Herpes Simplex in Gynecology and Obstetrics
Randall Bloomfield, MD, FACOG, Jorge R. Suarez, MD, Zenaida S. Roque, MD, and Prayuth Tantakasem, MD Brooklyn, New York
The problems of herpes simplex in gynecology and obstetrics are reviewed. There were 40 patients showing the characteristic cellular changes of herpetic infection among the 79,357 Papanicolaou smears taken. Four patients, with cytologic evidence of herpes virus, also had cervical dysplasia. The relationship between herpes virus and dysplasia, carcinoma in situ, and invasive carcinoma is discussed. The use of a properly timed Papanicolaou smear to alert the physician to the danger of an infected birth canal is described. Three cases of neonatal herpes are cited.
Herpes simplex virus (HSV) has been implicated in a wide spectrum of obstetric and gynecologic diseases ranging from congenital anomalies and neonatal deaths to vulvitis and cervical malignancy.1-5 Haas,3 in 1935, described neonatal herpes simplex as disseminated disease usually terminating in death. In 1946, HSV was isolated from the female genital tract.4 In 1936, the characteristic cytologic changes were described and proved by culture.6 The DNA virus with its vision of 100150 mm in diameter possesses a capsid with cubic symmetry, 162 capsomeres, and lipoprotein outer wall.7
From the Department of Obstetrics and Gynecology, Brooklyn Cumberland Medical Center, Brooklyn, New York. Requests for reprints should be addressed to Dr. Randall Bloomfield, State University of New York, Downstate Medical Center, Box 1216, 450 Clarkson Avenue, Brooklyn, NY 11203.
Herpes genitalis, which is generally due to HSV-2, occurs three to seven days following exposure to sexual contact.8 The patient complains of burning pain, itching, and develops vesicles on the vulva, vagina, or cervix, which ulcerate and become secondarily infected.8 This disease can recur at the same sites but then it is usually milder. In recurrent herpes, the virus may lie dormant in the tissue, especially the ganglion cell, only to reassert itself when stress or a hormonal modification occurs.4 The diagnosis may be suggested by the clinical picture, the Papanicolaou smear culture, or serum antibody titers.9 There are, moreover, methods to distinguish between HSV- 1 and HSV-2. 10 The treatment of this genital infection is largely symptomatic."1"'2 Virucidal agents are being investigated currently.'3 Amstey'4 cited a case of disseminated herpes with central nervous system seizures in a newborn that re-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
sponded favorably to an exchange transfusion and Ara-A.
Material and Results In a review of 79,357 Papanicolaou smears, at I3rooklyn-Cumberland Medical Center, there were 40 cases with cytologic evidence of herpetic infection for an occurrence of 1 in 2,000 smears. Eleven patients (27.5 percent) were pregnant and 29 (72.5 percent) were gynecologic patients. The mean age was 25.5 with 72.5 percent between the ages of 15 to 29 years (Table 1). In approximately one third of the 40 cases, the smears were repeated 1P/2 to six weeks after the initial positive smear. All were negative for herpes. Of the 11 pregnant patients who were found to have herpes on their first prenatal visit, seven (63.6 percent) delivered noninfected infants. Two patients did not deliver at the Center and two had elective induced abortions. 161
Table 1. Age Distribution of Patients with Positive Smears for Herpes Age
Number
Percent
15-19 20-24 25-29 30-34 35-39 40-44 45+
8 16 5
1
20.0 40.0 12.5 17.5 5.0 2.5 2.5
Total
40
100.0
7 2 1
In this series, there were four patients with smears showing dysplasia. One showed mild dysplasia which regressed, two, mild dysplasia which persisted, and one, severe dysplasia and was lost to followup. All the cases of smears positive for carcinoma of the cervix were reviewed during the period under study and none of these 341 showed the cytologic changes of herpes. Interestingly enough, after the study was concluded,
0. 01. 41,
Figure 1. Carcinoma in situ of the cervix adjacent to an area of herpetic cervicitis (x 100). (See Figure 2.)
Figure 2. Multinucleated giant cells characteristic of herpes in cervical epithelium adjacent to an area of carcinoma in situ (x 400). (See Figure 1.)
