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Rubella vaccination during pregnancy
FETUS, PLACENTA, AND NEWBORN
Rubella vaccination during pregnancy RONALD
J. BOLOGNESE,
STEPHEN JOHN
L. L.
DAVID
A.
KENNETH JACOB Philadelphia,
CORSON,
SEVER,
M.D.
M.D.
FUCCILLO, M.
M.D.
PH.D.
LAKOFF,
KLEIN, Pennsylvania,
M.D.
M.D. and Bethesda,
Maryland
Cendehill strain attenuated rubella virus was administered to 34 patients scheduled for termination of pregnancy by suction dilatation and evacuation or hysterotomy/hysterectomy. Eight patients were seronegative initially, and 7 of these converted by the time of or following an abortion as determined by hemagglutination-inhibition titers. Two pregnancies (in seropositive patients) were allowed to go to term. In no case was virus isolated from placental or fetal tissue. The implications of these findings are discussed.
Of live, attenuated rubella. vaccines, it is inevitable that any appreciable use will result in inoculation during unrecognized early pregnancy. The management of such cases presents a dilemw
IT
H
THE
ma, since the fetal teratogenic risk associated with maternal infection by the attenuated virus is undefined. Phillips and associates1 recently reported their experience with such a case. The seronegative patient had a long history of irregular menses and was certain that she was not pregnant at the time of vaccination. Following an abortion at approximately 8 weeks of gestation, rubella virus was recovered from the decidua. Larson and Meyer2 reported virus isolation in the decidua and/or the placenta in 2 of 9 gravidas inadvertently vaccinated prior to therapeutic abortion. Vaheri and colleagues3 isolated virus in 2 specimens of placental tissue and in 1 fetus. However, in the instance of fetal infection, National Institutes of Health laboratories could not isolate the virus. Thus, little information is available to
ADVENT
From the Department of Obstetrics and Gynecology, Pennsylvania Hospital, School of Medicine, University of Pennsylvania, and the Section on Infectious Dtseases and the Tissue Culture Unit, Perinatal Research Branch, National Institute of Neurological Diseases and Stroke. Appreciation is expressed for the support oflered by Dr. Jerry Gold from Smith, Kline B French Labs., Philadelphia, Pennsylvania. Received 1971.
for publication
December
22,
f;;;pted
for publication
December
29,
Reprint requests: Dr. R. J. Bolognese, 400 Franklin Medical Building, 829 Spruce St., Philadelphia, Pennsylvania 19107.
903
904
Bolognese
evaluate properly both the risk and extent of vaccine-induced fetal infection in both seronegative and seropositive women inadvertently inoculated in pregnancy. With this thought in mind, we embarked upon a study of abortus material from women who were purposely vaccinated with the Cendehill strain of attenuated rubella virus prior to voluntary interruption of pregnancy. Materials
Apil 1. lY7? Am. .J. Obstrt. Gynccol.
et al.
