- Email: [email protected]
Predictors of success with the use of donor sperm
Predictors of success with the use of donor sperm R. Stan Williams, MD, and Jennifer Alderman, MD Gainesville, Fla OBJECTIVE: This study was undertaken to assess the effect of multiple factors that influence the success rate and time to conception among couples undergoing donor sperm insemination. STUDY DESIGN: A retrospective analysis of 960 cycles of frozen donor sperm insemination was performed at the University of Florida. Cycle pregnancy rates and cumulative probability of pregnancy were compared using several variables. RESULTS: The pregnancy rate was 12.1% per treatment cycle, and the cumulative probability of pregnancy exceeded 80% for the entire cohort. Seventy percent of pregnancies resulted in a liveborn infant. Age had a profound impact on the cycle pregnancy rate. The cycle pregnancy rates for women younger than 30 years, between the ages of 30 and 35 years, between the ages of 35 and 40 years, and older than 40 years were 15.8%, 14.6%, 8.2%, and 0%, respectively. There was a trend toward higher cycle pregnancy rates in women with prior pregnancies versus women without prior pregnancies of 14.4% and 12.3%, respectively. Parity had no effect on the cycle pregnancy rate or the cumulative probability of pregnancy. There was a trend toward higher cumulative probability of pregnancy in women whose partners were azoospermic versus oligospermic. There was no difference in pregnancy rates obtained with the Percoll wash gradient versus the Isolate gradient. At >20 million total motile sperm per insemination, there was no threshold above which the pregnancy rate was improved. CONCLUSION: The most significant influence on pregnancy rates in the donor sperm insemination program at the University of Florida was maternal age. Nulligravidity and a diagnosis of mild oligospermia in the man may have a negative impact on pregnancy rates. (Am J Obstet Gynecol 2001;185:332-37.)
Key words: Donor sperm insemination, pregnancy rate, maternal age
The use of therapeutic insemination dates back to biblical times; donor inseminations were first performed in the United States in Philadelphia in 1884.1 Fresh sperm was used primarily for insemination until the 1990s, but, because of the concern regarding the transmission of infectious diseases, frozen semen is now used exclusively for donor intrauterine inseminations (IUIs). The use of frozen semen therapeutic IUIs has proven to be a highly effective and well-accepted means of achieving conception. Indeed, more infertile couples use donor insemination than newborn adoption as a means of building their families. Indications for donor IUI are varied and include male factor infertility, noncorrectable ejaculatory dysfunction, the desire to avoid transmission of genetic and infectious diseases, and, in some centers, single women who desire pregnancy.
From the Department of Obstetrics and Gynecology, University of Florida. Presented at the Sixty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 20-23, 2001. Reprint requests: R. Stan Williams, MD, Department of Obstetrics and Gynecology, PO Box 100294, University of Florida, Gainesville, FL 32610. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/116733 doi:10.1067/mob.2001.116733
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Although this treatment is well established and widely practiced, it is psychologically stressful to couples, especially as the duration of treatment increases without success. Therefore physicians practicing donor IUIs should be able to provide couples with an individualized prognosis regarding duration and likelihood of success. The factors that significantly influence the outcome of donor IUI cycles must be identified so that physicians can provide an educated prognosis for patients. Studies have shown that increasing maternal age has a significant negative impact on fecundity rates.2 In addition, other infertility factors3 and the presence of partners with oligospermia rather than azoospermia have been shown to decrease fecundity rates.4 No studies have adequately evaluated the effect of obstetric history on fecundity rates. By reviewing the 10-year experience at the University of Florida, this report evaluates the effect of multiple factors that may alter the success rate or time to conception of couples using donor sperm insemination. Material and methods Charts were reviewed on 213 infertility patients who received donor sperm IUIs while attending the private University of Florida infertility clinic, the Park Avenue Women’s Center, from January 1988 through February 1998. Factors analyzed included date, patient age, cycle
Williams and Alderman 333
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number, patient gravidity and parity, male infertility diagnosis, type of ovarian stimulation, number of total motile sperm inseminated, and the presence or absence of pregnancy. A total of 960 cycles were reviewed. The patient age category was determined by the woman’s age at the onset of treatment. The number of cycles per patient ranged from 1 to 18. Cycle number reverted to 1 after any pregnancy was achieved. Men were considered moderately oligospermic if there were between 1 and 20 million total motile sperm per ejaculate, severely oligospermic if there were <1 million total motile sperm per ejaculate, or azoospermic if there were no motile sperm. Men with ejaculatory dysfunction or infectious diseases were considered azoospermic because it was likely that their wives had no exposure to viable sperm. Types of ovarian stimulation used included natural (N = 689), clomiphene citrate (N = 123), clomiphene citrate and human menopausal gonadotropin (HMG) (N = 79), and HMG only (N = 43). Ovulation induction was primarily used either to correct anovulation or as superovulation therapy in women with mild to moderate endometriosis. Only cryopreserved semen was used for insemination. Semen had been obtained from healthy donors who had good quality semen and were free of sexually transmitted diseases and transmissible genetic disorders. The screening of donors followed all current recommendations for sperm donors. Semen was preserved in a glycerol-based medium. At the time of insemination, the semen was thawed and washed in either a Percoll gradient or, more recently, an Isolate gradient. Transcervical intrauterine insemination of 0.5 mL of washed semen was performed on the day after the luteinizing hormone surge was detected by self-test or approximately 36 to 40 hours after human chorionic gonadotropin administration in stimulated cycles. After resting in a recumbent position for 10 minutes, the patient resumed normal activities. A serum β-human chorionic gonadotropin test was performed 16 to 18 days after insemination if menses did not occur. Ultrasonographic confirmation of pregnancy was obtained 5 weeks after insemination. Women with positive findings on a β-human chorionic gonadotropin test and ultrasonographic evidence of pregnancy were considered pregnant. Pregnancies that resulted in the delivery of living infants were considered live births. Pregnancies that were spontaneously terminated before 20 weeks’ gestation were considered abortions. Ectopic pregnancies were diagnosed by ultrasonography and β-human chorionic gonadotropin levels. Molar pregnancies were diagnosed by pathologic examination. Per cycle pregnancy is defined as the probability of pregnancy per cycle, with each cycle considered independent of all other cycles. Results were obtained by generating cumulative pregnancy rate curves with life-table analysis to visually display and compare data sets. The pregnancy rate curves were
