- Email: [email protected]
Low ectopic pregnancy rates after in vitro fertilization: do practice habits matter?
Low ectopic pregnancy rates after in vitro fertilization: do practice habits matter? In a 6-year review of ectopic pregnancies (EPs) after fresh and frozen embryo transfers in IVF cycles conducted at a large university-based program, we report an overall 0.9% rate of EP that seems to have increased with the programmatic shift to routine blastocyst transfer, but remains lower than nationally reported rates. Aggressive management of tubal disease may contribute to low rates of EP, whereas blastocyst transfer may increase the rate. (Fertil Steril 2007;88:734–6. 2007 by American Society for Reproductive Medicine.)
Ectopic pregnancy (EP) is estimated to occur in 2%–5% of clinical pregnancies after IVF (1–3), whereas heterotopic pregnancy (HP), simultaneous intrauterine and extrauterine gestations, complicates far less than 1% (4). Outcomes data collected in 2000 from 383 clinics in the United States revealed an EP rate of 2.1% after fresh embryo transfer (2). This same rate was calculated when 94,118 ART pregnancies conceived between 1999 and 2001 were evaluated in a large retrospective study (5). This rate of 2.1% compares favorably to the estimated 2% incidence of EP (19.7 per 1,000 reported pregnancies) in the United States (6), despite the existing dogma that undergoing ART increases the risk for EP (7). Risk factors for EP after natural conception, including previous EP, pelvic inflammatory disease, tubal disease or surgery, and smoking, have been well described (8, 9). However, data on the risk factors for developing EP after IVF are inconsistent. As with naturally occurring pregnancy, tubal factor infertility has been identified as the most prominent risk factor for EP after IVF (10, 11). Studies have associated technical aspects of IVF with increased risk of EP, such as assisted hatching (12), frozen embryo transfer (11), higher transfer volume (13), deep fundal transfer (14, 15) and the practice of multiple embryo transfer (5). Proposed mechanisms to explain the development of tubal pregnancies after IVF include direct injection of the transfer media containing the embryos into the fallopian tubes, or migration of embryos into the fallopian tubes caused by uterine contractions (16). Blastocyst transfer does not appear to decrease the risk of EP (3). The objective of our study was to assess the rates of EP and HP in fresh and frozen embryo transfers in IVF cycles conducted at a large university-based program from 1998– 2003, and describe the concordant patient and cycle characteristics including a programmatic shift toward blastocyst transfer. Received August 18, 2006; revised November 29, 2006; accepted November 30, 2006. Presented at the 61st meeting of the American Society for Reproductive Medicine, Montreal, Quebec, Canada, October 15–19, 2005. Reprint requests: Debbra A. Keegan, M.D., NYU School of Medicine, Division of Reproductive Endocrinology and Infertility, 660 First Avenue, 5th Floor, New York, NY 10016 (FAX: 212-263-0059; E-mail: [email protected]).
