1
CASE REPORTS
Confirmed Rabies Exposure During Pregnancy: Treatment with Human Rabies Immune Globulin and Human Diploid Cell Vaccine* STEVEN CHABALA, D.O., MARILYN WILLIAMS, M.D., Dearborn, Michigan, RICHARD AMENTA, Pharm.D., MountClemens, Michigan, ANTHONY F. OGNJAN, D.O., Dearborn
and Mount
Clemens,
Michigan
A review of the literature shows 24 cases of pregnant human exposure to rabies virus through confirmed rabid animal bites. Historically, these patients received passive immunization with equine rabies immunoglobulin and/or purified vero cell vaccine or duck embryo vaccine. With the recent development of human-derived rabies vaccines, we report an additional case of human gestational rabies exposure, which was treated with human rabies immune globulin and human diploid cell vaccine.
uman rabies has never been common in the United States, with fewer than one case per year occurring during the 1980s. Nonetheless, approximately 20,000 people receive prophylaxis annually [l]. Under experimental conditions, transplacental rabies transmission occurs in several animal species, although transmission to the human fetus is not recorded [2]. However, few case reports of confirmed rabid animal bites among pregnant humans are documented. With the recent development of human-derived rabies vaccines, human rabies immune globulin (RIG) and human diploid cell vaccine (HDCV), the experience is even more limited. In 1982, Varner et al [3] reported the administration of both RIG and HDCV to a pregnant woman during the third trimester without adverse results. Unfortunately, the animal, a bat, although suspected rabid, was not caught, and confirmation of rabies exposure could not be completed. Nonetheless, the vaccines were shown to be safe and immunogenic during pregnancy. Expanding on this information, we report an additional case of human gestational rabies exposure to a confirmed rabid animal bite that was treated with RIG and HDCV.
H
*This is a rapid publication manuscript. From the Henry Ford Hospital-Fairlane (SC, MW. AFO), Dearborn, Michigan, and Mount Clemens General Hospital (RA. AFO), Mount Clemens, Michigan. Requestsfor reprintsshould beaddressed toAnthony F. Ognjan, D.O., Mount Clemens General Hospital, 1000 Harrington Boulevard, Mount Clemens, Michigan 48043. Manuscript submitted July 10, 1991, and accepted in revised form July 31,199l.
CASE REPORT A 27-year-old white woman presented to the Emergency Department on July 21, 1990, complaining of having been bitten by a bat. She described having discovered a bat in a tree and coaxed it into a cage with a stick. She had been feeding the bat when she was bitten on the tip of her left index finger. She arrived in the Emergency Department 2 hours later accompanied by a small, dark brown bat hanging upside down in a bird cage. The patient’s medical history was remarkable for her pregnancy that was approximately 14 weeks’ gestation by dates. The first day of her last menstrual period was June 14, 1990. Her pregnancy to date had progressed uneventfully. Her tetanus status was up to date. She denied medication allergies. Physical examination revealed a well-appearing gravid woman in no acute distress. Her vital signs were as follows: blood pressure 92/50 mm Hg, temperature 37”C, pulse rate lOO/minute, respiration rate 20/minute. She weighed 65 kg. Examination of the patient’s wound showed three tiny puncture wounds at the tip of her left index finger with one small area of ecchymosis at the base of one puncture wound. The entire wound measured no more than 4 or 5 mm across. The area was immediately scrubbed and irrigated with povidone-iodine solution. The patient consented to the initiation of rabies prophylaxis after discussion of the importance of treatment and potential risk to her pregnancy. An intramuscular injection of 1 mL of HDCV (Imovax) was followed by RIG (Hyperab) 4.5 mL into each deltoid for a total dose of 9 mL or 1,360 IU. The dose of RIG is 20 IU/kg with up to one half the total dose to be infiltrated directly into the wound. Because of the difficulty of local infiltration into a fingertip, the total dose was equally divided and injected into each deltoid. The patient completed the subsequent course of HDCV injections on Days 3, 7, 14, and 28 with no adverse reactions. Three days after initiation of prophylaxis, the Lansing Department of Public Health notified us that the bat tested positive for rabies virus by immunofluorescent antibody testing of the animal’s brain tissues. The patient went on to spontaneously deliver an 8-pound g-ounce male in-
October 1991 The American Journal of Medicine
Volume 91
423
RABIES EXPOSURE
DURING
PREGNANCY
/ CHABALA
ET AL
TABLE I Human Gestational Confirmed Rabies Exposure [41 Number of exposures Number treated Tri,mester of exposure
[51
\I,
Chabala
2
I*
Fatal (maternal) Follow-up (months)
Reference 161
11
3
b
00
8
l90
h
8
1
i 12
00 11
-
quine rabies immunoglobulin (ERIG) with duck embryo vaccine (DEW. RIG with DEV. urified verb cell vaccine IPVRV)alone: nonetotal; ERIGwith PVRV: 12 total. luman dtploid cell vaccine (HDCV) with rabtes immunoglobulin(RIG).