then analyzed with the Mantel-Haenszel statistical test. P values were considered significant if <.05. Results A total of 213 patients were included in the study, and 960 cycles were analyzed. Overall, 116 pregnancies were obtained to give a cycle pregnancy rate of 12.1% for all age groups and diagnoses. The cumulative probability of pregnancy exceeded 80% for all groups analyzed together. Seventy percent (81) of pregnancies resulted in liveborn infants. Of the 35 nonviable pregnancies, there were 28 (24%) that ended in spontaneous abortion, 5 (4.3%) that were ectopic, and 2 (1.7%) that were molar. The patients ranged in age from 22 to 44 years. Three hundred thirty cycles were performed in women younger than 30 years, 425 cycles in women between the ages of 30 and 35 years, 183 cycles in women between the ages of 35 and 40 years, and 21 cycles in women older than 40 years. There was a statistically significant decrease in the cumulative probability of pregnancy in women between the ages of 35 and 40 years (P < .01) and even more so in women older than 40 years (P < .001). Indeed, there were no pregnancies in women older than 40 years (Fig 1). The corresponding per cycle pregnancy rate also declined in women between the ages of 35 and 40 years (8.2%) and in women older than 40 years (0%) compared with younger women, with rates of 15.8% and 14.6% for women younger than 30 years and women between the ages of 30 and 35 years, respectively. Six hundred fifty-three cycles were performed on women without children and 307 cycles on women with children. Four hundred thirty-three cycles were performed on women without prior pregnancies, and 527 cycles were performed on women with prior pregnancies. Parity had no effect on the cumulative probability of pregnancy or the per cycle pregnancy rate for nulliparous and parous women (13.5% and 13.4%, respectively). There was a trend toward higher cumulative probability of pregnancy and improved pregnancy rate in women with prior pregnancies versus women without prior pregnancies, 14.4% and 12.3%, respectively (P = .15). Seven hundred fifty-one cycles were performed on women whose partners had azoospermia, 141 cycles were performed on women whose partners had severe oligospermia, and 68 cycles were performed on women whose partners had moderate oligospermia. There was a trend toward decreased cumulative probability of pregnancy in women if their partners had moderate oligospermia compared with women whose partners had severe oligospermia or azoospermia (P = .20). There was no significant difference between the overall cycle pregnancy rate between wash gradients with Percoll versus Isolate. At >20 million total motile sperm per insemination, which was the minimum inseminated per patient cycle, there was no threshold above which the
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Fig 1. Cumulative probability of pregnancy in women having donor sperm insemination according to the age of the women at time of insemination. x, <30 years old; square, 30-34 years of age; triangle, 35-39 years of age; plus sign, >39 years of age; circle, overall.
pregnancy rate was improved. There was no significant difference in cycle pregnancy rates in unstimulated cycles (13.8%), clomiphene-stimulated cycles (12.2%), clomiphene-HMG–stimulated cycles (15.2%), and HMG-stimulated cycles (7%). Comment With an increasing number of couples investing emotional energy in donor insemination and the everincreasing demand for cost-effectiveness in health care, it is more important than ever to accurately predict the likelihood of success and the expected duration and cost of treatment for couples presenting for donor IUI. This study demonstrates that there are highly significant differences in the fecundability of donor IUI recipients. Many studies have indicated that fertility diminishes in women after the age of 35 years.5, 6 The significance of this effect on success rates in donor IUI programs has not been fully elucidated. Byrd et al7 examined the outcome of pregnancy by age and reported that pregnancy rate decreased as age increased. However, there was no significant difference in pregnancy rate by age if women with other known infertility factors were eliminated. Kang and Wu2 demonstrated that age is a critical independent variable affecting success rates in donor IUI programs. Our study confirms these conclusions. A cycle pregnancy rate of 15% was achieved in women younger than 35 years, which compares favorably with other reported rates that range from 9% to 20%.8 In women older than 35 years, pregnancy rates decreased steadily to 8% before the age of 40. There were no pregnancies achieved in women older than 40 years. This lack of success in women older than 40 years may partially be caused by the small number of cycles performed on women older than 40 years, but the difference was significant even given the small number of cycles. Given the trend toward delayed child-
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bearing, this poor success rate warrants further study. Perhaps donor IUI is not appropriate or cost-effective for women older than 40 years. Perhaps tests of ovarian reserve should be used to aid in prognosis. Certainly, older women must be counseled on a significantly decreased probability of success and on the potential for a prolonged treatment period. The cumulative probability of pregnancy exceeded 80% during 12 cycles according to life-table analysis. Again, this compares favorably with other reported results.9, 10 We observed a plateau in cumulative probability of pregnancy at approximately 8 cycles. This is also comparable with the findings in the previously referenced studies. Therefore it seems reasonable to offer 8 to 12 cycles of treatment for women undergoing donor IUI before considering other options. Kovacs et al4 and Emperaire et al11 have demonstrated that women whose partners are azoospermic have a higher fecundability than women whose partners are oligospermic. Our results showed a similar trend. Cycle pregnancy rates in women whose partners were oligospermic were lower (10%) than in women whose partners were azoospermic (13.6%). Larger numbers may have yielded statistical significance. If this trend is real, the effect appears to be less than the effect of age on cycle fecundability. Kang and Wu2 and Byrd et al7 have reported increasing fecundability rates with increasing numbers of total motile sperm per insemination. Kang and Wu2 noted no improvement in pregnancy rate at >60 million total motile sperm per insemination. Byrd et al7 only subdivided groups with <20 million total motile sperm per insemination. Within this small range, they noted increasing pregnancy rates with increasing sperm concentration. We saw no association between higher numbers of sperm per insemination and pregnancy rate. The vast majority of women in our study were inseminated with >20 million total motile sperm. It is quite likely that a threshold below which pregnancy rates are decreased does exist. However, that threshold appears to be <20 million total motile sperm per insemination. No studies have investigated the effect of pregnancy history on pregnancy rates in women undergoing donor IUI. Theoretically, it seems that women with prior pregnancies would have a higher pregnancy rate than women without prior pregnancies because the first group would be less likely to suffer from undiagnosed female infertility factors. Women without prior pregnancies had a pregnancy rate of 12.3% per cycle, which was lower than the rate of 14.4% for women with prior pregnancies. This difference was not statistically significant. Given the large numbers of cycles in each group (433 and 527, respectively) and the lack of statistical significance, the effect of gravidity on success in donor IUI, if any, is small. When analyzing our data according to parity, there was no dif-
