Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles

Clomiphene citrate and intrauterine insemination:analysis of more than 4100 cycles Serena Dovey, Rita M. Sneeringer, M.D.,,and Alan S. Penzias, a Boston IVF, Waltham, Massachusetts; b Division of Reproductive Endocrinology and Infertility, Department of Obstetrics andGynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and c Harvard Medical School, Boston,Massachusetts Objective: To evaluate the outcomes of a large cohort of patients undergoing fertility treatment with clomiphenecitrate and intrauterine insemination.
Design: A retrospective cohort study.
Setting: Boston IVF, a large university-affiliated reproductive medicine practice.
Patient(s): A total of 4,199 cycles performed in 1,738 infertility patients between September 2002 and July 2007.
Intervention(s): All patients received oral clomiphene citrate, and patients with completed cycles had intrauterineinsemination performed.
Main Outcome Measure(s): Cumulative and per cycle pregnancy rates achieved among subsets of patients definedby age, completed cycles, and intention to treat (ITT).
Result(s): For women under age 35 years, 2,351 cycles were initiated in 983 patients. A total of 238 pregnanciesensued, yielding a pregnancy rate (PR) per completed cycle of 11.5% and 10.1% per cycle initiated with ITT. Inwomen aged 35–37 years, 947 cycles in 422 women lead to a PR per completed cycle and ITT of 9.2% and 8.2%,respectively. For patients aged 38-40 years, 614 cycles in 265 women lead to a PR per completed cycle and ITT of7.3% and 6.5%, respectively. In women aged 41–42 years, 166 cycles in 81 patients lead to a PR per completedcycle and ITT of 4.3% and 3.6%, respectively. For women above age 42 years, 120 cycles in 55 patients lead toa PR per completed cycle and ITT of 1.0% and 0.8%, respectively. On a per-patient treated basis, cumulativePRs were 24.2% under age 35, 18.5% ages 35–37, and 15.1% ages 38–40, whereas only 7.4% ages 41–42 and1.8% above 42 became pregnant (one pregnancy in 55 patients).
Conclusion(s): As anticipated, younger patients have a higher PR per cycle than older patients. The PR per cyclefor patients who initiate only one or only two treatment cycles is notably higher than the corresponding per cyclerates for cycles 3 through 9. The drop in success per patient among 41- and 42-year-olds is sharp, but the excep-tionally low success rate above age 42 suggests that CC with IUI has virtually no place in their treatment. (FertilSterilÒ 2008;90:2281–6. Ó2008 by American Society for Reproductive Medicine.) Key Words: Clomiphene citrate, intrauterine insemination, infertility, assisted reproductive technology, artificialinsemination, ART outcomes Clomiphene citrate (CC) has been a treatment of choice to receptors. By effectively diminishing the pool of available help correct ovulatory dysfunction and treat infertility for estrogen receptors within the hypothalamus, the negative over 40 years. Clomiphene citrate is both an agonist and feedback signal induced by estrogen is blocked, which in antagonist of estrogen, generally acting as a competitive turn, alters pulsatile GnRH secretion. This altered GnRH estrogen antagonist at physiologic female estrogen levels secretion then enhances gonadotropin release from the pitui- Clomiphene citrate is able to stimulate ovulation by com- tary. Increased gonadotropin release ultimately drives peting with estrogen for binding to the hypothalamic estrogen folliculogenesis at the level of the ovary Given its ability to induce ovulation in oligo-ovulatory and Received August 30, 2007; revised and accepted October 31, 2007.
anovulatory females, CC is considered a first-line medical Presented at the Society for Gynecologic Investigation, 54th Annual approach to improve fertility in this patient population Scientific Meeting Reno, Nevada, March 14–17, 2007.
Hammond et al. demonstrated that, in a group of an- Conflicts of interest: Serena Dovey, no conflicts to report; Rita Sneeringer, no conflicts to report; Alan Penzias, Ferring Pharmaceuticals—Re- ovulatory and oligomenorrheic women treated with CC, search Grant Support; Speakers Bureau; EMD Serono and Organon, 86% ovulated and 49% of those patients conceived. More recently, in a compilation of seven published studies looking Reprint requests: Alan S. Penzias, M.D., Boston IVF, 130 Second Avenue, at CC and ovulation, Homburg reported an ovulation rate of 73% with a pregnancy rate (PR) of 36%. In addition, Beck Fertility and Sterilityâ Vol. 90, No. 6, December 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
et al. analyzed 12 randomized controlled trials regarding is achieved through a hysterosalpingogram. A semen analysis oral antiestrogen treatment in patients with anovulatory infer- is also performed. In 2007, a basal antral follicle ultrasound tility and concluded that CC is effective in increasing the PR was added to the evaluation. Upon completion of the initial when compared with placebo. Thus, CC effectively stimu- evaluation patients with evidence of thyroid dysfunction or lates both ovulation and greatly improves fertility success hyperprolactinemia were further evaluated as indicated, and treated medically before proceeding with fertility therapy.
