Therapeutic Insemination

Artificial insemination involves placing sperm inside the female's reproductive tract where fertilization of the ovum occurs. This is distinctly different from in vitro fertilization (IVF), where fertilization occurs outside of the female's body. The sperm may be from the female's partner or may be donor sperm. There are also various techniques of insemination where sperm placement ranges from the vagina to the ovary. The traditional terminology for these techniques is artificial insemination. When donor sperm is used, it has been known as artificial insemination with donor (AID). With the advent of acquired immunodeficiency syndrome (AIDS), the term therapeutic donor insemination (TDI) has been preferred. Similarly, artificial insemination with husband sperm has recently been termed therapeutic husband insemination (THI).

There are a variety of techniques of inseminating the woman with her partner's sperm. In addition, several different types of semen processing may be used to prepare the sperm for insemination. The particular indication for the insemination should determine the type of insemination and the type of semen processing performed.

Indications

Abnormalities in either the male or female reproductive system may be cause for insemination (Table 1). Male factor indications may be classified as sperm deposition abnormalities or seminal abnormalities. Any condition that interferes with the intravaginal placement of sperm may impair fertility. Ejaculatory dysfunction is the most common abnormality interfering with sperm deposition. Patients may present with retrograde ejaculation in which semen is propulsed from the vas deferens into the urethra and, in a retrograde fashion, into the bladder. In other conditions, known as anejaculation, semen is not even propulsed into the urethra, and therefore no sperm will be found in the bladder. Retrograde ejaculation may be caused by procedures such as transurethral resection of the prostate or bladder neck surgery. Neurologic injuries, whether resulting from neurologic disease, pelvic surgery, or trauma, may also cause this condition. Diabetes mellitus occasionally causes retrograde ejaculation, although more commonly it results in anejaculation. Medications interfering with sympathetic outflow also may interfere with ejaculation. Finally, idiopathic retrograde ejaculation has been reported. This is a diagnosis of exclusion after a thorough evaluation of the patient. Therapy of retrograde ejaculation may involve pharmacologic attempts to convert ejaculation from retrograde to antegrade. If this is successful, the couple may conceive through normal intercourse. If conversion to antegrade ejaculation is not successful or possible, therapy is directed at sperm retrieval from the urine or bladder.¹ Typically, the patient alkalinizes the urine with oral sodium bicarbonate. This is commonly performed 2–12 hours before sample collection. The patient voids before masturbation then, after masturbation, the patient voids semen and any newly formed urine into a collection cup for semen processing. If this approach is not successful, sperm-washing media may be instilled into the patient's bladder before ejaculation.

Table 1. Indications for insemination

Anejaculation may be caused by conditions such as diabetes or neurologic disease or injury. Sympatholytic medications also may contribute to this condition. Additional causes include anorgasmia, in which the man is not able to have orgasm, and idiopathic anejaculation. Neurologic causes of anejaculation may be treated with vibratory stimulation or electroejaculation.² In addition, some cases respond to alpha-adrenergic agents. Patients who cannot be converted to retrograde or antegrade ejaculation may have sperm surgically retrieved for the assisted reproductive techniques.

Impotence may be either organic or psychogenic. Treatment of psychogenic impotence or ejaculatory dysfunction is best managed by psychological sexual counseling. Common conditions associated with organic impotence include vascular disease, neurologic disease, or hormonal insufficiency. Other conditions, such as diabetes and drug therapy, are commonly encountered. Appropriate treatment involves restoring potency, either through correction of the underlying condition or treatment directed at restoring erectile function. In cases in which this is not possible or appropriate, sperm may be collected by masturbation and subsequently used for insemination.