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ference in cycle pregnancy rate between nulliparous and parous women (13.5% and 13.4%, respectively). On the basis of our study and the studies of others, donor IUI is a very effective means of treating male factor infertility with long-term success rates >80%. The overall cycle pregnancy rate approaches that of the spontaneous conception rate in the general population. As seen in the general population, female age is a major prognostic indicator, particularly in women older than 35 years. Patients participating in a donor IUI program should be counseled about the declining success rate in women older than 35 years. Women older than 40 years should be aware of a low likelihood of success before pursuing this time-consuming, costly, and emotionally draining treatment. Both groups may benefit by undergoing ovarian reserve testing before the initiation of treatment. Additionally, sperm concentrations of >20 million total motile sperm should be used to optimize chances of success, and physicians should be aware of a potential small impact of gravidity and male factor diagnosis when counseling patients. REFERENCES
1. Azziz R. Donor insemination. Update in infertility and reproductive endocrinology. University of Alabama, Birmingham [newsletter]. 1998;10:1-4. 2. Kang BM, Wu TC. Effect of age on intrauterine insemination with frozen donor sperm. Obstet Gynecol 1998;88:93-8. 3. Chauhan M, Barratt CL, Cooke SM, Cooke ID. Differences in the fertility of donor insemination recipients: a study to provide prognostic guidelines as to its success and outcome. Fertil Steril 1989;51:815-9. 4. Kovacs GT, Leeton JF, Mathews CD. The outcome of artificial donor insemination compared to the husband’s fertility status. Clin Reprod Fertil 1982;1:295-9. 5. Hansen JP. Older maternal age and pregnancy outcome: a review of the literature. Obstet Gynecol Surv 1986;41:726-42. 6. Eaton JW, Mayer AJ. The social biology of very high fertility among the Hutterites: the demography of a unique population. Hum Biol 1953;25:206-64. 7. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and intracervical insemination using frozen donor sperm. Fertil Steril 1990;53:521-7. 8. Rose B. Use of a single intrauterine insemination of defrosted cryopreserved sperm for therapeutic donor insemination. Int J Fertil Menopausal Stud 1994;39:140-4. 9. Patton PE, Novy MJ, Burry KA, Wolf DP, Thurmond A. Intrauterine insemination outperforms intracervical insemination in a randomized, controlled study with frozen donor semen. Fertil Steril 1992;57:559-64. 10. Hurd WW, Menge AC, Randolph JF, Ohl DA, Ansbacher R, Brown AN. Comparison of intracervical, intrauterine, and intratubal techniques for donor insemination. Fertil Steril 1993;59:339-42. 11. Emperaire JC, Gauzere-Soumireu E, Audebert AJM. Female fertility and donor insemination. Fertil Steril 1982;1:90-3.
Discussion DR BARRY S. VERKAUF, Tampa, Florida. Although retrospective and descriptive in character, Dr Williams’ study is useful for the following reasons: (1) It deals with a large number of patients. (2) These patients were treated in the
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same environment over time by a stable group of welltrained reproductive endocrinologists. (3) Appropriate statistical analysis for comparative purposes has been used. This paper looks comprehensively at the outcome of donor insemination in an era of the human immunodeficiency virus and frozen semen, in which the use of thirdparty gametes, both sperm and eggs, is increasing. The following observations are reassuring and consistent with earlier ones regarding therapeutic donor insemination: (1) Cumulative pregnancy rates in this series are better than rates in many earlier series with frozen semen and approach those reported with fresh semen and in the normal fertile population. (2) Almost all pregnancies occur within 12 cycles of insemination; indeed, the great majority occur within 8 appropriately instituted cycles. (3) Pregnancy outcome in this series is similar to spontaneously conceived cycles and those with fresh semen, except for a slight increase in the incidence of ectopic and molar pregnancies. (4) If it is assumed that the raw semen is good, the gradient washes are technically well performed, and 20 million total motile sperm per inseminate is assured, high pregnancy rates can be achieved with a variety of gradient washes. (5) There is a tendency for better outcomes in women who have previously delivered. There was a trend toward higher pregnancy rates in women whose partners were azoospermic compared with women whose partners were oligospermic. This is consistent with prior observations.1, 2 Presumably this is related to the potential undetected presence of female contributory factors in couples in which men with oligospermia have the potential to impregnate their partners. Indeed, pregnancy rates with donor insemination have been reported to be reduced in couples in which the woman is oligo-ovulatory or concomitant pelvic abnormalities are present.3-5 At the 1993 meeting of this society, we presented data showing that the causes of infertility are often multiple, that the likelihood of conception differs with treatment depending on the specific cause, and that, if all factors present are identified and treated adequately and all untreatable couples extracted, these differences diminish over time.6 Therefore all infertile couples, including those entering a donor insemination program, must be evaluated and treated in some methodical manner. Although it is not stated in the paper, I assume that all patients underwent a standard contemporary infertility investigation and that all other identified factors were treated. Dr Williams, can you confirm this? Were there differences among your patients that were dependent on the specific factors involved and their multiplicity? In addition, do you think it is worth regularly doing two intrauterine inseminations per cycle or routinely using ovulation induction to enhance cycle fecundity? Is it really necessary, given today’s need for office efficiency, for patients to rest for 10 minutes in the office after an intrauterine insemination? I do not raise these questions to detract from the main point of the paper, which is that success with donor insemination diminishes with the age of the woman. Investigators have consistently observed this in relation to
