934
Letters
likely diagnosis in this patient is, in fact, non-insulindependent diabetes, which was presumably precipitated by danazol-induced insulin resistance and which was treated with insulin. It is probable that the patient would have responded to caloric restriction alone, which would not have been provided by the 2200calorie diet that is designed for insulin-dependent diabetics. The second point concerns the cause of danazolinduced hyperglycemia. Danazol causes postreceptor resistance to insulin, which is attributed to the androgenic properties of the drug.' Another possible action is through stimulation of glucagon secretion: danazol can induce hyperglucagonemia of the degree that is usually associated with glucagonoma! This would both aggravate insulin resistance and stimulate insulin secretion, which, if the l3-cell reserve were already compromised, might lead to exhaustion of insulin secretion and thus to non-insulin-dependent diabetes. A group of danazol-treated patients whom we described previously" were glucose-intolerant overall, and one patient had impaired glucose tolerance according to World Health Organization criteria. None of the patients in this group had any hyperglycemic symptoms, and the patient with impaired glucose tolerance reverted to normoglycemia after withdrawal of the drug. Stimulation of glucagon secretion may be an androgenic property, because oxymetholone can also cause "pseudoglucagonoma. ", In conclusion, it is clearly important to monitor glycemia in women who are being treated with danazol. Practitioners who prescribe this drug must also be aware that it can cause gross hyperglucagonemia. Recognition of this assocation may spare patients with danazol-induced "pseudoglucagonoma" from undergoing unnecessary and often invasive investigations.' Gareth Williams, MA, MD Department of Medicine, The University of Liverpool, P.O. Box 147, Liverpool, England L69 3BX
REFERENCES 1. Wynn V. Metabolic effect of danazol. J lnt Med Res 1977;5 (suppl 3):25-35. 2. Williams G, Lofts F, Fiiessl H, Bloom SR. Treatment with danazol and plasma glucagon concentration. Br Med J 1985;291;1155-6.
3. Williams G, Ghatei M, Burrin J, Bloom SR. Severe hyperglucagonaemia during treatment with oxymetholone. Br Med J 1986;292: 1637-8. 4. David J. Hyperglucagonaemia and treatment with danazol for systemic lupus erythematosus. Br Med J 1985;291: 1170-1. Reply To the Editors: Although it is possible that our patient had non-insulin-dependent diabetes mellitus, we favored a diagnosis of insulin-dependent diabetes in light of 3 + ketones in the urine, which was accompanied by a random blood glucose level of 461 mg/dl and symp-
March
1991
Am J Obstet Gynecol
toms that required insulin for control. We acknowledge the possible presence of hyperglucagonemia as a result of danazol therapy, which may have exacerbated her symptoms. David B. Seifer, MD Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510
Fetal subdural hematoma before labor
To the Editors: We are interested in the case report by Demir et al. (Demir RM, Gleicher N, Myers SA. Atraumatic antepartum subdural hematoma causing fetal death. AM J OBSTET GYNECOL 1989; 160:619-20) but cannot agree with their statement that "No previous report has documented the presence of an atraurna tic subdural hematoma resulting in fetal death before labor." In 1984 we described 16 stillborn infants who had large, often bilateral, subdural hematomas.' The maternal histories suggested that fetal deaths occurred at a mean of 10 days before the macerated infants were delivered at gestations from 26 to 41 weeks. All mothers were immigrants from the Pacific Islands. We studied an additional 27 stillborn Pacific Islander infants with similar subdural hemorrhages that preceded the onset of labor and are still not certain of the cause! There was no history of trauma or anticoagulation therapy and coagulation and platelet counts were normal in studies of the mothers and two similarly affected liveborn infants.' Isoimmune thrombocytopenic purpura is one of the few coagulation disorders known to be associated with intracranial hemorrhages before delivery 4 and Demir et al. do not state whether this was excluded in their case by showing the absence of maternal antibodies specifically directed against paternal platelets. Demir et al. suggest that the hemorrhage was the cause of chronic hydrocephalus in their case in which a dilated third ventricle was consistent with obstruction of the aqueduct of Sylvius. We reported two cases of congenital hydrocephalus associated with fetal intracranial hemorrhage, and in one there was evidence that hemorrhage caused narrowing of the aqueduct.' Other infants showed effects of intrauterine blood loss such as edema or erythroblastosis. We agree with Demir et al. that fetal subdural hematoma may be unrelated to birth trauma, but we are cautious about excluding other trauma on the basis of maternal history alone. There are many situations in which trauma to the mother might be denied subsequently and we speculate that the large number of cases in Pacific Islanders is caused by traditional forms of abdominal massage during pregnancy! The condition is much less common in other populations in New Zealand but recently a 35-year-old European woman was delivered of an 800 gm male stillborn infant with a large subdural hematoma. We have seen liveborn infants with the consequences of similar hemorrhages and we agree that it is important for both medical and
Letters
Volume 164 :-.iumber 3
legal reasons that birth trauma not be assumed to be the cause. T.R. Gunn, MD Department of Paediatrics, University of Auckland, School of Medicine, Park Road, Auckland, New Zealand
D.M.O. Becroft, MD Department of Pathology, University of Auckland, School of Medicine, Park Road, Auckland, New Zealand
REFERENCES I. Gunn TR, Becroft DMO. Unexplained intracranial hae-
2.
