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Ectopic Pregnancies After Induction of Ovulation and In Vitro Fertilization
Vol. 57, No. 1, January 1992
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright<> 1992 The American Fertility Society
Ectopic Pregnancies After Induction of Ovulation and In Vitro Fertilization
To the Editor: I read with great interest the article by Shoham et al. (1). The authors present a wide review of current experience with pregnancies associated with ovulation induction treatment and in vitro fertilization (IVF) and try to answer the questions raised concerning the adverse effects of the drugs on the conception and the abortion rate of these pregnancies. However, when describing complications after infertility treatment we should also have in mind the life-threatening complication of ectopic pregnancy (EP) that occurs three to four times more frequently after such treatment (2). Recently published works (3, 4) report even higher rates of EPs among gestations achieved in IVF and embryo transfer. Although it is well accepted that tubal pathology may explain the increased risk of EP, some researchers (3, 5) could not find a major predisposing factor in EPs occurrence in IVF, and some even noted relation to clomiphene citrate treatment (3). The factors responsible for the increased risk of ectopic gestation after infertility treatment are still to be explored, and wider studies are needed to evaluate properly their role in pathogenesis of EP.
Moshe Royburt, M.D. Sheba Medical Center Tel-Hashomer, Israel July 1, 1991 REFERENCES 1. Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril1991;55:1-11. 2. McBain JC, Evans JH, Pepperell RJ, Robinson HP, Smith MA. An unexpectedly high rate of ectopic pregnancy following the induction of ovulation with human pituitary and chorionic gonadotrophin. Br J Obstet Gynaecol 1980;87:5. 3. Cohen J, Mayaux MJ, Guihard-Moscato ML. Pregnancy outcomes after in vitro fertilization. A collaborative study of 2342 pregnancies. Ann NY Acad Sci 1988;541:1-5. 4. Medical Research International and the Society for Assisted Reproductive Technology, The American Fertility Society. In vitro fertilization-embryo transfer in the United States: 1988 results from the IVF-ET registry. Fertil Steril1990;53: 13-20. 5. Martinez F, Trounson A. An analysis of factors associated with ectopic pregnancy in a human in vitro fertilization program. Fertil Steril 1986;45:79-87. Vol. 57, No. 1, January 1992
Reply of the Authors: We thank the author for his comment regarding the increased rate of ectopic pregnancies after in vitro fertilization and embryo transfer, of which we are fully aware (1). Ectopic pregnancy is one of several severe complications after gonadotropin therapy, such as severe ovarian hyperstimulation syndrome (2) and adnexal torsion (3). However, the purpose of our review (4) was to address only two main topics: early pregnancy loss and fetal malformations.
Zeev Shoham, M.D. Vaclav Insler, M.D. Department of Obstetrics and Gynecology Kaplan Hospital (Affiliated with the Hebrew University and the Hadassah-School of Medicine, Jerusalem, Israel) Rehovot Israel September 5, 1991
REFERENCES 1. Barash A, Shoham Z, Blickstein I, Yamini M, Borenstein R. Simultaneous tubal and intrauterine pregnancy following in vitro fertilization and embryo transfer. Acta Obstet Gynecol Scand 1989;68:643-8. 2. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian hyperstimulation syndrome: a re-evaluated therapeutic approach. Fertil Steril1989;51:791-95. 3. Mashiach S, Bider D, Moran 0, Goldenberg M, Ben-Rafael Z. Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil Steril 1990;53:76-80. 4. Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril1991;55:1-11.