Severe hypospadias may impair delivery of sperm to the vagina. Treatment generally is directed at hypospadias repair, which allows the couple to conceive through intercourse. Semen collection and insemination also may be performed. Some patients use their own cryopreserved semen. These situations involve patients who are to receive chemotherapy or radiation therapy, patients who are out of town for prolonged periods of time while their female partner is ovulating, or patients who are to undergo ablative surgery. These samples may be used for intrauterine insemination (IUI) or IVF. Samples taken from patients with cancer, particularly testicular cancer before therapy, often are suboptimal and may be adequate only for IVF with intracytoplasmic sperm injection (ICSI).

Finally, suboptimal semen parameters are a common indication for THI. Generally, the cause of the male infertility should be treated if possible. In cases in which treatment is not possible or in couples in whom treatment fails, THI may be performed and usually should be combined with superovulation.

Female disorders also may interfere with intravaginal deposition of semen. Vaginal stenosis secondary to surgery or delivery as well as congenital conditions such as urogenital sinus, vaginal atresia, transverse vaginal septum, and imperforate hymen may interfere with vaginal intercourse. Similar to the male situation, treatment should be directed at correcting the anatomic abnormality interfering with intercourse. If this is not successful or possible, insemination may be appropriate. Severe dyspareunia, such as from endometriosis, uterine leiomyomata, pelvic inflammatory disease, vaginitis, and pelvic adhesions also may impair sexual function. Female psychogenic sexual dysfunction causing vaginismus or an avoidance of intercourse should be dealt with by appropriate sexual counseling. Insemination may play a useful role in some of these cases.

IUI has been commonly used for cervical factor infertility. In these cases, a poor postcoital test (PCT) result indicates the inability of the sperm to traverse the cervical mucus and reach the upper reproductive tract of the woman. Since IUI bypasses the cervical mucus, it should specifically treat this condition. However, an abnormal PCT finding may have many causes. Inappropriate timing of the PCT is the most common cause for an abnormal result. Despite this, increased recovery of motile sperm from the peritoneal cavity have been demonstrated after IUI compared with intracervical insemination (ICI) in patients with poor PCT results.³ In addition, most women have conceived when IUI has been performed for pure cervical factor infertility.^{4, 5, 6, 7} One study demonstrates a pregnancy rate per cycle of 12.1% for IUI compared with 7.8% for timed intercourse in couples with pure cervical factor infertility. However, this difference was not statistically significant.⁸

IUI has been used to treat both male and female immunologic infertility. When the man has antisperm antibodies, standard semen washing does not remove the antibodies. The presence of surface-bound antisperm antibodies from the man have been shown to interfere with the ability of sperm to bind to the zone pellucida and interfere with penetration of zona free hamster eggs.^{9, 10} Success combining IUI with chymotrypsin processing of the sperm and superovulation of the woman has been reported.¹¹

When antisperm antibodies occur strictly in the cervical mucus, bypassing these antibodies with IUI may improve pregnancy rates. However, it is not clear that antisperm antibodies are found only in the cervical mucus and not in the higher female reproductive tract. The role of IUI in these cases remains controversial. IUI is commonly used for less obvious indications such as in women with endometriosis and unexplained infertility. It also is commonly used in unilateral or mild tubal disease. Many couples prefer to undergo a trial of IUI before proceeding to IVF.

Semen Collection and Processing

For most patients, semen specimens should be collected into a sterile, wide-mouthed container and kept at room or body temperature until processing. Most specimens should be processed within approximately 30 minutes of collection. This allows adequate time for semen liquefaction. Some men are not able to masturbate to produce the specimen and therefore collect by having intercourse using special semen collection condoms. This technique is not preferred, since it results in more contamination of the semen with skin debris, cells, and bacteria. For patients with retrograde ejaculation, sperm are retrieved from either voided urine or voided media, which was instilled into the patient's bladder before ejaculation. The type of insemination performed and the source and quality of the semen specimen determine the type of semen processing. In cases where intravaginal or cervical placement of sperm is desired, raw unprocessed semen may be used. For patients who have cryopreserved specimens, simple thawing combined with cervical insemination may be performed; however, the samples are more commonly processed and used for IUI.