162
one patient with carcinoma in situ and herpes was seen (Figures 1 and 2). A parallel survey also revealed that three infants died from disseminated herpes infections. These three deaths occurred between 1972 and 1976 (Table 2).
Discussion The infectious nature of HSV represents a threat to the well-being of the fetus, and of parallel concern are the studies which relate HSV-2 to cervical cancer. Herpes virus has been linked to cancer in animals, eg, Marek disease of fowl and renal adenocarcinoma in Lucke's frog.'5 In man, the EpsteinBarr herpes virus has been implicated in Burkitt lymphoma. To this group has been added the question of HSV-2 and cervical cancer. There is evidence to suggest a definite relationship between HSV-2 and carcinoma. The oncogenic potential of HSV-2 is suggested by its ability to transform embryo fibroblasts in vitro. 16 The virus has also been isolated from a cell line derived from carcinoma in situ. 17.18 Several studies have shown that there are higher titers of HSV antibody in patients with dysplasia, carcinoma in situ, and invasive carcinoma as compared to their controls. 19-22 The cytologic frequency of genital herpes in a lower socioeconomic population is said to be one percent.23 At Brooklyn-Cumberland Medical Center, it had an occurrence of 0.5 percent. A quick, reliable method of detecting the presence of herpetic infection is the Papanicolaou smear. In all cases where herpes is suspected, regardless of whether genital lesions are present or absent, Papanicolaou smears should be done and the characteristic cellular changes sought. The results would be earlier diagnosis and prompt treatment to prevent the high neonatal morbidity and mortality. The cytologic picture is characteristic (Figure 3). In early stages, there is nuclear enlargement with a faint basophilia and opaque homogenization of the nuclear contents. This groundglass appearance is due to viral invasion of the nucleus. Large cell with multinucleation results from nuclear multiplication and cytoplasmic enlargement. The homogenous inclusions are localized in the center of the
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
Figure 3. An example of the characteristic multinucleated giant cells associated with genital herpes. Note the "molding" of nuclei and intranuclear inclusion (Papanicolaou vaginal smear, x 900).
Table 2. Infant Deaths from Disseminated Herpes Infections Infant
Delivery
Intrapartum
Neonatal
Postmortem Examination
G
Cesarean
Amnionitis
Fever, hepatomegaly, hemorrhagic diathesis, and vascular collapse
Y
Vaginal
Unremarkable
Fever, hepatomegaly,
Hepatic and adrenal necrosis Hemopericardium, hemothorax Hepatic and adrenal intranuclear inclusion bodies. Hepatic and adrenal necrosis Hepatic and adrenal intranuclear inclusion bodies Hepatic and adrenal necrosis Hemopericardlum Subarachnoid hemorrhage Hepatic and adrenal intranuclear inclusion bodies
nasal vesicles Hemorrhagic diathesis
C
Vaginal
Unremarkable
nucleus and are significantly larger than the nucleoli. There is a characteristic molding of the adjacent nucleus. Ng and his colleagues9 cite cytologic criteria for differentiating between primary and recurrent herpetic infection. Complement fixing antibody titers are helpful in distinguishing primary from recurrent herpes.9 A lower titer in the acute phase and a rise during the convalescent period indicates a primary infection, whereas a high titer in the acute phase with sustained elevation in the convalescent phase denotes recurrent disease.9 In the infected neonates, vesicular
Fever, oral vesicles, convulsions Hemorrhagic diathesis
eruptions began three-seven days after birth. Systemic spread occurred rapidly with fever, jaundice, and a bleeding tendency, as well as respiratory and circulatory failure. Postmortem examination showed widespread hepatic and adrenal cortical necrosis (Figure 4). The area of necrosis was surrounded by cells with inclusion bodies"(Figure 5). Herpes genitalis may be a mild maternal infection, but it can cause an abortion or be lethal to the neonate.'3"14 The serotype HSV-2 is most often implicated in disseminated infection of the newborn. " When the infant is delivered vaginally or by cesarean section, four
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
hours after rupture of membranes, the estimated risk of infection for the newborn is approximately 40 percent.23 If untreated, approximately one half of the infected infants will die or have severe neurologic or ocular sequelae.2: The most frequent source of infection in the newborn is probably the infected genital tract of the mother at delivery.23 In the case of an active infection and term fetus, elective cesarean section would avoid delivery through an infected birth canal. When premature rupture of the membranes has occurred, abdominal delivery without delay should be considered. 163
i~~~~~~~~~~~~~~~~~~~~~~~- -L -------
--- -- ----
)t X L-A
Figure 4. A section of the liver showing scattered, discrete, and confluent areas of necrosis.
