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Methotrexate affects ovarian reserve in treatment of ectopic pregnancies resulting from ART
underwent medical abortion by regimens containing combination of mifepristone followed by misoprostol or misoprostol only. Clinical assessment as well as sonographic evaluation of uterine cavity content and endometrial thickness and morphology was done after the second dose of the drug, 10 –14 days later and when necessary again after the next menstruation. Endometrial line with a maximum thickness less than 15 mm was defined as normal. In cases of thicker endometrium or intrauterine irregular hyperechogenic shadows a further sonographic evaluation was programmed after the first menstrual period. Patients were interviewed for clinical symptoms suspected for residual throphoblastic tissue as prolonged bleeding or spotting. Women with persistent gestational sac, heavy bleeding or intractable pain underwent surgical complementation of the abortion at any moment of the follow up. Patients completely asymptomatic but suspected for residual tissue, at ultrasonography were invited for diagnostic and if necessary operative hysteroscopy only after the next menstruation. The suspected lesion was removed and sent for hystologic analysis. RESULTS: 430 patients were studied. 193 of them underwent medical termination of pregnancy and 237 were treated because of spontaneous abortion. 17 patients in both groups were lost for follow up. The detection of pregnancy rests by vaginal ultrasonography achieved a sensitivity of 100% in both groups (TOP and SA) and a specificity of 98.7% for TOP and respectively 97.7% for SA. A management based only on clinical symptoms achieved a sensitivity of 68.2% with 99.4% specificity in cases of TOP but a sensitivity of 88.2% and specificity of 99.4% in cases of SA. CONCLUSION: The introduction of the ultrasound in the clinical management of patients requesting medical termination of pregnancy improves the detection of pregnancy rests (residua). In order to reduce the false positive cases the optimal time for scanning is after the next menstrual period and not longer than 35 days from the administration of the treatment. Supported by: Mifepristone for sa was provided as a non limited gift by A. Lapidot.
P-21 Risk factors for ectopic pregnancy in women with undiagnosed symptomatic first trimester pregnancy: Not what you think. K. T. Barnhart, M. D. Sammel, J. Chittams, A. Hummel, A. Shaunik. UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA. OBJECTIVE: Identification of women with ectopic pregnancy (EP) is still a quandary especially when the initial b-hCG values are low. Previous studies have focused on easily diagnosed ectopic or intrauterine pregnancies (IUP) of advance gestational age, or have used non-pregnant controls. The goal of this study was to determine risk factors predictive of EP in the high risk group of women with symptomatic first trimester pregnancies who could not be diagnosed upon initial presentation. DESIGN: Case control study. MATERIALS AND METHODS: Women presenting with pain/bleeding in first trimester, with no definitive diagnosis at presentation, were selected for study. They were prospectively followed until definitive diagnosis was established. Cases were those with an EP and Controls were women with viable IUP or miscarriage (SAB). Potential risk factors were derived from history and clinical presentation. A backward selection, logistic regression model was performed to control for confounding and effect modification. The final model restricted to variables with p-value of ⱕ0.05 or those that significantly affected the coefficient of estimates of other variables by 15%. Odds ratio ⱖ1 denotes a statistically significant risk factor, i.e. more prevalent in Cases than in Controls. RESULTS: 2026 women were studied: 366 Cases and 1660 Controls (467 IUP and 1192 SAB). The strongest risk factors were history of EP, OR⫽2.98 [95%CI: 1.88 – 4.73 p⬍0.01] for 1 prior EP, and OR⫽16.04 [5.39 – 47.72, p⬍0.01] for ⬎1 prior EP. Other significant risk factors were presentation with clinical symptoms of pain OR⫽1.42, [1.04 –1.93, p⫽0.02] and/or bleeding OR: 1.42, [1.06 –1.92, p⫽0.03] and laboratory finding of b-hCG titer of 501–2000 IU/ml (compared to ⱕ500 or greater ⬎2000) OR⫽1.73, [1.24 –2.42, p⬍0.01]. Other predictive factors were history of prior delivery OR⫽1.71, [1.21–2.42, p⬍0.01] and history of hospital admission for treatment of pelvic infection OR⫽1.50 [1.11–2.05, p⫽0.01]. If women had all of these risk factors the risk of EP was OR⫽48.38 [p⬍0.01]. Protective risk factors were previous history of induced abortion; OR⫽0.58, [0.61–1.6 p⫽0.02] and maternal age ⬎ 25 years; OR⫽0.34 [0.22– 0.52, p⬍0.01]. Notable are putative risk factors that showed no association with EP including: history of pelvic surgery, cesarean section, past use of IUD,