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donor insemination, and it is consistent with many observations in the medical literature. For example, epidemiologic studies clearly show that fecundity diminishes with age.7 Data from the Society of Assisted Reproductive Technology clearly show the diminished efficacy of in vitro fertilization after the age of 35,8 and information from the University of Iowa demonstrates that, regardless of the type of assisted reproductive technology used, pregnancy rates are diminished in older women.9 In this regard, it is fitting that these data are presented today at a meeting made up principally of general practitioners in obstetrics and gynecology. The age at which women present to the reproductive endocrinologist for infertility treatment has increased in my practice from 29 years in the interval from 1975 through 1980 to 36 years in current years. These findings are true both in private practices and in tertiary referral centers. In medicine, an ounce of prevention is always worth at least a pound of cure, and it is the general obstetrician-gynecologist and other primary care physicians who have the greatest opportunity to take advantage of the practical application of this study’s principal finding. Young women need to be educated and counseled in their early encounters with obstetrician-gynecologists regarding their plans for a family. At a time when American couples have generally been delaying marriage and starting a family, often for good but sometimes for less substantive reasons, we need to reinforce the effect of the ticking biologic clock on a couple’s ability to have children if family is truly of value and concern to them. I congratulate Dr Williams on a nicely packaged study that drives home an important observation with significant medical and social consequences. REFERENCES
1. Emperaire JC, Gauzere-Soumireu EG, Audebert AJM. Female fertility and donor insemination. Fertil Steril 1982;37:90-3. 2. Albrecht BH, Cramer D, Schiff I. Factors influencing the success of artificial insemination. Fertil Steril 1982;37:792-7. 3. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and cervical insemination using frozen donor sperm. Fertil Steril 1990;53:521-7. 4. Meeks GR, McDonald J, Gookin K, Gates GW. Insemination with fresh donor semen. Obstet Gynecol 1986;68:527-30. 5. Chauhan M, Barratt CL, Cooke SM, Cooke ID. Differences in the fertility of donor insemination recipients: a study to provide prognostic guidelines as to its success and outcome. Fertil Steril 1989;51:815-9. 6. Verkauf BS. The incidence and outcome of single-factor, multifactorial, and unexplained infertility. Am J Obstet Gynecol 1983;147:175-81. 7. Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol 1991;9:165-75. 8. Centers for Disease Control and Prevention. 1997 Assisted reproductive technology success rates. National Summary and Fertility Clinic Reports Centers for Disease Control and Prevention. Division of Reproductive Health [annual report] December 1998; Atlanta, Georgia. 9. Van Voorhis BJ, Stovall DW, Allen BD, Syrop CH. Cost-effective treatment of the infertile couple. Fertil Steril 1998;70:995-1005.
DR FRANK RIGALL, Orlando, Florida. Did you test for ovarian reserve in any of these women? And, if so, did
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that alter your management? Also, I was wondering how you counsel women older than 40 years who are currently presenting to your office and what your plan of management for them is. DR ED HORGER, Columbia, SC. I recognize that I know very little about donor insemination, but I was struck by the fact that 2 of your 116 pregnancies were hydatidiform molar pregnancies. Is that a recognized complication of donor insemination, or are there any further comments that you can make about this high incidence? DR WILLIAMS (Closing). I thank Dr Verkauf for sending his discussion and Dr Gambrell for reading his discussion. I will discuss Dr Verkauf’s questions first. Did all couples undergo a complete infertility evaluation? It is our standard practice that, if a couple presents with an obvious infertility problem such as azoospermia, we may not complete the rest of the infertility workup. We certainly get a complete history, including a menstrual history, which is a very good indicator of ovulation status. All of the inseminations are performed on the basis of luteinizing hormone kits, which further confirm ovulation. We obtain a history for risk factors for tubal disease and, if we have any suspicion, we proceed to hysterosalpingogram. The majority of those couples without risk factors may not have had a hysterosalpingogram. This also has to do with Dr Verkauf’s second question: Did we treat all known factors, and how did that affect our success rate? I think this is evidenced by comparing the study that was in Dr Verkauf’s discussion, which showed a discrepancy between success rates in men who are azoospermic versus men who are oligospermic, with this study, in which there was just a slight trend of increased success in the couples who were azoospermic and are less likely to have additional female contributory factors. I believe that the reason that there was not more of a discrepancy in our success rates is that we were successful in simultaneously identifying and correcting all other factors. His third question was whether two inseminations are better than one insemination. There have been reports in the medical literature that two inseminations have a higher success rate and, indeed, about a year ago, on the basis of those reports, we began routinely performing two inseminations. After a year of performing two inseminations, we compared the success rate with two inseminations with our historic success rate with one insemination, and we saw absolutely no difference. We have now changed our practice and continue to do only one insemination. Do we routinely perform superovulation along with the intrauterine inseminations? Again, it is our practice to perform ovulation induction in women who are anovulatory and oligo-ovulatory, but we reserve superovulation for women with known female contributory factors such as mild endometriosis. We also offer superovulation if the couple has not been successful after approximately 8 to 10 cycles of inseminations. Regarding Dr Verkauf’s last question about a 10minute rest after the insemination, that has been our practice all along. There was a recent report that actually looked at a randomized study that compared inseminations that were followed by 10 minutes of rest with insemi-
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nations that were followed by immediate ambulation and, indeed, there was a higher pregnancy rate after 10 minutes of rest. Fortunately, that matched what we have been doing all these years. Dr Rigall asked about routine ovarian reserve testing. We usually offer this to women who are older than 35 years. It is important to remember that this was a 10-year time frame, and ovarian reserve testing was not well described in 1988. We certainly think that, in women older than 35 years, it is an important test. If women have a very poor ovarian reserve, we counsel them about the unlikely
Williams and Alderman 337
success of donor inseminations and offer them donor oocytes. How do we counsel women who are older than 40? We tell them that, even with normal ovarian reserve, their age is still a very bad prognostic factor, but, as long as they are aware of this, we proceed with the appropriate therapy. Dr Horger asked about the high incidence of molar pregnancies. I have not seen that described elsewhere, and it was somewhat surprising to me. I have no explanation of why we would have a higher than normal molar pregnancy rate with donor inseminations.