@ Figure 5. A high magnification of an area of necrosis in the liver. Note the inclusion bodies surrounded by pale halos (x 400). Literature Cited 1. South MA, Tompkins WAF, Morris CR, et al: Congenital malformations of the central nervous system associated with genital type (type 2) herpes virus. J Pediatr 75:13-18, 1969 2. Florman AL, Gershon AA, Blackett PR, et al: Intrauterine infection with herpes simplex virus. JAMA 225:129-132, 1973 3. Haas GM: Hepato-adrenal necrosis with intranuclear inclusion bodies: Report of case. Am J Pathol 11:127-142, 1935 4. Slavin HB, Gavett E: Primary herpetic vulvovaginitis. Proc Soc Exp Biol Med 63:343345, 1946 5. Catalano LW, Johnson LD: Herpes virus antibody and carcinoma in situ of the cervix. JAMA 217:447-450, 1971 6. Stern E, Longo LD: Identification of herpes simplex virus in a case showing cytological features of viral vaginitis. Acta Cytol 7:295299, 1963 7. Melnick JL: The general nature of viruses. Clin Obstet Gynecol 15:858-876, 1972 8. Kaufman RH, Gardner HL, Rawls WE, et al: Clinical features of herpes genitalis. Cancer Res 33:1446-1451, 1973 9. Ng ABP, Reagan JW, Yen SC: Herpes
164
genitalis. Obstet Gynecol 36:645-651, 1970 10. Russell WC, Watson DH, Wildy P: Preliminary chemical studies on herpes simplex virus. Biochem J 87:26-27, 1963 11. Nahmias AJ, Josey WE, Naib ZM: Neonatal herpes simplex infection. JAMA 199:132-136, 1967 12. White JG: Fulminating infection with herpes simplex virus in premature and newborn infants. N Engl J Med 269:455-460, 1963 13. Henson D, SeverJL: Congenital viral infections. In Caplan RM, Sweeney WJ IlIl (eds): Advances in Obstetrics and Gynecology. Baltimore, Williams and Wilkins, 1978, p 135 14. Amstey MS, Lewin EB, Meyer MR: Herpes virus infection in the newborn: Its treatment by exchange transfusion and adenosine arabinoside. Obstet Gynecol 47:33s-35s, 1976. 15. Fenner FJ, White DO: Medical Virology. New York, Academic Press, 1970, p 235 16. Duff R, Rapp F: Properties of hamster embryo fibroblasts transformed in vitro after exposure to ultraviolet irradiated herpes simplex virus type 2. J Virol 8:469, 1971 17. Aurelian L, Strandberg JD, Melendez
LV, et al: Herpes virus type 2 isolated from cervical tumor cells grown in tissue culture. Science 174:704-707, 1971 18. Royston I, Aurelian L: Immunofluorescent detection of herpes virus antigens in exfoliated cells from human cervical carcinoma. Proc Natl Acad Sci USA 67:204-212, 1970 19. Skinner GR, Thouless ME, Jordan JA: Antibodies to type 1 and type 2 herpes virus in women with abnormal cervical cytology. J Obstet Gynecol Br Commonw 78:1031-1038, 1971 20. Nahmias AJ, Josey WE, Naib ZM, et al: Antibodies to herpes virus hominis types 1 and 2: II. Women with cervical cancer. Am J Epidemiol 91:549-552, 1970 21. Royston I, Aurelian L: The association of genital herpes virus with cervical atypia and carcinoma in situ. Am J Epidemiol 91:531-538, 1970 22. Simon JW: The association of herpes simplex virus and cervical cancer: A review. Gynecol Oncol 4:108-116, 1976 23. Nahmias AJ: Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol 1 10:825-837, 1971
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
Randall Bloomfield, MD, FACOG, Jorge R. Suarez, MD, Zenaida S. Roque, MD, and Prayuth Tantakasem, MD Brooklyn, New York
The problems of herpes simplex in gynecology and obstetrics are reviewed. There were 40 patients showing the characteristic cellular changes of herpetic infection among the 79,357 Papanicolaou smears taken. Four patients, with cytologic evidence of herpes virus, also had cervical dysplasia. The relationship between herpes virus and dysplasia, carcinoma in situ, and invasive carcinoma is discussed. The use of a properly timed Papanicolaou smear to alert the physician to the danger of an infected birth canal is described. Three cases of neonatal herpes are cited.
