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Opportunistic mycotic infections in pregnant women
Opportunistic DAVID
T.
Worcester,
Massachusetts
mycotic infections in pregnant women
PURTILO,
M.S.,
M.D.
Immunosuppression was the major factor associated with the deaths of 44 women who died opportunistic mycotic infections. The patients were immunosuppresscd by mali,qnancies, irradiation, cytotoxic drugs, and metabolic diseases. An additional four patients may have developed candidiasis as a result of antibiotic therapy. Coccidioidomycosis was the only mycosis solely associated with pregnancies not altered by e.uogenour immunosuppression.
f7om
CELL-MEDIATED IMMUNITY (CMI) iS reduced in pregnant women and thereby may help to protect the fetus from maternal immunologic rejection. Impaired transformation of lymphocytes from pregnant women by phytohemagglutinin and tuberculin are two in vitro manifestations of depressed T-lymphocyte function or CMI.‘-” An unfortunate consequence may be that the maternal immunologic surveillance becomes impaired and thus permits certain microorganisms to flourish and disseminate in pregnant women.‘.’ The files of the Armed Forces Institute of Pathology (AFIP) were searched for necropsied subjects of childbearing age who died from mycotic infections to determine whether opportunistic mycotic infections occur in pregnant women.
Methods The clinical scopic findings
Received
Accepted
Results The 44 women were from 15 to 48 years of age and averaged 30.3 years. The pregnant women averaged 29.6 years and the nonpregnant women averaged 3 1 .l years of age. The races represented were 34 white, six black, three yellow, and one mixed. Two subjects who had developed choriocarcinoma 2 months post partum were included among the 17 pregnant patients. Six subjects were at term ; two earh were in the eighth, seventh, and fourth months, and three women were in the sixth month of gestation at the tirlle of death. Candidiasis. All twenty-seven women who died from randidiasis had clinical conditions characterized by immunosuppression. For instance, many subjects had malignancies which had been treated with
records and the gross and nlicrofrom necropsies of 17 pregnant and
From the Department of Pathology. of Massachusetts Medical School.
Revised
27 nonpregnant women who died from mycotic infections which are in the AFIP file were studied. Attention \vas focused on the patient’s month of pregnancy during which the infection occurred, race, age, and underlying conditions of associated immnuosuppression which may have rendered the patients incapable of combating the infections. The organs involv-ed by fungi were microscopically studied with hematoxylin and eosin, Grocott’s methenamine silver, the periodic acid-Schiff reaction, and Rest’s mucicarrlline stains in order to identify and classify the fungi.
/or
publication
September September
II,
June
University
25, 1974.
1974. I I. 1974.
Reprint requests: Dr. David T. Purtilo, Department of Pathology, University of Massachusetts Medical School, 55 Lake Ave., N., Worcester, Massachusetts 01605.
607
Table I. Candidiasis \\ornen --
in 27 immunosuppressed
Table
infection
Disseminated (No.1
diseases
Nonpregnant subjects Leukemia* Uremia Hodgkin’s disease+ Malignancies* Collagen diseases? Diabetic ketoacidosis Pregnant subjects Uremia Leukemia* Choriocarcinoma Extensive burns Multiple sclerosist Total *Given three or more tReceived prednisone.
cytotoxic
Distal esophagus (No.1
‘1 2 3 ‘1 2 1
4 2
1 1 2 1 1 17
1
1 1
Total 20 6 4 3 3 3 1 7 ‘)
i 10
2 1 1 27
agents.
A 22-year-old month storm.
white woman of pregnancy She developed
moved to Arizona and was exposed fatigue, persistent
infection
during to a senausea,
womt’n I
IV,, L’l
Candidiasis* Coccidioidomycosis Aspergillosist BlastomycosisS Mucormycosisj Total
1 I L’i
*See Table I for associated clinical conditions, tAspergillomas in patients with adenocarcinomas. PDiabetic ketoacidosis.
Table
III.
Mycoses Mvcotic
in 17 pregnant
infection
women No.