734
The study was exempted from review by the NYU Institutional Review Board (H#05-163), as analysis involved pre-existing deidentified data that precluded identification of individual patients. Using the program database, 2,688 clinical pregnancies were selected from fresh IVF cycles and 285 clinical pregnancies from frozen embryo transfer cycles conducted between 1998 and 2003. Pregnancies were characterized based on location of gestational sacs. Clinical pregnancy was defined as the presence of at least one gestational sac visualized by transvaginal ultrasonography between cycle days 42 and 49. Ectopic pregnancy was defined as the presence of an extrauterine gestation, and HP was defined as EP coexisting with a synchronous intrauterine pregnancy (IUP). These definitions are consistent with Society of Assisted Reproductive Technology (SART) guidelines for outcomes reporting. Rate of EP by year was compared and day of embryo transfer was analyzed (day 3 or day 5). Patient and cycle characteristics were compared using Student’s t-test for continuous variables and c2 test for categorical variables. Of 2,688 clinical pregnancies, 24 (0.9%) were ectopic or heterotopic: 67% (n ¼ 16) were tubal EPs and 33% (n ¼ 8) were HPs. All HPs had a synchronous tubal pregnancy. Nineteen percent (n ¼ 3) of patients with tubal pregnancy were surgically managed, either by laparoscopy or laparotomy, depending on the clinical situation. The remaining 13 patients (81%) were treated with methotrexate (MTX). Thirty-one percent (n ¼ 4) of these patients failed medical management and subsequently underwent laparoscopy with unilateral salpingectomy. One MTX failure was diagnosed with a ruptured ectopic. The overall rate of HP in the study population was 0.3%. Heterotopic pregnancy accounted for 33% of all EPs. Six patients underwent salpingectomy and all subsequently delivered live infants (5 full term, 1 preterm). The remaining 2 patients were successfully treated with MTX after D&C for missed abortion. There were no differences between the EP and HP groups with respect to age, history of tubal disease, prior EP, or day of transfer. The average number of embryos transferred per group did not differ (EP 3.3 0.2; HP 2.9 0.3). Patients with HP demonstrated significantly higher day 28 serum
Fertility and Sterility Vol. 88, No. 3, September 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.169
b-hCG and E2 levels compared to EP patients (253 107 mIU/mL vs. 35 10 mIU/mL, P ¼.005, and 901 pg/mL vs. 127 pg/mL, P ¼.005, respectively). The cycle day of diagnosis ranged from 37 – 57 for tubal EP and 38 – 79 for HP. In 2000, SART reported a national rate of EP per clinical IVF pregnancy as 2.1%. In our study group, the EP rate, including HPs, was 0.5% of clinical pregnancies from 1998– 2000. Between 2000 and 2001, the rate doubled and remained greater than 1% for the next 3 years. The rate of HPs as a proportion of EPs was 83% in 2003, much higher than in previous years (Fig. 1). Of 1,681 clinical pregnancies resulting from day 3 transfer, 8 were EPs (0.5%). Of 1,107 clinical pregnancies resulting from day 5 transfer, 16 were EPs (1.6%), representing a statistically significant difference (P¼.006). Two hundred eighty-five clinical pregnancies occurred after frozen embryo transfer. The rate of EP after frozen embryo transfer was 0.7%, with one HP and one tubal EP identified, both resulting from day 3 embryo transfer. This rate is not statistically different from the rate associated with fresh IVF cycles (0.9%). In assessing our experience with EP, the frequency of EP observed was 0.9% per clinical pregnancy; less than the 2.1% – 2.2% national rate consistently reported by SART/ ASRM for US clinics (1, 2). Although it is still unclear if
FIGURE 1 Ectopic pregnancy (EP) and heterotopic pregnancy (HP) rates by year. Society of Assisted Reproductive Technology (SART) (dotted line) represents the 2.1% rate of ectopic pregnancies as reported by the ASRM and SART for 2000. From 1998–2000, the EP rate at our program remained relatively stable at around 0.5%. Between 2000 and 2001 the rate more than doubled, and remained more than 1% for the next 2 years. The proportion of EPs that were HPs is shown in black. Implementation of routine blastocyst transfer in our laboratory began in 2000.
Keegan. Low rates of ectopic pregnancy after IVF. Fertil Steril 2007.
