Predictive factors for intrauterine insemination outcomes: a review

We will next examine how different cycle factors, specifically stimulation regimen, use of a trigger, number of cycles and insemination procedure affect pregnancy outcomes. Accepted stimulation regimens to treat ovulatory dysfunction and infertility include CC, letrozole and gonadotropins. CC is a selective estrogen receptor modulator (SERM) which competes with estrogen for binding to the hypothalamic estrogen receptors, reducing negative feedback to the hypothalamus. This enhances hypothalamic Gonadotropin-Releasing Hormone (GnRH) secretion and subsequent gonadotropin release, driving ovarian stimulation [ 64 , 65 ]. CC also leads to thickened cervical mucous and possibly altered endometrial quality [ 66 ]. Letrozole is an aromatase inhibitor which blocks estrogen synthesis, preventing the conversion of androstenedione and testosterone to estrone and estradiol, respectively [ 67 ]. This decreases negative feedback to the pituitary, increasing FSH release. Letrozole does not negatively impact the endometrium or cervical mucus production [ 68 ]. Gonadotropin therapies include human menopausal gonadotropin (hMG), which contains a combination of FSH and Luteinizing Hormone (LH), urinary-derived FSH (uFSH), and recombinant human FSH (rhFSH). Exogenous gonadotropins directly stimulate ovarian follicular development similar to the endogenous pathway. While debates occur over which ovarian stimulation regimen is optimal and one should consider individual patient factors, some conclusions can be drawn from the available evidence. Several investigators have shown that pregnancy rates with FSH or hMG are superior to CC [ 69 , 70 ] and letrozole in IUI cycles, although use of gonadotropins is associated with increased multiple pregnancy rates [ 71 , 72 ] and risk of ovarian hyperstimulation syndrome (OHSS) [ 73 ]. Additionally, gonadotropins require frequent injections and are costlier compared to the oral regimens of CC and letrozole [ 70 ]. A retrospective study by Dickey et al. [ 70 ] compared CC alone, hMG alone, and sequential clomiphene followed by hMG and reported no difference in pregnancy rates per cycle between the CC-hMG group (22%) and hMG alone (18%), with significantly lower pregnancy rates in the CC group (11%). Given the comparable efficacy of combination CC and hMG with hMG alone, the authors concluded that the sequential regimen was superior, as it allowed for decreased utilization of hMG – reducing cost, number of injections, and monitoring. Diamond et al. [ 71 ] also demonstrated higher pregnancy rates and higher order multiple rates with gonadotropins over CC and letrozole in a randomized trial. They found no differences in miscarriage rates, ectopic rates, or OHSS. Given high rates of multiple pregnancies with gonadotropins, oral induction agents are typically preferred first line. Among patients with hypogonadotropic hypogonadism who lack endogenous gonadotropin formation, and thus would not respond to oral induction agents, the American Society for Reproductive Medicine (ASRM) recommends using gonadotropins for ovulation induction [ 74 ]. CC for ovulation induction with IUI is an established fertility treatment; however, the reported efficacy varies widely in the published literature. Pregnancy rates per cycle are reported to be 11.4%-21.5% [ 75 – 77 ] in ovulatory women and 9.7%-24.6% in anovulatory women [ 37 , 78 , 79 ]. Dovey et al. [ 80 ] conducted a retrospective cohort study with the largest series of CC data to date, totaling 4199 IUI cycles including patients who were both oligo-anovulatory and ovulatory. The authors stratified patients into age groups and found the following pregnancy rates for completed cycles: 11.5% for patients younger than 35y, 9.2% for patients 35 to 37y, 7.3% for patients 38 to 40y, 4.3% for patients 41 to 42y, and 1.0% for patients > 42y [ 80 ]. In the FORT-T study, pregnancy and live birth rates were equivalent among patients 38–42 years treated with CC or FSH and IUI, leading the authors to recommend the use of oral medications over injectables [ 40 ]. The Fast Track and Standard Treatment (FASTT) randomized trial [ 81 ] investigated time to conception and cost-effectiveness of IUI and IVF, comparing