Sperm Antibodies and Steroid Treatment
To the Editor: The paper by Howe et al. (1) was very interesting. Although this report dealt mostly with the detection of a subclass of sperm antibody, namely, antibody to the acrosin of the sperm cells, I wish to focus on one of the peripheral points of the report. This point deals with the efforts at treatment by use of steroid medication, along with inseminations. A total of 27 women were given prednisone that "varied from 10 Letters-to-the-editor
227
mg/d to 16 mg three times daily . . ." for 7 days beginning on day 21 of each cycle. First of all, it is not clear what the variation between 10 and 48 mg means-whether these were different amounts given to different people or were the same for all people but varied with different cycles, or some other meaning. Second, the steroid regimen, at least for the high-dose level of 48 mg/d, seems to be quite similar to our proposed method (2), in which the steroid was methylprednisolone and was used at 96 mg/d; nonetheless, it was maintained for 7 days and it did start on day 21 of the cycle. These same scheduling details were proposed in our very first report of the high-dose treatment (3). However, all of our reported cases involved treatment of men, not women. We have also suggested this same treatment for women with sperm antibody and we have had some success (not yet published), but we elected to start on day 1 of the cycle in those cases where women took the medication. We suggested this schedule to be absolutely sure that the woman was not pregnant when she took the steroid. The third point is the success rate. Howe et al. (1) describe very briefly the results of treatment for two groups of patients, those with sperm antibody that does include acrosin antibody and those with sperm antibody that does not include acrosin antibody. They reported that in the former group, 2 of 8 women, or 25%, became pregnant. On the other hand, of those women without acrosin antibody, 6 of 19 women, or 32%, became pregnant. Therefore, they concluded that no difference is found between these two groups. It seems quite true that there is no essential difference, but I would make an alternative point of emphasis. Perhaps we should conclude that the therapy, as far as we can tell from rather small groups, was quite effective for both groups, or to put it differently, that it was successful even in the presence of acrosin antibody. In our own study, we had achieved a pregnancy rate of 44% in a group of 71 men who were treated with the high-dose regimen for 1 to 6 months. Although we had not studied a control group, an excellent control study was conducted by Hargreave and Elton (4), who showed a much lower pregnancy rate in the partners of a group of men who had sperm antibody and took a placebo in contrast to those with antibody who were treated by the high-dose steroid procedure. In the report by Howe et al. (1) there is no mention of any control group; it would be interesting to know whether there were any women who had sperm antibody who were not treated and what kind of pregnancy rate that group had. Actually they do not seem 228
Letters-to-the-editor
to state the duration of time until the pregnancies were achieved, although their description seems to imply that these pregnancies occurred within the 6 months of the treatment period. One would also wish to know the length of time that was involved for any pregnancies that occurred in untreated women.
Sidney Shulman, Ph.D. Sperm Antibody Laboratory ·Fertility Antibody Diagnostics, Inc. New York, New York July 31, 1991 REFERENCES 1. Howe SE, Grider SL, Lynch DM, Fink LM. Antisperm an-
tibody binding to human acrosin: a study of patients with unexplained infertility. Fertil Steril1991;55:1176-82. 2. Shulman JF, Shulman S. Methylprednisolone treatment of immunologic infertility in the male. Fertil Steril1982;36:59199. 3. Shulman S. Treatment of immune male infertility with methylprednisolone. Lancet 1976;2:1243-6. 4. Hargreave TB, Elton RA. Treatment with intermittent high dose methylprednisolone or intermittent betamethasone for antisperm antibodies: preliminary communication. Fertil Steril 1982;38:586-90.
Reply of the Author: The emphasis and design of our study does not allow complete answers to Dr. Shulman's questions nor support for his alternative interpretations. We report that antisperm antibodies have specificity, including antiacrosin specificity that can be demonstrated using Western blotting in a significant number of patients, and that antiacrosin specificity does not preclude pregnancy. Patients studied were referred by attending physicians who made therapeutic decisions independent of the study. Dosages of prednisone varied with different patients and occasionally between cycles with only a few patients receiving the high dosages used in Dr. Shulman's studies. Data was not collected on the interval between treatment and pregnancy, the length of this interval with prednisone dosage, or variations in pregnancy rates with prednisone dosage. Group size and the absence of large untreated control groups further limit statistical comparisons. Dr. Shulman's questions and optimistic interpretations await an expanded study design.
