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Transplacental transmission of western equine encephalomyelitis
T R A N S P L A C E N T A L T R A N S M I S S I O N OF W E S T E R N EQUINE ENCEPHALOMYELITIS H E N R Y R . SHINEFIELD,
M.D., ~
AND TttOlY[AS E . TOWNSEND,
M.D. ~
BERKELEY, CALIF.
S E A R L Y as 1892 Ehrlich ~ demon-
ola or developed the disease before the eighth d a y of e x t r a u t e r i n e life. Schiek, 12 in a complete r e v i e w of the literature, has g a t h e r e d some f o r t y cases of infants who manifested lesions of smallpox at birth or too early in life to attribute the illness to contact with the disease. I n most of these eases, mothers had been rendered immune to the disease b y either vaccination or actual illness some time prior to their p r e g n a n c y but during the gestation lived in an area in which smallpox was clinically evident. Although the mothers, themselves, did not suffer a second clinical attack of smallpox, they apparently t r a n s m i t t e d the illness to their offspring in utero.
strated t h a t the semipermeable A m e m b r a n e of the h u m a n placenta t r a n s m i t t e d antibodies f r o m immune mothers to their infants. Since that time it has been well established that bacterial antitoxins such as tetanus, pertussis, and diphtheria pass from mother to i n f a n t via the placentad, 3, Similarly, antibodies to virus diseases such as poliomyelitis and influenza have been shown to traverse the placenta readilyP, 6 The in utero transmission of i m m u n i t y to the St. Louis encephalitis virus has been experimentally demonstrated by Smith 7 in mice. Morgan s showed similar evidence working with E a s t e r n equine encephalitis virus. Transp]acental transmission of exanthematous infections seems to be thoroughly established. Shuman, 9 in a review of the literature, cites six cases of congenital varicella and adds one of his own. E i g h t cases of in utero transmission of measles have been reported b y Kohn, 1~ and Marsden and Greenfield 11 report six cases of mothers who developed smallpox late in p r e g n a n c y and who subsequently gave birth to infants who were either born with vari-
Recently a case of congenital vaccinia has been reported in a 6-monthold p r e m a t u r e infant whose mother suffered a severe p r i m a r y reaction to a vaccination during her third month of pregnancy, la The infant was born with extensive skin lesions and died shortly a f t e r birth. I n t r a c y t o p l a s m i c bodies were demonstrated at a~ltopsy. Experimentally, the virus of lymphocytic choriomeningitis has been int r o d u c e d into p r e g n a n t mice b y Traub, ~* with subsequent demonstration of the virus either in the embryo in ntero or in the offspring. Similar experiments with l y m p h o g r a n u l o m a venereum virus have been done b y Hillendall. ~ Since (a) the particle size
F r o m the Division of Preventive lVfedical Services, California State Health D e p a r t m e n t and Communicable Disease Center, Public Health Service, Atlanta, Ga. *Senior Assistant Surgeon (R) USPHS. Epidemic Intelligence Officer assigned to the State of California from the Communicable Disease Center in Atlanta, Ga~ **Resident Pediatrician, K e r n General Hospital. 21
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for Western equine encephalomyelitis (W.E.E.) is smaller than either of the two above viruses mentioned, (b) it is generally accepted that a viremia exists prior to central nervous system invasion with W.E.E. 16, 17 and (c) the rodent and the human being have a hemochorionic type of placenta, IS it seems logical that this virus should be capable of causing disease in utero in both mice and human beings. The only report of possible transplacental transmission of arthropodborne encephalitis in the literature is presented b y Mendovy in 194329 Two cases are reported in infants who were seen at the age of 6 and 7 months, respectively, because of gross neurological d i s t u r b a n c e . The diagnosis in one instance was based on a positive neutralization test for W.E.E. on the sera of the infant and mother. The second infant and mother had blood taken for complement fixation with a report from the Rockefeller Institute showing "the baby's blood to be positive for Western equine encephalitis in a 1:16 dilution and the mother's positive in a 1:4 dilution." Both infants had a febrile illness within five days of birth but the chronology of illness in the mother is not detailed. The following are case reports on twins observed in K e r n County in the epidemic of W . E . E : in California in 1952. 20 CASE R E P O R T S