and
methods
To date, 34 women ranging in age from 16 to 36 have received 0.5 ml. of live, attenuated rubella virus vaccine, Cendehill strain, grown in rabbit kidney cell cultures. The hemagglutination inhibition U-W microtiter determinations were obtained via blind testing at the laboratories of Smith, Kline & French on coded samples of serum obtained prior to inoculation and following termination of pregnancy. Immediate vaccination was accomplished in an attempt to obtain a minimal time of 3 weeks prior to the abortion to allow for seronegative conversions. Initial titers of < 8 indicated susceptibility. Conversion was considered to have been accomplished when a titer of 1: 8 had been reached. A fourfold increase in the presence of an existing prevaccination titer was interpreted as a booster reaction. Suction dilatation and evacuation was performed in 18 patients ranging from 8 to 12 weeks of gestation. In pregnancies from 16 to 18 weeks, hysterotomy and concomitant tubal ligation were accomplished in 13 instances. Hysterectomy was performed in one patient following conization diagnosis of carcinoma in situ of the cervix. Two pregnancies ended in term deliveries following a reversal of the patients’ desires for therapeutic abortion. Although both were seropositive, they were informed of the unknown risk to the fetus but refused termination. On completion of the procedure, the abortus material was immediately transferred to sterile containers. In hysterotomy cases, an attempt was made to deliver the amniotic sac unruptured. The specimens, packed in ice, were then transported to the Laboratories of Infectious Diseases, Perinatal Re-
search Branch, National Institute of Ncurological Diseases and Stroke. The virus isolation procedure consisted of making 10 per cent suspensions of specimens with the use of Hanks’ balanced salt solution and 1 per cent SPAM (Mycostatin,” Achromycin,S erythromycin, and streptomycin) as diluent. Four roller tubes of African green monkey kidney tissue were inoculated with each specimen and incubated for 8 to 10 days at 37O C. The maintenance medium was changed, and 2 of the 4 tubes were challenged with Coxsackie A-9 virus. The challenged tubes were read on the fourth day. Blind passage was performed on scraped cells and supernatant in the unchallenged tubes and placed into 4 more roller tubes. After 14 days, the challenge with Coxsackie virus was repeated. Three blind passages were done in addition to the original inoculation. Results Eight of thirty-four patients were identified as seronegative as defined by an HI antibody titer of < 8. Seropositive conversion occurred in 7 with postvaccination titers ranging from 8 to 128, 21 to 36 days later. One gravida failed to demonstrate a conversion since she was aborted only 14 days post inoculation. In addition, 2 patients demonstrated borderline prevaccination titers of 8 which subsequently increased to 16 and 128, respectively. It has been observed that patients with initially low titers may respond to revaccination with a rise in antibody level. No virus was isolated from the products of conception in any of these patients (Table 1). Twenty-two additional seropositive patients were identified with initial HI titers ranging from 32 to 512. The titer response to vaccination over a 15 to 27 day span varied with postabortal values unchanged in 14, lower in 5, and increased in two (32 to 64 and 32 to 128). One prevaccination titer was not recorded in a patient with a positive ‘E.
R. Squibb
tLederle
Labs.,
& Sons, Pearl
New River,
York,
New
New
York.
York.
Rubella
Table I.
Borderline 9 10 D & E =
Preoperative titer
Patient
No pre-existing 1 ‘> :1 4 .i 6 7 8
S. L. D. P. B. H. M. A.
during
pregnancy
905
immunization
Rubella
Case NO.
vaccinarion
antibody F. w. R. B. N. H. V. A.
and
Table II. Rubella
Procedure
Findings Negatiw Negative Negative Negative Negative Negative Negativr .Negati\.,r
16 16 32 32 128
D&E Hysterotomy Hysterotomy D&E D&E D&E D&E Hysterotomy
8
16
13
8
128
‘1
Hysterectomy (carcinoma situ of cervix) Hvsterotomy
8
2: :i <8
G. N.
Interval (days) 36 14 26 32 21 2 ‘15 L’ 1
<8
titer (I :8) G. w.
dilatation
Postoperative titer
in
Negative Negative
evacuation.