The use of a split ejaculate is based on the finding that in 90% of semen samples, the first portion of the ejaculate contains the highest concentration of motile sperm. The higher concentration is found in the second portion in 5% of samples, whereas in the remaining 5%, there is no difference between the first and second portions. Before the use of semen processing, insemination with the first portion of the ejaculate was commonly performed. Although this often yields a fraction with a higher percent motility than a total unwashed sample, this offers no benefit when the samples are to be washed. By including only the first portion of the ejaculate, the total motile count in the processed sample is reduced. Currently, there is little role for the collection of split ejaculates.¹² Another approach is to have the man collect two samples 1–4 hours apart. Unlike normospermic men, oligospermic men often produce equal or greater numbers of sperm in the second sample.¹³ There are no studies comparing pregnancy rates in IUI after collection of a single sample versus multiple samples. Currently, we find this technique useful if the patient's first sample is significantly worse than his usual baseline samples.

Semen consists of seminal plasma, live sperm (both motile and nonmotile), dead sperm, cellular debris, and bacteria. Seminal plasma contains many components, including prostaglandins. Under normal circumstances, after intercourse, cervical mucus acts as a filter, allowing only motile sperm with normal morphologic features to reach the upper endocervical canal.¹⁴ The remainder of the ejaculate containing nonmotile and nonviable sperm, as well as nonsperm cells and seminal plasma, never reaches the upper female reproductive tract. Although IUI of raw, unwashed semen has been performed in the past, this generally has been abandoned. Seminal plasma contains bacteria and prostaglandins, which induce uterine contractions. Thus, insemination of unwashed semen may result in excess uterine cramping and a higher risk of pelvic infection. Finally, uterine instillation of volumes of more than approximately 0.5 mL may induce uterine contractions, which may expel the inseminated sample.

Semen processing techniques, at a minimum, remove seminal plasma and concentrate the specimen into a small volume. More sophisticated semen processing techniques separate motile sperm from the remainder of the seminal components. Finally, sperm stimulation techniques chemically stimulate sperm to improve their fertilizing capacity. Sperm recovery rate after semen processing is generally 50% or less. Simple techniques like the sperm wash typically have greater yields than more sophisticated techniques that separate motile from nonmotile sperm, which may have yields in the range of 5–20%.^{15, 16} Remember that the percentage of sperm that are motile in a sample after processing is not an indication of sperm yield. Thus, in a sample with a sperm count of 10 million and 50% motility, the presemen processing total motile count is 5 million. After a sperm wash, the sample may demonstrate 50% motility; however, 50% of the sperm may have been lost in the processing. Thus, a total motile count may be 2.5 million. In contrast, the same sample subject to a technique that removes nonmotile sperm might yield a sample with 80% motility; however, to achieve this, 90% of the sperm may have been lost. Thus, total motile count may be 500,000.

Sperm washing involves mixing the ejaculate with media followed by centrifugation at approximately 300 g for 10 minutes. The supernatant is discarded, and the pellet is commonly resuspended in additional media followed by a second centrifugation step. The final pellet is resuspended in approximately 0.5 mL of media. Sperm washing removes seminal plasma but does not separate motile sperm from the remainder of the cellular constituents of the semen. Because this technique is relatively simple and quick, it is the most commonly used semen preparation technique for IUI. Frequently used media include modified human tubal fluid; Ham's F10 media; Biggers, Whitten, and Whittingham media, Earle's media; or Dulbecco's media. Often, a source of protein such as human or bovine serum albumin may be present in the media. The swim-up technique involves layering media over either an aliquot of raw semen or pelleted sperm. Motile sperm swim up into the media over approximately 1 1/2 hours and are collected by removing the supernatant. This process separates highly motile sperm from the remainder of the ejaculate. Sperm yields by this approach typically are poor: less than 5%. Therefore, this process often is unsuitable for samples with low sperm counts or poor motility.^{17, 18} Percoll consists of a solution of silicone particles coated with polyvinylpyrrolidone. This is no longer available in the United States.  Other preparatioins are commercially available to create density gradients. Unfortunately, these cost 5–10 times the cost of Percoll. Typical processing with these solutions involves the creation of a discontinuous gradient of differing concentrations. One common protocol involves layers of 95%, 70%, and 50% of the solution. These gradients are created with the highest concentration of the solution on the bottom of the tube. The sperm, either raw in semen or washed, are placed on top of discontinuous gradients and are centrifuged. Motile sperm travel to the bottom of the tube, whereas nonmotile sperm, nonsperm cells, and seminal plasma remain in the upper layers. The pellet in the lower gradient is collected and washed to remove the gradient solution. There are many protocols, some with two layers and others with three or more layers. A standard centrifugation typically uses 0.5-mL aliquots of gradient solution, whereas severely oligospermic samples usually are treated with smaller volumes of gradient solution using 0.3-mL aliquots.¹⁹ Yields of motile sperm after processing typically are greater than with the swim-up technique. Studies suggest a higher fertilizing capacity of sperm in both the sperm penetration assay and IVF after gradient processing.^{20, 21, 22}