IgG ResponseAfter Vaccination in Current Patient*
~,, *HDCV wtth RIG. ‘0.5 IUimL is acceptableresponse
fant at 40 weeks’ gestation. The infant was cyanotic at birth and diagnosed with transposition of the great vessels. The infant is thriving and has an excellent prognosis after a successful surgical repair, and the mother is well after 11 months of follow-up.
COMMENTS A literature review contains three studies totaling 24 cases of pregnant human rabies exposure through confirmed rabid animal bites [4-6]. All but one mother received appropriate postexposure prophylaxis, representing the single case fatality of clinical rabies (Table I). Significant exposure occurred in 11 individuals during the first trimester, 11 during the second trimester, and three during the third trimester. Historically, these patients received equine rabies globulin (ERIG) for passive immunization. Active immunization was accomplished by either the purified tissue culture vaccine, purified vero cell rabies vaccine, or the duck embryo-derived vaccine (DEV). Among the infants, two were premature, one spontaneous abortion occurred, and the infant of the untreated mother (whose exposure occurred several days prior to parturition) survived. The infants showed no physical or mental abnormalities, and growth and development were comparable with that in nonexposed infants. Rabies vaccine was originally developed by Pasteur and first used in humans in 1885 [1,7]. The most recent advance in vaccine development includes the propagation of the virus in human cell culture. The results include improved vaccine safety, purity, and immunogenicity. This has allowed a 424
October
1991
The American
Journal
of Medicine
Volume
reduction in the number of vaccine doses required while achieving a greater antibody response [7]. Presently, HDCV for active vaccination and RIG for passive immunization are available in the U.S. The older animal-derived vaccines, DEV and ERIG, are of historical interest, and not generally used [l]. After exposure, the usual dose of RIG is 20 IV/kg (approximately one half of the dose infiltrating the wound), administered simultaneously with HDCV. A total series of five HDCV vaccines is administered, including 3,7,14, and 28 days after the first dose. The World Health Organization specifies an antirabies IgG titer of 0.5 IU/mL as an acceptable immune response [7,8]. This case report demonstrates the successful use of HDCV and RIG in confirmed gestational rabies exposure. The vaccination combination (HDCV and RIG) appears safe and efficacious when given during pregnancy, as demonstrated by the IgG antibody response at 8 and 24 weeks (parturition) for the mother and at parturition for the infant (Table II). With respect to rabies incubation, clinical effectiveness is suggested because both mother and infant are doing well during follow-up. The association of great vessel transposition is interesting. It is noted that embryologically, the heart is completely formed by 10 weeks’ gestation. This patient received her first dose of HDCV and RIG approximately 4 weeks after cardiac development. Consequently, this clinical association remains interesting but of unclear significance. In conclusion, RIG and HDCV appear safe and immunogenic when given during pregnancy. The combination appears to offer protective immunity to the mother and infant. Because of the high likelihood of fatal disease following a rabid animal bite, this case report supports the recommendation that pregnancy is not a contraindication to post-rabies exposure prophylaxis [2,3,9,10].
REFERENCES 1. Fishbein DB. Rabres. Infect DIS Clin North Am 1991: 5: 53-71. 2. Arvin AM, Yeager AS. Other viral infections of the fetus and newborn: rabies. In: Remington JS, Klein JO, editors. Infectiousdiseases of thefetusand newborn infant. Philadelphia: WB Saunders, 1990: 516-27. 3. Varner MW, McGuinness GA, Galask RP. Rabies vaccination in pregnancy. Am J Obstet Gynecol 1982: 143: 717-8. 4. Cates W Jr. Treatment of rabies exposure during pregnancy. Obstet Gynecol 1974; 44: 893-5. 5. Spence MR, Davrdson DE, Dill GS. Boonthai P. Sagartz JW. Rabies exposure during pregnancy. Am J Obstet Gynecol 1975; 123: 655. 6. Chutivonase S. Wilde. Postexposure rabies vaccination during pregnancy: experience with 21 patients. Vaccine 1989; 7: 546-8. 7. Wiktor T. Plotkrn SA, Koprowski H. Rabies vaccine. In: Plotkin SA, Mortimer EA, editors. Vaccines. Philadelphia: WB Saunders, 1988: 474-9. 6. McEvoy GK. editor. American Hospital Formulary Service, Drug Information ‘90. Bethesda, Maryland: American Society of Hospital Pharmacists, 1990: 1958-61. 9. Rabies preventron-United States, 1991. MMWR 1991; 40: 1-19. 10. Guide for adult immunization. 2nd ed. Philadelphia: American College of Physicians, 1990: 99-105.