immunization,
pre-existing
antibody .- -___
Interval vaccination Procedure Hysterotomy Suction dilation Term delivery
and evacuation
No. 9 13 2
past history for rubella and the highest postoperative titer recorded. Again, no virus was isolated in specimens from any patient (Table II) . Two pregnancies of seropositive gravidas vaccinated at 8 and 14 weeks of gestation, respectively, ended in term deliveries of normal infants without any signs of congenital malformation or rubella infection. Virus isolation of placental tissue was negative. Thus, at this point in our study, no virus has been isolated from any placental or fetal tissue in 8 seronegative and 24 seropositive terminated pregnancies. Two normal term infants have been delivered from vaccinated seropositive patients. Comment Congenital rubella results from maternal viremia, placental infection, and spread of the virus to the fetus. Other investigators have demonstrated decidua and placental infection following inoculation with a live, attenuated rubella virus of the HPV-77 strain.l, 4 We have been unable to duplicate
between and abortion f days)
15 2.5 ‘O-27 240-258
Virus Placenta 0 0 0
isolations
---Fetal
0 (I Not done
these findings with the use of the Cendehill strain in either seronegative or seropositive gravidas. Our plan is to continue evaluating only specimens obtained from seronegative women. Many more data need to be collected before a reasonable assessment of the fetal risk from maternal vaccine-induced infection can be made. Unfortunately, the numbers of pregnant women in the general urban population with HI titers of < 1:8 range from 1O.35 to 13 per cent.* Hence, it will require some time before significant data can be accumulated. When abortions are accomplished 1 or more months after maternal infection with wild rubella virus, fetal involvement is common.’ The attenuated virus could pose less threat to the fetus since the symptoms of infection and viremia in the vaccinated subject are minimal.” Experiments with the attenuated virus in monkeys suggested a reduced risk to the fetus.B Thus, the failure to isolate virus in any abortus specimen in this study would correlate with these findings. The validity of our findings and the
906
Bolognese
et al.
uniqueness of Cendehill strain behavior, compared with other strains of attenuated rubella virus, rests on our inability to identify successfully Cendehill virus in the specimens. This laboratory has been able to culture a variety of both wild and attenuated strains after 2 years of frozen storage and up to 1 week after thawing. Specimens from this study were frozen for 1 to 14 days and prepared immediately after receipt. The fact that 7 of 8 seronegative patients converted by the time of abortion indicates maternal viremia with resultant antibody formation. Therefore, our preliminary conclusion from the above data is that Cendehill virus may bring about maternal antibody response in the absence of fetoplacental infection and differs in this last respect from other attenuated viral strains. In addition to the danger of inoculation of women during unrecognized early pregnancy, should obstetricians be concerned with the risk of exposure of susceptible gravidas to rubella vacinees and of reinfection of previously vaccinated gravidas exposed to wild rubella virus? Although virus shedding from 7 to 28 days post inoculation has been observed, infection of seronegative contacts has not occurred in most studies. Scott and Byrne6 studied 31 expectant mothers who had repeated exposures to vaccinated children. Only one showed seroconversion; however, the single case occurred under circumstances excluding vaccine virus transmission. Meyer and ParkmanlO in a review of rubella vaccination experience stated, “The vaccine strains should be regarded its theoretically communicable, but if transmission occurs, it is, indeed, a rare event.” What is the risk of reinfection (defined as a fourfold or greater change in titer) after vaccination, and how does this jeopardize the fetus if the patient is pregnant? In
1.
2.
REFERENCES Phillips, C. A., Maeck, J. V. S., Rogers, W. H.: J. A. M. A. 213: 624, A., and Savel, 1970. Larson, H. E., and Meyer, H. A., Jr.: N. Engl. J. Med. 284: 870, 1971.
April 1, 1972 Am. .I. Obstet. Gyncro?.
a classic paper, Horstmann and co-workers” reported an 80 per cent reinfection rate based on HI and complement-fixing antibody response in vaccinated military recruits exposed to wild rubella virus. This represents experience in a closed population whereas a much lower rate would be expected in an open community. Davis and associateGz maintain from their studies that “ . . . vaccinees with antibodies even if reinfected, are not likely to develop disease, become viremic, or participate in spread of virus in communities.” Dudgeon13 studying both naturally acquired and vaccine-induced immunity concluded that “. . . on present evidence there is no indication that fetal damage is caused by maternal reinfection.” Mass vaccination of children is underway to eliminate a major source of the wild rubella virus transmission to the pregnant patient. Adolescent vaccination generally has been avoided because of the possibility of pregnancy. Since vaccine-induced immunity could prove less durable than naturally acquired immunity, the vaccination of children could theoretically lead in time to an increase in the reservoir of rubella-susceptible women. The lower antibody response initiated by attenuated rubella virus compared to the natural infection lends support to this concept. Repeated vaccination could help overcome this problem. Thus, our preliminary data indicate that the Cendehill strain attenuated virus has not infected placental or fetal tissue when administered during pregnancy. If this finding can be substantiated in a larger group of women, the use of Cendehill vaccine in women of the reproductive age might be advised to reduce the potential risk of fetal infection associated with inadvertent vaccination in early pregnancy or an unplanned gestation shortly after vaccination.
