highest risk period for viremia and fetal defects (1 week before to 4 weeks after conception) (7,8). 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 121 children, however, based on the 95% confidence limits of the binomial distribution, may be as high as 3.0%. (If the 95 infants exposed to other rubella vaccines are included, the maximum theoretical risk is 1.7%.) 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) and is no greater than the 4%-5% rate of birth defects in the absence of exposure to rubella vaccine (9,10).

These favorable data are consistent with the German experience cited at the International Symposium on the Prevention of Congenital Rubella Infection recently held at the Pan American Health Organization.* A total of 91 susceptible women vaccinated with either the Cendehill or RA 27/3 strain of vaccine gave birth to normal-appearing infants. Limited data presented at the symposium from the United Kingdom also support the CDC observations.

The occurrence of any congenital defect following maternal vaccination deserves careful analysis and follow-up. Two infants born to susceptible mothers had asymptomatic glandular hypospadias. While hypospadias has been noted in CRS cases (11,12), there are no data to suggest that glandular hypospadias should be considered a CRS-associated defect. In any case, neither of the two infants in question had serologic evidence of rubella virus infection. Ten other infants born to mothers of unknown immune status (eight) or known to be immune (two) at the time of vaccination had some type of defect (13). However, none of the defects were compatible with CRS and serologic testing, when done, did not confirm rubella virus infection.

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 1%-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 3% (1/32), the rate of virus isolation 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.

In view of the data collected through 1983, the Immunization Practices Advisory Committee (ACIP) continues to state that: (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 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 ordinarily be a reason to consider interruption of pregnancy. The patient and her physician, however, should make the final decision (14).

Since the inception of its vaccine-in-pregnancy register, CDC has encouraged reporting of all such cases. Because of the increasing

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