I
7 6 ‘) i 1 17
Candidiasis* Coccidioidomycosis Cryptococcosis Aspergillosist Histoplasmosist Total *Associated diseases tpregnancy-associated
cytotoxic drugs and irradiation. Leukopenia was a common finding among these patients (Table I). All of the seven pregnant women with candidiasis also had immunosuppression related to other concurrent conditions. All but one of the pregnant women had disseminated candidiasis, whereas in the nonpregnant women dissemination occurred less frequently. Coccidioidomycosis. Disseminated Coccidioides immitis was the second most frequent mycotic infection (Tables II and III). Six of the 9 patients who died from disseminated coccidioidomycosis were pregnant, and three were nonpregnant (Table II). One of the latter patients was a Mexican-American woman who had received irradiation and chemotherapy for Hodgkin’s disease. Two other nonpregnant patients with chronic coccidioidomycosis experienced exacerbations during pregnancies and later died from coccidioidomycosis but were not pregnant when they died. Coccidioidomycosis occurred in the latter half of pregnancy in three black and three white pregnant women (Table III). The following case is presented because it illustrates the severity of coccidioidomycosis occurring in a pregnant woman.
her third vere dust
in 27 nonpregnant
Mvcotic
of
Distribution
Associated
II. Mycoses
are listed in Table choriocarcinomas.
I.
and vomiting and experienced an 8 pound loss of weight during the next month and subsequent frontal headaches, anemia, moderate eosinophilia, and marked hilar mediastinal lymphadenopathy. A cough appeared during the fifth month of gestation and she developed supraclavicular lymphadenopathy. The hemoglobin was 9 Gm. white blood cell count, 14,000 per cubic per cent; milliliter; erythrocyte sedimentation rate, 36 mm. per hour. A coccidioidin skin test was unreactive, but a coccidioides complement-fixation determination waq reactive at 1 : 128, and a precipitin determination was reactive at 1 :40. A supraclavicular lymph node biopsy specimen contained Coccidioides immitis microorganisms. Shr was treated with a 500 ml. transfusion of convalescent “coccidioides” plasma. Subsequently, she developed nuchal rigidity; a lumbar puncture revealed a pressure of 252 mm. Hg and the cerebrospinal fluid was xanthophilic. During the seventh month of gestation the abdomen became tender, and she died. A postmortem cesarean section yielded a three-pound edematous fetus which lived for ten hours. Necropsy of thr mother revealed marked coccidioidomycosis involvement of lungs, meninges, spleen, liver, kidneys, ovaries, and the placenta, but the baby was free of coccidioidomycosis.
The placentas from all of the 6 patients were infected by coccidioidomycosis. The various mycotic infections occurring in the 17 pregnant women are listed in Table III. Coccidioidomycosis was the only mycotic infection which led to the death of pregnant women who were not immunosuppressed by
Vdumc Number-
122 5
other conditions. Five of the 15 fetuses died because of prematurity which was caused by the maternal mycotic infections. In no instance was a fetus infected by a fungus. Other mycoses. Two nonpregnant subjects had diabetes mellitus and ketoacidosis; one patient developed extensive pulmonary blastomycosis, and the other women developed mucormycosis of the orbit, eye, and meninges. The two nonpregnant patients with aspergillosis had metastatic adenocarcinomas that were treated with irradiation, chemotherapy, and high doses of prednisone, but solitary pulmonary aspergillomas rather than dissernination developed. Concurrent leukemia and lymphorna were associated with pregnancy in the two women who died from cryptococcosis. Mycotic infections occurred in three individuals within two weeks following rnajor operative procedures. Four patients who had received antibiotics for bacterial sepsis eventually died from disseminated candidiasis. Comment
