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Predictive Factors for Intrauterine Insemination Outcomes: a Review Anabel Starosta*, Catherine E

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Predictive Factors for Intrauterine Insemination Outcomes: a Review Anabel Starosta*, Catherine E Starosta et al. Fertility Research and Practice (2020) 6:23 https://doi.org/10.1186/s40738-020-00092-1 REVIEW Open Access Predictive factors for intrauterine insemination outcomes: a review Anabel Starosta*, Catherine E. Gordon and Mark D. Hornstein Abstract Purpose: Intrauterine insemination (IUI) is a frequently utilized method of assisted reproduction for patients with mild male factor infertility, anovulation, endometriosis, and unexplained infertility. The purpose of this review is to discuss factors that affect IUI outcomes, including infertility diagnosis, semen parameters, and stimulation regimens. Methods: We reviewed the published literature to evaluate how patient and cycle specific factors affect IUI outcomes, specifically clinical pregnancy rate, live birth rate, spontaneous abortion rate and multiple pregnancy rate. Results: Most data support IUI for men with a total motile count > 5 million and post-wash sperm count > 1 million. High sperm DNA fragmentation does not consistently affect pregnancy rates in IUI cycles. Advancing maternal and paternal age negatively impact pregnancy rates. Paternal obesity contributes to infertility while elevated maternal BMI increases medication requirements without impacting pregnancy outcomes. For ovulation induction, letrozole and clomiphene citrate result in similar pregnancy outcomes and are recommended over gonadotropins given increased risk for multiple pregnancies with gonadotropins. Letrozole is preferred for obese women with polycystic ovary syndrome. 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 ovulation trigger or spontaneous ovulatory surge, and ovulation may be monitored by urine or serum. Most pregnancies occur within the first four IUI cycles, after which in vitro fertilization should be considered. Conclusions: Providers recommending IUI for treatment of infertility should take into account all of these factors when evaluating patients and making treatment recommendations. Keywords: intrauterine insemination, IUI, infertility, total motile count, sperm parameters, ovulation induction Introduction infertility [3]. In vitro fertilization (IVF) is generally used Approximately 12–18% of couples in the United States for severe male factor infertility [4]. struggle with infertility, with 20% of infertility caused Many factors affect IUI outcomes, including infertility solely by male factors and 30–40% of infertility caused by diagnosis, semen parameters, and stimulation regimens. a combination of male and female factors [1, 2]. Intrauter- In this article, we review the current evidence regarding ine insemination (IUI) is a commonly used method of how patient and cycle specific factors affect IUI outcomes, assisted reproduction for patients with mild male factor specifically clinical pregnancy rate (CPR), live birth rate infertility, anovulation, endometriosis, and unexplained (LBR), spontaneous abortion (SAB) rate, ectopic rate, and multiple pregnancy rate. Couples may have multiple con- tributors to their fertility and IUI outcomes. Factors such * Correspondence: [email protected] Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, as infertility diagnosis cannot be appropriately understood Harvard Medical School, Massachusetts, Boston, USA without considering other contributors such as semen © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Starosta et al. Fertility Research and Practice (2020) 6:23 Page 2 of 11 parameters and stimulation regimen. Despite these limita- is limited [6]. IUI is an effective treatment for mild male tions, we attempt to stratify the data by paternal, maternal factor infertility [3]. Even when other infertility etiologies and cycle factors in order to most rigorously draw conclu- are suspected, paternal factors such as total motile count sions. The current data on variables leading to IUI success (TMC), post-wash sperm count, and DNA Fragmentation are very heterogeneous. This review is meant to offer a Index (DFI) are important considerations in predicting thoughtful and concise interpretation of the data to help IUI success rates. Paternal age and BMI may also impact guide practice patterns and patient counseling. We aim to clinical outcomes. However, the ability to predict preg- address each of the following questions: nancy based on sperm parameters alone is limited, as out- comes also depend on female factors, such as age and 1. How do paternal factors such as total motile count, infertility diagnosis, and stimulation regimens, which will inseminated sperm count, DNA fragmentation be discussed in subsequent sections. index, age and body mass index affect pregnancy outcomes? Total Motile Count 2. How do maternal factors such as infertility There are conflicting recommendations in the literature diagnosis, body mass index and race/ethnicity affect regarding the threshold value for total motile count to pregnancy outcomes? best achieve pregnancy in IUI cycles. Many retrospective 3. How do cycle factors such as stimulation regimens, studies have evaluated cycle outcomes based on sperm ovulation trigger medication and timing, total parameters across a variety of ovulation induction (OI) number of cycles, and IUI procedure affect regimens and infertility diagnoses. While this heterogen- pregnancy outcomes? eity limits direct comparisons, most studies have demon- strated cut-offs for TMC of 5–10 million sperm. A 2001 Methods study evaluated 1039 couples ≤43y who underwent 3,479 For this review, we first performed a computerized search IUI cycles with natural cycles or ovulation induction of the published literature, limited to English language lit- with gonadotropins or clomiphene citrate (CC) to deter- erature and conducted between April and November mine the prognostic factors for achieving pregnancy rate 2020. Databases searched were PubMed and Ovid. MeSH [3]. The authors found increased pregnancy rates at a keywords used for the search included: “sperm count,” threshold of 10 million. During the first IUI cycle, 1.5% “ovulation induction,”“ovarian stimulation,”“body mass of couples with TMC < 10 million conceived compared index,”“obesity,”“healthcare disparities,”“clomiphene to 10.5% and 12.0% of patients with TMC 10–30 million citrate,”“letrozole,”“gonadotropins,”“polycystic ovary and > 30 million, respectively. Studies investigating IUI syndrome,” and “endometriosis.” Additional search terms with natural cycles or ovulation induction in couples included: intrauterine insemination, IUI, total motile with male factor infertility alone have also shown similar count, post wash sperm count, stimulation regimen, ovu- results. A randomized controlled trial (RCT) of 308 nat- lation trigger, cycles, paternal age, paternal body mass ural and ovulation induction IUI cycles showed a thresh- index (BMI), maternal BMI, and cervical factor. Literature old effect at TMC of 10 million, with no improvement searches identified retrospective and prospective cohort in pregnancy rates with ovarian stimulation among cou- studies, randomized controlled trials, and systematic re- ples with TMC < 10 million [7] while two retrospective views and metanalyses. Upon reviewing the content of the studies of 4,056 [8] and 2,062 [9] natural and OI/IUI cy- retrieved articles, we also utilized their references to iden- cles, respectively, showed a lower threshold of 5 million. tify additional articles of interest. A total of 220 articles Some authors have found lower cut-offs, with one study were reviewed, 102 of which were selected for inclusion. setting thresholds as low as 0.3 million [10] and another Article selection was initiated by AS (Anabel Starosta) at 1 million [11], although these findings have not been with guidance and final approval by CG. We prioritized widely replicated. A recent retrospective study of 310 the most recent and relevant publications with inclusion women undergoing 655 IUI cycles found no live births of all randomized control trials, case control studies, retro- in the 28 IUI cycles when the prewash TMC was < 2 mil- spective and prospective cohort studies, and well-designed lion [12], although specific female infertility diagnoses in observational studies that contributed to the literature. this group were not identified. These findings have led Case reports, case series and meta-analyses were excluded. some authors to
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