3. 4. 5.
morrhage in utero: the battered fetus? Aust NZ J Obstet Gynaecol 1984;24: 17-22. Becroft DMO, Gunn TR. Prenatal cranial haemorrhages in 47 Pacific Islander infants: is traditional massage the cause? NZ MedJ 1989;102:207-10. Gunn TR, Mok PM, Becroft DMO. Subdural hemorrhage in utero. Pediatrics 1985;76:605-10. Zalneraitis EL, Young RSK, Krishnamoorthy KS. Intracranial hemorrhage in utero as a complication of isoimmune thrombocytopenia. J Pediatr 1979;95:611-4. Gunn TR,. Mora JD, Becroft DMO. Congenital hydrocephalus secondary to prenatal intracranial haemorrhage. Aust NZ J Obstet Gynaecol 1988;28: 197 -200.
Reply To the Editors: We appreciate the interest that Drs. Gunn and Becroft expressed in our earlier work. Whereas we were aware of the extensive experience these authors have in the field, editorial limitations did not allow us to fully acknowledge their contribution to the literature. Our interpretation of their work was that whereas they clearly had shown that such an entity as antepartum subdural hematoma exists, it had either not caused death antepartum or alternatively had caused death but was not diagnosed antepartum. Two of their works (references 2 and 5 of their letter) were not available to us at the time of our manuscript preparation. If we misinterpreted any of their earlier work, we apologize. Stephen Myers, DO DefJartment of Obstetrics and Gynecology, Mount Sinai Hospital Medical Center, California Ave. at 15th St., Chicago, IL 60608
935
and human immunodeficiency virus (HIV) infection may have been useful. Cytomegalovirus has been reported as infecting the genital tract in HIV -seropositive women I and should be considered as a possible cause of ulceration in this patient. In a case reported from this unit,2 extensive genital ulceration developed in a 23 year-old HI V-seropositive woman as a result of herpes simplex virus, which was originally sensitive to acyclovir but after 9 months continuous therapy became resistant with clinical deterioration. Zidovudine therapy led to almost complete resolution of this lesion; however, IS months later a necrotizing proximal myopathy developed and zidovudine therapy ceased. The lesions recurred within 2 weeks, but treatment with intravenous foscarnet was commenced and the lesions completely resolved within 2 weeks. Inasmuch as foscarnet is active against cytomegalovirus, HIV, and herpes simplex virus, we believe that it may be a useful empirical therapy in such cases. Third, there is no mention of other drugs that this patient may have been taking, for instance prophylaxis against Pneumocystis carinii pneumonia. Such a drug history is vital because a fixed drug eruption is an important differential diagnosis in this case. Fourth, we agree that treatment of genital ulceration in HIV-infected patients is difficult. Zidovudine may have been successful because of its direct antiretroviral activity but also because of a stimulatory effect on the CD4 count. Thalidomide has also been reported to be effective in resistant mucosal ulcers associated with HIV, as have intralesional steroid i~ections." However, the potential teratogenic effects of the former must be considered before its use in women of child-bearing age. We believe that a combined team including dermatologists, gynecologists, and genitourinary physicians provides the best management in these difficult cases. P.D. Kelt, MD, and S.E. Barton, MD Department of Genitourinary Medicine, St. Stephens Clinic, 369 Fulham Road, London, England SWlO 9TH
REFERENCES