Greater morbidity and higher mortality rates are described in pregnant women who are infected by certain intracellular microorganisms which are controlled by cell-mediated immunity: hepatitis,’ variala,” influenza,” varicella,’ cryptococcosis,+” coccidioidolll)cosis,7 and malaria’” can be associated with grave prognoses in pregnant women. Reduced maternal CM1 possibly allows microorganisms to proliferate, disseminate, and kill some women.’ Mycotic infections are categorized as to their pathogenicity and virulence. For example, candidiasis and coccidioidomycosis, which accounted for 36 of the 44 fungal infections described herein, are both highly pathogenic but have low virulence.“‘, ” Other opportunistic fungi, such as aspergillosis, cryptococcosis, and mucormycosis have low pathogenicity, except when occurring in patients who are immunosuppressed. Candidiasis, the mycosis most frequently occurring in compromised hosts,“‘-‘” occurred in 27 immunosuppressed patients in the present study, and 17 died from dissemination. The use of cytotoxic drugs was the major immunosuppressive factor leading to mycoses in the 44 patients described herein. Most of the patients had malignancies which were treated with chemotherapy and radiotherapy, but others were uremic, diabetic, had severe burns, or
Opportunistic
mycotic
infections
609
were given high doses of prednisone. Pregnancy seemed to be associated with candidiasis only as a secondary phenomenon. The patients had concurrent malignancies or other conditions of altered immunity which were of greater importance. Race, pregnancy. and immunosuppression are important factors linked with severe infections by Coccidioides immitis. Death rates are much greater for Mexicans, Negroes, and Filipinos as compared to Caucasians.17 The nine subjects with disseminated coccidioides in this series included four black, one Mexican-American, and four white. Six were pregnant, and two recently had been pregnant: only one was nonpregnant, but she had a lyrnphoma. Kate, pregnancy, and immunosuppression were important factors in the nine patients dying from disseminated coccidioidomycosis. Death caused by coccidioides occurs in 100 per cent of pregnant women who are not treated and in endemic areas may be the leading cause of maternal deaths.7, ” Ordinarily, dissemination occurs much more frequently in men than in women. The increases in plasma corticosteroids, progesterone, and estrogen in pregnant M:omen probably account for the higher mortality rates in pregnancy. The depression of CM1 by these hormones possibly enables Coccidioides immitis to proliferate and disseminate. Cryptococcosis is a well-known opportunistic infectious disease and has been reported in at least 18 pregnant women who were allegedly immunocompetent,+” but the two patients in the present study had concurrent malignancies. Treatment of coccidioidomycosis and cryptococcosis with amphotericin R has been successfully accomplished in pregnant women without harming the fetus or the maternal kidneys.“, lx In conclusion, coccidioidomycosis was the only opportunistic mycotic infection occurring in healthy pregnant women. Candidiasis, cryptococcosis, aspergillosis, mucormycosis, and histoplasmosis all occurred as opportunistic infectious diseases in womthe majority of whom were immunosupen, pressed. Rut at least four of the women may have been rendered vulnerable to opportunistic candidiasis as a result of antibiotic therapy. A physician should be alert for the occurrence of a variety of opportunistic infections in patients who may be immunosuppressed as a result of the effects of hyperalimentation, malnutrition, roncurrent chronic infectious diseases, burns, and other conditions.‘!‘, “‘I
REFERENCES 1.
2.
3.
4. r i: 7. 8. 9.
Purtilo, D. T., Hallgren, H. M., and Yunis, E. J.: Lanret 1: 769, 1972. Finn, R., St. Hill, C. A., Govan, A. J., Ralfs, I. G., Gurney, F. J., and Deny-e, V.: Br. Med. J. 111: 150, 1972. Nelson, J. H., Lu, T., Hall, J. E., Krown, S., Nelson, J. M., and Fox, C. W.: AM. J. OBSTET. GYNECOL. 117: 692, 1973. D’Cruz, I. A., Balani, S. G., and Iyer, L. S.: Obstet. Gynecol. 31: 449, 1968. Rao. A. R.: I. Indian Med. Assoc. 43: 224. 1964. Mendelow, D: A., and Lewis, G. C.: Obstet.‘Gynecol. 33: 98, 1968. Vaughn, J. E., and Ramirez, H.: Calif. Med. 74: 121, 3953. Pickard, R. E.: AM. J. OBSTET. GYNECOL. 101: 504, 1968. Frey, D., and Durie, E. B.: Med. J. Aust. 2: 1117, 1970.
10. 11. 12.
13. 14. 1.5. 16. 17. 18. 19. 20.
Philpot, C. R., and Lo, D.: Med. J. Aust. 2: 1005, 1972. Silberfarb, P. M., Sarosi, G. A., and Josh, I. I:. A>:. J. OBSTET. GYNECOL. 112: 714, 1972. Gilles, H. M., Lawson, J. B., Sibelas, M., \.oller, I\., and Allen, N.: Ann. Trap. Med. Parasitol. 63: 245, 1969. Utz, J. P.: Lab. Invest. 11: 1018, 1962. Lurie, H. I., and Duma, R. J,: Hum. Pathol. 1: 233. 1970. Bodey, J. P.: J. Chronic Dis. 19: 667, 1966. Young, R. C., Bennett, J. E., Geelhoed, G. W., and Levine, A. S.: Ann. Int. Med. 80: 605, 1974. Wilson, J. W.: Lab. Invest. 11: 1146, 1962. Smale, L. E., and Waechter, K. G.: AM. J. OBSTET. GYNECOL. 107: 356, 1962. Purtilo, D. T., Meyers, W. M., and Connor, D. H.: Am. J. Med. 56: 488, 1974. Purtilo, D. T.. and Connor, D. H.: Arch. Dis. Childhood 50: 149, 1975.