3. 4. 5.
Vaheri, A., Vesikari, T., Oker-Blom, N., et al.: Am. J. Dis. Child. 118: 243, 1969. Karson, D. T.: Personal communication. Guenter, K. E., and Estela, L. A.: Obstet. Gynecol. 37: 343, 1971.
Volume 112 Number 7
6.
Scott,
Rubella
D.
H.,
and
Byrne,
E. B.:
J. A. M.
A.
11.
215: 609, 1971. 7.
Rawls,
1968. 8. 9.
10.
W.
E.:
Progr.
Med.
Virol.
10: 238,
Meyer, H. M., Jr., Parkman, P. D., and Hopps, H. E.: Pediatrics 44: 5, 1969. Parkman, P. D., Phillips, P. E., and Meyer, H. M., Jr.: Am. J. Dis. Child. 110: 390, 1965. Meyer, H. M., Jr., and Parkman, P. D.: J. A. M. A. 215, 613, 1971.
12.
13.
vaccination
during
pregnancy
907
Horstmann, D. M., Liebhaber, H., Le Bouvier, G. L., Rosenberg, D. A., and Halstead, S. B.: N. Engl. J. Med. 283: 771, 1970. Davis, W. J., Larson, H. E., Simsarian, J. P., Parkman, P. D., and Meyer, H. M.. Jr.: J. A. M. A. 215: 600, 1971. Dudgeon, J. A.: Am. J. Dis. Child. 118: 35, 1969.
Rubella vaccination during pregnancy RONALD
J. BOLOGNESE,
STEPHEN JOHN
L. L.
DAVID
A.
KENNETH JACOB Philadelphia,
CORSON,
SEVER,
M.D.
M.D.
FUCCILLO, M.
M.D.
PH.D.
LAKOFF,
KLEIN, Pennsylvania,
M.D.
M.D. and Bethesda,
Maryland
Cendehill strain attenuated rubella virus was administered to 34 patients scheduled for termination of pregnancy by suction dilatation and evacuation or hysterotomy/hysterectomy. Eight patients were seronegative initially, and 7 of these converted by the time of or following an abortion as determined by hemagglutination-inhibition titers. Two pregnancies (in seropositive patients) were allowed to go to term. In no case was virus isolated from placental or fetal tissue. The implications of these findings are discussed.
Of live, attenuated rubella. vaccines, it is inevitable that any appreciable use will result in inoculation during unrecognized early pregnancy. The management of such cases presents a dilemw
IT
H
THE
ma, since the fetal teratogenic risk associated with maternal infection by the attenuated virus is undefined. Phillips and associates1 recently reported their experience with such a case. The seronegative patient had a long history of irregular menses and was certain that she was not pregnant at the time of vaccination. Following an abortion at approximately 8 weeks of gestation, rubella virus was recovered from the decidua. Larson and Meyer2 reported virus isolation in the decidua and/or the placenta in 2 of 9 gravidas inadvertently vaccinated prior to therapeutic abortion. Vaheri and colleagues3 isolated virus in 2 specimens of placental tissue and in 1 fetus. However, in the instance of fetal infection, National Institutes of Health laboratories could not isolate the virus. Thus, little information is available to
ADVENT
From the Department of Obstetrics and Gynecology, Pennsylvania Hospital, School of Medicine, University of Pennsylvania, and the Section on Infectious Dtseases and the Tissue Culture Unit, Perinatal Research Branch, National Institute of Neurological Diseases and Stroke. Appreciation is expressed for the support oflered by Dr. Jerry Gold from Smith, Kline B French Labs., Philadelphia, Pennsylvania. Received 1971.
for publication
December
22,
f;;;pted
for publication
December
29,
Reprint requests: Dr. R. J. Bolognese, 400 Franklin Medical Building, 829 Spruce St., Philadelphia, Pennsylvania 19107.
