Procedure for intrauterine insemination (IUI) using processed sperm

INTRODUCTION — Intrauterine insemination (IUI) is a procedure in which processed and concentrated motile sperm are placed directly into the uterine cavity to increase the likelihood of conception. The procedure is timed with ovulation, which may be natural or a result of ovarian hyperstimulation. The procedure is typically used by patients with sexual dysfunction and certain types of infertility (eg, cervical factor, mild male factor).

This topic will discuss the details of IUI, including sperm collection, timing of ovulation, and the IUI procedure itself. Related content on infertility is presented separately.

●(See "Overview of infertility".)

●(See "Donor insemination".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

DESCRIPTION AND CLINICAL USE

Description — IUI is based on the hypothesis that placing a large number of sperm high in the reproductive tract enhances the likelihood of conception. The minimum requirements for performing the procedure are ovulation in the IUI cycle, patency of at least one fallopian tube, inseminate with an adequate number of motile sperm, and absence of documented or suspected active cervical, intrauterine, or pelvic infection.

Indications — Because coitus can be avoided, IUI is particularly useful in couples with some types of severe sexual dysfunction (eg, severe vaginismus, ejaculatory dysfunction). For cervical factor or mild male factor infertility, IUI allows sperm to bypass potentially hostile cervical factors, thus increasing the number of sperm that gain access to the uterine cavity (and oocyte). For women undergoing ovulation induction, including those with unexplained infertility or minimal or mild endometriosis, pregnancy rates are thought to be higher when IUI is used as an adjunctive procedure instead of timed natural intercourse. In these couples, IUI is often used as an intermediate level and cost-effective intervention prior to proceeding to in vitro fertilization (IVF). The pregnancy rate after IUI depends on male factors, female factors, and technical factors.

Clinical indications for IUI are discussed in more detail in related content:

●(See "Unexplained infertility", section on 'Intrauterine insemination (IUI)'.)

●(See "Endometriosis: Treatment of infertility in females".)

●(See "Overview of ovulation induction".)

●(See "Use of assisted reproduction in HIV- and hepatitis-infected couples".)

●(See "Female infertility: Treatments", section on 'Cervical factor infertility'.)

Selection of IUI versus IVF — IUI is less medically intensive and lower cost compared with in vitro fertilization. However, IVF is typically preferred for patients with tubal factor and/or severe male factor infertility. (See "In vitro fertilization: Overview of clinical issues and questions".)

SPERM COLLECTION AND PROCESSING — IUI is usually performed with fresh sperm from the woman's partner. IUI with donor sperm, which is frozen, is discussed separately. (See "Donor insemination".)

Semen collection — We ask men to produce a semen specimen in the morning after two or three days of sexual abstinence [1,2]. The specimen is produced by masturbation, ideally in a private room designated for this purpose in the laboratory/office. The entire ejaculate is collected in a sterile cup to minimize the risk of uterine infection from contaminants. We advise avoidance of lubricants, as most are toxic to sperm [3,4]. If a lubricant is needed, we instruct the client to prevent contact between the lubricant and glans.

Sperm processing — It is critical to separate sperm in the ejaculate from prostaglandin-rich prostatic secretions and seminal fluid, which can cause uterine cramping and, rarely, anaphylaxis, when placed directly into the uterine cavity. In addition, sperm preparation maximizes the number of motile sperm for insemination, removes cellular debris, and concentrates the specimen.

Two commonly employed techniques for sperm processing are the "swim up" method and use of "density gradient centrifugation." A systematic review of randomized trials comparing these two techniques did not find a statistically significant difference in pregnancy rates [5] . However, the percentage of motile sperm recovered after processing is generally higher with density gradient centrifugation than with the swim up technique [6]. Therefore, we prefer this method in men with oligo- or asthenospermia.