R. C. and T. C., fraternal twin girls, were born at the K e r n General Hospital on Aug. 2, 1952. The infants were delivered by low forceps after a full-term pregnancy and there were no neonatal complications. At birth, T. C. weighed 6 pounds 5 ounces and R. C. 5 pounds 10 ounces. They were in a n u r s e r y with ten other infants and taken out for bottle feedings at four-
OF P E D I A T R I C S
hour intervals. At the age of 4 days, on August 6, the infants were discharged with no apparent abnormality. The mother who was admitted in labor on August 2 was described as preeclamptic with a blood pressure of 180/ 90. A f t e r delivery, she stfffered postp a r t u m shock with blood pressure falling to 90/50 and was given 2,000 c.c. of blood. She recovered rapidly, ran an afebrile hospital course, and was discharged with the infants on August 6. Twenty-four hours after discharge from the hospital, R. C. refused food, ran a temperature of 104 ~ F., and had twitching movements of the extremities. Twelve hours later, the twin, T. C., became ill with a similar clinical picture. They were both readmitted to the hospital the following day, August 9. On physical examination, R. C. was described as a jaundiced, mildly dehydrated, lethargic infant who was acutely ill. Neck was 4+ rigid and the fontanel bulging; temperature was 102 ~ F. L a b o r a t o r y data revealed a hemoglobin of 14.3; white blood count 18,100 with a shift to the left. Lumbar puncture showed xanthochromie spinal fluid with 695 cells of which 58 per cent were polymorphonuclears. Sugar was 61 rag. per cent, protein was 240 rag. per cent, and culture was negative. T. C. was described as an acutely ill, dehydrated infant with a " v e r y tense" fontaneh Neck rigidity was 4+ and there was "definite rigidity of extremities." Laboratory data revealed hemoglobin of 16.2; white blood count 22,400 with a shift to left. Immbar puncture showed xanthoehromic fluid with 511 cells of which 76 per cent were polymorphonuelears. Sugar was 68 rag. per cent, protein 238 rag. per cent, with a negative culture. Admission diagnosis on both patients was probable meningitis, and intensive chemotherapy with penicillin and streptomycin was initiated. The hospital course for both infants was stormy. Temperature ran from 101 ~ to 104 ~ F. for three days. They suffered r e p e a t e d convulsive episodes.
SttINEFIELD AND TOWNSEND:
WESTERN EQUINE ENCEPHALOMYELITIS
Oxygen was required for six days, during which time they were extremely lethargic and refused formula. Clinical improvement w a s noted on the seventh day and they were discharged after thirteen days of hospitalization apparently well but noted to take formula slowly. Blood specimens during tile acute and convalescent phase of the illness were t a k e n for examination for W.E.E. because the infants were admitted to K e r n General Hospital at a time when m a n y eases of W.E.E. were being seen and blood for antibody examination was drawn routinely on all patients with a febrile central nervous system disease. Blood drawn on August 11, during the acute phase of illness, showed no significant complement fixing (C.F.) antibodies to be present. This was reported by the Viral and Rickettsial Disease Laboratory, California State D e p a r t m e n t of Public Health, as a titer of less than 1:8. Blood drawn on August 21 showed T. C. to have a titer of 1:16 and R. C. to have a titer of 1:128. (A fourfold rise in titer is considered evidence of a recent infection. In this case, a rise from < 1:8 to 1:16 would have been significant.) Thus, with this positive evidence for infection with W.E.E. in infants who were only 5 days old and who were out of the hospital less than thirty-six hours prior to the first day of illness, it was felt that f u r t h e r interrogation of the mother was in order. The following were the significant chronological facts elicited: (1) On J u l y 21, 1952, the C.'s house was shaken by a rather severe e~rthquake. Because of this, Mrs. C., who was close to the expected date of delivery, decided to live with her parents in a rural area near Bakersfield. (2) On J u l y 22, Mrs. C. and her husband slept on the unscreened porch of the parents. They were severely bitten by mosquitoes and decided they would rather r e t u r n home than spend another night exposed to the mosquitoes. The young mother-t0-be had evi-
23