Stephen E. Howe, M.D. Reproductive Immunology Department of Pathology Rose Medical Center Denver, Colorado September 16, 1991 Fertility and Sterility
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright<> 1992 The American Fertility Society
Ectopic Pregnancies After Induction of Ovulation and In Vitro Fertilization
To the Editor: I read with great interest the article by Shoham et al. (1). The authors present a wide review of current experience with pregnancies associated with ovulation induction treatment and in vitro fertilization (IVF) and try to answer the questions raised concerning the adverse effects of the drugs on the conception and the abortion rate of these pregnancies. However, when describing complications after infertility treatment we should also have in mind the life-threatening complication of ectopic pregnancy (EP) that occurs three to four times more frequently after such treatment (2). Recently published works (3, 4) report even higher rates of EPs among gestations achieved in IVF and embryo transfer. Although it is well accepted that tubal pathology may explain the increased risk of EP, some researchers (3, 5) could not find a major predisposing factor in EPs occurrence in IVF, and some even noted relation to clomiphene citrate treatment (3). The factors responsible for the increased risk of ectopic gestation after infertility treatment are still to be explored, and wider studies are needed to evaluate properly their role in pathogenesis of EP.
Moshe Royburt, M.D. Sheba Medical Center Tel-Hashomer, Israel July 1, 1991 REFERENCES 1. Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril1991;55:1-11. 2. McBain JC, Evans JH, Pepperell RJ, Robinson HP, Smith MA. An unexpectedly high rate of ectopic pregnancy following the induction of ovulation with human pituitary and chorionic gonadotrophin. Br J Obstet Gynaecol 1980;87:5. 3. Cohen J, Mayaux MJ, Guihard-Moscato ML. Pregnancy outcomes after in vitro fertilization. A collaborative study of 2342 pregnancies. Ann NY Acad Sci 1988;541:1-5. 4. Medical Research International and the Society for Assisted Reproductive Technology, The American Fertility Society. In vitro fertilization-embryo transfer in the United States: 1988 results from the IVF-ET registry. Fertil Steril1990;53: 13-20. 5. Martinez F, Trounson A. An analysis of factors associated with ectopic pregnancy in a human in vitro fertilization program. Fertil Steril 1986;45:79-87. Vol. 57, No. 1, January 1992
Reply of the Authors: We thank the author for his comment regarding the increased rate of ectopic pregnancies after in vitro fertilization and embryo transfer, of which we are fully aware (1). Ectopic pregnancy is one of several severe complications after gonadotropin therapy, such as severe ovarian hyperstimulation syndrome (2) and adnexal torsion (3). However, the purpose of our review (4) was to address only two main topics: early pregnancy loss and fetal malformations.
Zeev Shoham, M.D. Vaclav Insler, M.D. Department of Obstetrics and Gynecology Kaplan Hospital (Affiliated with the Hebrew University and the Hadassah-School of Medicine, Jerusalem, Israel) Rehovot Israel September 5, 1991
REFERENCES 1. Barash A, Shoham Z, Blickstein I, Yamini M, Borenstein R. Simultaneous tubal and intrauterine pregnancy following in vitro fertilization and embryo transfer. Acta Obstet Gynecol Scand 1989;68:643-8. 2. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian hyperstimulation syndrome: a re-evaluated therapeutic approach. Fertil Steril1989;51:791-95. 3. Mashiach S, Bider D, Moran 0, Goldenberg M, Ben-Rafael Z. Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil Steril 1990;53:76-80. 4. Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril1991;55:1-11.