Unraveling the mysteries of vulval ulceration in human immunodeficiency virus-seropositive women To the Editors: We believe that the case reported by Covino and McCormack (Covino 1M, McCormack WM. Vulval ulcer of unknown etiology in a human immunodeficiency virus-infected woman: response to treatment with zidovudine. AM J OBSTET GYNECOL 1990; 163: 116-8) raises several points of interest. First, although mention is made of oral aphthous ulceration, there is neither further comment on the significance of this nor apparent consideration of other diagnoses such as lichen planus or Crohn's disease. A review of the histopathology of the biopsy specimen with regard to such diagnoses may be worthwhile. Second, immunocytochemical staining of the biopsy specimen by specific monoclonal antibodies to search for evidence of cytomegalovirus, herpes simplex virus,
I. Brown S, Senekjian E, Montag A. Cytomegalovirus infec-
tion of the uterine cervix in a patient with acquired immune deficiency syndrome. Obstet Gynecol 1988;71 :3:489-91. 2. Youle M, Hawkins D, Collins P, Shanson D, Evans R, Oliver N, Lawrence A. Acyclovir-resistant herpes in AIDS treated with Foscarnet. Lancet 1988;2:341. 3. You Ie M, Hawkins D, Gazzard B. Thalidomide in hyperalgic pharyngeal ulceration in AIDS. Lancet 1990; I: 1591. Reply To the Editors: We thank Drs. Kell and Barton for their comments regarding our article and for the opportunity to provide additional information regarding our patient. First, histopathologic examination of the biopsy specimens from the vestibular ulcer disclosed only acute and chronic inflammation, granulation tissue, dysplasia, and condylomatous changes. Biopsy specimens of the oral aphthae were not obtained. There was no evidence of either lichen planus or Crohn's disease.
Letters
likely diagnosis in this patient is, in fact, non-insulindependent diabetes, which was presumably precipitated by danazol-induced insulin resistance and which was treated with insulin. It is probable that the patient would have responded to caloric restriction alone, which would not have been provided by the 2200calorie diet that is designed for insulin-dependent diabetics. The second point concerns the cause of danazolinduced hyperglycemia. Danazol causes postreceptor resistance to insulin, which is attributed to the androgenic properties of the drug.' Another possible action is through stimulation of glucagon secretion: danazol can induce hyperglucagonemia of the degree that is usually associated with glucagonoma! This would both aggravate insulin resistance and stimulate insulin secretion, which, if the l3-cell reserve were already compromised, might lead to exhaustion of insulin secretion and thus to non-insulin-dependent diabetes. A group of danazol-treated patients whom we described previously" were glucose-intolerant overall, and one patient had impaired glucose tolerance according to World Health Organization criteria. None of the patients in this group had any hyperglycemic symptoms, and the patient with impaired glucose tolerance reverted to normoglycemia after withdrawal of the drug. Stimulation of glucagon secretion may be an androgenic property, because oxymetholone can also cause "pseudoglucagonoma. ", In conclusion, it is clearly important to monitor glycemia in women who are being treated with danazol. Practitioners who prescribe this drug must also be aware that it can cause gross hyperglucagonemia. Recognition of this assocation may spare patients with danazol-induced "pseudoglucagonoma" from undergoing unnecessary and often invasive investigations.' Gareth Williams, MA, MD Department of Medicine, The University of Liverpool, P.O. Box 147, Liverpool, England L69 3BX
REFERENCES 1. Wynn V. Metabolic effect of danazol. J lnt Med Res 1977;5 (suppl 3):25-35. 2. Williams G, Lofts F, Fiiessl H, Bloom SR. Treatment with danazol and plasma glucagon concentration. Br Med J 1985;291;1155-6.