stepwise treatment of CC/IUI, FSH/IUI and IVF to accelerated treatment with IVF for couples who did not conceive after 3 IUI cycles. Pregnancy rates per cycle were 7.6% CC, 9.8% FSH and 30.7% IVF. Additional results showed shorter time to pregnancy (8 months accelerated versus 11 months conventional), fewer treatment cycles, and lower healthcare costs when patients proceeded from CC/IUI to IVF instead of first attempting FSH/IUI [ 81 ]. As letrozole has grown in popularity, multiple studies have compared its efficacy to that of CC. Diamond et al. evaluated 900 couples with unexplained infertility and randomized them to gonadotropins, CC or letrozole and IUI [ 71 ]. Results showed CPRs of 35.5% with gonadotropins, 28.3% with clomiphene and 22.4% with letrozole, and LBRs of 32.3%; 23.3% and 18.7%, respectively. CPRs and LBRs were lower in the letrozole group compared to gonadotropins alone or gonadotropins and CC. However, there were no significant differences between letrozole and CC alone. SAB rates, time to pregnancy, and rates of multiple gestation were also equivalent between letrozole and CC [ 71 ]. Letrozole does appear to be more effective than CC in patients with PCOS and those with at least Class I obesity. In a randomized trial of 750 women with PCOS treated with either letrozole or CC and regular intercourse, the letrozole group had higher CPRs (41.2% letrozole versus 27.4% CC) and cumulative LBR (27.5%; 19.5%) with no difference in multiple pregnancy or SAB rates [ 82 ]. LBR was higher for all patients receiving letrozole, with the largest difference between the letrozole and CC groups among patients with BMI 30.3–39.3 [ 82 ]. This data can be extrapolated to patients undergoing IUI cycles. One potential advantage of letrozole over CC was the proposed decrease in multiple pregnancies given primarily unifollicular development with letrozole [ 83 ]. However, the rate of multiples remains similar across studies as noted above. Early letrozole studies raised concern regarding its teratogenicity; however, a subsequent retrospective study demonstrated no difference in overall rates of congenital malformations [ 84 ]. In normo-ovulatory women, IUI may be performed either with a spontaneous LH surge or with a human Chorionic Gonadotropin (hCG) ovulation trigger. Spontaneous LH surge measured in the urine has been compared to administration of an hCG trigger in natural cycles in a retrospective study [ 85 ] and to CC-stimulated cycles in a randomized study [ 86 ]. Both studies found comparable pregnancy rates with urinary LH measurement versus use of an hCG trigger. The former study found no difference in live birth rates and the latter study found no differences in cumulative pregnancy rates over three cycles. A randomized study evaluated measurement of LH surge via serum blood draw, and demonstrated higher pregnancy rates in the spontaneous LH group as compared to use of an hCG trigger [ 87 ]. Cycle cancellation rates are higher when urinary LH is measured, possibly due to decreased sensitivity of urinary tests compared to serum tests, but cumulative pregnancy rates are unaffected. The available evidence suggests that LH monitoring is at least comparable to the use of an hCG trigger. If an hCG trigger is used, most studies start ultrasound follicular monitoring by cycle day 11–13 and trigger ovulation when follicles reach ≥ 18 mm in mean diameter [ 88 ]. Most authors recommend avoiding an hCG trigger if a patient has four follicles ≥ 20 mm in mean diameter given the risk of OHSS, with consideration of cycle cancellation or conversion to IVF [ 86 ]. The hCG trigger may be given as a subcutaneous (SC) or intramuscular (IM) injection. IM and SC administrations result in similar serum hCG levels in women with BMI < 30 [ 89 , 90 ]. Data from the IVF literature suggests that IM hCG injection is preferred over SC injection in obese women given significantly lower serum levels in the SC group [ 91 ]. Additionally, the typical needle length of 1.5 inches for IM injections may be insufficient to administer hCG in a number of these obese women, so tailored patient counseling is recommended. Most investigators recommend proceeding with IVF after three to four cycles given most pregnancies occur within the first four IUI cycles [ 37 , 38 , 80 ]. Studies have demonstrated up to 95% of pregnancies from OI/IUI with gonadotropins or CC are achieved within the first three cycles, with up to 98% [ 80 ] within the first four, resulting in little benefit derived from subsequent cycles. One study did show pregnancy rates up to 5.6% per cycle for cycles 7–9 with a cumulative pregnancy rate of 41% after the 9th cycle, but this was in a young patient population (< 35y) and only 12% of patients chose to continue with IUI after 6 total cycles [ 92 ]. The decision to continue IUI cycles should be guided by female age and ovulatory status, cost of treatment, and patient goals. Some practice variations in insemination procedure exist. In stimulated cycles, the timing of insemination varies from 24 to 40 hours after hCG injection with no difference in pregnancy rates [ 93 – 95 ]; as a result, exact timing may be guided by provider and patient preference. In natural cycles, IUI should be performed 24 hours after LH surge [ 96 ]. Single IUI is recommended. Double IUI, in which patients undergo insemination twice per cycle, has not been shown to increase pregnancy rates [ 97 – 100 ]. Following insemination, studies have evaluated whether 15 minutes of post-procedural rest is necessary. One randomized trial of 391 couples showed higher ongoing pregnancy rates (27% versus 18%) and live birth rates (27% versus 17%) among rested patients compared to mobile patients [ 101 ], while another randomized trial of 498 women reported no difference in cumulative pregnancy rates between groups [ 102 ]. Given the negligible risks and potential benefit, some providers may recommend post-procedural rest. In summary, ovulation induction regimens include CC, letrozole and gonadotropins. Gonadotropins achieve the highest pregnancy rates, but also increase risk of multiple gestation and OHSS. CC and letrozole appear to have similar efficacy with no difference in CPRs, LBRs, SAB rates or multiple gestation among women with unexplained infertility. For patients with PCOS, letrozole increases LBR and CPR. For women who do not conceive on CC/IUI, proceeding to IVF rather than attempting FSH/IUI may be beneficial. For women ≥ 38y who undergo IUI, stimulation with CC or FSH achieves comparable outcomes. IUI may be performed with a spontaneous LH surge or with an hCG ovulation trigger with comparable pregnancy rates. If an hCG trigger is used, it may be given SC or IM, although IM is preferred for women with BMI > 30. Most pregnancies occur within the first three to four IUI cycles, after which alternate therapies should be considered. Insemination may occur 24–40 hours after hCG injection, or 24 hours after LH surge in natural cycles. Single IUI is preferred to double IUI. Brief rest after insemination may increase pregnancy rates.

For this review, we first performed a computerized search of the published literature, limited to English language literature and conducted between April and November 2020. Databases searched were PubMed and Ovid. MeSH keywords used for the search included: “sperm count,” “ovulation induction,” “ovarian stimulation,” “body mass index,” “obesity,” “healthcare disparities,” “clomiphene citrate,” “letrozole,” “gonadotropins,” “polycystic ovary syndrome,” and “endometriosis.” Additional search terms included: intrauterine insemination, IUI, total motile count, post wash sperm count, stimulation regimen, ovulation trigger, cycles, paternal age, paternal body mass index (BMI), maternal BMI, and cervical factor. Literature searches identified retrospective and prospective cohort studies, randomized controlled trials, and systematic reviews and metanalyses. Upon reviewing the content of the retrieved articles, we also utilized their references to identify additional articles of interest. A total of 220 articles were reviewed, 102 of which were selected for inclusion. Article selection was initiated by AS (Anabel Starosta) with guidance and final approval by CG. We prioritized the most recent and relevant publications with inclusion of all randomized control trials, case control studies, retrospective and prospective cohort studies, and well-designed observational studies that contributed to the literature. Case reports, case series and meta-analyses were excluded.