FERTILITY & STERILITY威
outpatient treatment for pelvic infection, concurrent infection with Chlamydia and/or Gonorrhea, prior SAB, prior live birth or initial non-diagnostic ultrasound. CONCLUSION: Identification of risk factors may aid in classifying women at high risk for EP. As anticipated, strongest risk factor in this clinically relevant group of women, with undiagnosed symptomatic first trimester pregnancy, was history of EP. Importantly, putative risk factors such as history of tubal surgery, IUD use, PID and cervicitis were weakly associated and/or not predictive, which drastically limits their clinical utility. Supported by: NIH grant RO1: HD-36455– 05
P-22 Comparison of age related pregnancy rates (PR) in women using different ovulation induction (OI) methods. C. Morelli, N. Virji, J. Stelling, K. Cain, G. San Roman. Reproductive Specialists of New York; Dept. of OB/GYN, Winthrop University Hospital, Mineola, NY; Reproductive Specialists of New York, Mineola, NY; Reproductive Specialists of New York; Dept. of OB/GYN, Winthrop University Hospital; Dept. of OB/GYN, Stony Brook University of New York, Stony Brook, NY. OBJECTIVE: To determine if a specific OI method is beneficial for the treatment of infertility in patients of a particular age group. DESIGN: A retrospective analysis of 4448 OI cycles with intrauterine inseminations (IUIs) in women undergoing treatment for infertility. MATERIALS AND METHODS: Women undergoing IUI cycles using different OI methods from January 2001 to December 2003 were analyzed for clinical PR. Clinical pregnancy was defined as the presence of an intrauterine sac documented by ultrasound. Patients were grouped according to ovulation induction METHOD: Natural, Clomiphene citrate (CC) 25, CC50, CC100, CC150, ⬎CC150, and FSH. In each of these groups, the patients were further divided according to age: ⬍ 30, 30 –34, 35–39, 40 – 42, and ⬎ 42. Age related PR differences between OI groups were determined statistically by Chi Square analysis. RESULTS: Significant differences in PR were seen for women 30 –39 amongst the different OI methods as shown in Tables 1 and 2.
p values are as follows: ap⬍0.05 vs. Natural; bp⬍0.05 vs. Total CC
p values are as follows: ap⬍0.05 vs CC50; bp⬍0.05 vs. CC150 CONCLUSION: This study has shown that women 30 –39 years of age undergoing IUI with FSH stimulation have the greatest chance of pregnancy. For women 35–39 years of age who fail to conceive on CC, the next choice of treatment should be FSH rather than incremental increases in CC dosing. CC100 use in women ⬍35 years of age was associated with the highest PR and therefore should be considered the ideal starting dose for these patients. Supported by: Reproductive Specialists of New York
P-23 Methotrexate affects ovarian reserve in treatment of ectopic pregnancies resulting from ART. M. Payson, J. Allard, R. Alvero, J. Segars, F. Larsen. Walter Reed Army Medical Center, Washington, DC; University of Colorado Health Sciences, Aurora, CO; National Institute of Health, Bethesda, MD.
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OBJECTIVE: The success of methotrexate in treating ectopic pregnancy is well established and few patients are currently treated with surgical therapy. Many patients undergoing ART have limited ovarian reserve prior to the initiation of therapy. In ART programs, ectopic pregnancies are frequently observed, and due to the close monitoring of these patients, are generally diagnosed early and may be treated with methotrexate (MTX). The possible adverse affects on ovarian function of methotrexate are unknown. Our objective was to determine whether methotrexate therapy for ART-associated gestations had an effect on ovarian reserve and success in subsequent ART cycles. DESIGN: Retrospective chart review. MATERIALS AND METHODS: After IRB approval, a retrospective chart review was performed of all IVF cycles at our institution from July 1998 to March 2004. A total of 2900 cycles were reviewed. Patients who had undergone IVF, had an ectopic pregnancy treated with methotrexate, and then reenrolled in our program were selected for analysis. A paired t test with alpha⬍0.05 was considered significant. RESULTS: Fourteen patients were identified that met inclusion criteria. Eleven patients have completed a second IVF cycle; 9 of these did not achieve a clinical pregnancy, 1 had a repeat ectopic, and 2 went on to deliver singletons (a post MTX clinical pregnancy rate of 18%). Nine patients had day 3 FSH values from both before and after their ectopic pregnancies. Basal FSH values in these patients increased from a mean of 6.4 to 7.6 (p⫽0.08); with 6 of the 9 increased. CONCLUSION: This review suggested that MTX may adversely affect an ovary stimulated with exogenous gonadotropins. Increased granulosa cell activity associated with ART may render ovaries particularly sensitive to the chemotherapeutic effects of MTX. The use of MTX for management of ectopic pregnancy in ART patients deserves further study. Supported by: None