Fertility and Sterility
surgical management of tubal disease improves chances of pregnancy with IVF (17), it is suggested that should pregnancy occur in the presence of damaged tubes, a higher risk for EP exists (5, 10, 11, 18). According to the 2004 SART clinical summary report, only 5% of patients undergoing IVF at our program carried a primary diagnosis of tubal factor. We recognize that this number does not account for those with clandestine tubal disease. Still, although not evaluated in this study, in our practice aggressive management of documented tubal disease with salpingectomy may help prevent EP after IVF. Only a randomized, controlled trial of salpingectomy in patients with clinically or surgically diagnosed tubal disease can conclusively verify the merit of our clinical practice. A high proportion of HP (as high as 83% of all EPs in 2003) was observed in our study population. As seen in Figure 1, the increase in the HP rate is seen with the shift in our program from day 3 embryo transfer to routine blastocyst transfer for patients meeting criteria. The higher proportion of HP with blastocyst transfer cannot be attributed to the number of embryos transferred, as the mean number transferred in day 5 cycles was significantly lower than in day 3 cycles (2.8 vs. 3.6, P ¼.04). Rather, this finding may result from a higher implantation rate per embryo at the blastocyst stage when compared to day 3, even into damaged tubes. It is unclear why this phenomenon is observed. Contrary to existing reports (3), EP was significantly more common after blastocyst than day 3 transfer. As stated, this finding cannot be explained by a difference between groups in the number of embryos transferred. It has been proposed that decreased uterine contractility later in the luteal phase and the larger diameter of the blastocyst would interfere with its ability to reflux through the tubal ostium, protecting against tubal implantation (3). The observations in this study suggest otherwise. Again, we see the shift to higher rates of EP in our practice concordant with the shift to routine blastocyst transfer in qualifying patients in 2001. The higher implantation rate per embryo at the blastocyst stage may negate these effects. Although other technical variables such as assisted hatching, higher transfer volume, and deep fundal transfer have been reported as factors potentially associated with EP (12 – 15), there is no difference in our practice between day 3 and day 5 transfers (with the exception of assisted hatching, which is performed only with day 3 transfers). All patients are transferred with 15 – 20 mL of media. Deep fundal transfer cannot be adequately assessed as a variable as not all transfers are performed under ultrasound guidance. There was no difference in the rate of EP between fresh and frozen embryo transfer cycles. Various reports have shown conflicting data (11, 19, 20), but given a similar or slightly lower implantation rate for frozen embryos, our finding is to be expected. However, the power of our study may
735
not be sufficient to detect small statistical differences. Fresh embryo transfer typically outperforms frozen embryo transfer. A lower implantation rate (and a possibly lower EP rate) may be expected on a per embryo basis, although an increase in the average number of embryos transferred to offset the diminished reproductive capacity of frozen-thawed embryos may negate this difference on a per transfer basis. In summary, our data suggest that individual practices should evaluate their EP rate in an attempt to identify factors that may increase or decrease the rate compared to national statistics. We report an overall 0.9% rate of EP during 6 years, which seems to have increased with the programmatic shift to routine blastocyst transfer, but remains lower than nationally reported rates. It is possible that this may in part be due to the higher implantation rate of blastocysts over day 3 embryos, but this can only be hypothesized with the existing data. If this is the case, however, it may be prudent to aggressively manage documented tubal disease in a program such as ours where the higher implantation rate per blastocyst may contribute to the higher rate of EP and HP. Acknowledgments: The authors wish to thank Lewis Krey, Ph.D., Frederick Licciardi, M.D., Lisa Kump, M.D., and the embryology and nursing staff at the NYU Fertility Center for their assistance in data collection.
Debbra A. Keegan, M.D. Sara S. Morelli, M.D. Nicole Noyes, M.D. Eric D. Flisser, M.D. Alan S. Berkeley, M.D. Jamie A. Grifo, M.D., Ph.D. Division of Reproductive Endocrinology and Infertility, NYU School of Medicine, New York, New York REFERENCES
Keegan et al.
4.
5.
6. 7.
8.
9. 10. 11.
12. 13.
14.
15.
16. 17.
18.
1. Society for Assisted Reproductive Technology and The American Society for Reproductive Medicine. Assisted Reproductive Technology in the United States: 1999 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2002;78:918–31. 2. Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted Reproductive Technology in the United States: 2000 results generated from the American Society
736
3.
Corrrespondence
19.