deuce of mosquito bites on her arms and legs. (3) On J u l y 3], Mrs. C. suffered "feverishness," severe headache, and marked lethargy. She did not seek medical advice. (4) On August 1, she was taken to Kern County Hospital because of labor pains. It was felt by the examiner that she was not in true labor and was sent home. Although the symptoms of the previous day persisted, she did not relate them to the examining physiMan because "I was afraid they would keep me in the hospital." The symptoms were less severe than the preceding day. (5) On August 2, she was admitted to K e r n County Hospital in active labor. Because no history of illness was obtained at time of labor, no lumbar puncture or acute blood specimen was obtained from the mother. However, on j August 22, or twenty-three days after the onset of the disease, the complement fixing antibodies in the mother's sera were present in a titer of 1:128. DISCUSSION
It has been established that the usual transmission of W.E.E. is via mosquito bite and the incubation period is from four to twenty-one daysY 1 Since the twins were home less than thirtysix hours prior to the onset of their illness, the disease could only have been contracted either in utero or in the n u r s e r y during the first few days of life. It is doubtful that mosquitoes penetrated the nursery but to make this possibility even more remote, the other ten infants in the nursery at the time the twins were there were visited. At the time of the visit, the infants were 5 to 6 weeks old and no history of illness could be elicited. Nine out of ten were bled and C.F. antibody titers in all eases were < 1:8. A group of twenty nurses and doctors and other employees who were on the nursery
24
THE JOURNAL OF PEDIATRICS
floor at the onset of illness were also bled and C.F. titers here too were 1:8. The house of the parents of the y o u n g couple was visited and a n e x t door neighbor and f o r t y chickens free in the y a r d less t h a n 100 y a r d s from the back porch where the couple slept. Twelve of the chickens were bled and 25 per cent of them had a significant titer (an LDso of more t h a n 100) of neutralizing antibodies for W.E.E. I n K e r n County over the past three years, neutralizing antibodies were present in about 25 per cent of chicken flocks r a n d o m l y sampled. 22 I t has been shown that mosquitoes may transmit W.E.E. experimentally from chicken to chicken, 2a and it is believed that m a n y birds m a y play an import a n t role a s a reservoir host for the W.E.E. virus. The importance of the role of the chicken in the n a t u r a l transmission of the disease is not clear and indeed it is felt t h a t others of the avian species are p r o b a b l y more imp o r t a n t factors. 24 However, t h e y should not be overlooked in the present situation which may be summarized as follows: A p r e g n a n t female was severely bitten b y mosquitoes eleven days before term while living in an area where an epidemic of encephalitis in human beings was observed and where infection in chickens (either past or present) has been established. Two days before delivery, the patient had a clinical illness that resembled encephalitis and, subsequently, complement fixing antibodies for W.E.E. were present in the serum. Twin infants were born and on the fifth day of life had
clinical and serological evidence of encephalitis. The low initial titers and the subsequent high titers rule out
transplacental transmission of antibody and establish a definite etiological diagnosis. The evidence strongly points to transplacental transmission of the virus. Unfortunately, no att e m p t was made to isolate the viral agent in the acute blood sample. The infants, seen on Sept. 18, 1952, at 6 weeks of age, were in good health. C.F. titer on T. C. had risen to 1:256 and on R. C. to 1:512. THe mother's titer was 1:64. In conclusion it must be mentioned that just as in the viral exanthematous infections, W.E.E. in the last stages os p r e g n a n c y does not consistently produce disease in the offspring. Local factors such as placental defects which m a y be necessary for in utero transmission of disease are discussed by Goodpasture. 2~ In view of the known pathological changes in the placenta associated with pre-eclampsia, 26 the maternal pre-eclamptic state in the present cases m a y have been an imp o r t a n t f a c t o r in the in utero infection. D u r i n g the present epidemic two other cases of clinical W.E.E. with serological confirmation were observed in p r e g n a n t women, the onsets of illness being within one to three days of delivery. The pregnancies were uncomplicated. The infants in both cases were a p p a r e n t l y unaffected and did not show any serological evidence of disease either at birth or at 2 months of age. SUMMARY