Other Techniques

Passage of washed sperm over columns packed with glass wool has been used to separate motile sperm from semen.²³ This technique has not been commonly used because fragments of glass wool have been found in the effluent, and there is evidence that glass wool may cause damage to sperm membranes.²⁴ Gradients of albumin have been used to separate motile from nonmotile sperm.^{25, 26} Yields by this technique generally have been less that with Percoll, and the processing time with albumin is greater than Percoll. As a result, albumin gradients are not commonly used in most centers.

Sperm Enhancement

Various compounds have been added to sperm in vitro to improve sperm motility in asthenospermic samples and hopefully improve fertilizing capacity. Inhibitors of cyclic adenosine monophosphate (cAMP) phosphodiesterase cause increased levels of cAMP, ultimately leading to increased levels of adenosine triphosphate, an energy source for spermatozoa.²⁷ Compounds such as caffeine, theophylline, and pentoxifylline have been reported to enhance sperm motility in vitro. It is likely that the mechanism is more complicated than simple inhibition of phosphodiesterase.²⁷ While increasing motility as well as acrosome reaction ability and fertilizing ability in vitro, there are little data evaluating its effect in IUI.²⁸ Most studies use pentoxifylline in IVF. One retrospective study reports a 27.5% pregnancy rate in couples with sperm preparation with pentoxifylline compared with an 11.5% pregnancy rate in couples using a standard sperm preparation procedure.²⁹ With the advent of ICSI, chemical stimulation of sperm has become much less common. Currently, no studies demonstrate a clear role for this approach in IUI.  While there are few comparative studies, a recent review of published studies on semen processing and pregnancy rates after IUI concluded that there was insufficient evidence to recommend any one particular processing method.³⁰

Insemination Techniques

The underlying etiology for the couple's infertility and the anatomy of the female partner should dictate which insemination technique is used. For cases of pure sperm deposition abnormalities, when a semen sample cannot be deposited in the vagina through intercourse, intravaginal insemination (IVI) or ICI may be used. Notice that this approach has no role if the cause of the infertility is an abnormal semen specimen. The couple may perform IVI at home, or it may be performed in the office. A simple technique that may be used by the couple at home involves placement of a syringe without a catheter into the woman's vagina to deposit sperm in the upper third of the vagina. The advantages of this approach include minimal expense and enhanced privacy for the couple. Some advocate the use of a cervical cap with a tube attached that exits through the vagina. This may be used by the physician or by the couple. The cervical cap is placed over the cervix. The semen sample is squirted with a syringe into the tube, and the tube is clamped.^{31, 32} The use of cervical caps has been justified on the basis of preventing semen from coming in contact with the acidic vaginal environment and minimizing loss of seminal fluid from the vagina. Whereas pregnancies have been reported using this approach, no studies indicate that the use of a cervical cap improves pregnancy rates above what would be obtained without the use of a cervical cap. If IVI is performed in the office, it is commonly performed with the use of a speculum to allow accurate placement of the semen in the upper third of the vagina. In these cases, either no lubricant or a minimal amount of lubricant should be used, since most commercially available lubricants have been found to be detrimental to sperm motility.³³ Although some advocate the use of vaginal sponges or nonabsorbent tampons, there is no evidence that these improve pregnancy rates.