We evaluate a tiny drop of the processed sample prior to insemination to ensure that an adequate number of moving sperm has been recovered. The minimum post-wash total motile sperm count for IUI is controversial [7,8]. Although pregnancies from IUI have occurred with a post-wash total motile sperm count less than 5 million, a count greater than 5 to 10 million is associated with higher pregnancy rates [9-12]. A count less than this warrants further evaluation and possible treatment by a urologist. If samples consistently have less than 3 to 5 million motile sperm, pregnancy rates will be less than 1 percent per cycle. In these cases, in vitro fertilization (IVF), possibly with intracytoplasmic sperm injection (ICSI), is the appropriate course of treatment to overcome severe male factor infertility.

LABORATORY REQUIREMENTS AND TESTING — Guidelines govern the management, operation, and accreditation of andrology laboratories [13-17]. One example is available through the American Society for Reproductive Medicine [13]. The requirements and testing of sperm for donor insemination is presented in related content. (See "Donor insemination", section on 'Donor evaluation'.)

TIMING THE INSEMINATION

Detection of ovulation — The timing of ovulation is commonly predicted by detection of a luteinizing hormone (LH) surge using either blood or urine. LH surge can be detected in serum starting 36 hours before ovulation; serum and urine LH levels peak approximately 24 hours before ovulation. Urine testing minimizes disruption of the patient's life and is as effective as blood LH testing for IUI timing. The IUI is performed the day after the LH surge, which is the day of ovulation. The oocyte can be fertilized up to 24 hours after ovulation; sperm are most capable of fertilization up to 48 hours after entering the female genital tract. Timing the IUI is based on these relationships.

An alternate approach includes ultrasound monitoring of ovarian follicle size and injection of exogenous human chorionic gonadotropin (hCG) to trigger follicular maturation and rupture, which occurs approximately 36 hours after administration. In contrast to urine LH testing, ultrasound monitoring requires visits to a clinical site, which may limit the utility of this approach given. A meta-analysis including 13 studies reported similar pregnancy rates between the two approaches (odds ratio [OR] 0.92, 95% CI 0.69-1.22) [18]. Similar pregnancy rates were also reported for the techniques in the subgroup analyses of natural cycle IUI and ovarian stimulation IUI.

Timing of IUI procedure — The optimum time for IUI is controversial [19-23]. A 2010 systematic review of trials that evaluated the effectiveness of different synchronization methods in natural and stimulated cycles for IUI in subfertile couples concluded the choice should be based on hospital facilities, convenience for the patient, medical staff, costs and drop-out levels as no method was clearly superior to another [19].

Unstimulated cycles — Natural (unstimulated) cycle procedures are most appropriate for patients with ejaculatory dysfunction, vaginismus, or cervical factor infertility or for individuals using IUI to achieve pregnancy in absence of fertility issues (eg, same-sex couples). Ovulation should be documented prior to proceeding with the unstimulated (natural) cycle IUI. The most cost-effective method is use of an over-the-counter urine ovulation predictor kit. Once the LH surge is documented in first morning urine, IUI is performed the next day. A large randomized trial showed that ovulation monitoring resulted in higher pregnancy rates than human chorionic gonadotropin (hCG) triggering to time insemination in natural cycles [24].

In our experience, couples are nearly always able to arrange their schedules to allow IUI timed by urinary LH monitoring. In many offices, male partners drop semen samples in the office between 7:00 and 8:30 AM, with IUI processing performed subsequently. Processed sperm can be incubated without significant loss of motility for many hours. The use of LH for timing ovulation in natural cycles actually might be the best way to maximize the probability of pregnancy for patients undergoing IUI. In a randomized trial of clomiphene citrate with IUI, pregnancy rates were higher with urinary LH surge monitoring than with hCG-timed IUI [24].

In the United States, several types of health care professionals (eg, physician, nurse, nurse practitioner, etc) are permitted to perform and/or bill for IUIs, but this varies from state to state as well as by country.

Stimulated cycles — Controlled ovarian hyperstimulation is commonly used with IUI for treatment of infertility in couples with unexplained infertility. Clomiphene citrate is the standard first-line therapy; if unsuccessful, the aromatase inhibitor letrozole, injectable gonadotropins, or IVF can be the next step [25]. Letrozole may be preferable to gonadotropins because of the lower cost, ease of use, and lower risk of multiple gestations, particularly triplet gestations or higher [26,27]. Data on the use of aromatase inhibitors with IUI are not extensive, but trial data suggest that letrozole yields equivalent pregnancy rates as clomiphene citrate in combination with IUI in unexplained infertility [26,28]. In a trial by the Reproductive Medicine Network (RMN) without IUI, letrozole was superior to clomiphene for treating anovulatory infertility in patients with polycystic ovary syndrome [29].