Men with severe semen parameter abnormalities were Given the fertility success seen in the anovulatory popula- referred for urologic evaluation. Patients were deemed eligi- tion, CC has more recently been used as an approach to initial ble for ovulation induction and IUI if they had at a structurally treatment in patients with unexplained infertility, on the normal uterine cavity with at least one open fallopian tube premise that CC will increase the number of mature follicles without radiographic evidence of peritubal adhesions, were that develop every month and thus increase the likelihood of ovulatory or oligo-anovulatory, and had adequate sperm pregnancy. Additionally, it has been postulated that CC may available for insemination defined as the presence at least 5 help to overcome subtle ovulatory defects . In a retro- million total motile sperm postprocessing. Thus, the patients spective analysis of 45 published studies on CC success in pa- treated in the present analysis represent multiple infertility tients with unexplained infertility, Guzick reported a 5.6% diagnoses. Treatment with CC began at a dose of 50 mg in PR per cycle in patients undergoing CC treatment with timed oligo-anovulatory patients or 100 mg in ovulatory infertile intercourse, and an 8.3% PR per cycle in CC plus intrauterine patients for 5 consecutive days. Cycles were cancelled insemination treatment (CC/IUI). Furthermore, in one of the when the patient [1] failed to respond to the prescribed largest series to date, Dickey et al. reported a 9.2% PR per dose of CC as evidenced by the absence of an LH surge using cycle in 3,381 CC/IUI cycles in a population of infertility a home-based urine ovulation predictor kit and confirmed by patients that included both ovulatory and anovulatory the absence of at least one follicle >15 mm by pelvic ultra- patients. Thus, given that CC is an orally administered, sound, [2] ovulated spontaneously before scheduled cycle cost-effective means of improving PRs among a variety of monitoring as evidenced by a serum progesterone >3 ng/ patients, it can be reasonably argued that it should be the first mL, or [3] had no motile sperm detected following sperm- therapy offered to patients seeking infertility treatment.
washing procedures. Patients whose treatment cycles were However, the reported efficacy of CC varies widely in the published literature. In the ovulatory infertility population,published PRs per cycle with CC range anywhere from12% to 35% . In an infertility population consisting of both ovulatory and anovulatory patients, efficacy rates of In September 2002, Boston IVF began using an electronic CC are even more variable, with published PRs ranging medical record (eIVF,, Inc, Irving, TX) from 4% to 27% per cycle . In this study, we report to track cycles of ovulation induction and IUI. All patients the largest series of CC data to date in a population of infertile undergoing ovarian stimulation with or without IUI at Boston patients who were either ovulatory or oligo-anovulatory, with IVF between September 2002 and the present are in the data- at least one open fallopian tube undergoing IUI. We also base. The database contains in excess of 10,000 ovarian stim- stratify the efficacy of CC by age groups and examine out- ulation cycles. Using the eIVF database query tool, data from come on a per-cycle and per-patient-treated basis to highlight all cycles of CC with IUI were exported in July 2007 to when CC is effective and when it should be bypassed in favor a Microsoft Excel spreadsheet for analysis.
of other treatment alternatives that may better maximizepregnancy success.
Information recorded in the database for each stimulation cycle included a unique numeric patient identifier, thepatient’s name, age at cycle start, treatment start date, last menstrual period, peak estradiol level, pregnancy outcome, and cancellation date and cancellation reason (if applicable).
The cycle outcome descriptions logged within the database All patients in the present study were evaluated and treated at included the following: pregnant, not pregnant, cancelled, Boston IVF, a large university affiliated reproductive medi- stopped, in progress, blank, or awaiting results. Pregnancy cine practice. The data analysis was performed under an as defined in our study include only those patients who had institutional review board protocol approved by Beth Israel ultrasound evidence of a gestational sac. A separate field in Deaconess Medical Center. Patients in the data set ranged the database ‘‘pregnancy test’’ with possible entries of posi- in age from 20–48 years, with a mean age of 34.5 years.
tive or negative was not included in this analysis. We found All patients underwent a comprehensive fertility evaluation.
that a large percentage of subjects had a blank entry in the At Boston IVF a comprehensive fertility evaluation includes ‘‘pregnancy test’’ field, indicating that the field was not cycle day 3 measurement of estradiol, FSH, TSH, free thy- consistently recorded at the time of cycle closure.
roxin, and prolactin. Women aged 40 and older also undergoa CC challenge test to further assess their ovarian reserve.