91
CASE REPORTS
Confirmed Rabies Exposure During Pregnancy: Treatment with Human Rabies Immune Globulin and Human Diploid Cell Vaccine* STEVEN CHABALA, D.O., MARILYN WILLIAMS, M.D., Dearborn, Michigan, RICHARD AMENTA, Pharm.D., MountClemens, Michigan, ANTHONY F. OGNJAN, D.O., Dearborn
and Mount
Clemens,
Michigan
A review of the literature shows 24 cases of pregnant human exposure to rabies virus through confirmed rabid animal bites. Historically, these patients received passive immunization with equine rabies immunoglobulin and/or purified vero cell vaccine or duck embryo vaccine. With the recent development of human-derived rabies vaccines, we report an additional case of human gestational rabies exposure, which was treated with human rabies immune globulin and human diploid cell vaccine.
uman rabies has never been common in the United States, with fewer than one case per year occurring during the 1980s. Nonetheless, approximately 20,000 people receive prophylaxis annually [l]. Under experimental conditions, transplacental rabies transmission occurs in several animal species, although transmission to the human fetus is not recorded [2]. However, few case reports of confirmed rabid animal bites among pregnant humans are documented. With the recent development of human-derived rabies vaccines, human rabies immune globulin (RIG) and human diploid cell vaccine (HDCV), the experience is even more limited. In 1982, Varner et al [3] reported the administration of both RIG and HDCV to a pregnant woman during the third trimester without adverse results. Unfortunately, the animal, a bat, although suspected rabid, was not caught, and confirmation of rabies exposure could not be completed. Nonetheless, the vaccines were shown to be safe and immunogenic during pregnancy. Expanding on this information, we report an additional case of human gestational rabies exposure to a confirmed rabid animal bite that was treated with RIG and HDCV.
H
*This is a rapid publication manuscript. From the Henry Ford Hospital-Fairlane (SC, MW. AFO), Dearborn, Michigan, and Mount Clemens General Hospital (RA. AFO), Mount Clemens, Michigan. Requestsfor reprintsshould beaddressed toAnthony F. Ognjan, D.O., Mount Clemens General Hospital, 1000 Harrington Boulevard, Mount Clemens, Michigan 48043. Manuscript submitted July 10, 1991, and accepted in revised form July 31,199l.
CASE REPORT A 27-year-old white woman presented to the Emergency Department on July 21, 1990, complaining of having been bitten by a bat. She described having discovered a bat in a tree and coaxed it into a cage with a stick. She had been feeding the bat when she was bitten on the tip of her left index finger. She arrived in the Emergency Department 2 hours later accompanied by a small, dark brown bat hanging upside down in a bird cage. The patient’s medical history was remarkable for her pregnancy that was approximately 14 weeks’ gestation by dates. The first day of her last menstrual period was June 14, 1990. Her pregnancy to date had progressed uneventfully. Her tetanus status was up to date. She denied medication allergies. Physical examination revealed a well-appearing gravid woman in no acute distress. Her vital signs were as follows: blood pressure 92/50 mm Hg, temperature 37”C, pulse rate lOO/minute, respiration rate 20/minute. She weighed 65 kg. Examination of the patient’s wound showed three tiny puncture wounds at the tip of her left index finger with one small area of ecchymosis at the base of one puncture wound. The entire wound measured no more than 4 or 5 mm across. The area was immediately scrubbed and irrigated with povidone-iodine solution. The patient consented to the initiation of rabies prophylaxis after discussion of the importance of treatment and potential risk to her pregnancy. An intramuscular injection of 1 mL of HDCV (Imovax) was followed by RIG (Hyperab) 4.5 mL into each deltoid for a total dose of 9 mL or 1,360 IU. The dose of RIG is 20 IU/kg with up to one half the total dose to be infiltrated directly into the wound. Because of the difficulty of local infiltration into a fingertip, the total dose was equally divided and injected into each deltoid. The patient completed the subsequent course of HDCV injections on Days 3, 7, 14, and 28 with no adverse reactions. Three days after initiation of prophylaxis, the Lansing Department of Public Health notified us that the bat tested positive for rabies virus by immunofluorescent antibody testing of the animal’s brain tissues. The patient went on to spontaneously deliver an 8-pound g-ounce male in-
October 1991 The American Journal of Medicine
Volume 91
423
RABIES EXPOSURE
DURING
PREGNANCY
/ CHABALA
ET AL
TABLE I Human Gestational Confirmed Rabies Exposure [41 Number of exposures Number treated Tri,mester of exposure
[51
\I,
Chabala
2
I*
Fatal (maternal) Follow-up (months)
Reference 161
11
3
b
00
8
l90
h
8
1
i 12
00 11
-
quine rabies immunoglobulin (ERIG) with duck embryo vaccine (DEW. RIG with DEV. urified verb cell vaccine IPVRV)alone: nonetotal; ERIGwith PVRV: 12 total. luman dtploid cell vaccine (HDCV) with rabtes immunoglobulin(RIG).