In four randomized trials of patients with unexplained subfertility, pregnancy rates were higher when IUI was performed in stimulated cycles than in natural cycles (odds ratio [OR] 2.14, 95% CI 1.26-3.61; 25 versus 14 percent; 26 patients received clomiphene citrate, 370 patients received gonadotropins) [30]. However, another randomized trial in couples with unexplained infertility found that in vitro fertilization (IVF) resulted in the highest pregnancy rate (per cycle pregnancy rate with IVF 31 percent; per cycle pregnancy rate with clomiphene/IUI and follicle-stimulating hormone [FSH]/IUI cycles 8 and 10 percent, respectively) [31]. (See "Overview of ovulation induction".)

Clomiphene citrate — For most women, our first-line approach for ovarian stimulation is clomiphene citrate (CC) 100 mg for five consecutive days beginning on cycle day 3 or 5, depending on the woman's natural cycle length. Letrozole 5 mg for five consecutive days, days 3 through 7, may also be used [26]. Urine LH testing starts on cycle day 10 to 12. Detailed instructions on when to begin LH testing are included in the ovulation predictor kits. Once an LH surge is documented in the first morning urine, IUI is performed the next day. For women who are known to be ovulatory but unable to identify the LH surge with a urine kit, we prescribe CC 100 mg for five consecutive days beginning on cycle day 3 or 5 as above, and then perform serum LH testing starting cycle day 12.

For women undergoing CC ovarian stimulation, higher pregnancy rates have been reported when IUI is performed following spontaneous ovulation as documented by LH surge compared with IUI following hCG injection to trigger ovulation. In a meta-analysis of seven studies including over 2500 women, women who received IUI after hCG injection had a 25 percent reduction in clinical pregnancy rates compared with women who had IUI after LH surge (OR 0.74, 95% CI 0.57-0.96) [32]. Additionally, follicle monitoring with ultrasound and hCG triggering of ovulation increases the patient's visit burden and cost, and therefore is rarely performed in place of CC therapy in our practice. We reserve ultrasound monitoring of the ovarian follicles for women in whom a serum LH is missed.

For women who do not tolerate or respond to clomiphene and women with unexplained infertility, the aromatase inhibitor letrozole can be a second line option for ovarian stimulation [32]. (See "Unexplained infertility", section on 'Aromatase inhibitors plus IUI'.)

Gonadotropin and hCG — For older women and younger women with diminished ovarian reserve, we induce ovulation with injectable gonadotropins rather than clomiphene [33,34] or we perform IVF [31]. Injectable gonadotropins (recombinant FSH) are given per provider dosing preference beginning on cycle day 2 or 3. It is the standard of care to follow serum estradiol levels and ovarian follicle size with transvaginal ultrasounds. When at least one follicle has a mean diameter of 15 to 18 mm, the patient self-administers 5000 to 10,000 units of hCG as a subcutaneous or intramuscular injection to trigger ovulation. The minimum size (15 to 23 mm) of the leading follicle before hCG injection is controversial [35-38]. One IUI is performed 36 hours after hCG injection. (See "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

The addition of a gonadotropin releasing hormone (GnRH) antagonist to recombinant FSH during controlled ovarian stimulation may improve pregnancy rates by reducing the incidence of premature luteinization in women with some types of ovulatory dysfunction [39,40]. Alternatively, a GnRH antagonist can be added to the controlled ovarian stimulation cycle when the lead follicle is 14 mm in size. This delays luteinization, thus allowing development of additional follicles, which is particularly useful if only one follicle has developed. Use of GnRH antagonists may also be beneficial in preventing luteinization when IUI is delayed over a weekend or holiday in practices with staffing restrictions [41]. (See "Unexplained infertility", section on 'Gonadotropin injections with or without IUI'.)