Sperm Antibodies and Steroid Treatment
To the Editor: The paper by Howe et al. (1) was very interesting. Although this report dealt mostly with the detection of a subclass of sperm antibody, namely, antibody to the acrosin of the sperm cells, I wish to focus on one of the peripheral points of the report. This point deals with the efforts at treatment by use of steroid medication, along with inseminations. A total of 27 women were given prednisone that "varied from 10 Letters-to-the-editor
227
mg/d to 16 mg three times daily . . ." for 7 days beginning on day 21 of each cycle. First of all, it is not clear what the variation between 10 and 48 mg means-whether these were different amounts given to different people or were the same for all people but varied with different cycles, or some other meaning. Second, the steroid regimen, at least for the high-dose level of 48 mg/d, seems to be quite similar to our proposed method (2), in which the steroid was methylprednisolone and was used at 96 mg/d; nonetheless, it was maintained for 7 days and it did start on day 21 of the cycle. These same scheduling details were proposed in our very first report of the high-dose treatment (3). However, all of our reported cases involved treatment of men, not women. We have also suggested this same treatment for women with sperm antibody and we have had some success (not yet published), but we elected to start on day 1 of the cycle in those cases where women took the medication. We suggested this schedule to be absolutely sure that the woman was not pregnant when she took the steroid. The third point is the success rate. Howe et al. (1) describe very briefly the results of treatment for two groups of patients, those with sperm antibody that does include acrosin antibody and those with sperm antibody that does not include acrosin antibody. They reported that in the former group, 2 of 8 women, or 25%, became pregnant. On the other hand, of those women without acrosin antibody, 6 of 19 women, or 32%, became pregnant. Therefore, they concluded that no difference is found between these two groups. It seems quite true that there is no essential difference, but I would make an alternative point of emphasis. Perhaps we should conclude that the therapy, as far as we can tell from rather small groups, was quite effective for both groups, or to put it differently, that it was successful even in the presence of acrosin antibody. In our own study, we had achieved a pregnancy rate of 44% in a group of 71 men who were treated with the high-dose regimen for 1 to 6 months. Although we had not studied a control group, an excellent control study was conducted by Hargreave and Elton (4), who showed a much lower pregnancy rate in the partners of a group of men who had sperm antibody and took a placebo in contrast to those with antibody who were treated by the high-dose steroid procedure. In the report by Howe et al. (1) there is no mention of any control group; it would be interesting to know whether there were any women who had sperm antibody who were not treated and what kind of pregnancy rate that group had. Actually they do not seem 228
Letters-to-the-editor
to state the duration of time until the pregnancies were achieved, although their description seems to imply that these pregnancies occurred within the 6 months of the treatment period. One would also wish to know the length of time that was involved for any pregnancies that occurred in untreated women.
Sidney Shulman, Ph.D. Sperm Antibody Laboratory ·Fertility Antibody Diagnostics, Inc. New York, New York July 31, 1991 REFERENCES 1. Howe SE, Grider SL, Lynch DM, Fink LM. Antisperm an-
tibody binding to human acrosin: a study of patients with unexplained infertility. Fertil Steril1991;55:1176-82. 2. Shulman JF, Shulman S. Methylprednisolone treatment of immunologic infertility in the male. Fertil Steril1982;36:59199. 3. Shulman S. Treatment of immune male infertility with methylprednisolone. Lancet 1976;2:1243-6. 4. Hargreave TB, Elton RA. Treatment with intermittent high dose methylprednisolone or intermittent betamethasone for antisperm antibodies: preliminary communication. Fertil Steril 1982;38:586-90.
Reply of the Author: The emphasis and design of our study does not allow complete answers to Dr. Shulman's questions nor support for his alternative interpretations. We report that antisperm antibodies have specificity, including antiacrosin specificity that can be demonstrated using Western blotting in a significant number of patients, and that antiacrosin specificity does not preclude pregnancy. Patients studied were referred by attending physicians who made therapeutic decisions independent of the study. Dosages of prednisone varied with different patients and occasionally between cycles with only a few patients receiving the high dosages used in Dr. Shulman's studies. Data was not collected on the interval between treatment and pregnancy, the length of this interval with prednisone dosage, or variations in pregnancy rates with prednisone dosage. Group size and the absence of large untreated control groups further limit statistical comparisons. Dr. Shulman's questions and optimistic interpretations await an expanded study design.
Stephen E. Howe, M.D. Reproductive Immunology Department of Pathology Rose Medical Center Denver, Colorado September 16, 1991 Fertility and Sterility