1. Evidence for transp]acental transmission of antibodies and viruses is reviewed. 2. Two clinical and serologically proved cases of Western equine encephalomyelitis in twin infants 5 days old
SHINEFIELD
AND
TOWNSEND:
WESTERN
are presented. Evidence strongly suggests transplacental transmission of the virus. 3. Maternal infection with Western equine encephalomyelitis in the late stages of pregnancy does not invariably infect the infant. In utero infection may be dependent upon local placental defects. The authors would like to t h a n k Dr. E d w i n If. L e n n e t t e , Director of the Viral and R i c k e t t s i a l Disease L a b o r a t o r y , of the S t a t e of California, for p e r f o r m i n g the diagnostic serological tests. REFERENCES 1. Ehrlich, cited b y Gay, F . P . : Agents of Disease and }Iost Resistance, Springfield, Ill., 1935, Charles C Thomas, p. 450, 2. Ten Broeck, C, and Bauer, J. H.: Transmission of Tetanus A n t i t o x i n Through Placenta, Prec. See. Exper. Biol. & M e d . 20: 399, 1922. 3. Cohen, P., and Scadron, S. J.: Effects of A c t i v e Immunization of the Miother Upon the Offspring, J. PEDIA~. 29: 609, 1946. 4. K u t t n e r , A. G., a n d Ratner, B.: Importance of Colostrum to the N e w b o r n Inf a n t , Am. J. Dis. Child. 25: 413, 1923. 5. Aycock, W. L.. and Kramer, S . D . : Imm u m t y to P o h o m y e h t m 111 iV[others and Newborns as Shown by N e u t r a l i z a t i o n Tests, J. Eper. IVied. 52: 457, 1930. 6. Richard, E. R., and tIorsfal], F. D.: Relation B e t w e e n N e u t r a l Antibodies Against Influenza A Virus in Sera of Mothers and Infants, J. Immuno]. 42: 267, 19419 7. Smlth~ M. G.: Placenta] Transmission of Immunity to St. Louis Encephalitis Virus Inoculated Intraperltoneally in Mice, Prec. See. Exper. Biol. & Mad. 52: 83, 1943. 8. Morgan, I. Mi.: Influence of Age on Susceptibility and on I m m u n e Response of Mice to E E E Virus, J. Exper. Mied. 74: 115, 1941. 9. Shuman, H. H.: Varicella in the Newborn, Am. J. Dis. Child. 58: 564, ]939. 10. Kohn, J. L.: 1Vleasles in N e w b o r n Infants, J. PEDIA~. 3: 176, 1933. 11. 1V[arsden, J., and Greenfield, C. R. MI.: I n h e r i t e d Smallpox, Arch Dis. Child. 8-9: 309, 1933-1934.
EQUINE
ENCEPHALOMYELITIS
25
12. Schick, B.: Diaplacental I n f e c t i o n of F e t u s W i t h Virus of German Measles, A c t a pediat. 38: 563, 1949. 13. MiacArthur, P.: Congenital Vaccinia and Vaceinia Gravidarum, Lancet 2: 1104, 1952. 14. Traub, E.: Epidemiology of Lymphocytic Chorlomeningitis in W h i t e Milce, J. Exper. Ivied. 64: 186, 1936. 15. IIillendalI, H.: E x p e r i m e n t a l Transmission of L y m p h o g r a n u l o m a Venereum Virus, Am. J. Surg. 70: 320, 1945. 16. Howitt, B. F.: Recovery of the Virus of WEE From IIuman Blood Serum, Science 89: 541, 1939. 17. Hurst, E. W.: Infection of Rhesus Mionkey and Guinea Pig With Virus of Equine Encephalomyelitis, J. P a t h . Bact. 42: 271, 1936. 18. Crosser, cited b y ~ u t t n e r and R a t t u e r : I m p o r t a n c e of Colostrum to the Newb o r n I n f a n t , Am. J. Dis. Child. 25: 416, 1923. 19..Mendovy, H.: W E E in I n f a n t s , J. PEDIAT. 22: 308} 1943. 20. ]~alverson, W. L., Longshore~ W. A., a n d Peters, R. F.: The 1952 Encephalitis Outbreak in California, Pub. Health Rep. 68: April, 1953. 21. Rivers, T. M.: Viral and Rickettsia] I n f e c t i o n s of Man, Philadelphia, 1948, J. B. L i p p l n e o t t Co., p. 181. 22. Reeves, W. C.: Personal communication. Unpnb]ished data. 23. Hammon, W. MeD., and Reeves, W. C.: L a b o r a t o r y Transmission of W E E by MIosquitoes of the Genera Culex and Culiseta, J. Exper. Ivied. 78: 425, 1943. 24. Hammon, W. M c D , and Reeves, W. C.: W E E Control Studies in Kern County, California, in 1945, Am. J. Hyg. 47: 93, ]948. 25. Goodpasture, E. W.: Virus I n f e c t i o n of the M a m m a l i a n Fetus, Science 95: 39], 1942. 26. E a s t m a n , J. N.: Williams Obstetrics, New York, 1950, Appleton-Century Crofts, Inc., p. 678. ADDENDUM
The twins were examined again at 7 months of age and development to date appeared normal. Blood drawn on April 9, 1953 (seven months after illness), demonstrated complement fixing antibodies in a titer of 1:255 in both T. C. and R. C.; Mrs. C.'s titer remained at 1:128.