studies to look into luteal phase adequacy and hypothalamo-pituitary ovarian axis with aromatase inhibition treatment are warranted. Supported by: Operating research grant by the CIHR
P-24 LH surge is associated with higher LH levels and more physiologic estradiol levels in aromatase inhibitor ovarian stimulation cycles. M. F. Mitwally, R. F. Casper. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI; Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada. OBJECTIVE: To study LH & estradiol (E2) levels associated with LH surge in cycles treated with an aromatase inhibitor for ovarian stimulation. DESIGN: Retrospective MATERIALS AND METHODS: We analyzed charts of 263 patients with polycystic ovarian syndrome (PCOS) and 563 patients with unexplained infertility who underwent ovarian stimulation with the aromatase inhibitor, letrozole, alone (92cycles) or with FSH (128cycles), clomiphene (CC), alone (225cycles) or with FSH (49cycles), and FSH alone (222cycles) as regards occurrence of LH surge. LH & E2 levels, and day of LH surge (or hCG day) were comapred between cycles with and without LH surge among stimulation protocols and to a control group of natural cycles (no treatment). LH surge occurred in 377cycles (51 with letrozole, 54 with letrozole⫹FSH, 76 with CC, 14 with CC⫹FSH and 105 with FSH). In the control group (110cycles) with no ovarian stimulation (natural cycles), LH surge occurred in 77cycles. LH surge was defined as LH level ⱖtwice mean of LH levels on two days prior to LH surge day. RESULTS: LH surge was associated with significantly higher LH levels in letrozole cycles (alone or ⫹FSH) compared to other stimulation protocols (CC alone or ⫹FSH & FSH). Significantly lower E2 levels (within physiologic range) triggered LH surge in letrozole cycles compared to other ovarian stimulation protocols. When compared to LH surge in the control group (natural cycles), LH and E2 levels were comparable with letrozole treatment while treatment with CC (alone or ⫹FSH) and FSH was associated with significantly lower LH and significantly higher E2 levels. These findings were true for all cycles for PCOS and unexplained infertility patients separately. In PCOS patients, LH surge occurred on a significantly later day irrespective to stimulation ptotocol when compared to unexplained infertility. CONCLUSION: Ovarian stimulation with an aromatase inhibitor is associated with more physiologic LH surge. Short half life of the aromatase inhibitor allows rise of E2 to more physiologic levels without E2 receptor depletion. This would leave an intact hypothalamo-pituitary ovarian axis with preservation of both negative and positive feedback mechanisms involved in endogenous gonadotropins release mediated by E2. Further
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P-25 Searching for the ideal donor in an oocyte donation program. G. E. Fiszbajn, K. Maero, R. Lipowicz, S. De Vincentiis, S. Papier, C. Chillik. CEGYR, Buenos Aires, Argentina. OBJECTIVE: Since February 2002 our center has incorporated young healthy women as volunteer oocyte donors (pure donors) in order to opti-
Vol. 82, Suppl. 2, September 2004
P-21 Risk factors for ectopic pregnancy in women with undiagnosed symptomatic first trimester pregnancy: Not what you think. K. T. Barnhart, M. D. Sammel, J. Chittams, A. Hummel, A. Shaunik. UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA. OBJECTIVE: Identification of women with ectopic pregnancy (EP) is still a quandary especially when the initial b-hCG values are low. Previous studies have focused on easily diagnosed ectopic or intrauterine pregnancies (IUP) of advance gestational age, or have used non-pregnant controls. The goal of this study was to determine risk factors predictive of EP in the high risk group of women with symptomatic first trimester pregnancies who could not be diagnosed upon initial presentation. DESIGN: Case control study. MATERIALS AND METHODS: Women presenting with pain/bleeding in first trimester, with no definitive diagnosis at presentation, were selected for study. They were prospectively followed until definitive