IUI PROCEDURE

Equipment

●Prepared sperm specimen

●Speculum

●1 cc sterile syringe with blunt cannula

●Disposable polyethylene insemination catheter

Patient preparation — Proper identification of both the patient and sperm sample in the laboratory and the clinic is essential. Antibiotic prophylaxis is unnecessary. Povidone iodine should not be used to cleanse the cervix because it is toxic to sperm.

Technique — We perform a single IUI the day after a urinary LH surge.

●Single versus double IUI – Double IUI is of unclear benefit and increases the number of patient visits, cost, and, potentially, stress.

•Pregnancy rate – In a meta-analysis of 15 trials, there were no differences in clinical pregnancy rates between women who underwent single versus double IUI (relative risk 1.22, 95% CI 0.97-1.54, 15 trials, 3795 women) [42].

•Live birth rate – A different meta-analysis reported similar live birth rates for double compared with single IUI (odds ratio [OR] 1.15, 95% CI 0.71-1.88, 3 studies, 468 participants), although the source data was deemed to be of low quality [43].

●Our approach:

•Obtain fresh or frozen ejaculate for IUI preparation and processing (see 'Sperm collection and processing' above). Once processed, care should be taken to maintain the specimen at body temperature until insemination.

•The patient should undress from the waist down and lie on an examination table in dorsal lithotomy position with her feet in stirrups. Although not mandatory, consider asking women with an anteverted uterus to maintain a full bladder to facilitate straightening of the uterus. This is not useful for women with retroverted uteri.

•Open a 1-cc syringe and draw up approximately 0.3 to 0.5 mL of air.

•Attach a blunt sterile needle (eg, MONOJECT blunt cannula).

•Aspirate the processed sperm and its suspension media into the syringe. Ideally, the sperm is suspended in a small volume of media, no more than 0.5 mL, to prevent expulsion or reflux from the cervix and uterine contractions after it is inseminated into the uterus.

•Attach the syringe to an 18 cm polyethylene insemination catheter. Two types of catheters are available: (1) relatively rigid single sheath catheters (straight or with a preformed curve) that cannot be bent and (2) double sheath catheters with an external flexible sheath that will maintain a curve and a very soft internal catheter. In a 2010 meta-analysis of six randomized trials, pregnancy and live birth rates were the same for flexible and rigid catheters [44]. However, other factors should be considered. We prefer a soft flexible catheter, as it can be formed to accommodate the curve of the patient's uterus and is less traumatic to the endometrium. An internal wire or rigid stylet may be used with the external sheath for difficult IUIs. If it is difficult to pass the IUI catheter through the internal os, transabdominal ultrasound guidance with the patient having a full bladder may be helpful. In our experience, patients barely feel the IUI procedure with these catheters. Stiffer catheters are easier to insert into the uterine cavity because they do not bend, but they are more uncomfortable for the patient and more traumatic to the endometrium, and thus associated with more vaginal bleeding [45].

•Insert the speculum to obtain adequate visualization of the cervix.

•Without touching the end of the catheter that will enter the sterile uterine cavity, insert the catheter through the cervical os, through the endocervical canal, and into the uterus to a depth of approximately 6 to 6.5 cm. Try not to let the catheter touch the fundus, as this will cause cramping and, in some cases, disruption of the endometrium and bleeding, which is toxic to embryo development. If difficulty is encountered with insertion of the catheter, use of a rigid stylet or abdominal ultrasound guidance may be helpful. We avoid use of a tenaculum because it causes uterine contractions and patient discomfort.

•Inject the sperm and then slowly withdraw the catheter.

•Sperm are present in the fallopian tubes as early as five minutes after insemination [46]. We have our patients rest in supine or reverse Trendelenburg position for 10 minutes after sperm injection. Although only limited data are available on whether rest is of any value in enhancing pregnancy fertilization rates, one randomized trial reported higher pregnancy rates in rested patients compared with those who were immediately mobile post-IUI (pregnancy rate 16/55 [25 percent] versus 4/40 [10 percent]) [47]. However, a subsequent trial with nearly 500 women reported no difference in ongoing pregnancy rates among women who were immobilized for 15 minutes following IUI and those who were not [48]. Psychologically, patients are often reassured by a period of rest following the procedure.