3. Williams G, Ghatei M, Burrin J, Bloom SR. Severe hyperglucagonaemia during treatment with oxymetholone. Br Med J 1986;292: 1637-8. 4. David J. Hyperglucagonaemia and treatment with danazol for systemic lupus erythematosus. Br Med J 1985;291: 1170-1. Reply To the Editors: Although it is possible that our patient had non-insulin-dependent diabetes mellitus, we favored a diagnosis of insulin-dependent diabetes in light of 3 + ketones in the urine, which was accompanied by a random blood glucose level of 461 mg/dl and symp-
March
1991
Am J Obstet Gynecol
toms that required insulin for control. We acknowledge the possible presence of hyperglucagonemia as a result of danazol therapy, which may have exacerbated her symptoms. David B. Seifer, MD Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510
Fetal subdural hematoma before labor
To the Editors: We are interested in the case report by Demir et al. (Demir RM, Gleicher N, Myers SA. Atraumatic antepartum subdural hematoma causing fetal death. AM J OBSTET GYNECOL 1989; 160:619-20) but cannot agree with their statement that "No previous report has documented the presence of an atraurna tic subdural hematoma resulting in fetal death before labor." In 1984 we described 16 stillborn infants who had large, often bilateral, subdural hematomas.' The maternal histories suggested that fetal deaths occurred at a mean of 10 days before the macerated infants were delivered at gestations from 26 to 41 weeks. All mothers were immigrants from the Pacific Islands. We studied an additional 27 stillborn Pacific Islander infants with similar subdural hemorrhages that preceded the onset of labor and are still not certain of the cause! There was no history of trauma or anticoagulation therapy and coagulation and platelet counts were normal in studies of the mothers and two similarly affected liveborn infants.' Isoimmune thrombocytopenic purpura is one of the few coagulation disorders known to be associated with intracranial hemorrhages before delivery 4 and Demir et al. do not state whether this was excluded in their case by showing the absence of maternal antibodies specifically directed against paternal platelets. Demir et al. suggest that the hemorrhage was the cause of chronic hydrocephalus in their case in which a dilated third ventricle was consistent with obstruction of the aqueduct of Sylvius. We reported two cases of congenital hydrocephalus associated with fetal intracranial hemorrhage, and in one there was evidence that hemorrhage caused narrowing of the aqueduct.' Other infants showed effects of intrauterine blood loss such as edema or erythroblastosis. We agree with Demir et al. that fetal subdural hematoma may be unrelated to birth trauma, but we are cautious about excluding other trauma on the basis of maternal history alone. There are many situations in which trauma to the mother might be denied subsequently and we speculate that the large number of cases in Pacific Islanders is caused by traditional forms of abdominal massage during pregnancy! The condition is much less common in other populations in New Zealand but recently a 35-year-old European woman was delivered of an 800 gm male stillborn infant with a large subdural hematoma. We have seen liveborn infants with the consequences of similar hemorrhages and we agree that it is important for both medical and
Letters
Volume 164 :-.iumber 3
legal reasons that birth trauma not be assumed to be the cause. T.R. Gunn, MD Department of Paediatrics, University of Auckland, School of Medicine, Park Road, Auckland, New Zealand
D.M.O. Becroft, MD Department of Pathology, University of Auckland, School of Medicine, Park Road, Auckland, New Zealand
REFERENCES I. Gunn TR, Becroft DMO. Unexplained intracranial hae-
2.
3. 4. 5.
morrhage in utero: the battered fetus? Aust NZ J Obstet Gynaecol 1984;24: 17-22. Becroft DMO, Gunn TR. Prenatal cranial haemorrhages in 47 Pacific Islander infants: is traditional massage the cause? NZ MedJ 1989;102:207-10. Gunn TR, Mok PM, Becroft DMO. Subdural hemorrhage in utero. Pediatrics 1985;76:605-10. Zalneraitis EL, Young RSK, Krishnamoorthy KS. Intracranial hemorrhage in utero as a complication of isoimmune thrombocytopenia. J Pediatr 1979;95:611-4. Gunn TR,. Mora JD, Becroft DMO. Congenital hydrocephalus secondary to prenatal intracranial haemorrhage. Aust NZ J Obstet Gynaecol 1988;28: 197 -200.