diagnosis was established. Cases were those with an EP and Controls were women with viable IUP or miscarriage (SAB). Potential risk factors were derived from history and clinical presentation. A backward selection, logistic regression model was performed to control for confounding and effect modification. The final model restricted to variables with p-value of ⱕ0.05 or those that significantly affected the coefficient of estimates of other variables by 15%. Odds ratio ⱖ1 denotes a statistically significant risk factor, i.e. more prevalent in Cases than in Controls. RESULTS: 2026 women were studied: 366 Cases and 1660 Controls (467 IUP and 1192 SAB). The strongest risk factors were history of EP, OR⫽2.98 [95%CI: 1.88 – 4.73 p⬍0.01] for 1 prior EP, and OR⫽16.04 [5.39 – 47.72, p⬍0.01] for ⬎1 prior EP. Other significant risk factors were presentation with clinical symptoms of pain OR⫽1.42, [1.04 –1.93, p⫽0.02] and/or bleeding OR: 1.42, [1.06 –1.92, p⫽0.03] and laboratory finding of b-hCG titer of 501–2000 IU/ml (compared to ⱕ500 or greater ⬎2000) OR⫽1.73, [1.24 –2.42, p⬍0.01]. Other predictive factors were history of prior delivery OR⫽1.71, [1.21–2.42, p⬍0.01] and history of hospital admission for treatment of pelvic infection OR⫽1.50 [1.11–2.05, p⫽0.01]. If women had all of these risk factors the risk of EP was OR⫽48.38 [p⬍0.01]. Protective risk factors were previous history of induced abortion; OR⫽0.58, [0.61–1.6 p⫽0.02] and maternal age ⬎ 25 years; OR⫽0.34 [0.22– 0.52, p⬍0.01]. Notable are putative risk factors that showed no association with EP including: history of pelvic surgery, cesarean section, past use of IUD,
FERTILITY & STERILITY威
outpatient treatment for pelvic infection, concurrent infection with Chlamydia and/or Gonorrhea, prior SAB, prior live birth or initial non-diagnostic ultrasound. CONCLUSION: Identification of risk factors may aid in classifying women at high risk for EP. As anticipated, strongest risk factor in this clinically relevant group of women, with undiagnosed symptomatic first trimester pregnancy, was history of EP. Importantly, putative risk factors such as history of tubal surgery, IUD use, PID and cervicitis were weakly associated and/or not predictive, which drastically limits their clinical utility. Supported by: NIH grant RO1: HD-36455– 05
P-22 Comparison of age related pregnancy rates (PR) in women using different ovulation induction (OI) methods. C. Morelli, N. Virji, J. Stelling, K. Cain, G. San Roman. Reproductive Specialists of New York; Dept. of OB/GYN, Winthrop University Hospital, Mineola, NY; Reproductive Specialists of New York, Mineola, NY; Reproductive Specialists of New York; Dept. of OB/GYN, Winthrop University Hospital; Dept. of OB/GYN, Stony Brook University of New York, Stony Brook, NY. OBJECTIVE: To determine if a specific OI method is beneficial for the treatment of infertility in patients of a particular age group. DESIGN: A retrospective analysis of 4448 OI cycles with intrauterine inseminations (IUIs) in women undergoing treatment for infertility. MATERIALS AND METHODS: Women undergoing IUI cycles using different OI methods from January 2001 to December 2003 were analyzed for clinical PR. Clinical pregnancy was defined as the presence of an intrauterine sac documented by ultrasound. Patients were grouped according to ovulation induction METHOD: Natural, Clomiphene citrate (CC) 25, CC50, CC100, CC150, ⬎CC150, and FSH. In each of these groups, the patients were further divided according to age: ⬍ 30, 30 –34, 35–39, 40 – 42, and ⬎ 42. Age related PR differences between OI groups were determined statistically by Chi Square analysis. RESULTS: Significant differences in PR were seen for women 30 –39 amongst the different OI methods as shown in Tables 1 and 2.
p values are as follows: ap⬍0.05 vs. Natural; bp⬍0.05 vs. Total CC
p values are as follows: ap⬍0.05 vs CC50; bp⬍0.05 vs. CC150 CONCLUSION: This study has shown that women 30 –39 years of age undergoing IUI with FSH stimulation have the greatest chance of pregnancy. For women 35–39 years of age who fail to conceive on CC, the next choice of treatment should be FSH rather than incremental increases in CC dosing. CC100 use in women ⬍35 years of age was associated with the highest PR and therefore should be considered the ideal starting dose for these patients. Supported by: Reproductive Specialists of New York
P-23 Methotrexate affects ovarian reserve in treatment of ectopic pregnancies resulting from ART. M. Payson, J. Allard, R. Alvero, J. Segars, F. Larsen. Walter Reed Army Medical Center, Washington, DC; University of Colorado Health Sciences, Aurora, CO; National Institute of Health, Bethesda, MD.