T.
Worcester,
Massachusetts
mycotic infections in pregnant women
PURTILO,
M.S.,
M.D.
Immunosuppression was the major factor associated with the deaths of 44 women who died opportunistic mycotic infections. The patients were immunosuppresscd by mali,qnancies, irradiation, cytotoxic drugs, and metabolic diseases. An additional four patients may have developed candidiasis as a result of antibiotic therapy. Coccidioidomycosis was the only mycosis solely associated with pregnancies not altered by e.uogenour immunosuppression.
f7om
CELL-MEDIATED IMMUNITY (CMI) iS reduced in pregnant women and thereby may help to protect the fetus from maternal immunologic rejection. Impaired transformation of lymphocytes from pregnant women by phytohemagglutinin and tuberculin are two in vitro manifestations of depressed T-lymphocyte function or CMI.‘-” An unfortunate consequence may be that the maternal immunologic surveillance becomes impaired and thus permits certain microorganisms to flourish and disseminate in pregnant women.‘.’ The files of the Armed Forces Institute of Pathology (AFIP) were searched for necropsied subjects of childbearing age who died from mycotic infections to determine whether opportunistic mycotic infections occur in pregnant women.
Methods The clinical scopic findings
Received
Accepted
Results The 44 women were from 15 to 48 years of age and averaged 30.3 years. The pregnant women averaged 29.6 years and the nonpregnant women averaged 3 1 .l years of age. The races represented were 34 white, six black, three yellow, and one mixed. Two subjects who had developed choriocarcinoma 2 months post partum were included among the 17 pregnant patients. Six subjects were at term ; two earh were in the eighth, seventh, and fourth months, and three women were in the sixth month of gestation at the tirlle of death. Candidiasis. All twenty-seven women who died from randidiasis had clinical conditions characterized by immunosuppression. For instance, many subjects had malignancies which had been treated with
records and the gross and nlicrofrom necropsies of 17 pregnant and
From the Department of Pathology. of Massachusetts Medical School.
Revised
27 nonpregnant women who died from mycotic infections which are in the AFIP file were studied. Attention \vas focused on the patient’s month of pregnancy during which the infection occurred, race, age, and underlying conditions of associated immnuosuppression which may have rendered the patients incapable of combating the infections. The organs involv-ed by fungi were microscopically studied with hematoxylin and eosin, Grocott’s methenamine silver, the periodic acid-Schiff reaction, and Rest’s mucicarrlline stains in order to identify and classify the fungi.
/or
publication
September September
II,
June
University
25, 1974.
1974. I I. 1974.
Reprint requests: Dr. David T. Purtilo, Department of Pathology, University of Massachusetts Medical School, 55 Lake Ave., N., Worcester, Massachusetts 01605.
607
Table I. Candidiasis \\ornen --
in 27 immunosuppressed
Table
infection
Disseminated (No.1
diseases
Nonpregnant subjects Leukemia* Uremia Hodgkin’s disease+ Malignancies* Collagen diseases? Diabetic ketoacidosis Pregnant subjects Uremia Leukemia* Choriocarcinoma Extensive burns Multiple sclerosist Total *Given three or more tReceived prednisone.
cytotoxic
Distal esophagus (No.1
‘1 2 3 ‘1 2 1
4 2
1 1 2 1 1 17
1
1 1
Total 20 6 4 3 3 3 1 7 ‘)
i 10
2 1 1 27
agents.
A 22-year-old month storm.
white woman of pregnancy She developed
moved to Arizona and was exposed fatigue, persistent
infection
during to a senausea,
womt’n I
IV,, L’l
Candidiasis* Coccidioidomycosis Aspergillosist BlastomycosisS Mucormycosisj Total
1 I L’i
*See Table I for associated clinical conditions, tAspergillomas in patients with adenocarcinomas. PDiabetic ketoacidosis.
Table
III.
Mycoses Mvcotic
in 17 pregnant
infection
women No.