Herpes simplex virus (HSV) has been implicated in a wide spectrum of obstetric and gynecologic diseases ranging from congenital anomalies and neonatal deaths to vulvitis and cervical malignancy.1-5 Haas,3 in 1935, described neonatal herpes simplex as disseminated disease usually terminating in death. In 1946, HSV was isolated from the female genital tract.4 In 1936, the characteristic cytologic changes were described and proved by culture.6 The DNA virus with its vision of 100150 mm in diameter possesses a capsid with cubic symmetry, 162 capsomeres, and lipoprotein outer wall.7
From the Department of Obstetrics and Gynecology, Brooklyn Cumberland Medical Center, Brooklyn, New York. Requests for reprints should be addressed to Dr. Randall Bloomfield, State University of New York, Downstate Medical Center, Box 1216, 450 Clarkson Avenue, Brooklyn, NY 11203.
Herpes genitalis, which is generally due to HSV-2, occurs three to seven days following exposure to sexual contact.8 The patient complains of burning pain, itching, and develops vesicles on the vulva, vagina, or cervix, which ulcerate and become secondarily infected.8 This disease can recur at the same sites but then it is usually milder. In recurrent herpes, the virus may lie dormant in the tissue, especially the ganglion cell, only to reassert itself when stress or a hormonal modification occurs.4 The diagnosis may be suggested by the clinical picture, the Papanicolaou smear culture, or serum antibody titers.9 There are, moreover, methods to distinguish between HSV- 1 and HSV-2. 10 The treatment of this genital infection is largely symptomatic."1"'2 Virucidal agents are being investigated currently.'3 Amstey'4 cited a case of disseminated herpes with central nervous system seizures in a newborn that re-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
sponded favorably to an exchange transfusion and Ara-A.
Material and Results In a review of 79,357 Papanicolaou smears, at I3rooklyn-Cumberland Medical Center, there were 40 cases with cytologic evidence of herpetic infection for an occurrence of 1 in 2,000 smears. Eleven patients (27.5 percent) were pregnant and 29 (72.5 percent) were gynecologic patients. The mean age was 25.5 with 72.5 percent between the ages of 15 to 29 years (Table 1). In approximately one third of the 40 cases, the smears were repeated 1P/2 to six weeks after the initial positive smear. All were negative for herpes. Of the 11 pregnant patients who were found to have herpes on their first prenatal visit, seven (63.6 percent) delivered noninfected infants. Two patients did not deliver at the Center and two had elective induced abortions. 161
Table 1. Age Distribution of Patients with Positive Smears for Herpes Age
Number
Percent
15-19 20-24 25-29 30-34 35-39 40-44 45+
8 16 5
1
20.0 40.0 12.5 17.5 5.0 2.5 2.5
Total
40
100.0
7 2 1
In this series, there were four patients with smears showing dysplasia. One showed mild dysplasia which regressed, two, mild dysplasia which persisted, and one, severe dysplasia and was lost to followup. All the cases of smears positive for carcinoma of the cervix were reviewed during the period under study and none of these 341 showed the cytologic changes of herpes. Interestingly enough, after the study was concluded,
0. 01. 41,
Figure 1. Carcinoma in situ of the cervix adjacent to an area of herpetic cervicitis (x 100). (See Figure 2.)
Figure 2. Multinucleated giant cells characteristic of herpes in cervical epithelium adjacent to an area of carcinoma in situ (x 400). (See Figure 1.)