903
904
Bolognese
evaluate properly both the risk and extent of vaccine-induced fetal infection in both seronegative and seropositive women inadvertently inoculated in pregnancy. With this thought in mind, we embarked upon a study of abortus material from women who were purposely vaccinated with the Cendehill strain of attenuated rubella virus prior to voluntary interruption of pregnancy. Materials
Apil 1. lY7? Am. .J. Obstrt. Gynccol.
et al.
and
methods
To date, 34 women ranging in age from 16 to 36 have received 0.5 ml. of live, attenuated rubella virus vaccine, Cendehill strain, grown in rabbit kidney cell cultures. The hemagglutination inhibition U-W microtiter determinations were obtained via blind testing at the laboratories of Smith, Kline & French on coded samples of serum obtained prior to inoculation and following termination of pregnancy. Immediate vaccination was accomplished in an attempt to obtain a minimal time of 3 weeks prior to the abortion to allow for seronegative conversions. Initial titers of < 8 indicated susceptibility. Conversion was considered to have been accomplished when a titer of 1: 8 had been reached. A fourfold increase in the presence of an existing prevaccination titer was interpreted as a booster reaction. Suction dilatation and evacuation was performed in 18 patients ranging from 8 to 12 weeks of gestation. In pregnancies from 16 to 18 weeks, hysterotomy and concomitant tubal ligation were accomplished in 13 instances. Hysterectomy was performed in one patient following conization diagnosis of carcinoma in situ of the cervix. Two pregnancies ended in term deliveries following a reversal of the patients’ desires for therapeutic abortion. Although both were seropositive, they were informed of the unknown risk to the fetus but refused termination. On completion of the procedure, the abortus material was immediately transferred to sterile containers. In hysterotomy cases, an attempt was made to deliver the amniotic sac unruptured. The specimens, packed in ice, were then transported to the Laboratories of Infectious Diseases, Perinatal Re-
search Branch, National Institute of Ncurological Diseases and Stroke. The virus isolation procedure consisted of making 10 per cent suspensions of specimens with the use of Hanks’ balanced salt solution and 1 per cent SPAM (Mycostatin,” Achromycin,S erythromycin, and streptomycin) as diluent. Four roller tubes of African green monkey kidney tissue were inoculated with each specimen and incubated for 8 to 10 days at 37O C. The maintenance medium was changed, and 2 of the 4 tubes were challenged with Coxsackie A-9 virus. The challenged tubes were read on the fourth day. Blind passage was performed on scraped cells and supernatant in the unchallenged tubes and placed into 4 more roller tubes. After 14 days, the challenge with Coxsackie virus was repeated. Three blind passages were done in addition to the original inoculation. Results Eight of thirty-four patients were identified as seronegative as defined by an HI antibody titer of < 8. Seropositive conversion occurred in 7 with postvaccination titers ranging from 8 to 128, 21 to 36 days later. One gravida failed to demonstrate a conversion since she was aborted only 14 days post inoculation. In addition, 2 patients demonstrated borderline prevaccination titers of 8 which subsequently increased to 16 and 128, respectively. It has been observed that patients with initially low titers may respond to revaccination with a rise in antibody level. No virus was isolated from the products of conception in any of these patients (Table 1). Twenty-two additional seropositive patients were identified with initial HI titers ranging from 32 to 512. The titer response to vaccination over a 15 to 27 day span varied with postabortal values unchanged in 14, lower in 5, and increased in two (32 to 64 and 32 to 128). One prevaccination titer was not recorded in a patient with a positive ‘E.