ICI is performed by placing a catheter in the cervical canal but not into the uterus. The sample then may be delivered into the canal. Any thin, flexible catheter may be used for this procedure. As with IVI, some advocate the use of cervical caps; however, there is no evidence as to their beneficial effect. With the exception of pure sperm deposition abnormalities, IVI and ICI rarely are used. Most centers use IUI. In this technique, the woman is placed in the standard dorsal lithotomy position, and the speculum is inserted into the vagina. The cervix usually is cleaned with a cotton or gauze applicator. The use of antiseptics should be avoided. Some advocate wiping the cervix with insemination media, whereas others may use saline. It is unlikely that the choice of solution affects success rates as long as it is not spermatotoxic. Similarly, some centers routinely perform cervical cultures before insemination, whereas other centers reserve this for cases with clinical evidence of infection. Knowing the position of the uterus through the performance of a pelvic examination may be useful in directing the catheter. The processed semen specimen may be loaded into a 1-mL syringe and attached to a thin, flexible catheter. Multiple catheters are available.  A recent literature review concluded that the type of insemination catheter likely had no effect on IUI pregnancy rates.³⁴ The cervix then is cannulated with the insemination catheter until it reaches the upper uterus. Care should be taken not to injure the endometrium and induce bleeding. In cases in which a catheter does not pass through the cervical canal, the cervix may be grasped with a tenaculum to straighten out the canal. Some women experience menstrual-like cramping on uterine placement of the catheter. This usually resolves within several seconds. The processed semen then is slowly injected into the uterus and the catheter withdrawn. As with ICI and IVI, some advocate the use of a cervical cap or intravaginal sponge; however, there is no evidence that this improves pregnancy rates. Some physicians elevate the woman's hips for 20 or 30 minutes after the insemination, whereas others allow the woman to get up immediately after the procedure. There are no studies comparing these two approaches.

After intercourse, sperm enters the cervical mucus, which acts as a reservoir from which sperm are gradually released into the upper female reproductive tract. To mimic this normal physiologic event, a slow-release method of IUI has been developed.³⁵ In this technique, 50,000 motile sperm per minute are automatically injected into the uterus for a total of 3 hours. This was compared with the bolus injection of a 0.6-mL aliquot of the same number of motile sperm. Whereas a significantly higher number of pregnancies (15%) occurred in the slow-release group compared with the bolus injection group (6%), this was a small study and has not been repeated. Additional studies need to be performed before this technique can be recommended.

To place the sperm even closer to the ova, intratubal insemination has been developed (ITI).³⁶ This may be accomplished with the use of laparoscopy, but it has most commonly been performed transvaginally. In this technique, a catheter is passed transvaginally through the cervix and then manipulated into the cornua of the fallopian tube on the side with the largest follicle. Although originally described using 200 μL of processed sperm, other studies report using volumes of 4 mL to flush out the fallopian tube, forcing some sperm into the peritoneal cavity. After injection, the catheter is withdrawn. Ultrasonic guidance has commonly been used to direct placement of the catheter; however, others have attempted this using tactile sensation.^{37, 38} Direct intraperitoneal insemination (DIPI) places motile sperm even closer to the ova to improve pregnancy rates over IUI while avoiding higher technology techniques such as IVF and gamete intrafallopian transfer. In this technique, motile sperm obtained after semen processing are injected into the pouch of Douglas through the posterior vaginal fornix. Needle placement may be confirmed using transvaginal ultrasound or by the aspiration of peritoneal fluid.³⁹ DIPI usually is done in conjunction with ovulation induction.⁴⁰ Motile sperm generally have been obtained using the swim-up procedure, although Percoll separation also has been used.