I
7 6 ‘) i 1 17
Candidiasis* Coccidioidomycosis Cryptococcosis Aspergillosist Histoplasmosist Total *Associated diseases tpregnancy-associated
cytotoxic drugs and irradiation. Leukopenia was a common finding among these patients (Table I). All of the seven pregnant women with candidiasis also had immunosuppression related to other concurrent conditions. All but one of the pregnant women had disseminated candidiasis, whereas in the nonpregnant women dissemination occurred less frequently. Coccidioidomycosis. Disseminated Coccidioides immitis was the second most frequent mycotic infection (Tables II and III). Six of the 9 patients who died from disseminated coccidioidomycosis were pregnant, and three were nonpregnant (Table II). One of the latter patients was a Mexican-American woman who had received irradiation and chemotherapy for Hodgkin’s disease. Two other nonpregnant patients with chronic coccidioidomycosis experienced exacerbations during pregnancies and later died from coccidioidomycosis but were not pregnant when they died. Coccidioidomycosis occurred in the latter half of pregnancy in three black and three white pregnant women (Table III). The following case is presented because it illustrates the severity of coccidioidomycosis occurring in a pregnant woman.
her third vere dust
in 27 nonpregnant
Mvcotic
of
Distribution
Associated
II. Mycoses
are listed in Table choriocarcinomas.
I.
and vomiting and experienced an 8 pound loss of weight during the next month and subsequent frontal headaches, anemia, moderate eosinophilia, and marked hilar mediastinal lymphadenopathy. A cough appeared during the fifth month of gestation and she developed supraclavicular lymphadenopathy. The hemoglobin was 9 Gm. white blood cell count, 14,000 per cubic per cent; milliliter; erythrocyte sedimentation rate, 36 mm. per hour. A coccidioidin skin test was unreactive, but a coccidioides complement-fixation determination waq reactive at 1 : 128, and a precipitin determination was reactive at 1 :40. A supraclavicular lymph node biopsy specimen contained Coccidioides immitis microorganisms. Shr was treated with a 500 ml. transfusion of convalescent “coccidioides” plasma. Subsequently, she developed nuchal rigidity; a lumbar puncture revealed a pressure of 252 mm. Hg and the cerebrospinal fluid was xanthophilic. During the seventh month of gestation the abdomen became tender, and she died. A postmortem cesarean section yielded a three-pound edematous fetus which lived for ten hours. Necropsy of thr mother revealed marked coccidioidomycosis involvement of lungs, meninges, spleen, liver, kidneys, ovaries, and the placenta, but the baby was free of coccidioidomycosis.
The placentas from all of the 6 patients were infected by coccidioidomycosis. The various mycotic infections occurring in the 17 pregnant women are listed in Table III. Coccidioidomycosis was the only mycotic infection which led to the death of pregnant women who were not immunosuppressed by
Vdumc Number-
122 5
other conditions. Five of the 15 fetuses died because of prematurity which was caused by the maternal mycotic infections. In no instance was a fetus infected by a fungus. Other mycoses. Two nonpregnant subjects had diabetes mellitus and ketoacidosis; one patient developed extensive pulmonary blastomycosis, and the other women developed mucormycosis of the orbit, eye, and meninges. The two nonpregnant patients with aspergillosis had metastatic adenocarcinomas that were treated with irradiation, chemotherapy, and high doses of prednisone, but solitary pulmonary aspergillomas rather than dissernination developed. Concurrent leukemia and lymphorna were associated with pregnancy in the two women who died from cryptococcosis. Mycotic infections occurred in three individuals within two weeks following rnajor operative procedures. Four patients who had received antibiotics for bacterial sepsis eventually died from disseminated candidiasis. Comment