IgG ResponseAfter Vaccination in Current Patient*
~,, *HDCV wtth RIG. ‘0.5 IUimL is acceptableresponse
fant at 40 weeks’ gestation. The infant was cyanotic at birth and diagnosed with transposition of the great vessels. The infant is thriving and has an excellent prognosis after a successful surgical repair, and the mother is well after 11 months of follow-up.
COMMENTS A literature review contains three studies totaling 24 cases of pregnant human rabies exposure through confirmed rabid animal bites [4-6]. All but one mother received appropriate postexposure prophylaxis, representing the single case fatality of clinical rabies (Table I). Significant exposure occurred in 11 individuals during the first trimester, 11 during the second trimester, and three during the third trimester. Historically, these patients received equine rabies globulin (ERIG) for passive immunization. Active immunization was accomplished by either the purified tissue culture vaccine, purified vero cell rabies vaccine, or the duck embryo-derived vaccine (DEV). Among the infants, two were premature, one spontaneous abortion occurred, and the infant of the untreated mother (whose exposure occurred several days prior to parturition) survived. The infants showed no physical or mental abnormalities, and growth and development were comparable with that in nonexposed infants. Rabies vaccine was originally developed by Pasteur and first used in humans in 1885 [1,7]. The most recent advance in vaccine development includes the propagation of the virus in human cell culture. The results include improved vaccine safety, purity, and immunogenicity. This has allowed a 424
October
1991
The American
Journal
of Medicine
Volume
reduction in the number of vaccine doses required while achieving a greater antibody response [7]. Presently, HDCV for active vaccination and RIG for passive immunization are available in the U.S. The older animal-derived vaccines, DEV and ERIG, are of historical interest, and not generally used [l]. After exposure, the usual dose of RIG is 20 IV/kg (approximately one half of the dose infiltrating the wound), administered simultaneously with HDCV. A total series of five HDCV vaccines is administered, including 3,7,14, and 28 days after the first dose. The World Health Organization specifies an antirabies IgG titer of 0.5 IU/mL as an acceptable immune response [7,8]. This case report demonstrates the successful use of HDCV and RIG in confirmed gestational rabies exposure. The vaccination combination (HDCV and RIG) appears safe and efficacious when given during pregnancy, as demonstrated by the IgG antibody response at 8 and 24 weeks (parturition) for the mother and at parturition for the infant (Table II). With respect to rabies incubation, clinical effectiveness is suggested because both mother and infant are doing well during follow-up. The association of great vessel transposition is interesting. It is noted that embryologically, the heart is completely formed by 10 weeks’ gestation. This patient received her first dose of HDCV and RIG approximately 4 weeks after cardiac development. Consequently, this clinical association remains interesting but of unclear significance. In conclusion, RIG and HDCV appear safe and immunogenic when given during pregnancy. The combination appears to offer protective immunity to the mother and infant. Because of the high likelihood of fatal disease following a rabid animal bite, this case report supports the recommendation that pregnancy is not a contraindication to post-rabies exposure prophylaxis [2,3,9,10].
REFERENCES 1. Fishbein DB. Rabres. Infect DIS Clin North Am 1991: 5: 53-71. 2. Arvin AM, Yeager AS. Other viral infections of the fetus and newborn: rabies. In: Remington JS, Klein JO, editors. Infectiousdiseases of thefetusand newborn infant. Philadelphia: WB Saunders, 1990: 516-27. 3. Varner MW, McGuinness GA, Galask RP. Rabies vaccination in pregnancy. Am J Obstet Gynecol 1982: 143: 717-8. 4. Cates W Jr. Treatment of rabies exposure during pregnancy. Obstet Gynecol 1974; 44: 893-5. 5. Spence MR, Davrdson DE, Dill GS. Boonthai P. Sagartz JW. Rabies exposure during pregnancy. Am J Obstet Gynecol 1975; 123: 655. 6. Chutivonase S. Wilde. Postexposure rabies vaccination during pregnancy: experience with 21 patients. Vaccine 1989; 7: 546-8. 7. Wiktor T. Plotkrn SA, Koprowski H. Rabies vaccine. In: Plotkin SA, Mortimer EA, editors. Vaccines. Philadelphia: WB Saunders, 1988: 474-9. 6. McEvoy GK. editor. American Hospital Formulary Service, Drug Information ‘90. Bethesda, Maryland: American Society of Hospital Pharmacists, 1990: 1958-61. 9. Rabies preventron-United States, 1991. MMWR 1991; 40: 1-19. 10. Guide for adult immunization. 2nd ed. Philadelphia: American College of Physicians, 1990: 99-105.
91