S143
OBJECTIVE: The success of methotrexate in treating ectopic pregnancy is well established and few patients are currently treated with surgical therapy. Many patients undergoing ART have limited ovarian reserve prior to the initiation of therapy. In ART programs, ectopic pregnancies are frequently observed, and due to the close monitoring of these patients, are generally diagnosed early and may be treated with methotrexate (MTX). The possible adverse affects on ovarian function of methotrexate are unknown. Our objective was to determine whether methotrexate therapy for ART-associated gestations had an effect on ovarian reserve and success in subsequent ART cycles. DESIGN: Retrospective chart review. MATERIALS AND METHODS: After IRB approval, a retrospective chart review was performed of all IVF cycles at our institution from July 1998 to March 2004. A total of 2900 cycles were reviewed. Patients who had undergone IVF, had an ectopic pregnancy treated with methotrexate, and then reenrolled in our program were selected for analysis. A paired t test with alpha⬍0.05 was considered significant. RESULTS: Fourteen patients were identified that met inclusion criteria. Eleven patients have completed a second IVF cycle; 9 of these did not achieve a clinical pregnancy, 1 had a repeat ectopic, and 2 went on to deliver singletons (a post MTX clinical pregnancy rate of 18%). Nine patients had day 3 FSH values from both before and after their ectopic pregnancies. Basal FSH values in these patients increased from a mean of 6.4 to 7.6 (p⫽0.08); with 6 of the 9 increased. CONCLUSION: This review suggested that MTX may adversely affect an ovary stimulated with exogenous gonadotropins. Increased granulosa cell activity associated with ART may render ovaries particularly sensitive to the chemotherapeutic effects of MTX. The use of MTX for management of ectopic pregnancy in ART patients deserves further study. Supported by: None
studies to look into luteal phase adequacy and hypothalamo-pituitary ovarian axis with aromatase inhibition treatment are warranted. Supported by: Operating research grant by the CIHR
P-24 LH surge is associated with higher LH levels and more physiologic estradiol levels in aromatase inhibitor ovarian stimulation cycles. M. F. Mitwally, R. F. Casper. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI; Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada. OBJECTIVE: To study LH & estradiol (E2) levels associated with LH surge in cycles treated with an aromatase inhibitor for ovarian stimulation. DESIGN: Retrospective MATERIALS AND METHODS: We analyzed charts of 263 patients with polycystic ovarian syndrome (PCOS) and 563 patients with unexplained infertility who underwent ovarian stimulation with the aromatase inhibitor, letrozole, alone (92cycles) or with FSH (128cycles), clomiphene (CC), alone (225cycles) or with FSH (49cycles), and FSH alone (222cycles) as regards occurrence of LH surge. LH & E2 levels, and day of LH surge (or hCG day) were comapred between cycles with and without LH surge among stimulation protocols and to a control group of natural cycles (no treatment). LH surge occurred in 377cycles (51 with letrozole, 54 with letrozole⫹FSH, 76 with CC, 14 with CC⫹FSH and 105 with FSH). In the control group (110cycles) with no ovarian stimulation (natural cycles), LH surge occurred in 77cycles. LH surge was defined as LH level ⱖtwice mean of LH levels on two days prior to LH surge day. RESULTS: LH surge was associated with significantly higher LH levels in letrozole cycles (alone or ⫹FSH) compared to other stimulation protocols (CC alone or ⫹FSH & FSH). Significantly lower E2 levels (within physiologic range) triggered LH surge in letrozole cycles compared to other ovarian stimulation protocols. When compared to LH surge in the control group (natural cycles), LH and E2 levels were comparable with letrozole treatment while treatment with CC (alone or ⫹FSH) and FSH was associated with significantly lower LH and significantly higher E2 levels. These findings were true for all cycles for PCOS and unexplained infertility patients separately. In PCOS patients, LH surge occurred on a significantly later day irrespective to stimulation ptotocol when compared to unexplained infertility. CONCLUSION: Ovarian stimulation with an aromatase inhibitor is associated with more physiologic LH surge. Short half life of the aromatase inhibitor allows rise of E2 to more physiologic levels without E2 receptor depletion. This would leave an intact hypothalamo-pituitary ovarian axis with preservation of both negative and positive feedback mechanisms involved in endogenous gonadotropins release mediated by E2. Further
S144
P-25 Searching for the ideal donor in an oocyte donation program. G. E. Fiszbajn, K. Maero, R. Lipowicz, S. De Vincentiis, S. Papier, C. Chillik. CEGYR, Buenos Aires, Argentina. OBJECTIVE: Since February 2002 our center has incorporated young healthy women as volunteer oocyte donors (pure donors) in order to opti-
Vol. 82, Suppl. 2, September 2004