R. Squibb
tLederle
Labs.,
& Sons, Pearl
New River,
York,
New
New
York.
York.
Rubella
Table I.
Borderline 9 10 D & E =
Preoperative titer
Patient
No pre-existing 1 ‘> :1 4 .i 6 7 8
S. L. D. P. B. H. M. A.
during
pregnancy
905
immunization
Rubella
Case NO.
vaccinarion
antibody F. w. R. B. N. H. V. A.
and
Table II. Rubella
Procedure
Findings Negatiw Negative Negative Negative Negative Negative Negativr .Negati\.,r
16 16 32 32 128
D&E Hysterotomy Hysterotomy D&E D&E D&E D&E Hysterotomy
8
16
13
8
128
‘1
Hysterectomy (carcinoma situ of cervix) Hvsterotomy
8
2: :i <8
G. N.
Interval (days) 36 14 26 32 21 2 ‘15 L’ 1
<8
titer (I :8) G. w.
dilatation
Postoperative titer
in
Negative Negative
evacuation.
immunization,
pre-existing
antibody .- -___
Interval vaccination Procedure Hysterotomy Suction dilation Term delivery
and evacuation
No. 9 13 2
past history for rubella and the highest postoperative titer recorded. Again, no virus was isolated in specimens from any patient (Table II) . Two pregnancies of seropositive gravidas vaccinated at 8 and 14 weeks of gestation, respectively, ended in term deliveries of normal infants without any signs of congenital malformation or rubella infection. Virus isolation of placental tissue was negative. Thus, at this point in our study, no virus has been isolated from any placental or fetal tissue in 8 seronegative and 24 seropositive terminated pregnancies. Two normal term infants have been delivered from vaccinated seropositive patients. Comment Congenital rubella results from maternal viremia, placental infection, and spread of the virus to the fetus. Other investigators have demonstrated decidua and placental infection following inoculation with a live, attenuated rubella virus of the HPV-77 strain.l, 4 We have been unable to duplicate
between and abortion f days)
15 2.5 ‘O-27 240-258
Virus Placenta 0 0 0
isolations
---Fetal
0 (I Not done
these findings with the use of the Cendehill strain in either seronegative or seropositive gravidas. Our plan is to continue evaluating only specimens obtained from seronegative women. Many more data need to be collected before a reasonable assessment of the fetal risk from maternal vaccine-induced infection can be made. Unfortunately, the numbers of pregnant women in the general urban population with HI titers of < 1:8 range from 1O.35 to 13 per cent.* Hence, it will require some time before significant data can be accumulated. When abortions are accomplished 1 or more months after maternal infection with wild rubella virus, fetal involvement is common.’ The attenuated virus could pose less threat to the fetus since the symptoms of infection and viremia in the vaccinated subject are minimal.” Experiments with the attenuated virus in monkeys suggested a reduced risk to the fetus.B Thus, the failure to isolate virus in any abortus specimen in this study would correlate with these findings. The validity of our findings and the
906
Bolognese
et al.
uniqueness of Cendehill strain behavior, compared with other strains of attenuated rubella virus, rests on our inability to identify successfully Cendehill virus in the specimens. This laboratory has been able to culture a variety of both wild and attenuated strains after 2 years of frozen storage and up to 1 week after thawing. Specimens from this study were frozen for 1 to 14 days and prepared immediately after receipt. The fact that 7 of 8 seronegative patients converted by the time of abortion indicates maternal viremia with resultant antibody formation. Therefore, our preliminary conclusion from the above data is that Cendehill virus may bring about maternal antibody response in the absence of fetoplacental infection and differs in this last respect from other attenuated viral strains. In addition to the danger of inoculation of women during unrecognized early pregnancy, should obstetricians be concerned with the risk of exposure of susceptible gravidas to rubella vacinees and of reinfection of previously vaccinated gravidas exposed to wild rubella virus? Although virus shedding from 7 to 28 days post inoculation has been observed, infection of seronegative contacts has not occurred in most studies. Scott and Byrne6 studied 31 expectant mothers who had repeated exposures to vaccinated children. Only one showed seroconversion; however, the single case occurred under circumstances excluding vaccine virus transmission. Meyer and ParkmanlO in a review of rubella vaccination experience stated, “The vaccine strains should be regarded its theoretically communicable, but if transmission occurs, it is, indeed, a rare event.” What is the risk of reinfection (defined as a fourfold or greater change in titer) after vaccination, and how does this jeopardize the fetus if the patient is pregnant? In
1.