M.D., ~
AND TttOlY[AS E . TOWNSEND,
M.D. ~
BERKELEY, CALIF.
S E A R L Y as 1892 Ehrlich ~ demon-
ola or developed the disease before the eighth d a y of e x t r a u t e r i n e life. Schiek, 12 in a complete r e v i e w of the literature, has g a t h e r e d some f o r t y cases of infants who manifested lesions of smallpox at birth or too early in life to attribute the illness to contact with the disease. I n most of these eases, mothers had been rendered immune to the disease b y either vaccination or actual illness some time prior to their p r e g n a n c y but during the gestation lived in an area in which smallpox was clinically evident. Although the mothers, themselves, did not suffer a second clinical attack of smallpox, they apparently t r a n s m i t t e d the illness to their offspring in utero.
strated t h a t the semipermeable A m e m b r a n e of the h u m a n placenta t r a n s m i t t e d antibodies f r o m immune mothers to their infants. Since that time it has been well established that bacterial antitoxins such as tetanus, pertussis, and diphtheria pass from mother to i n f a n t via the placentad, 3, Similarly, antibodies to virus diseases such as poliomyelitis and influenza have been shown to traverse the placenta readilyP, 6 The in utero transmission of i m m u n i t y to the St. Louis encephalitis virus has been experimentally demonstrated by Smith 7 in mice. Morgan s showed similar evidence working with E a s t e r n equine encephalitis virus. Transp]acental transmission of exanthematous infections seems to be thoroughly established. Shuman, 9 in a review of the literature, cites six cases of congenital varicella and adds one of his own. E i g h t cases of in utero transmission of measles have been reported b y Kohn, 1~ and Marsden and Greenfield 11 report six cases of mothers who developed smallpox late in p r e g n a n c y and who subsequently gave birth to infants who were either born with vari-
Recently a case of congenital vaccinia has been reported in a 6-monthold p r e m a t u r e infant whose mother suffered a severe p r i m a r y reaction to a vaccination during her third month of pregnancy, la The infant was born with extensive skin lesions and died shortly a f t e r birth. I n t r a c y t o p l a s m i c bodies were demonstrated at a~ltopsy. Experimentally, the virus of lymphocytic choriomeningitis has been int r o d u c e d into p r e g n a n t mice b y Traub, ~* with subsequent demonstration of the virus either in the embryo in ntero or in the offspring. Similar experiments with l y m p h o g r a n u l o m a venereum virus have been done b y Hillendall. ~ Since (a) the particle size
F r o m the Division of Preventive lVfedical Services, California State Health D e p a r t m e n t and Communicable Disease Center, Public Health Service, Atlanta, Ga. *Senior Assistant Surgeon (R) USPHS. Epidemic Intelligence Officer assigned to the State of California from the Communicable Disease Center in Atlanta, Ga~ **Resident Pediatrician, K e r n General Hospital. 21
22
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for Western equine encephalomyelitis (W.E.E.) is smaller than either of the two above viruses mentioned, (b) it is generally accepted that a viremia exists prior to central nervous system invasion with W.E.E. 16, 17 and (c) the rodent and the human being have a hemochorionic type of placenta, IS it seems logical that this virus should be capable of causing disease in utero in both mice and human beings. The only report of possible transplacental transmission of arthropodborne encephalitis in the literature is presented b y Mendovy in 194329 Two cases are reported in infants who were seen at the age of 6 and 7 months, respectively, because of gross neurological d i s t u r b a n c e . The diagnosis in one instance was based on a positive neutralization test for W.E.E. on the sera of the infant and mother. The second infant and mother had blood taken for complement fixation with a report from the Rockefeller Institute showing "the baby's blood to be positive for Western equine encephalitis in a 1:16 dilution and the mother's positive in a 1:4 dilution." Both infants had a febrile illness within five days of birth but the chronology of illness in the mother is not detailed. The following are case reports on twins observed in K e r n County in the epidemic of W . E . E : in California in 1952. 20 CASE R E P O R T S
