By Michael A. Thomas, MD
Professor, Fellowship and Division Director, Section of Reproductive Endocrinology and Infertility, University of Cincinnati Academic Health Center
Dr. Thomas reports no financial relationships relevant to this field of study.
Performing intrauterine insemination with the use of donor sperm twice during a natural or stimulated ovulation induction cycle did not increase pregnancy rates over a single insemination.
Zarek SM, et al. Single-donor and double-donor sperm intrauterine insemination cycles: Does double intrauterine insemination increase clinical pregnancy rates? Fertil Steril 2014;102:739-743.
To determine whether a single or double intrauterine insemination (IUI) improves pregnancy outcomes, the authors used a retrospective cohort design in a large private practice fertility center to observe clinical pregnancy rates after a natural or stimulated cycle. A total of 3159 donor IUI cycles were studied, of which 673 single and 2486 double inseminations were performed. Only cycles utilizing donor sperm were included in the evaluation and no other exclusions were used. Prior to each insemination, frozen donor sperm was thawed and washed to remove the seminal fluid; then the supernatant was re-suspended in sterile media. A catheter containing the sperm was placed directly into the uterus, bypassing the vagina and cervix to concentrate the male gametes in an area closer to the fallopian tubes. Timing of the insemination cycle was done using a urinary test kit to detect the luteinizing hormone (LH) surge or following injection of human chorionic gonadotropin (hCG) to mimic the LH surge. The two study groups (single or double) were similar in age, body mass index, number of cycles prior to the study, chance of having diminished ovarian reserve, and type of cycle (natural vs stimulated). Whether a patient underwent a single or double insemination was up to the physician and patient. Utilizing univariate regression and generalized estimation equation modeling, multiple subanalyses were performed to observe potential differences between the methods of IUI and other factors, including patient demographics, stimulation parameters, first and multiple cycle outcomes, best prognosis patients (< 35 years of age without polycystic ovary syndrome or ovarian reserve issues), and patients with a decrease in ovarian reserve parameters. The overall clinical pregnancy rates (heartbeat noted on ultrasound in the first trimester) were not significant between the two groups: single 16.4% and double 13.6%. Also, no differences in outcome were noted during the first cycle (single 17%, double 14.4%) or in good prognosis patients (single 23.3%, double 18.9%). From a cost-effectiveness perspective, the authors noted that the cost of an extra insemination at their institution added an additional $800 to the cost of the total cycle without noted benefit.
COMMENTARY
The use of intrauterine insemination with partner or donor sperm is a useful technique for couples with unexplained and male infertility without utilizing higher cost techniques such as in vitro fertilization. Whether a single or double insemination should be performed during an individual ovulation induction cycle is a matter of hot debate. Prior studies examining this issue have involved small numbers of subjects and have demonstrated conflicting results; double insemination was superior in two studies1,2 and another showed no difference between the two modalities (though the investigators of this study hypothesized double insemination superiority without significant findings).3 The rationale for double insemination (12 and 36 hours after LH trigger) is that you place sperm in the uterus the day of and after ovulation to increase the odds that the sperm will be in the fallopian tubes at the correct time for conception. The rationale for a single insemination (36 hours after LH trigger) is that insemination is timed at or closer to ovulation, therefore increasing the chance of fertilizing the newly released egg. Our center previously demonstrated that no differences were noted with a single IUI at 24 or 36 hours after the use of hCG to trigger ovulation; therefore, sperm placed in the uterus within 12-14 hours before the egg is released does not adversely affect chances at conception.4
The strengths of this study include the use of donor sperm as this negates the male factor as a confounding variable with these patients. It also increases the pool of patients to be studied, including single women and same-sex female couples. Though no female factor exclusions were permitted during analysis, analytic modeling techniques were used to remove a number of confounding factors and allow the investigators to observe the data many ways including first cycles, best prognosis patients, and those with a decrease in ovarian reserve. Despite these maneuvers, no differences were noted between the use of single and double insemination with donor sperm, which agrees with some of the previous data in smaller studies. Though this was the largest study to compare these two IUI treatment modalities, the authors noted weaknesses. One inherent weakness is the retrospective study design. Patients and/or physicians were allowed to choose the number of inseminations, thereby allowing three times more double inseminations over single.
This study is important for a number of reasons. First, it takes away the need for physicians to use double insemination to justify enhanced pregnancy rates. This eliminates cost for the patient already burdened with the high price of assisted reproductive technology.
Patients have a hand in pushing clinicians to do more to "increase the odds of success." There are a plethora of patient-to-patient Internet chat rooms that give antidotal "evidence" of unheralded success rates associated with double inseminations, specific vitamins/oils/lotions from for-profit companies, alternative therapies (acupuncture, aromatherapy, relaxation tapes, etc.), and different sexual positions. Clinicians sometimes buy in to the pressure to perform more interventions from desperate, but well-meaning, patients who may threaten to go to other practices if their demands aren’t met.
This study highlights the fact that large practices are often a wealth of untapped research data. Many clinical questions can be studied since high volume is available. The ability to ask a simple question and then look at all the parameters using sophisticated modeling techniques is like moving a Rubik’s cube around to look at all the possible combinations. In this case, one important clinical question has been answered. Hopefully, double insemination will fade away.
REFERENCES
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Khalifa Y, et al. The value of single vs repeated insemination in intra-uterine donor insemination cycles. Hum Reprod 1995;10:153-154.
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Chavkin DE, et al. Donor sperm insemination cycles: Are two inseminations better than one? J Androl 2012;33:375-380.
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Matilsky M, et al. Two-day IUI treatment cycles are more successful than one day IUI cycles when using frozen-thawed donor sperm. J Androl 1998;19:603-607.
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Robb PA, et al. The timing of hCG administration does not affect pregnancy rates in couples undergoing intrauterine insemination using clomiphene citrate. J Natl Med Assoc 2005;96:1431-1433.
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Check JH, et al. Improvement of cervical factor infertility with guaifenesin. Fertil Steril 1982;37:707-708.