To obtain the closest placement of sperm to ova, intrafollicular insemination (IFI) has been described.⁴¹ In this procedure, washed sperm are injected into 1–3 preovulatory follicles with the use of a transvaginal needle under ultrasound guidance. A small volume (50 μL) of processed sperm is placed in each follicle. This usually is done in conjunction with ovulation induction.⁴²

Timing of Insemination

For successful insemination, motile sperm must be inside of the female reproductive tract during the time when the released ova are viable. Methods to detect ovulation include basal body temperature (BBT) charts, evaluation of cervical mucus quality, serum luteinizing hormone (LH) assay, urinary LH detection kits, and ovarian ultrasound. BBT charts, although simple and inexpensive, may be inaccurate and often are more useful for detecting ovulation that has taken place than predicting when ovulation will occur. Similarly, cervical mucus evaluation may be subjective. Serum LH and estradiol assays are reliable, but because of the expense, usually are reserved for evaluation of ovulation induction cycles. Urinary LH surge detection is reliable and relatively easy to perform.⁴³ Ovarian ultrasound is accurate compared with other methods, but because of the expense, usually is reserved for ovulation induction cycles.^{44, 45, 46} After intercourse, IVI, or ICI, motile sperm may be found within the cervical mucus for 48 hours. Thus, if these types of insemination are performed within 48 hours of ovulation, motile sperm should be present when the ovum is released. In view of this, it is not surprising that there is no clear evidence that the more accurate methods of ovulation monitoring translate to improved pregnancy rates with ICI or IVI. Also, since the ova is viable for only approximately 12 hours after ovulation, intercourse after ovulation is unlikely to result in pregnancy.⁴⁷ Since IVI and ICI are physiologically similar to intercourse, it might be expected that insemination after ovulation also would be unlikely to result in pregnancy.

Whereas the cervical mucus acts as a reservoir for motile sperm after ICI and IVI, it is not clear that this is the case after IUI and is unlikely after ITI, DIPI, or IFI. It is generally believed that the insemination window is much shorter after these procedures, requiring more accurate methods of ovulation detection. Because of the inaccuracy of the BBT method, if this approach is used, two inseminations should be performed 1 day apart. Inseminations beyond two have not been demonstrated to improve pregnancy rates.⁴⁸ Urinary LH testing with the use of over-the-counter kits is widely used for the detection of ovulation in natural cycles and clomiphene citrate-stimulated cycles. After the onset of the LH surge, ovulation typically occurs within 12–36 hours.^{43, 49} Although patients frequently are instructed to perform LH testing in the morning, it may be preferred to have them perform it in the afternoon for several reasons. The LH surge is more commonly detected in the evening. In addition, insemination may be scheduled for the next morning, shortening the time between detection and insemination versus if the detection was performed in the morning and insemination performed the next day.⁵⁰ Whereas urine LH testing may be performed twice per day, because of the expense of the kits, most couples test only once per day beginning several days before the expected date of the LH surge. IUI usually is performed the day after the detection of the LH surge in cases when LH testing was performed in the afternoon. When LH testing is performed early in the morning, insemination should be performed on the day of detection. Whereas many centers prefer LH surge detection as opposed to estimations of the time of ovulation using BBT charts and cervical mucus, no well-designed studies demonstrate improved pregnancy rates with this approach. Several studies examining pregnancy after donor insemination show no difference in pregnancy rates between the use of LH kits and BBT charts.^{51, 52}