20.
for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2004;81:1207–20. Milki AA, Jun SH. Ectopic pregnancy rates with day 3 versus day 5 embryo transfer: a retrospective analysis. BMC Pregnancy Childbirth 2003;3:7–10. Chin HY, Chen FP, Wang CJ, Shui LT, Liu YH, Soong YK. Heterotopic pregnancy after in vitro fertilization–embryo transfer. Int J Gynaecol Obstet 2004;86:411–6. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol 2006;107:595–604. Anonymous. From the Centers for Disease Control and Prevention. Ectopic pregnancy—United States, 1990–1992. JAMA 1995;273:533. Fernandez H, Coste J, Job-Spira N. Controlled ovarian hyperstimulation as a risk factor for ectopic pregnancy. Obstet Gynecol 1991;78: 656–9. Bouyer J, Coste J, Shojaei T, Pouly JL, Fernandez H, Gerbaud L, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control population-based study in France. Am J Epidemiol 2003;157:185–94. Pisarska MD, Carson SA. Incidence and risk factors for ectopic pregnancy. Clin Obstet Gynecol 1999;42:2–8. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999;71:282–6. Pyrgiotis E, Sultan KM, Neal GS, Liu HC, Grifo JA, Rosenwaks Z. Ectopic pregnancies after in vitro fertilization and embryo transfer. J Assist Reprod Genet 1994;11:79–84. Jun SH, Milki AA. Assisted hatching is associated with a higher ectopic pregnancy rate. Fertil Steril 2004;81:1701–3. Marcus S, Brinsden P. Analysis of the incidence and risk factors associated with ectopic pregnancy following in-vitro fertilization and embryo transfer. Hum Reprod 1995;10:199–203. Yovich JL, Turner S, Murphy A. Embryo transfer technique as a cause of ectopic pregnancies in in vitro fertilization. Fertil Steril 1985;44: 318–21. Nazari A, Askari HA, Check JH, O’Shaughnessy A. Embryo transfer technique as a cause of ectopic pregnancy in in vitro fertilization. Fertil Steril 1993;60:919–21. Russell JB. The etiology of ectopic pregnancy. Clin Obstet Gynecol 1987;30:181–90. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease in women due to undergo in vitro fertilization. Cochrane Database Syst Rev 2005;3:CD002125. Ng EH, Yeung WS, Ho PC. The presence of hydrosalpinx may not adversely affect the implantation and pregnancy rates in in vitro fertilization treatment. J Assist Reprod Genet 1997;14:508–12. Ng EHY, Yeung WSB, So WWK, Ho PC. An analysis of ectopic pregnancies following in vitro fertilization treatment in a 10-year period. J Obstet Gynecol 1998;18:359–64. Check JH, Choe JK, Katsoff B, Krotec JW, Nazari A. Ectopic pregnancy is not more likely following fresh vs frozen embryo transfer. Clin Exp Obstet Gynecol 2005;32:95–6.
Vol. 88, No. 3, September 2007
Ectopic pregnancy (EP) is estimated to occur in 2%–5% of clinical pregnancies after IVF (1–3), whereas heterotopic pregnancy (HP), simultaneous intrauterine and extrauterine gestations, complicates far less than 1% (4). Outcomes data collected in 2000 from 383 clinics in the United States revealed an EP rate of 2.1% after fresh embryo transfer (2). This same rate was calculated when 94,118 ART pregnancies conceived between 1999 and 2001 were evaluated in a large retrospective study (5). This rate of 2.1% compares favorably to the estimated 2% incidence of EP (19.7 per 1,000 reported pregnancies) in the United States (6), despite the existing dogma that undergoing ART increases the risk for EP (7). Risk factors for EP after natural conception, including previous EP, pelvic inflammatory disease, tubal disease or surgery, and smoking, have been well described (8, 9). However, data on the risk factors for developing EP after IVF are inconsistent. As with naturally occurring pregnancy, tubal factor infertility has been identified as the most prominent risk factor for EP after IVF (10, 11). Studies have associated technical aspects of IVF with increased risk of EP, such as assisted hatching (12), frozen embryo transfer (11), higher transfer volume (13), deep fundal transfer (14, 15) and the practice of multiple embryo transfer (5). Proposed mechanisms to explain the development of tubal pregnancies after IVF include direct injection of the transfer media containing the embryos into the fallopian tubes, or migration of embryos into the fallopian tubes caused by uterine contractions (16). Blastocyst transfer does not appear to decrease the risk of EP (3). The objective of our study was to assess the rates of EP and HP in fresh and frozen embryo transfers in IVF cycles conducted at a large university-based program from 1998– 2003, and describe the concordant patient and cycle characteristics including a programmatic shift toward blastocyst transfer. Received August 18, 2006; revised November 29, 2006; accepted November 30, 2006. Presented at the 61st meeting of the American Society for Reproductive Medicine, Montreal, Quebec, Canada, October 15–19, 2005. Reprint requests: Debbra A. Keegan, M.D., NYU School of Medicine, Division of Reproductive Endocrinology and Infertility, 660 First Avenue, 5th Floor, New York, NY 10016 (FAX: 212-263-0059; E-mail: [email protected]).