Key words: Donor sperm insemination, pregnancy rate, maternal age
The use of therapeutic insemination dates back to biblical times; donor inseminations were first performed in the United States in Philadelphia in 1884.1 Fresh sperm was used primarily for insemination until the 1990s, but, because of the concern regarding the transmission of infectious diseases, frozen semen is now used exclusively for donor intrauterine inseminations (IUIs). The use of frozen semen therapeutic IUIs has proven to be a highly effective and well-accepted means of achieving conception. Indeed, more infertile couples use donor insemination than newborn adoption as a means of building their families. Indications for donor IUI are varied and include male factor infertility, noncorrectable ejaculatory dysfunction, the desire to avoid transmission of genetic and infectious diseases, and, in some centers, single women who desire pregnancy.
From the Department of Obstetrics and Gynecology, University of Florida. Presented at the Sixty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 20-23, 2001. Reprint requests: R. Stan Williams, MD, Department of Obstetrics and Gynecology, PO Box 100294, University of Florida, Gainesville, FL 32610. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/116733 doi:10.1067/mob.2001.116733
332
Although this treatment is well established and widely practiced, it is psychologically stressful to couples, especially as the duration of treatment increases without success. Therefore physicians practicing donor IUIs should be able to provide couples with an individualized prognosis regarding duration and likelihood of success. The factors that significantly influence the outcome of donor IUI cycles must be identified so that physicians can provide an educated prognosis for patients. Studies have shown that increasing maternal age has a significant negative impact on fecundity rates.2 In addition, other infertility factors3 and the presence of partners with oligospermia rather than azoospermia have been shown to decrease fecundity rates.4 No studies have adequately evaluated the effect of obstetric history on fecundity rates. By reviewing the 10-year experience at the University of Florida, this report evaluates the effect of multiple factors that may alter the success rate or time to conception of couples using donor sperm insemination. Material and methods Charts were reviewed on 213 infertility patients who received donor sperm IUIs while attending the private University of Florida infertility clinic, the Park Avenue Women’s Center, from January 1988 through February 1998. Factors analyzed included date, patient age, cycle
Williams and Alderman 333
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number, patient gravidity and parity, male infertility diagnosis, type of ovarian stimulation, number of total motile sperm inseminated, and the presence or absence of pregnancy. A total of 960 cycles were reviewed. The patient age category was determined by the woman’s age at the onset of treatment. The number of cycles per patient ranged from 1 to 18. Cycle number reverted to 1 after any pregnancy was achieved. Men were considered moderately oligospermic if there were between 1 and 20 million total motile sperm per ejaculate, severely oligospermic if there were <1 million total motile sperm per ejaculate, or azoospermic if there were no motile sperm. Men with ejaculatory dysfunction or infectious diseases were considered azoospermic because it was likely that their wives had no exposure to viable sperm. Types of ovarian stimulation used included natural (N = 689), clomiphene citrate (N = 123), clomiphene citrate and human menopausal gonadotropin (HMG) (N = 79), and HMG only (N = 43). Ovulation induction was primarily used either to correct anovulation or as superovulation therapy in women with mild to moderate endometriosis. Only cryopreserved semen was used for insemination. Semen had been obtained from healthy donors who had good quality semen and were free of sexually transmitted diseases and transmissible genetic disorders. The screening of donors followed all current recommendations for sperm donors. Semen was preserved in a glycerol-based medium. At the time of insemination, the semen was thawed and washed in either a Percoll gradient or, more recently, an Isolate gradient. Transcervical intrauterine insemination of 0.5 mL of washed semen was performed on the day after the luteinizing hormone surge was detected by self-test or approximately 36 to 40 hours after human chorionic gonadotropin administration in stimulated cycles. After resting in a recumbent position for 10 minutes, the patient resumed normal activities. A serum β-human chorionic gonadotropin test was performed 16 to 18 days after insemination if menses did not occur. Ultrasonographic confirmation of pregnancy was obtained 5 weeks after insemination. Women with positive findings on a β-human chorionic gonadotropin test and ultrasonographic evidence of pregnancy were considered pregnant. Pregnancies that resulted in the delivery of living infants were considered live births. Pregnancies that were spontaneously terminated before 20 weeks’ gestation were considered abortions. Ectopic pregnancies were diagnosed by ultrasonography and β-human chorionic gonadotropin levels. Molar pregnancies were diagnosed by pathologic examination. Per cycle pregnancy is defined as the probability of pregnancy per cycle, with each cycle considered independent of all other cycles. Results were obtained by generating cumulative pregnancy rate curves with life-table analysis to visually display and compare data sets. The pregnancy rate curves were
then analyzed with the Mantel-Haenszel statistical test. P values were considered significant if <.05. Results A total of 213 patients were included in the study, and 960 cycles were analyzed. Overall, 116 pregnancies were obtained to give a cycle pregnancy rate of 12.1% for all age groups and diagnoses. The cumulative probability of pregnancy exceeded 80% for all groups analyzed together. Seventy percent (81) of pregnancies resulted in liveborn infants. Of the 35 nonviable pregnancies, there were 28 (24%) that ended in spontaneous abortion, 5 (4.3%) that were ectopic, and 2 (1.7%) that were molar. The patients ranged in age from 22 to 44 years. Three hundred thirty cycles were performed in women younger than 30 years, 425 cycles in women between the ages of 30 and 35 years, 183 cycles in women between the ages of 35 and 40 years, and 21 cycles in women older than 40 years. There was a statistically significant decrease in the cumulative probability of pregnancy in women between the ages of 35 and 40 years (P < .01) and even more so in women older than 40 years (P < .001). Indeed, there were no pregnancies in women older than 40 years (Fig 1). The corresponding per cycle pregnancy rate also declined in women between the ages of 35 and 40 years (8.2%) and in women older