Karl R Hansen1, Jennifer D Peck1,2, R Matthew Coward3,4, Robert A Wild1,2, J C Trussell5, Stephen A Krawetz6, Michael P Diamond7,8, Richard S Legro9, Christos Coutifaris10, Ruben Alvero11,12, Randal D Robinson13, Peter Casson14,15, Gregory M Christman16,17, Nanette Santoro11, Heping Zhang18. 1. Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USA. 2. Department of Biostatistics and Epidemiology, University of Oklahoma College of Public Health, Oklahoma City, OK 73104, USA. 3. Department of Urology, UNC School of Medicine, 2113 Physicians Office Building CB#7235, Chapel Hill, NC 27599-7235, USA. 4. UNC Fertility, 7920 ACC Blvd #300, Raleigh, NC 27617, USA. 5. Department of Urology, Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, USA. 6. Department of Obstetrics and Gynecology and Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. 7. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA. 8. Department of Obstetrics and Gynecology, Augusta University, Augusta, GA 30912, USA. 9. Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA 17033, USA. 10. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA. 11. Department of Obstetrics and Gynecology, University of Colorado Denver, Aurora, CO 80045, USA. 12. Department of Obstetrics and Gynecology, Stanford University, Sunnyvale, CA 94087, USA. 13. Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, TX 78229, USA. 14. Department of Obstetrics and Gynecology, University of Vermont, Burlington, VT 05446, USA. 15. Northeastern Reproductive Medicine, 105 W View Rd, #302, Colchester, VT 05446, USA. 16. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA. 17. Department of Obstetrics and Gynecology, University of Florida College of Medicine, PO Box 100294, Gainesville, FL 32610, USA. 18. Department of Biostatistics, Yale University School of Public Health, New Haven, CT 06520, USA.
Abstract
STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER: Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success. WHAT IS ALREADY KNOWN: We previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome. STUDY DESIGN, SIZE, DURATION: This was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16-0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1-20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31-3.33)). However, live births did occur with TMC ≤ 1 million (5.1%). LIMITATIONS, REASONS FOR CAUTION: This investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI. WIDER IMPLICATIONS OF THE FINDINGS: Most factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI. STUDY FUNDING/COMPETING INTEREST(S): Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work. TRIAL REGISTRATION NUMBER: n/a.
STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER: Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success. WHAT IS ALREADY KNOWN: We previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome. STUDY DESIGN, SIZE, DURATION: This was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16-0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1-20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31-3.33)). However, live births did occur with TMC ≤ 1 million (5.1%). LIMITATIONS, REASONS FOR CAUTION: This investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI. WIDER IMPLICATIONS OF THE FINDINGS: Most factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI. STUDY FUNDING/COMPETING INTEREST(S): Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work. TRIAL REGISTRATION NUMBER: n/a.
Authors: David C Miller; Brent K Hollenbeck; Gary D Smith; John F Randolph; Gregory M Christman; Yolanda R Smith; Dan I Lebovic; Dana A Ohl Journal: Urology Date: 2002-09 Impact factor: 2.649
Authors: Louise Lemmens; Snjezana Kos; Cornelis Beijer; Jacoline W Brinkman; Frans A L van der Horst; Leonie van den Hoven; Dorit C Kieslinger; Netty J van Trooyen-van Vrouwerff; Albert Wolthuis; Jan C M Hendriks; Alex M M Wetzels Journal: Fertil Steril Date: 2016-03-02 Impact factor: 7.329
Authors: Annelies Thijssen; An Creemers; Wim Van der Elst; Eva Creemers; Eva Vandormael; Nathalie Dhont; Willem Ombelet Journal: Reprod Biomed Online Date: 2017-02-24 Impact factor: 3.828
Authors: LaTasha B Craig; Sushila Arya; Heather R Burks; Kaitlin Warta; Christen Jarshaw; Karl R Hansen; Jennifer D Peck Journal: Fertil Steril Date: 2021-08-18 Impact factor: 7.329
Authors: Richard S Legro; Karl R Hansen; Michael P Diamond; Anne Z Steiner; Christos Coutifaris; Marcelle I Cedars; Kathleen M Hoeger; Rebecca Usadi; Erica B Johnstone; Daniel J Haisenleder; Robert A Wild; Kurt T Barnhart; Jennifer Mersereau; J C Trussell; Stephen A Krawetz; Penny M Kris-Etherton; David B Sarwer; Nanette Santoro; Esther Eisenberg; Hao Huang; Heping Zhang Journal: PLoS Med Date: 2022-01-18 Impact factor: 11.069