Reply To the Editors: We appreciate the interest that Drs. Gunn and Becroft expressed in our earlier work. Whereas we were aware of the extensive experience these authors have in the field, editorial limitations did not allow us to fully acknowledge their contribution to the literature. Our interpretation of their work was that whereas they clearly had shown that such an entity as antepartum subdural hematoma exists, it had either not caused death antepartum or alternatively had caused death but was not diagnosed antepartum. Two of their works (references 2 and 5 of their letter) were not available to us at the time of our manuscript preparation. If we misinterpreted any of their earlier work, we apologize. Stephen Myers, DO DefJartment of Obstetrics and Gynecology, Mount Sinai Hospital Medical Center, California Ave. at 15th St., Chicago, IL 60608
935
and human immunodeficiency virus (HIV) infection may have been useful. Cytomegalovirus has been reported as infecting the genital tract in HIV -seropositive women I and should be considered as a possible cause of ulceration in this patient. In a case reported from this unit,2 extensive genital ulceration developed in a 23 year-old HI V-seropositive woman as a result of herpes simplex virus, which was originally sensitive to acyclovir but after 9 months continuous therapy became resistant with clinical deterioration. Zidovudine therapy led to almost complete resolution of this lesion; however, IS months later a necrotizing proximal myopathy developed and zidovudine therapy ceased. The lesions recurred within 2 weeks, but treatment with intravenous foscarnet was commenced and the lesions completely resolved within 2 weeks. Inasmuch as foscarnet is active against cytomegalovirus, HIV, and herpes simplex virus, we believe that it may be a useful empirical therapy in such cases. Third, there is no mention of other drugs that this patient may have been taking, for instance prophylaxis against Pneumocystis carinii pneumonia. Such a drug history is vital because a fixed drug eruption is an important differential diagnosis in this case. Fourth, we agree that treatment of genital ulceration in HIV-infected patients is difficult. Zidovudine may have been successful because of its direct antiretroviral activity but also because of a stimulatory effect on the CD4 count. Thalidomide has also been reported to be effective in resistant mucosal ulcers associated with HIV, as have intralesional steroid i~ections." However, the potential teratogenic effects of the former must be considered before its use in women of child-bearing age. We believe that a combined team including dermatologists, gynecologists, and genitourinary physicians provides the best management in these difficult cases. P.D. Kelt, MD, and S.E. Barton, MD Department of Genitourinary Medicine, St. Stephens Clinic, 369 Fulham Road, London, England SWlO 9TH
REFERENCES
Unraveling the mysteries of vulval ulceration in human immunodeficiency virus-seropositive women To the Editors: We believe that the case reported by Covino and McCormack (Covino 1M, McCormack WM. Vulval ulcer of unknown etiology in a human immunodeficiency virus-infected woman: response to treatment with zidovudine. AM J OBSTET GYNECOL 1990; 163: 116-8) raises several points of interest. First, although mention is made of oral aphthous ulceration, there is neither further comment on the significance of this nor apparent consideration of other diagnoses such as lichen planus or Crohn's disease. A review of the histopathology of the biopsy specimen with regard to such diagnoses may be worthwhile. Second, immunocytochemical staining of the biopsy specimen by specific monoclonal antibodies to search for evidence of cytomegalovirus, herpes simplex virus,
I. Brown S, Senekjian E, Montag A. Cytomegalovirus infec-
tion of the uterine cervix in a patient with acquired immune deficiency syndrome. Obstet Gynecol 1988;71 :3:489-91. 2. Youle M, Hawkins D, Collins P, Shanson D, Evans R, Oliver N, Lawrence A. Acyclovir-resistant herpes in AIDS treated with Foscarnet. Lancet 1988;2:341. 3. You Ie M, Hawkins D, Gazzard B. Thalidomide in hyperalgic pharyngeal ulceration in AIDS. Lancet 1990; I: 1591. Reply To the Editors: We thank Drs. Kell and Barton for their comments regarding our article and for the opportunity to provide additional information regarding our patient. First, histopathologic examination of the biopsy specimens from the vestibular ulcer disclosed only acute and chronic inflammation, granulation tissue, dysplasia, and condylomatous changes. Biopsy specimens of the oral aphthae were not obtained. There was no evidence of either lichen planus or Crohn's disease.