R. C. and T. C., fraternal twin girls, were born at the K e r n General Hospital on Aug. 2, 1952. The infants were delivered by low forceps after a full-term pregnancy and there were no neonatal complications. At birth, T. C. weighed 6 pounds 5 ounces and R. C. 5 pounds 10 ounces. They were in a n u r s e r y with ten other infants and taken out for bottle feedings at four-
OF P E D I A T R I C S
hour intervals. At the age of 4 days, on August 6, the infants were discharged with no apparent abnormality. The mother who was admitted in labor on August 2 was described as preeclamptic with a blood pressure of 180/ 90. A f t e r delivery, she stfffered postp a r t u m shock with blood pressure falling to 90/50 and was given 2,000 c.c. of blood. She recovered rapidly, ran an afebrile hospital course, and was discharged with the infants on August 6. Twenty-four hours after discharge from the hospital, R. C. refused food, ran a temperature of 104 ~ F., and had twitching movements of the extremities. Twelve hours later, the twin, T. C., became ill with a similar clinical picture. They were both readmitted to the hospital the following day, August 9. On physical examination, R. C. was described as a jaundiced, mildly dehydrated, lethargic infant who was acutely ill. Neck was 4+ rigid and the fontanel bulging; temperature was 102 ~ F. L a b o r a t o r y data revealed a hemoglobin of 14.3; white blood count 18,100 with a shift to the left. Lumbar puncture showed xanthochromie spinal fluid with 695 cells of which 58 per cent were polymorphonuclears. Sugar was 61 rag. per cent, protein was 240 rag. per cent, and culture was negative. T. C. was described as an acutely ill, dehydrated infant with a " v e r y tense" fontaneh Neck rigidity was 4+ and there was "definite rigidity of extremities." Laboratory data revealed hemoglobin of 16.2; white blood count 22,400 with a shift to left. Immbar puncture showed xanthoehromic fluid with 511 cells of which 76 per cent were polymorphonuelears. Sugar was 68 rag. per cent, protein 238 rag. per cent, with a negative culture. Admission diagnosis on both patients was probable meningitis, and intensive chemotherapy with penicillin and streptomycin was initiated. The hospital course for both infants was stormy. Temperature ran from 101 ~ to 104 ~ F. for three days. They suffered r e p e a t e d convulsive episodes.
SttINEFIELD AND TOWNSEND:
WESTERN EQUINE ENCEPHALOMYELITIS
Oxygen was required for six days, during which time they were extremely lethargic and refused formula. Clinical improvement w a s noted on the seventh day and they were discharged after thirteen days of hospitalization apparently well but noted to take formula slowly. Blood specimens during tile acute and convalescent phase of the illness were t a k e n for examination for W.E.E. because the infants were admitted to K e r n General Hospital at a time when m a n y eases of W.E.E. were being seen and blood for antibody examination was drawn routinely on all patients with a febrile central nervous system disease. Blood drawn on August 11, during the acute phase of illness, showed no significant complement fixing (C.F.) antibodies to be present. This was reported by the Viral and Rickettsial Disease Laboratory, California State D e p a r t m e n t of Public Health, as a titer of less than 1:8. Blood drawn on August 21 showed T. C. to have a titer of 1:16 and R. C. to have a titer of 1:128. (A fourfold rise in titer is considered evidence of a recent infection. In this case, a rise from < 1:8 to 1:16 would have been significant.) Thus, with this positive evidence for infection with W.E.E. in infants who were only 5 days old and who were out of the hospital less than thirty-six hours prior to the first day of illness, it was felt that f u r t h e r interrogation of the mother was in order. The following were the significant chronological facts elicited: (1) On J u l y 21, 1952, the C.'s house was shaken by a rather severe e~rthquake. Because of this, Mrs. C., who was close to the expected date of delivery, decided to live with her parents in a rural area near Bakersfield. (2) On J u l y 22, Mrs. C. and her husband slept on the unscreened porch of the parents. They were severely bitten by mosquitoes and decided they would rather r e t u r n home than spend another night exposed to the mosquitoes. The young mother-t0-be had evi-
23