than 40 years (0%) compared with younger women, with rates of 15.8% and 14.6% for women younger than 30 years and women between the ages of 30 and 35 years, respectively. Six hundred fifty-three cycles were performed on women without children and 307 cycles on women with children. Four hundred thirty-three cycles were performed on women without prior pregnancies, and 527 cycles were performed on women with prior pregnancies. Parity had no effect on the cumulative probability of pregnancy or the per cycle pregnancy rate for nulliparous and parous women (13.5% and 13.4%, respectively). There was a trend toward higher cumulative probability of pregnancy and improved pregnancy rate in women with prior pregnancies versus women without prior pregnancies, 14.4% and 12.3%, respectively (P = .15). Seven hundred fifty-one cycles were performed on women whose partners had azoospermia, 141 cycles were performed on women whose partners had severe oligospermia, and 68 cycles were performed on women whose partners had moderate oligospermia. There was a trend toward decreased cumulative probability of pregnancy in women if their partners had moderate oligospermia compared with women whose partners had severe oligospermia or azoospermia (P = .20). There was no significant difference between the overall cycle pregnancy rate between wash gradients with Percoll versus Isolate. At >20 million total motile sperm per insemination, which was the minimum inseminated per patient cycle, there was no threshold above which the
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Fig 1. Cumulative probability of pregnancy in women having donor sperm insemination according to the age of the women at time of insemination. x, <30 years old; square, 30-34 years of age; triangle, 35-39 years of age; plus sign, >39 years of age; circle, overall.
pregnancy rate was improved. There was no significant difference in cycle pregnancy rates in unstimulated cycles (13.8%), clomiphene-stimulated cycles (12.2%), clomiphene-HMG–stimulated cycles (15.2%), and HMG-stimulated cycles (7%). Comment With an increasing number of couples investing emotional energy in donor insemination and the everincreasing demand for cost-effectiveness in health care, it is more important than ever to accurately predict the likelihood of success and the expected duration and cost of treatment for couples presenting for donor IUI. This study demonstrates that there are highly significant differences in the fecundability of donor IUI recipients. Many studies have indicated that fertility diminishes in women after the age of 35 years.5, 6 The significance of this effect on success rates in donor IUI programs has not been fully elucidated. Byrd et al7 examined the outcome of pregnancy by age and reported that pregnancy rate decreased as age increased. However, there was no significant difference in pregnancy rate by age if women with other known infertility factors were eliminated. Kang and Wu2 demonstrated that age is a critical independent variable affecting success rates in donor IUI programs. Our study confirms these conclusions. A cycle pregnancy rate of 15% was achieved in women younger than 35 years, which compares favorably with other reported rates that range from 9% to 20%.8 In women older than 35 years, pregnancy rates decreased steadily to 8% before the age of 40. There were no pregnancies achieved in women older than 40 years. This lack of success in women older than 40 years may partially be caused by the small number of cycles performed on women older than 40 years, but the difference was significant even given the small number of cycles. Given the trend toward delayed child-
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bearing, this poor success rate warrants further study. Perhaps donor IUI is not appropriate or cost-effective for women older than 40 years. Perhaps tests of ovarian reserve should be used to aid in prognosis. Certainly, older women must be counseled on a significantly decreased probability of success and on the potential for a prolonged treatment period. The cumulative probability of pregnancy exceeded 80% during 12 cycles according to life-table analysis. Again, this compares favorably with other reported results.9, 10 We observed a plateau in cumulative probability of pregnancy at approximately 8 cycles. This is also comparable with the findings in the previously referenced studies. Therefore it seems reasonable to offer 8 to 12 cycles of treatment for women undergoing donor IUI before considering other options. Kovacs et al4 and Emperaire et al11 have demonstrated that women whose partners are azoospermic have a higher fecundability than women whose partners are oligospermic. Our results showed a similar trend. Cycle pregnancy rates in women whose partners were oligospermic were lower (10%) than in women whose partners were azoospermic (13.6%). Larger numbers may have yielded statistical significance. If this trend is real, the effect appears to be less than the effect of age on cycle fecundability. Kang and Wu2 and Byrd et al7 have reported increasing fecundability rates with increasing numbers of total motile sperm per insemination. Kang and Wu2 noted no improvement in pregnancy rate at >60 million total motile sperm per insemination. Byrd et al7 only subdivided groups with <20 million total motile sperm per insemination. Within this small range, they noted increasing pregnancy rates with increasing sperm concentration. We saw no association between higher numbers of sperm per insemination and pregnancy rate. The vast majority of women in our study were inseminated with >20 million total motile sperm. It is quite likely that a threshold below which pregnancy rates are decreased does exist. However, that threshold appears to be <20 million total motile sperm per insemination. No studies have investigated the effect of pregnancy history on pregnancy rates in women undergoing donor IUI. Theoretically, it seems that women with prior pregnancies would have a higher pregnancy rate than women without prior pregnancies because the first group would be less likely to suffer from undiagnosed female infertility factors. Women without prior pregnancies had a pregnancy rate of 12.3% per cycle, which was lower than the rate of 14.4% for women with prior pregnancies. This difference was not statistically significant. Given the large numbers of cycles in each group (433 and 527, respectively) and the lack of statistical significance, the effect of gravidity on success in donor IUI, if any, is small. When analyzing our data according to parity, there was no dif-