Postprocedure care — The patient may resume her normal activities after insemination. Increased wetness after the procedure is due to loosened and watery cervical mucus, it does not mean the sperm specimen has flowed out; patients should be reassured about this. Abdominal cramping or discomfort may occur; we suggest acetaminophen if the patient requests treatment. Light bleeding or spotting may also occur.

Patients may have intercourse after IUI if they wish to do so. However, patients who have pelvic discomfort due to ovarian enlargement from clomiphene or gonadotropins should avoid intercourse. A urinary or serum pregnancy test is performed two weeks after IUI. If the patient has received human chorionic gonadotropin (hCG) for ovulatory triggering, it is important to inform the patient that a urinary or serum pregnancy test may remain positive up to 12 days after the injection.

A systematic review of randomized trials of vaginal progesterone luteal support after ovulation induction/IUI found a higher live birth rate with progesterone support compared with no progesterone support (odds ratio [OR] 2.11, 95% CI 1.21-3.67, three trials, 1196 cycles) [49]. In subgroup analysis, the benefit was restricted to gonadotropin-stimulated cycles. The authors did not perform a subgroup analysis based on baseline characteristics of the subjects. We do not use luteal progesterone in clomiphene-induced cycles, but give luteal vaginal progesterone support in women with a luteal phase <10 days. (See "Recurrent pregnancy loss: Management", section on 'Progesterone'.)

INTRAVAGINAL INSEMINATION — Intravaginal insemination is a low-cost, low-resource alternative to IUI that is sometimes used by couples who are unable to have, or choose to avoid, vaginal intercourse (table 1).

COMPLICATIONS — Upper genital tract infection is a rare potential complication. It is unclear whether the risk of ectopic pregnancy is increased compared with women with similar risk factors for ectopic pregnancy who become pregnant without IUI.

Ovarian hyperstimulation syndrome is a complication of ovulation induction, but it is usually only observed in exogenous gonadotropin cycles following administration of human chorionic gonadotropin (hCG) or after administration of gonadotropin releasing hormone (GnRH) agonist; it rarely occurs in women treated with clomiphene citrate. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation syndrome".)

The risk of multiple gestation, especially high order multiple gestation, is significantly increased with IUI after superovulation induced by gonadotropins. The risk is much lower with clomiphene citrate.

NUMBER OF IUI CYCLES — Pregnancy rates are significantly lower after the third IUI cycle, irrespective of the ovulation induction method [50]. At that point, we generally move on to more aggressive treatment. European guidelines (Denmark, England, Wales, France, the Netherlands) suggest three to six IUIs, depending on the cause of infertility [51].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications – Intrauterine insemination (IUI) alone is a useful technique for achieving pregnancy in couples with severe sexual dysfunction, but can also be useful in patients with cervical factor infertility as long as at least one fallopian tube is patent. (See 'Description and clinical use' above.)

●Timing – When IUI is performed during an unstimulated (natural cycle) or a clomiphene or letrozole stimulated cycle, we suggest use of an over-the-counter ovulation predictor kit to schedule the optimum time for the procedure. (See 'Timing the insemination' above.)

●Ovarian hyperstimulation – For patients with mild male factor, early stage endometriosis, or unexplained infertility, we suggest controlled ovarian hyperstimulation with IUI rather than natural cycle IUI (Grade 2B) (see 'Stimulated cycles' above). Ovarian stimulation may employ clomiphene or gonadotropins.

●Preference for single IUI – For women undergoing IUI, we recommend a single IUI procedure (Grade 1A). When compared with double IUI, single IUI has the same efficacy with fewer visits and lower cost.

●Semen processing – Semen processing for IUI is not difficult to learn and can be adapted to use in clinical offices, but care must be taken to ensure that adequate quality measures are in place. (See 'Sperm collection and processing' above.)