Greater morbidity and higher mortality rates are described in pregnant women who are infected by certain intracellular microorganisms which are controlled by cell-mediated immunity: hepatitis,’ variala,” influenza,” varicella,’ cryptococcosis,+” coccidioidolll)cosis,7 and malaria’” can be associated with grave prognoses in pregnant women. Reduced maternal CM1 possibly allows microorganisms to proliferate, disseminate, and kill some women.’ Mycotic infections are categorized as to their pathogenicity and virulence. For example, candidiasis and coccidioidomycosis, which accounted for 36 of the 44 fungal infections described herein, are both highly pathogenic but have low virulence.“‘, ” Other opportunistic fungi, such as aspergillosis, cryptococcosis, and mucormycosis have low pathogenicity, except when occurring in patients who are immunosuppressed. Candidiasis, the mycosis most frequently occurring in compromised hosts,“‘-‘” occurred in 27 immunosuppressed patients in the present study, and 17 died from dissemination. The use of cytotoxic drugs was the major immunosuppressive factor leading to mycoses in the 44 patients described herein. Most of the patients had malignancies which were treated with chemotherapy and radiotherapy, but others were uremic, diabetic, had severe burns, or
Opportunistic
mycotic
infections
609
were given high doses of prednisone. Pregnancy seemed to be associated with candidiasis only as a secondary phenomenon. The patients had concurrent malignancies or other conditions of altered immunity which were of greater importance. Race, pregnancy. and immunosuppression are important factors linked with severe infections by Coccidioides immitis. Death rates are much greater for Mexicans, Negroes, and Filipinos as compared to Caucasians.17 The nine subjects with disseminated coccidioides in this series included four black, one Mexican-American, and four white. Six were pregnant, and two recently had been pregnant: only one was nonpregnant, but she had a lyrnphoma. Kate, pregnancy, and immunosuppression were important factors in the nine patients dying from disseminated coccidioidomycosis. Death caused by coccidioides occurs in 100 per cent of pregnant women who are not treated and in endemic areas may be the leading cause of maternal deaths.7, ” Ordinarily, dissemination occurs much more frequently in men than in women. The increases in plasma corticosteroids, progesterone, and estrogen in pregnant M:omen probably account for the higher mortality rates in pregnancy. The depression of CM1 by these hormones possibly enables Coccidioides immitis to proliferate and disseminate. Cryptococcosis is a well-known opportunistic infectious disease and has been reported in at least 18 pregnant women who were allegedly immunocompetent,+” but the two patients in the present study had concurrent malignancies. Treatment of coccidioidomycosis and cryptococcosis with amphotericin R has been successfully accomplished in pregnant women without harming the fetus or the maternal kidneys.“, lx In conclusion, coccidioidomycosis was the only opportunistic mycotic infection occurring in healthy pregnant women. Candidiasis, cryptococcosis, aspergillosis, mucormycosis, and histoplasmosis all occurred as opportunistic infectious diseases in womthe majority of whom were immunosupen, pressed. Rut at least four of the women may have been rendered vulnerable to opportunistic candidiasis as a result of antibiotic therapy. A physician should be alert for the occurrence of a variety of opportunistic infections in patients who may be immunosuppressed as a result of the effects of hyperalimentation, malnutrition, roncurrent chronic infectious diseases, burns, and other conditions.‘!‘, “‘I
REFERENCES 1.
2.
3.
4. r i: 7. 8. 9.
Purtilo, D. T., Hallgren, H. M., and Yunis, E. J.: Lanret 1: 769, 1972. Finn, R., St. Hill, C. A., Govan, A. J., Ralfs, I. G., Gurney, F. J., and Deny-e, V.: Br. Med. J. 111: 150, 1972. Nelson, J. H., Lu, T., Hall, J. E., Krown, S., Nelson, J. M., and Fox, C. W.: AM. J. OBSTET. GYNECOL. 117: 692, 1973. D’Cruz, I. A., Balani, S. G., and Iyer, L. S.: Obstet. Gynecol. 31: 449, 1968. Rao. A. R.: I. Indian Med. Assoc. 43: 224. 1964. Mendelow, D: A., and Lewis, G. C.: Obstet.‘Gynecol. 33: 98, 1968. Vaughn, J. E., and Ramirez, H.: Calif. Med. 74: 121, 3953. Pickard, R. E.: AM. J. OBSTET. GYNECOL. 101: 504, 1968. Frey, D., and Durie, E. B.: Med. J. Aust. 2: 1117, 1970.
10. 11. 12.
13. 14. 1.5. 16. 17. 18. 19. 20.
Philpot, C. R., and Lo, D.: Med. J. Aust. 2: 1005, 1972. Silberfarb, P. M., Sarosi, G. A., and Josh, I. I:. A>:. J. OBSTET. GYNECOL. 112: 714, 1972. Gilles, H. M., Lawson, J. B., Sibelas, M., \.oller, I\., and Allen, N.: Ann. Trap. Med. Parasitol. 63: 245, 1969. Utz, J. P.: Lab. Invest. 11: 1018, 1962. Lurie, H. I., and Duma, R. J,: Hum. Pathol. 1: 233. 1970. Bodey, J. P.: J. Chronic Dis. 19: 667, 1966. Young, R. C., Bennett, J. E., Geelhoed, G. W., and Levine, A. S.: Ann. Int. Med. 80: 605, 1974. Wilson, J. W.: Lab. Invest. 11: 1146, 1962. Smale, L. E., and Waechter, K. G.: AM. J. OBSTET. GYNECOL. 107: 356, 1962. Purtilo, D. T., Meyers, W. M., and Connor, D. H.: Am. J. Med. 56: 488, 1974. Purtilo, D. T.. and Connor, D. H.: Arch. Dis. Childhood 50: 149, 1975.