The eIVF Query tool identified 4,229 cycles of CC with Assessment of uterine anatomy and fallopian tube patency IUI. Thirty cycles were removed from the analysis as they Clomiphene/intrauterine insemination results in 4100 cycles belonged to hypothetic test patients placed into the electronic For women above age 42 years, 120 cycles in 55 patients medical record for training purposes.
yielded one pregnancy, a rate of 1.8% per patient. The PRper completed cycle and ITT were 1.0% and 0.8%, respec- Each record in the database represented an individual cycle. Because each patient undergoing treatment hasa unique identifier it was possible to identify each patient.
With the exception of ages 41–42, approximately 90% or There were a total of 1,738 patients who initiated 4,199 treat- more of the pregnancies seen in each age stratum was ment cycles. It was further possible to determine the number achieved in three initiated CC/IUI cycles or fewer ( of cycles each patient undertook. The data shows that 95% ofthe patients initiated four cycles of CC/IUI or fewer. In thisanalysis we chose to examine individual cohorts of patients as a function of the number of treatment cycles initiated.
This study is the largest single-center study to date reporting Therefore, patients who initiated three cycles are not a nested on the efficacy of CC and IUI. Although the variation among subset of those who initiated four cycles.
CC success rates in the literature is wide, our PR per cycle doescorrelate closely with some of the larger published trials The data was stratified by patient age at cycle start into five categories. Four of the categories are concordant with the age Our study is unique in that we have analyzed both the PR strata used by the United Stated Department of Health and per cycle but further stratified by the number of initiated Human Services, Centers for Disease Control and Prevention cycles. Patients continue or discontinue treatment with CC/ in their annual Assisted Reproductive Technology Report.
IUI for a number of reasons. Treatment-dependent pregnancy They are: [1] <35 years of age, [2] 35 to 37, [3] 38 to 40, is clearly one reason for discontinuation, but other reasons for and [4] 41 to 42. The final stratum in the present study was discontinuation include treatment-independent pregnancy, moving on to alternative treatment options or child-freeliving, financial constraints, and stress The data is further stratified by the number of cycles initi- ated by each patient, ranging from 1 to 9. Outcomes are We chose to report PRs where the results were clearly reported in three ways for each age stratum by number of known as well as by ITT. By doing so we hoped not to bias cycles initiated: [1] pregnancy rate per cycle of known out- the results by showing only completed cycles. If there was come (pregnant or not pregnant), [2] pregnancy rate per cycle a significant dropout or cancellation rate at a particular age initiated regardless of outcome status (intention to treat), and or cycle number we believed that studying the two extreme ends of outcome calculation that we would be able to detectsuch an anomaly, if it existed. The largest difference between% pregnant with known outcome and % pregnant by ITT was seen in all age strata (except those >42) among patients who The statistical package available in Excel was used to calcu- initiated only one cycle. This is not a surprise in that patients, who for one reason or another, had a cycle cancelled, wouldbe less likely to proceed on to another cycle. The lack of dif-ference in the oldest age stratum is because of the lack of pregnancy among any of the 25 patients who initiated theirfirst cycle of CC/IUI at that age.
For women under age 35 years, 2,351 cycles were initiated in983 patients. A total of 238 pregnancies ensued yielding Our data demonstrated a PR per cycle that is higher than the a pregnancy rate (PR) per completed cycle of 11.5% and PR among natural cycles in patients with unexplained infertil- 10.1% per cycle initiated with intention to treat (ITT).
ity. In a retrospective analysis of 45 published reports looking Among the 938 patients in this age category treated, 24.2% at the efficacy of various ovulation induction protocols, Guzick et al described a natural PR per cycle of only 1.3%–4.1% inan unexplained infertility population. Thus, we can infer that In women aged 35–37 years, 947 cycles in 422 women lead CC/IUI increases the chance of pregnancy two- to 10-fold to a PR per completed cycle and ITT of 9.2% and 8.2%, over timed intercourse in this patient population.
respectively. The 422 patients in this age category achieved78 pregnancies for a rate of 18.5%.