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ference in cycle pregnancy rate between nulliparous and parous women (13.5% and 13.4%, respectively). On the basis of our study and the studies of others, donor IUI is a very effective means of treating male factor infertility with long-term success rates >80%. The overall cycle pregnancy rate approaches that of the spontaneous conception rate in the general population. As seen in the general population, female age is a major prognostic indicator, particularly in women older than 35 years. Patients participating in a donor IUI program should be counseled about the declining success rate in women older than 35 years. Women older than 40 years should be aware of a low likelihood of success before pursuing this time-consuming, costly, and emotionally draining treatment. Both groups may benefit by undergoing ovarian reserve testing before the initiation of treatment. Additionally, sperm concentrations of >20 million total motile sperm should be used to optimize chances of success, and physicians should be aware of a potential small impact of gravidity and male factor diagnosis when counseling patients. REFERENCES
1. Azziz R. Donor insemination. Update in infertility and reproductive endocrinology. University of Alabama, Birmingham [newsletter]. 1998;10:1-4. 2. Kang BM, Wu TC. Effect of age on intrauterine insemination with frozen donor sperm. Obstet Gynecol 1998;88:93-8. 3. Chauhan M, Barratt CL, Cooke SM, Cooke ID. Differences in the fertility of donor insemination recipients: a study to provide prognostic guidelines as to its success and outcome. Fertil Steril 1989;51:815-9. 4. Kovacs GT, Leeton JF, Mathews CD. The outcome of artificial donor insemination compared to the husband’s fertility status. Clin Reprod Fertil 1982;1:295-9. 5. Hansen JP. Older maternal age and pregnancy outcome: a review of the literature. Obstet Gynecol Surv 1986;41:726-42. 6. Eaton JW, Mayer AJ. The social biology of very high fertility among the Hutterites: the demography of a unique population. Hum Biol 1953;25:206-64. 7. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and intracervical insemination using frozen donor sperm. Fertil Steril 1990;53:521-7. 8. Rose B. Use of a single intrauterine insemination of defrosted cryopreserved sperm for therapeutic donor insemination. Int J Fertil Menopausal Stud 1994;39:140-4. 9. Patton PE, Novy MJ, Burry KA, Wolf DP, Thurmond A. Intrauterine insemination outperforms intracervical insemination in a randomized, controlled study with frozen donor semen. Fertil Steril 1992;57:559-64. 10. Hurd WW, Menge AC, Randolph JF, Ohl DA, Ansbacher R, Brown AN. Comparison of intracervical, intrauterine, and intratubal techniques for donor insemination. Fertil Steril 1993;59:339-42. 11. Emperaire JC, Gauzere-Soumireu E, Audebert AJM. Female fertility and donor insemination. Fertil Steril 1982;1:90-3.
Discussion DR BARRY S. VERKAUF, Tampa, Florida. Although retrospective and descriptive in character, Dr Williams’ study is useful for the following reasons: (1) It deals with a large number of patients. (2) These patients were treated in the
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same environment over time by a stable group of welltrained reproductive endocrinologists. (3) Appropriate statistical analysis for comparative purposes has been used. This paper looks comprehensively at the outcome of donor insemination in an era of the human immunodeficiency virus and frozen semen, in which the use of thirdparty gametes, both sperm and eggs, is increasing. The following observations are reassuring and consistent with earlier ones regarding therapeutic donor insemination: (1) Cumulative pregnancy rates in this series are better than rates in many earlier series with frozen semen and approach those reported with fresh semen and in the normal fertile population. (2) Almost all pregnancies occur within 12 cycles of insemination; indeed, the great majority occur within 8 appropriately instituted cycles. (3) Pregnancy outcome in this series is similar to spontaneously conceived cycles and those with fresh semen, except for a slight increase in the incidence of ectopic and molar pregnancies. (4) If it is assumed that the raw semen is good, the gradient washes are technically well performed, and 20 million total motile sperm per inseminate is assured, high pregnancy rates can be achieved with a variety of gradient washes. (5) There is a tendency for better outcomes in women who have previously delivered. There was a trend toward higher pregnancy rates in women whose partners were azoospermic compared with women whose partners were oligospermic. This is consistent with prior observations.1, 2 Presumably this is related to the potential undetected presence of female contributory factors in couples in which men with oligospermia have the potential to impregnate their partners. Indeed, pregnancy rates with donor insemination have been reported to be reduced in couples in which the woman is oligo-ovulatory or concomitant pelvic abnormalities are present.3-5 At the 1993 meeting of this society, we presented data showing that the causes of infertility are often multiple, that the likelihood of conception differs with treatment depending on the specific cause, and that, if all factors present are identified and treated adequately and all untreatable couples extracted, these differences diminish over time.6 Therefore all infertile couples, including those entering a donor insemination program, must be evaluated and treated in some methodical manner. Although it is not stated in the paper, I assume that all patients underwent a standard contemporary infertility investigation and that all other identified factors were treated. Dr Williams, can you confirm this? Were there differences among your patients that were dependent on the specific factors involved and their multiplicity? In addition, do you think it is worth regularly doing two intrauterine inseminations per cycle or routinely using ovulation induction to enhance cycle fecundity? Is it really necessary, given today’s need for office efficiency, for patients to rest for 10 minutes in the office after an intrauterine insemination? I do not raise these questions to detract from the main point of the paper, which is that success with donor insemination diminishes with the age of the woman. Investigators have consistently observed this in relation to