deuce of mosquito bites on her arms and legs. (3) On J u l y 3], Mrs. C. suffered "feverishness," severe headache, and marked lethargy. She did not seek medical advice. (4) On August 1, she was taken to Kern County Hospital because of labor pains. It was felt by the examiner that she was not in true labor and was sent home. Although the symptoms of the previous day persisted, she did not relate them to the examining physiMan because "I was afraid they would keep me in the hospital." The symptoms were less severe than the preceding day. (5) On August 2, she was admitted to K e r n County Hospital in active labor. Because no history of illness was obtained at time of labor, no lumbar puncture or acute blood specimen was obtained from the mother. However, on j August 22, or twenty-three days after the onset of the disease, the complement fixing antibodies in the mother's sera were present in a titer of 1:128. DISCUSSION
It has been established that the usual transmission of W.E.E. is via mosquito bite and the incubation period is from four to twenty-one daysY 1 Since the twins were home less than thirtysix hours prior to the onset of their illness, the disease could only have been contracted either in utero or in the n u r s e r y during the first few days of life. It is doubtful that mosquitoes penetrated the nursery but to make this possibility even more remote, the other ten infants in the nursery at the time the twins were there were visited. At the time of the visit, the infants were 5 to 6 weeks old and no history of illness could be elicited. Nine out of ten were bled and C.F. antibody titers in all eases were < 1:8. A group of twenty nurses and doctors and other employees who were on the nursery
24
THE JOURNAL OF PEDIATRICS
floor at the onset of illness were also bled and C.F. titers here too were 1:8. The house of the parents of the y o u n g couple was visited and a n e x t door neighbor and f o r t y chickens free in the y a r d less t h a n 100 y a r d s from the back porch where the couple slept. Twelve of the chickens were bled and 25 per cent of them had a significant titer (an LDso of more t h a n 100) of neutralizing antibodies for W.E.E. I n K e r n County over the past three years, neutralizing antibodies were present in about 25 per cent of chicken flocks r a n d o m l y sampled. 22 I t has been shown that mosquitoes may transmit W.E.E. experimentally from chicken to chicken, 2a and it is believed that m a n y birds m a y play an import a n t role a s a reservoir host for the W.E.E. virus. The importance of the role of the chicken in the n a t u r a l transmission of the disease is not clear and indeed it is felt t h a t others of the avian species are p r o b a b l y more imp o r t a n t factors. 24 However, t h e y should not be overlooked in the present situation which may be summarized as follows: A p r e g n a n t female was severely bitten b y mosquitoes eleven days before term while living in an area where an epidemic of encephalitis in human beings was observed and where infection in chickens (either past or present) has been established. Two days before delivery, the patient had a clinical illness that resembled encephalitis and, subsequently, complement fixing antibodies for W.E.E. were present in the serum. Twin infants were born and on the fifth day of life had
clinical and serological evidence of encephalitis. The low initial titers and the subsequent high titers rule out
transplacental transmission of antibody and establish a definite etiological diagnosis. The evidence strongly points to transplacental transmission of the virus. Unfortunately, no att e m p t was made to isolate the viral agent in the acute blood sample. The infants, seen on Sept. 18, 1952, at 6 weeks of age, were in good health. C.F. titer on T. C. had risen to 1:256 and on R. C. to 1:512. THe mother's titer was 1:64. In conclusion it must be mentioned that just as in the viral exanthematous infections, W.E.E. in the last stages os p r e g n a n c y does not consistently produce disease in the offspring. Local factors such as placental defects which m a y be necessary for in utero transmission of disease are discussed by Goodpasture. 2~ In view of the known pathological changes in the placenta associated with pre-eclampsia, 26 the maternal pre-eclamptic state in the present cases m a y have been an imp o r t a n t f a c t o r in the in utero infection. D u r i n g the present epidemic two other cases of clinical W.E.E. with serological confirmation were observed in p r e g n a n t women, the onsets of illness being within one to three days of delivery. The pregnancies were uncomplicated. The infants in both cases were a p p a r e n t l y unaffected and did not show any serological evidence of disease either at birth or at 2 months of age. SUMMARY