2.
REFERENCES Phillips, C. A., Maeck, J. V. S., Rogers, W. H.: J. A. M. A. 213: 624, A., and Savel, 1970. Larson, H. E., and Meyer, H. A., Jr.: N. Engl. J. Med. 284: 870, 1971.
April 1, 1972 Am. .I. Obstet. Gyncro?.
a classic paper, Horstmann and co-workers” reported an 80 per cent reinfection rate based on HI and complement-fixing antibody response in vaccinated military recruits exposed to wild rubella virus. This represents experience in a closed population whereas a much lower rate would be expected in an open community. Davis and associateGz maintain from their studies that “ . . . vaccinees with antibodies even if reinfected, are not likely to develop disease, become viremic, or participate in spread of virus in communities.” Dudgeon13 studying both naturally acquired and vaccine-induced immunity concluded that “. . . on present evidence there is no indication that fetal damage is caused by maternal reinfection.” Mass vaccination of children is underway to eliminate a major source of the wild rubella virus transmission to the pregnant patient. Adolescent vaccination generally has been avoided because of the possibility of pregnancy. Since vaccine-induced immunity could prove less durable than naturally acquired immunity, the vaccination of children could theoretically lead in time to an increase in the reservoir of rubella-susceptible women. The lower antibody response initiated by attenuated rubella virus compared to the natural infection lends support to this concept. Repeated vaccination could help overcome this problem. Thus, our preliminary data indicate that the Cendehill strain attenuated virus has not infected placental or fetal tissue when administered during pregnancy. If this finding can be substantiated in a larger group of women, the use of Cendehill vaccine in women of the reproductive age might be advised to reduce the potential risk of fetal infection associated with inadvertent vaccination in early pregnancy or an unplanned gestation shortly after vaccination.
3. 4. 5.
Vaheri, A., Vesikari, T., Oker-Blom, N., et al.: Am. J. Dis. Child. 118: 243, 1969. Karson, D. T.: Personal communication. Guenter, K. E., and Estela, L. A.: Obstet. Gynecol. 37: 343, 1971.
Volume 112 Number 7
6.
Scott,
Rubella
D.
H.,
and
Byrne,
E. B.:
J. A. M.
A.
11.
215: 609, 1971. 7.
Rawls,
1968. 8. 9.
10.
W.
E.:
Progr.
Med.
Virol.
10: 238,
Meyer, H. M., Jr., Parkman, P. D., and Hopps, H. E.: Pediatrics 44: 5, 1969. Parkman, P. D., Phillips, P. E., and Meyer, H. M., Jr.: Am. J. Dis. Child. 110: 390, 1965. Meyer, H. M., Jr., and Parkman, P. D.: J. A. M. A. 215, 613, 1971.
12.
13.
vaccination
during
pregnancy
907
Horstmann, D. M., Liebhaber, H., Le Bouvier, G. L., Rosenberg, D. A., and Halstead, S. B.: N. Engl. J. Med. 283: 771, 1970. Davis, W. J., Larson, H. E., Simsarian, J. P., Parkman, P. D., and Meyer, H. M.. Jr.: J. A. M. A. 215: 600, 1971. Dudgeon, J. A.: Am. J. Dis. Child. 118: 35, 1969.