162
one patient with carcinoma in situ and herpes was seen (Figures 1 and 2). A parallel survey also revealed that three infants died from disseminated herpes infections. These three deaths occurred between 1972 and 1976 (Table 2).
Discussion The infectious nature of HSV represents a threat to the well-being of the fetus, and of parallel concern are the studies which relate HSV-2 to cervical cancer. Herpes virus has been linked to cancer in animals, eg, Marek disease of fowl and renal adenocarcinoma in Lucke's frog.'5 In man, the EpsteinBarr herpes virus has been implicated in Burkitt lymphoma. To this group has been added the question of HSV-2 and cervical cancer. There is evidence to suggest a definite relationship between HSV-2 and carcinoma. The oncogenic potential of HSV-2 is suggested by its ability to transform embryo fibroblasts in vitro. 16 The virus has also been isolated from a cell line derived from carcinoma in situ. 17.18 Several studies have shown that there are higher titers of HSV antibody in patients with dysplasia, carcinoma in situ, and invasive carcinoma as compared to their controls. 19-22 The cytologic frequency of genital herpes in a lower socioeconomic population is said to be one percent.23 At Brooklyn-Cumberland Medical Center, it had an occurrence of 0.5 percent. A quick, reliable method of detecting the presence of herpetic infection is the Papanicolaou smear. In all cases where herpes is suspected, regardless of whether genital lesions are present or absent, Papanicolaou smears should be done and the characteristic cellular changes sought. The results would be earlier diagnosis and prompt treatment to prevent the high neonatal morbidity and mortality. The cytologic picture is characteristic (Figure 3). In early stages, there is nuclear enlargement with a faint basophilia and opaque homogenization of the nuclear contents. This groundglass appearance is due to viral invasion of the nucleus. Large cell with multinucleation results from nuclear multiplication and cytoplasmic enlargement. The homogenous inclusions are localized in the center of the
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
Figure 3. An example of the characteristic multinucleated giant cells associated with genital herpes. Note the "molding" of nuclei and intranuclear inclusion (Papanicolaou vaginal smear, x 900).
Table 2. Infant Deaths from Disseminated Herpes Infections Infant
Delivery
Intrapartum
Neonatal
Postmortem Examination
G
Cesarean
Amnionitis
Fever, hepatomegaly, hemorrhagic diathesis, and vascular collapse
Y
Vaginal
Unremarkable
Fever, hepatomegaly,
Hepatic and adrenal necrosis Hemopericardium, hemothorax Hepatic and adrenal intranuclear inclusion bodies. Hepatic and adrenal necrosis Hepatic and adrenal intranuclear inclusion bodies Hepatic and adrenal necrosis Hemopericardlum Subarachnoid hemorrhage Hepatic and adrenal intranuclear inclusion bodies
nasal vesicles Hemorrhagic diathesis
C
Vaginal
Unremarkable
nucleus and are significantly larger than the nucleoli. There is a characteristic molding of the adjacent nucleus. Ng and his colleagues9 cite cytologic criteria for differentiating between primary and recurrent herpetic infection. Complement fixing antibody titers are helpful in distinguishing primary from recurrent herpes.9 A lower titer in the acute phase and a rise during the convalescent period indicates a primary infection, whereas a high titer in the acute phase with sustained elevation in the convalescent phase denotes recurrent disease.9 In the infected neonates, vesicular
Fever, oral vesicles, convulsions Hemorrhagic diathesis
eruptions began three-seven days after birth. Systemic spread occurred rapidly with fever, jaundice, and a bleeding tendency, as well as respiratory and circulatory failure. Postmortem examination showed widespread hepatic and adrenal cortical necrosis (Figure 4). The area of necrosis was surrounded by cells with inclusion bodies"(Figure 5). Herpes genitalis may be a mild maternal infection, but it can cause an abortion or be lethal to the neonate.'3"14 The serotype HSV-2 is most often implicated in disseminated infection of the newborn. " When the infant is delivered vaginally or by cesarean section, four
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
hours after rupture of membranes, the estimated risk of infection for the newborn is approximately 40 percent.23 If untreated, approximately one half of the infected infants will die or have severe neurologic or ocular sequelae.2: The most frequent source of infection in the newborn is probably the infected genital tract of the mother at delivery.23 In the case of an active infection and term fetus, elective cesarean section would avoid delivery through an infected birth canal. When premature rupture of the membranes has occurred, abdominal delivery without delay should be considered. 163
i~~~~~~~~~~~~~~~~~~~~~~~- -L -------
--- -- ----
)t X L-A
Figure 4. A section of the liver showing scattered, discrete, and confluent areas of necrosis.