1. Evidence for transp]acental transmission of antibodies and viruses is reviewed. 2. Two clinical and serologically proved cases of Western equine encephalomyelitis in twin infants 5 days old
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are presented. Evidence strongly suggests transplacental transmission of the virus. 3. Maternal infection with Western equine encephalomyelitis in the late stages of pregnancy does not invariably infect the infant. In utero infection may be dependent upon local placental defects. The authors would like to t h a n k Dr. E d w i n If. L e n n e t t e , Director of the Viral and R i c k e t t s i a l Disease L a b o r a t o r y , of the S t a t e of California, for p e r f o r m i n g the diagnostic serological tests. REFERENCES 1. Ehrlich, cited b y Gay, F . P . : Agents of Disease and }Iost Resistance, Springfield, Ill., 1935, Charles C Thomas, p. 450, 2. Ten Broeck, C, and Bauer, J. H.: Transmission of Tetanus A n t i t o x i n Through Placenta, Prec. See. Exper. Biol. & M e d . 20: 399, 1922. 3. Cohen, P., and Scadron, S. J.: Effects of A c t i v e Immunization of the Miother Upon the Offspring, J. PEDIA~. 29: 609, 1946. 4. K u t t n e r , A. G., a n d Ratner, B.: Importance of Colostrum to the N e w b o r n Inf a n t , Am. J. Dis. Child. 25: 413, 1923. 5. Aycock, W. L.. and Kramer, S . D . : Imm u m t y to P o h o m y e h t m 111 iV[others and Newborns as Shown by N e u t r a l i z a t i o n Tests, J. Eper. IVied. 52: 457, 1930. 6. Richard, E. R., and tIorsfal], F. D.: Relation B e t w e e n N e u t r a l Antibodies Against Influenza A Virus in Sera of Mothers and Infants, J. Immuno]. 42: 267, 19419 7. Smlth~ M. G.: Placenta] Transmission of Immunity to St. Louis Encephalitis Virus Inoculated Intraperltoneally in Mice, Prec. See. Exper. Biol. & Mad. 52: 83, 1943. 8. Morgan, I. Mi.: Influence of Age on Susceptibility and on I m m u n e Response of Mice to E E E Virus, J. Exper. Mied. 74: 115, 1941. 9. Shuman, H. H.: Varicella in the Newborn, Am. J. Dis. Child. 58: 564, ]939. 10. Kohn, J. L.: 1Vleasles in N e w b o r n Infants, J. PEDIA~. 3: 176, 1933. 11. 1V[arsden, J., and Greenfield, C. R. MI.: I n h e r i t e d Smallpox, Arch Dis. Child. 8-9: 309, 1933-1934.
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12. Schick, B.: Diaplacental I n f e c t i o n of F e t u s W i t h Virus of German Measles, A c t a pediat. 38: 563, 1949. 13. MiacArthur, P.: Congenital Vaccinia and Vaceinia Gravidarum, Lancet 2: 1104, 1952. 14. Traub, E.: Epidemiology of Lymphocytic Chorlomeningitis in W h i t e Milce, J. Exper. Ivied. 64: 186, 1936. 15. IIillendalI, H.: E x p e r i m e n t a l Transmission of L y m p h o g r a n u l o m a Venereum Virus, Am. J. Surg. 70: 320, 1945. 16. Howitt, B. F.: Recovery of the Virus of WEE From IIuman Blood Serum, Science 89: 541, 1939. 17. Hurst, E. W.: Infection of Rhesus Mionkey and Guinea Pig With Virus of Equine Encephalomyelitis, J. P a t h . Bact. 42: 271, 1936. 18. Crosser, cited b y ~ u t t n e r and R a t t u e r : I m p o r t a n c e of Colostrum to the Newb o r n I n f a n t , Am. J. Dis. Child. 25: 416, 1923. 19..Mendovy, H.: W E E in I n f a n t s , J. PEDIAT. 22: 308} 1943. 20. ]~alverson, W. L., Longshore~ W. A., a n d Peters, R. F.: The 1952 Encephalitis Outbreak in California, Pub. Health Rep. 68: April, 1953. 21. Rivers, T. M.: Viral and Rickettsia] I n f e c t i o n s of Man, Philadelphia, 1948, J. B. L i p p l n e o t t Co., p. 181. 22. Reeves, W. C.: Personal communication. Unpnb]ished data. 23. Hammon, W. MeD., and Reeves, W. C.: L a b o r a t o r y Transmission of W E E by MIosquitoes of the Genera Culex and Culiseta, J. Exper. Ivied. 78: 425, 1943. 24. Hammon, W. M c D , and Reeves, W. C.: W E E Control Studies in Kern County, California, in 1945, Am. J. Hyg. 47: 93, ]948. 25. Goodpasture, E. W.: Virus I n f e c t i o n of the M a m m a l i a n Fetus, Science 95: 39], 1942. 26. E a s t m a n , J. N.: Williams Obstetrics, New York, 1950, Appleton-Century Crofts, Inc., p. 678. ADDENDUM
The twins were examined again at 7 months of age and development to date appeared normal. Blood drawn on April 9, 1953 (seven months after illness), demonstrated complement fixing antibodies in a titer of 1:255 in both T. C. and R. C.; Mrs. C.'s titer remained at 1:128.