734
The study was exempted from review by the NYU Institutional Review Board (H#05-163), as analysis involved pre-existing deidentified data that precluded identification of individual patients. Using the program database, 2,688 clinical pregnancies were selected from fresh IVF cycles and 285 clinical pregnancies from frozen embryo transfer cycles conducted between 1998 and 2003. Pregnancies were characterized based on location of gestational sacs. Clinical pregnancy was defined as the presence of at least one gestational sac visualized by transvaginal ultrasonography between cycle days 42 and 49. Ectopic pregnancy was defined as the presence of an extrauterine gestation, and HP was defined as EP coexisting with a synchronous intrauterine pregnancy (IUP). These definitions are consistent with Society of Assisted Reproductive Technology (SART) guidelines for outcomes reporting. Rate of EP by year was compared and day of embryo transfer was analyzed (day 3 or day 5). Patient and cycle characteristics were compared using Student’s t-test for continuous variables and c2 test for categorical variables. Of 2,688 clinical pregnancies, 24 (0.9%) were ectopic or heterotopic: 67% (n ¼ 16) were tubal EPs and 33% (n ¼ 8) were HPs. All HPs had a synchronous tubal pregnancy. Nineteen percent (n ¼ 3) of patients with tubal pregnancy were surgically managed, either by laparoscopy or laparotomy, depending on the clinical situation. The remaining 13 patients (81%) were treated with methotrexate (MTX). Thirty-one percent (n ¼ 4) of these patients failed medical management and subsequently underwent laparoscopy with unilateral salpingectomy. One MTX failure was diagnosed with a ruptured ectopic. The overall rate of HP in the study population was 0.3%. Heterotopic pregnancy accounted for 33% of all EPs. Six patients underwent salpingectomy and all subsequently delivered live infants (5 full term, 1 preterm). The remaining 2 patients were successfully treated with MTX after D&C for missed abortion. There were no differences between the EP and HP groups with respect to age, history of tubal disease, prior EP, or day of transfer. The average number of embryos transferred per group did not differ (EP 3.3 0.2; HP 2.9 0.3). Patients with HP demonstrated significantly higher day 28 serum
Fertility and Sterility Vol. 88, No. 3, September 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.169
b-hCG and E2 levels compared to EP patients (253 107 mIU/mL vs. 35 10 mIU/mL, P ¼.005, and 901 pg/mL vs. 127 pg/mL, P ¼.005, respectively). The cycle day of diagnosis ranged from 37 – 57 for tubal EP and 38 – 79 for HP. In 2000, SART reported a national rate of EP per clinical IVF pregnancy as 2.1%. In our study group, the EP rate, including HPs, was 0.5% of clinical pregnancies from 1998– 2000. Between 2000 and 2001, the rate doubled and remained greater than 1% for the next 3 years. The rate of HPs as a proportion of EPs was 83% in 2003, much higher than in previous years (Fig. 1). Of 1,681 clinical pregnancies resulting from day 3 transfer, 8 were EPs (0.5%). Of 1,107 clinical pregnancies resulting from day 5 transfer, 16 were EPs (1.6%), representing a statistically significant difference (P¼.006). Two hundred eighty-five clinical pregnancies occurred after frozen embryo transfer. The rate of EP after frozen embryo transfer was 0.7%, with one HP and one tubal EP identified, both resulting from day 3 embryo transfer. This rate is not statistically different from the rate associated with fresh IVF cycles (0.9%). In assessing our experience with EP, the frequency of EP observed was 0.9% per clinical pregnancy; less than the 2.1% – 2.2% national rate consistently reported by SART/ ASRM for US clinics (1, 2). Although it is still unclear if
FIGURE 1 Ectopic pregnancy (EP) and heterotopic pregnancy (HP) rates by year. Society of Assisted Reproductive Technology (SART) (dotted line) represents the 2.1% rate of ectopic pregnancies as reported by the ASRM and SART for 2000. From 1998–2000, the EP rate at our program remained relatively stable at around 0.5%. Between 2000 and 2001 the rate more than doubled, and remained more than 1% for the next 2 years. The proportion of EPs that were HPs is shown in black. Implementation of routine blastocyst transfer in our laboratory began in 2000.