In addition, patients who initiate any treatment are inter- ested in knowing if their chance of conception declines For patients aged 38–40 years, 614 cycles in 265 women over repeated months of treatment. We looked at the % of lead to a PR per completed cycle and ITT of 7.3% and all pregnancies achieved in each age stratum as a function 6.5%, respectively. There were 40 pregnancies in the 265 of the number of cycles initiated. For women aged 40 and younger 89%–95% are achieved with three or fewer cycles In women aged 41–42 years, 166 cycles in 81 patients initiated with 92%–98% achieved with four or fewer cycles lead to a PR per completed cycle and ITT of 4.3% and initiated. The same was not observed for patients aged 41– 3.6%, respectively. Only 6 of the 81 patients (7.4%) became 42; however, there were only six pregnancies achieved in the 166 cycles initiated in 81 patients. Thus, the overall low Cycle Cycles Cycles Cycles Cycles Cycles Cycles Cycles Cycles 16.5% 13.5% 19.2% 50.0% 33.3% 50.0% 100.0% 1 Cycle 2 Cycles 3 Cycles 4 Cycles 5 Cycles 6 Cycles 7 Cycles Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. Fertil Steril 2008.
Clomiphene/intrauterine insemination results in 4100 cycles a Total cycles initiated ¼ intention to treat þ patient not pregnant þ patient pregnant.
Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. Fertil Steril 2008.
PR in that age group makes the percentage less relevant.
coids, and gonadotropins, with promising preliminary Because the overwhelming majority of pregnancies to be achieved with each age stratum occur within three to four ini- Another concern broached in recent publications is whether tiated cycles, there seems to be little benefit to continued use the antiestrogen effects of CC interfere with implantation and pregnancy Several invesitgators have noted that PRs Our data also highlights a significant reduction in efficacy of with CC are less than expected based on achieved ovulation CC/IUI with advancing maternal age. This finding is not sur- rates, and this discrepancy has been theorized to be secondary prising, given that an overall decline in fertility with advancing to CC’s antiestrogenic effects on cervical mucus and endome- age has been well documented In our population, trial differentiation. It has been suggested that the aromatase women 41 and 42 years old only had a 3.6%–4.3% PR per cy- inhibitor class of medications, which are not associated with cle with CC/IUI, and only 7.4% of the patients ever achieved such adverse antiestrogen effects, may thus replace CC as pregnancy with this modality. This rate is less than half the the mainstay of infertility therapy However, trials pregnancy incidence per patient of women aged 38–40.
comparing the efficacy of CC to letrozole, one of the most Patients who were 43 years of age and older only had a 1% or less PR per cycle. More pointedly, only 1 patient of 55 treated ever achieved a pregnancy. This suggests the absenceof efficacy of CC/IUI for patients age 43 years and older.
Although CC/IUI has been the mainstay of initial therapy for both oligo-anovulatory infertility as well as unexplained infertility for many years, concerns have been raised in the literature regarding its overall efficacy in certain patient pop-ulations . Specifically, some studies have identified a subset of anovulatory women who are resistant to CC . The incidence of CC resistance is approximately 25%, and although the etiology behind failure to ovulate is unclear, studies have demonstrated that these patients tend to be obese and insulin resistant However, several therapiesare being studied in this patient population to use in conjunc- Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. FertilSteril 2008.
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The strength of this study is its large size. This is a popula- 13. Vlahos NF, Coker L, Lawler C, Zhao Y, Bankowski B, Wallach EE.
Women with ovulatory dysfunction undergoing ovarian stimulation tion-based study of sorts in that all patients treated in our fa- with clomiphene citrate for intrauterine insemination may benefit from cility are included. This facilitates comparison within and administration of human chorionic gonadotropin. Fertil Steril 2005;83: between age strata. Although the diagnoses of the patients varied, the generally good outcomes in most age strata sug- 14. Yilmaz B, Kelekci S, Savan K, Oral H, Mollamahmutoglu L. Addition of gest that it is reasonable to offer CC/IUI as first-line therapy human chorionic gonadotropin to clomiphene citrate ovulation inductiontherapy does not improve pregnancy outcomes and luteal function. Fertil to patients without regard to ovulatory status, with at least one open fallopian tube and with at least 5 million motile 15. Manganiello PD, Stern JE, Stukel TA, Crow H, Brinck-Johnsen T, sperm following preparation; in other words, a simplified fer- Weiss JE. A comparison of clomiphene citrate and human menopausal tility evaluation. This study demonstrates the utility of a lim- gonadotropin for use in conjunction with intrauterine insemination. Fer- ited number of CC/IUI treatments in this population under 16. Zreik TG, Garcia-Velasco JA, Habboosh MS, Olive DL, Arici A.
age 41. Further study of patients aged 41 and older is criti- Prospective, randomized, crossover study to evaluate the benefit of cally needed to determine the most effective treatment mo- human chorionic gonadotropin-timed versus urinary luteinizing hor- dality for those patients. For the foreseeable future, CC/IUI mone-timed intrauterine inseminations in clomiphene citrate-stimulated will remain the mainstay of initial treatment for wide range treatment cycles. Fertil Steril 1999;71:1070–4.
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Clomiphene/intrauterine insemination results in 4100 cycles


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