IUI is a frequently utilized and effective treatment for infertility, but outcomes depend on patient and cycle specific factors. Conclusions regarding outcomes and optimal management stratified by specific male, female and cycle factors are difficult to draw given the heterogeneity of studies and limited RCTs, but the following can be considered. Most data support IUI for men with a TMC > 5 million sperm, with some studies showing a threshold effect at a TMC of 10 million. Post-wash sperm count > 1 million is recommended, with increasing pregnancy rates as count increases but with a plateau in pregnancy rates after post-wash sperm count reaches 4 million. High sperm DFI reflects sperm DNA abnormalities but does not consistently impact pregnancy rates. Paternal overweight and obesity also contribute to infertility. Maternal obesity leads to increased medication requirements for ovulation induction, but does not affect pregnancy outcomes. Advancing maternal and paternal age negatively impact pregnancy rates, although the effects of paternal age are inconsistent in the literature while the negative impacts of maternal age are well documented. Given lower pregnancy rates with IUI, women ≥ 38y may benefit from IVF. While IUI data on race and ethnicity is sparse, there is evidence that disparities negatively impact access to fertility treatment and subsequent outcomes. Ovulation induction with gonadotropins, letrozole or CC may be used in conjunction with IUI to maximize pregnancy rates. Letrozole and CC result in similar pregnancy, SAB and multiple gestation rates and these treatments are recommended over gonadotropins given the high multiple gestation rate with the latter. For obese women with PCOS, letrozole is preferred over CC. IUI is most effective for women with ovulatory dysfunction and unexplained infertility, and least effective for women with tubal factor and stage III-IV endometriosis. Outcomes are similar when IUI is performed with an hCG trigger or a spontaneous LH surge, and LH may be monitored by urine or serum. When triggers are used, hCG may be given IM or SC, with IM injection preferred for obese women. Most pregnancies occur within the first four IUI cycles, after which IVF should be considered. Insemination may occur 24–40 hours after hCG injection, or 24 hours after LH surge in natural cycles. Single IUI is preferred to double IUI given similar pregnancy rates. Brief rest after insemination may increase pregnancy rates. Providers recommending IUI for treatment of infertility should take into account all of these factors. As inconsistencies and uncertainties in the IUI literature persist, this review raises questions that invite further research to maximize successful pregnancy outcomes.

Approximately 12–18% of couples in the United States struggle with infertility, with 20% of infertility caused solely by male factors and 30–40% of infertility caused by a combination of male and female factors [ 1 , 2 ]. Intrauterine insemination (IUI) is a commonly used method of assisted reproduction for patients with mild male factor infertility, anovulation, endometriosis, and unexplained infertility [ 3 ]. In vitro fertilization (IVF) is generally used for severe male factor infertility [ 4 ]. Many factors affect IUI outcomes, including infertility diagnosis, semen parameters, and stimulation regimens. In this article, we review the current evidence regarding how patient and cycle specific factors affect IUI outcomes, specifically clinical pregnancy rate (CPR), live birth rate (LBR), spontaneous abortion (SAB) rate, ectopic rate, and multiple pregnancy rate. Couples may have multiple contributors to their fertility and IUI outcomes. Factors such as infertility diagnosis cannot be appropriately understood without considering other contributors such as semen parameters and stimulation regimen. Despite these limitations, we attempt to stratify the data by paternal, maternal and cycle factors in order to most rigorously draw conclusions. The current data on variables leading to IUI success are very heterogeneous. This review is meant to offer a thoughtful and concise interpretation of the data to help guide practice patterns and patient counseling. We aim to address each of the following questions: How do paternal factors such as total motile count, inseminated sperm count, DNA fragmentation index, age and body mass index affect pregnancy outcomes? How do maternal factors such as infertility diagnosis, body mass index and race/ethnicity affect pregnancy outcomes? How do cycle factors such as stimulation regimens, ovulation trigger medication and timing, total number of cycles, and IUI procedure affect pregnancy outcomes? How do paternal factors such as total motile count, inseminated sperm count, DNA fragmentation index, age and body mass index affect pregnancy outcomes? How do maternal factors such as infertility diagnosis, body mass index and race/ethnicity affect pregnancy outcomes? How do cycle factors such as stimulation regimens, ovulation trigger medication and timing, total number of cycles, and IUI procedure affect pregnancy outcomes?