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donor insemination, and it is consistent with many observations in the medical literature. For example, epidemiologic studies clearly show that fecundity diminishes with age.7 Data from the Society of Assisted Reproductive Technology clearly show the diminished efficacy of in vitro fertilization after the age of 35,8 and information from the University of Iowa demonstrates that, regardless of the type of assisted reproductive technology used, pregnancy rates are diminished in older women.9 In this regard, it is fitting that these data are presented today at a meeting made up principally of general practitioners in obstetrics and gynecology. The age at which women present to the reproductive endocrinologist for infertility treatment has increased in my practice from 29 years in the interval from 1975 through 1980 to 36 years in current years. These findings are true both in private practices and in tertiary referral centers. In medicine, an ounce of prevention is always worth at least a pound of cure, and it is the general obstetrician-gynecologist and other primary care physicians who have the greatest opportunity to take advantage of the practical application of this study’s principal finding. Young women need to be educated and counseled in their early encounters with obstetrician-gynecologists regarding their plans for a family. At a time when American couples have generally been delaying marriage and starting a family, often for good but sometimes for less substantive reasons, we need to reinforce the effect of the ticking biologic clock on a couple’s ability to have children if family is truly of value and concern to them. I congratulate Dr Williams on a nicely packaged study that drives home an important observation with significant medical and social consequences. REFERENCES
1. Emperaire JC, Gauzere-Soumireu EG, Audebert AJM. Female fertility and donor insemination. Fertil Steril 1982;37:90-3. 2. Albrecht BH, Cramer D, Schiff I. Factors influencing the success of artificial insemination. Fertil Steril 1982;37:792-7. 3. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and cervical insemination using frozen donor sperm. Fertil Steril 1990;53:521-7. 4. Meeks GR, McDonald J, Gookin K, Gates GW. Insemination with fresh donor semen. Obstet Gynecol 1986;68:527-30. 5. Chauhan M, Barratt CL, Cooke SM, Cooke ID. Differences in the fertility of donor insemination recipients: a study to provide prognostic guidelines as to its success and outcome. Fertil Steril 1989;51:815-9. 6. Verkauf BS. The incidence and outcome of single-factor, multifactorial, and unexplained infertility. Am J Obstet Gynecol 1983;147:175-81. 7. Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol 1991;9:165-75. 8. Centers for Disease Control and Prevention. 1997 Assisted reproductive technology success rates. National Summary and Fertility Clinic Reports Centers for Disease Control and Prevention. Division of Reproductive Health [annual report] December 1998; Atlanta, Georgia. 9. Van Voorhis BJ, Stovall DW, Allen BD, Syrop CH. Cost-effective treatment of the infertile couple. Fertil Steril 1998;70:995-1005.
DR FRANK RIGALL, Orlando, Florida. Did you test for ovarian reserve in any of these women? And, if so, did
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that alter your management? Also, I was wondering how you counsel women older than 40 years who are currently presenting to your office and what your plan of management for them is. DR ED HORGER, Columbia, SC. I recognize that I know very little about donor insemination, but I was struck by the fact that 2 of your 116 pregnancies were hydatidiform molar pregnancies. Is that a recognized complication of donor insemination, or are there any further comments that you can make about this high incidence? DR WILLIAMS (Closing). I thank Dr Verkauf for sending his discussion and Dr Gambrell for reading his discussion. I will discuss Dr Verkauf’s questions first. Did all couples undergo a complete infertility evaluation? It is our standard practice that, if a couple presents with an obvious infertility problem such as azoospermia, we may not complete the rest of the infertility workup. We certainly get a complete history, including a menstrual history, which is a very good indicator of ovulation status. All of the inseminations are performed on the basis of luteinizing hormone kits, which further confirm ovulation. We obtain a history for risk factors for tubal disease and, if we have any suspicion, we proceed to hysterosalpingogram. The majority of those couples without risk factors may not have had a hysterosalpingogram. This also has to do with Dr Verkauf’s second question: Did we treat all known factors, and how did that affect our success rate? I think this is evidenced by comparing the study that was in Dr Verkauf’s discussion, which showed a discrepancy between success rates in men who are azoospermic versus men who are oligospermic, with this study, in which there was just a slight trend of increased success in the couples who were azoospermic and are less likely to have additional female contributory factors. I believe that the reason that there was not more of a discrepancy in our success rates is that we were successful in simultaneously identifying and correcting all other factors. His third question was whether two inseminations are better than one insemination. There have been reports in the medical literature that two inseminations have a higher success rate and, indeed, about a year ago, on the basis of those reports, we began routinely performing two inseminations. After a year of performing two inseminations, we compared the success rate with two inseminations with our historic success rate with one insemination, and we saw absolutely no difference. We have now changed our practice and continue to do only one insemination. Do we routinely perform superovulation along with the intrauterine inseminations? Again, it is our practice to perform ovulation induction in women who are anovulatory and oligo-ovulatory, but we reserve superovulation for women with known female contributory factors such as mild endometriosis. We also offer superovulation if the couple has not been successful after approximately 8 to 10 cycles of inseminations. Regarding Dr Verkauf’s last question about a 10minute rest after the insemination, that has been our practice all along. There was a recent report that actually looked at a randomized study that compared inseminations that were followed by 10 minutes of rest with insemi-
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nations that were followed by immediate ambulation and, indeed, there was a higher pregnancy rate after 10 minutes of rest. Fortunately, that matched what we have been doing all these years. Dr Rigall asked about routine ovarian reserve testing. We usually offer this to women who are older than 35 years. It is important to remember that this was a 10-year time frame, and ovarian reserve testing was not well described in 1988. We certainly think that, in women older than 35 years, it is an important test. If women have a very poor ovarian reserve, we counsel them about the unlikely
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success of donor inseminations and offer them donor oocytes. How do we counsel women who are older than 40? We tell them that, even with normal ovarian reserve, their age is still a very bad prognostic factor, but, as long as they are aware of this, we proceed with the appropriate therapy. Dr Horger asked about the high incidence of molar pregnancies. I have not seen that described elsewhere, and it was somewhat surprising to me. I have no explanation of why we would have a higher than normal molar pregnancy rate with donor inseminations.