VACCINE, YELLOW FEVER

Fetal Risk Summary

Yellow fever vaccine is a live, attenuated virus vaccine (1,2). Yellow fever is a serious infectious disease with high morbidity and mortality. The risk to the fetus from the vaccine is unknown (1,2). The American College of Obstetricians and Gynecologists lists the vaccine as contraindicated in pregnancy except if exposure is unavoidable (1).

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 3 of which had 1st trimester exposure to yellow fever vaccine (3). There were no birth defects.

A 1993 report described the use of yellow fever vaccine (vaccine strain 17D) in 101 women at various stages of pregnancy during the 1986 outbreak of yellow fever in Nigeria (4). The women received the vaccine during gestation either because of an unknown pregnancy or because they feared acquiring the disease. The vaccine was administered to 4 women in the 1st trimester, 8 in the 2nd trimester, and 89 in the 3rd trimester, with the gestational ages ranging from 6 to 38 weeks. Serum samples were obtained before and after vaccination from the women as well as from 115 vaccinated, nonpregnant controls. Measurements of immunoglobulin M (IgM) antibody and neutralizing antibody in these samples revealed that the immune response of pregnant women was significantly lower than that of controls. One woman, with symptoms of acute yellow fever during the week before vaccination, suffered a spontaneous abortion 8 weeks after vaccination. Although the cause of the abortion was unknown, the investigators concluded that it was not caused by the vaccine. No evidence was found for transplacental passage of the attenuated virus. Nine of the mothers produced IgM antibody after vaccination, but the antibody was not detected in their newborns. Neutralizing antibody either crossed the placenta or was transferred via colostrum in 14 of 16 newborns delivered from mothers with this antibody. No adverse effects on physical or mental development were observed in the offspring during a 3- to 4- year follow-up period (4).

The first reported case of congenital infection following vaccination was described in a study in which attenuated yellow fever vaccine, in response to a threat of epidemic yellow fever, was administered to 400,000 people in Trinidad (5). Pregnant women, all of whom received the vaccine during the 1st trimester during pregnancies unrecognized at the time of vaccination, were identified retrospectively. Serum samples were collected from 47 women and 41 term infants, including 35 mother-child pairs. Women who delivered prematurely and those suffering spontaneous abortions were not sampled. One of the 41 infants had IgM and elevated neutralizing antibodies to yellow fever, indicating congenital infection. Natural exposure to the virus was thought to be unlikely because virus transmission during that period was limited to forest monkeys with no human cases reported. The infected, 2920-g infant, the product of a normal, full-term pregnancy, appeared healthy on examination and without observable effect on morphogenesis. However, because the neurotropism of yellow fever virus for the developing nervous system has been well documented (e.g., vaccine-induced encephalitis occurs almost exclusively in infants and young children), the authors considered this case as further evidence that the vaccine should be avoided during pregnancy (5).

A 1999 report from the European Network of Teratology Information Services described the prospectively ascertained outcomes in 58 of 74 pregnancies exposed to yellow fever vaccine (6). Timing of exposure was before the last menstrual period (LMP), in the 1st trimester, or in the 2nd trimester in 3, 69, and 2, respectively. Sixteen of the cases did not have complete follow-up data and were excluded from the analysis. The pregnancy outcomes included 7 spontaneous abortions, 5 induced abortions, and 46 live births. In the newborns, there were two major malformations: ureteral stenosis and triphalangeal hallux. There were also three cases of minor anomalies: bilateral pes varus, slight deviation of the nasal wall, and mild ventricular septal defect. Vaccination in all of these five cases occurred early in gestation. The rates of abortion and congenital malformations are within expected ranges. The investigators also found 4 cases exposed in utero to yellow fever vaccine among 23,925 cases of birth defects reported between 1980 and 1995 to the France/Central-East registry of malformations. The defects in these cases were (timing of exposure in parentheses) right ectromelia of upper limb (1st trimester), a VATER association (2nd trimester), stenosis of the aortic orificium (1st trimester), and hydrocephalus in an infant stillborn near term (2nd trimester). Two other cases of spontaneous abortion (respectively at 6 and 13 weeks after the LMP) were reported by a French manufacturer to the investigators. The authors concluded that although their sample was far too small to rule out a moderate increased risk of adverse outcome, their data do not support such an association and could be used to reassure pregnant women who have inadvertently received the vaccine (6).

A 1994 review concluded that pregnant women should be vaccinated, preferably after the 1st trimester, if exposure to a yellow fever epidemic is unavoidable (7).

Breast Feeding Summary

No data are available.

References

1. American College of Obstetricians and Gynecologists. Immunization during pregnancy. Technical Bulletin. No. 160, October 1991.
2. Amstey MS. Vaccination in pregnancy. Clin Obstet Gynaecol 1983;10:13–22.
3. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:315.
4. Nasidi A, Monath TP, Vandenberg J, Tomori O, Calisher CH, Hurtgen X, Munube GRR, Sorungbe AOO, Okafor GC, Wali S. Yellow fever vaccination and pregnancy: a four-year prospective study. Trans R Soc Trop Med Hyg 1993;87:337–9.
5. Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993;168:1520–3.
6. Robert E, Vial T, Schaefer C, Arnon J, Reuvers M. Exposure to yellow fever vaccine in early pregnancy. Vaccine 1999;17:283–5.
7. Linder N, Ohel G. In utero vaccination. Clin Perinatol 1994;21:663–74.