@ Figure 5. A high magnification of an area of necrosis in the liver. Note the inclusion bodies surrounded by pale halos (x 400). Literature Cited 1. South MA, Tompkins WAF, Morris CR, et al: Congenital malformations of the central nervous system associated with genital type (type 2) herpes virus. J Pediatr 75:13-18, 1969 2. Florman AL, Gershon AA, Blackett PR, et al: Intrauterine infection with herpes simplex virus. JAMA 225:129-132, 1973 3. Haas GM: Hepato-adrenal necrosis with intranuclear inclusion bodies: Report of case. Am J Pathol 11:127-142, 1935 4. Slavin HB, Gavett E: Primary herpetic vulvovaginitis. Proc Soc Exp Biol Med 63:343345, 1946 5. Catalano LW, Johnson LD: Herpes virus antibody and carcinoma in situ of the cervix. JAMA 217:447-450, 1971 6. Stern E, Longo LD: Identification of herpes simplex virus in a case showing cytological features of viral vaginitis. Acta Cytol 7:295299, 1963 7. Melnick JL: The general nature of viruses. Clin Obstet Gynecol 15:858-876, 1972 8. Kaufman RH, Gardner HL, Rawls WE, et al: Clinical features of herpes genitalis. Cancer Res 33:1446-1451, 1973 9. Ng ABP, Reagan JW, Yen SC: Herpes
164
genitalis. Obstet Gynecol 36:645-651, 1970 10. Russell WC, Watson DH, Wildy P: Preliminary chemical studies on herpes simplex virus. Biochem J 87:26-27, 1963 11. Nahmias AJ, Josey WE, Naib ZM: Neonatal herpes simplex infection. JAMA 199:132-136, 1967 12. White JG: Fulminating infection with herpes simplex virus in premature and newborn infants. N Engl J Med 269:455-460, 1963 13. Henson D, SeverJL: Congenital viral infections. In Caplan RM, Sweeney WJ IlIl (eds): Advances in Obstetrics and Gynecology. Baltimore, Williams and Wilkins, 1978, p 135 14. Amstey MS, Lewin EB, Meyer MR: Herpes virus infection in the newborn: Its treatment by exchange transfusion and adenosine arabinoside. Obstet Gynecol 47:33s-35s, 1976. 15. Fenner FJ, White DO: Medical Virology. New York, Academic Press, 1970, p 235 16. Duff R, Rapp F: Properties of hamster embryo fibroblasts transformed in vitro after exposure to ultraviolet irradiated herpes simplex virus type 2. J Virol 8:469, 1971 17. Aurelian L, Strandberg JD, Melendez
LV, et al: Herpes virus type 2 isolated from cervical tumor cells grown in tissue culture. Science 174:704-707, 1971 18. Royston I, Aurelian L: Immunofluorescent detection of herpes virus antigens in exfoliated cells from human cervical carcinoma. Proc Natl Acad Sci USA 67:204-212, 1970 19. Skinner GR, Thouless ME, Jordan JA: Antibodies to type 1 and type 2 herpes virus in women with abnormal cervical cytology. J Obstet Gynecol Br Commonw 78:1031-1038, 1971 20. Nahmias AJ, Josey WE, Naib ZM, et al: Antibodies to herpes virus hominis types 1 and 2: II. Women with cervical cancer. Am J Epidemiol 91:549-552, 1970 21. Royston I, Aurelian L: The association of genital herpes virus with cervical atypia and carcinoma in situ. Am J Epidemiol 91:531-538, 1970 22. Simon JW: The association of herpes simplex virus and cervical cancer: A review. Gynecol Oncol 4:108-116, 1976 23. Nahmias AJ: Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol 1 10:825-837, 1971
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
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