Keegan. Low rates of ectopic pregnancy after IVF. Fertil Steril 2007.
Fertility and Sterility
surgical management of tubal disease improves chances of pregnancy with IVF (17), it is suggested that should pregnancy occur in the presence of damaged tubes, a higher risk for EP exists (5, 10, 11, 18). According to the 2004 SART clinical summary report, only 5% of patients undergoing IVF at our program carried a primary diagnosis of tubal factor. We recognize that this number does not account for those with clandestine tubal disease. Still, although not evaluated in this study, in our practice aggressive management of documented tubal disease with salpingectomy may help prevent EP after IVF. Only a randomized, controlled trial of salpingectomy in patients with clinically or surgically diagnosed tubal disease can conclusively verify the merit of our clinical practice. A high proportion of HP (as high as 83% of all EPs in 2003) was observed in our study population. As seen in Figure 1, the increase in the HP rate is seen with the shift in our program from day 3 embryo transfer to routine blastocyst transfer for patients meeting criteria. The higher proportion of HP with blastocyst transfer cannot be attributed to the number of embryos transferred, as the mean number transferred in day 5 cycles was significantly lower than in day 3 cycles (2.8 vs. 3.6, P ¼.04). Rather, this finding may result from a higher implantation rate per embryo at the blastocyst stage when compared to day 3, even into damaged tubes. It is unclear why this phenomenon is observed. Contrary to existing reports (3), EP was significantly more common after blastocyst than day 3 transfer. As stated, this finding cannot be explained by a difference between groups in the number of embryos transferred. It has been proposed that decreased uterine contractility later in the luteal phase and the larger diameter of the blastocyst would interfere with its ability to reflux through the tubal ostium, protecting against tubal implantation (3). The observations in this study suggest otherwise. Again, we see the shift to higher rates of EP in our practice concordant with the shift to routine blastocyst transfer in qualifying patients in 2001. The higher implantation rate per embryo at the blastocyst stage may negate these effects. Although other technical variables such as assisted hatching, higher transfer volume, and deep fundal transfer have been reported as factors potentially associated with EP (12 – 15), there is no difference in our practice between day 3 and day 5 transfers (with the exception of assisted hatching, which is performed only with day 3 transfers). All patients are transferred with 15 – 20 mL of media. Deep fundal transfer cannot be adequately assessed as a variable as not all transfers are performed under ultrasound guidance. There was no difference in the rate of EP between fresh and frozen embryo transfer cycles. Various reports have shown conflicting data (11, 19, 20), but given a similar or slightly lower implantation rate for frozen embryos, our finding is to be expected. However, the power of our study may
735
not be sufficient to detect small statistical differences. Fresh embryo transfer typically outperforms frozen embryo transfer. A lower implantation rate (and a possibly lower EP rate) may be expected on a per embryo basis, although an increase in the average number of embryos transferred to offset the diminished reproductive capacity of frozen-thawed embryos may negate this difference on a per transfer basis. In summary, our data suggest that individual practices should evaluate their EP rate in an attempt to identify factors that may increase or decrease the rate compared to national statistics. We report an overall 0.9% rate of EP during 6 years, which seems to have increased with the programmatic shift to routine blastocyst transfer, but remains lower than nationally reported rates. It is possible that this may in part be due to the higher implantation rate of blastocysts over day 3 embryos, but this can only be hypothesized with the existing data. If this is the case, however, it may be prudent to aggressively manage documented tubal disease in a program such as ours where the higher implantation rate per blastocyst may contribute to the higher rate of EP and HP. Acknowledgments: The authors wish to thank Lewis Krey, Ph.D., Frederick Licciardi, M.D., Lisa Kump, M.D., and the embryology and nursing staff at the NYU Fertility Center for their assistance in data collection.
Debbra A. Keegan, M.D. Sara S. Morelli, M.D. Nicole Noyes, M.D. Eric D. Flisser, M.D. Alan S. Berkeley, M.D. Jamie A. Grifo, M.D., Ph.D. Division of Reproductive Endocrinology and Infertility, NYU School of Medicine, New York, New York REFERENCES
Keegan et al.
4.
5.
6. 7.
8.
9. 10. 11.
12. 13.
14.
15.
16. 17.
18.
1. Society for Assisted Reproductive Technology and The American Society for Reproductive Medicine. Assisted Reproductive Technology in the United States: 1999 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2002;78:918–31. 2. Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted Reproductive Technology in the United States: 2000 results generated from the American Society
736
3.
Corrrespondence
19.
20.
for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2004;81:1207–20. Milki AA, Jun SH. Ectopic pregnancy rates with day 3 versus day 5 embryo transfer: a retrospective analysis. BMC Pregnancy Childbirth 2003;3:7–10. Chin HY, Chen FP, Wang CJ, Shui LT, Liu YH, Soong YK. Heterotopic pregnancy after in vitro fertilization–embryo transfer. Int J Gynaecol Obstet 2004;86:411–6. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol 2006;107:595–604. Anonymous. From the Centers for Disease Control and Prevention. Ectopic pregnancy—United States, 1990–1992. JAMA 1995;273:533. Fernandez H, Coste J, Job-Spira N. Controlled ovarian hyperstimulation as a risk factor for ectopic pregnancy. Obstet Gynecol 1991;78: 656–9. Bouyer J, Coste J, Shojaei T, Pouly JL, Fernandez H, Gerbaud L, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control population-based study in France. Am J Epidemiol 2003;157:185–94. Pisarska MD, Carson SA. Incidence and risk factors for ectopic pregnancy. Clin Obstet Gynecol 1999;42:2–8. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999;71:282–6. Pyrgiotis E, Sultan KM, Neal GS, Liu HC, Grifo JA, Rosenwaks Z. Ectopic pregnancies after in vitro fertilization and embryo transfer. J Assist Reprod Genet 1994;11:79–84. Jun SH, Milki AA. Assisted hatching is associated with a higher ectopic pregnancy rate. Fertil Steril 2004;81:1701–3. Marcus S, Brinsden P. Analysis of the incidence and risk factors associated with ectopic pregnancy following in-vitro fertilization and embryo transfer. Hum Reprod 1995;10:199–203. Yovich JL, Turner S, Murphy A. Embryo transfer technique as a cause of ectopic pregnancies in in vitro fertilization. Fertil Steril 1985;44: 318–21. Nazari A, Askari HA, Check JH, O’Shaughnessy A. Embryo transfer technique as a cause of ectopic pregnancy in in vitro fertilization. Fertil Steril 1993;60:919–21. Russell JB. The etiology of ectopic pregnancy. Clin Obstet Gynecol 1987;30:181–90. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease in women due to undergo in vitro fertilization. Cochrane Database Syst Rev 2005;3:CD002125. Ng EH, Yeung WS, Ho PC. The presence of hydrosalpinx may not adversely affect the implantation and pregnancy rates in in vitro fertilization treatment. J Assist Reprod Genet 1997;14:508–12. Ng EHY, Yeung WSB, So WWK, Ho PC. An analysis of ectopic pregnancies following in vitro fertilization treatment in a 10-year period. J Obstet Gynecol 1998;18:359–64. Check JH, Choe JK, Katsoff B, Krotec JW, Nazari A. Ectopic pregnancy is not more likely following fresh vs frozen embryo transfer. Clin Exp Obstet Gynecol 2005;32:95–6.
Vol. 88, No. 3, September 2007