For cycles with gonadotropin ovulation induction, ultrasound combined with estradiol measurements is commonly used to predict ovulation. This allows an accurate estimate as to when ovulation will occur. In this setting, human chorionic gonadotropin is given to induce ovulation. Inseminations often are performed 24–36 hours after human chorionic gonadotropin injection. A recent retrospective study reports the highest pregnancy rates when the patient had a spontaneous LH surge before human chorionic gonadotropin administration, particularly when human chorionic gonadotropin was administered 8–20 hours after the LH surge.⁵³ Animal studies report that less than 10% of inseminated sperm are found in the upper reproductive tract of the woman 12 hours after IUI.⁵⁴ After human chorionic gonadotropin administration, oocytes are released in waves, not all at the same time.⁵⁵ This argues for performing more than one insemination per cycle to assure live sperm being present whenever ova were released. On the other hand, in many male factor couples, the second specimen on the day after the first insemination may demonstrate decreased semen parameters.⁵⁶ There has been no consensus in the literature as to the benefit of two inseminations versus one. Studies showing a beneficial effect of two inseminations⁵⁷ and showing no significant difference in pregnancy rates have been reported.⁵⁸ A recent metanalysis of published studies found a higher but statistically insignificant pregnancy rate with two inseminations compared to one.⁵⁹ Unfortunately the included studies were quite heterogenous limiting the utility of the analysis.^{60, 61, 62}  Our current policy is to perform one timed insemination in ovulation induction cycles. In natural cycle inseminations or those with clomiphene, two inseminations per cycle often are performed when the timing of ovulation is not as clear.

Results

Intravaginal Insemination

Intravaginal insemination should be reserved for couples where there is a semen deposition abnormality. Dixon and coworkers report a 40% pregnancy rate after IVI in a small group of patients with semen deposition abnormalities, although no spontaneous pregnancies occurred in this group.⁶³ In couples with semen abnormalities or unexplained infertility, a spontaneous pregnancy rate of 18% was reported compared with a 9.5% rate after IVI.

Intracervical Insemination

The indications for ICI are similar to those for IVI, and it is not clear that ICI has any significant benefits over IVI. There is a lack of data comparing these two techniques. In a report examining ICI, IUI, and intercourse, no benefit of ICI over intercourse was demonstrated.⁶⁴ Pregnancy rates in male factor couples have been disappointing.⁶⁵ IVI and ICI should be reserved for semen deposition abnormalities.

Intrauterine Insemination

There have been many publications reporting results of IUI in the treatment of male and female infertility. Despite this, controversy remains as to the value of IUI in infertile couples. Unfortunately, most studies have been uncontrolled and include different ovulation management protocols. The two most important factors in examining IUI success rates are the etiology of the infertility and the type of ovulation management. Other variables that also should be considered include the age of the man and woman, the number of inseminations performed per cycle, the timing of the inseminations, and the technique of semen processing. Results should be examined in terms of pregnancy rates per cycle.

Intrauterine Insemination for Male Factor Infertility Caused by Defects in Semen Parameters

There have been many reports on the use of IUI for male factor infertility. Unfortunately, results vary tremendously. Definitions of male factor infertility have not been consistent. Some studies reporting good success rates include semen parameters that many would consider normal. Fortunately, there have been several controlled studies comparing IUI for male infertility to intercourse (Table 2).^{8, 66, 67, 68, 69, 70}  Most of these studies show either no benefit or a small benefit from IUI. The highest pregnancy rate has been reported by Kerin and associates in 1984.⁶⁶ However, these male factor couples had minimal seminal impairments. We believe that generally there is no role for natural cycle IUI for impaired semen parameters.

Table 2. Pregnancy rate per cycle in controlled studies on natural cycle intrauterine insemination for male factor infertility

IUI = intrauterine insemination

Because of the poor results with natural cycle IUI in male factor couples, ovulation induction often is added to the regimen. A variety of controlled studies have been reported, most of which demonstrate improved pregnancies with this approach.^{71, 72, 73, 74, 75, 76, 77, 78} Unfortunately, well designed large scale studies reporting live birh rates are lacking.  A recent meta-analyis concluded there was insufficient evidence to deterimine if IUI with our without ovulation induction was beneficial for male factor patients.⁷⁹ Despite these deficiencies in adequate studies, some generalizations can be suggested from review of published data.  Since both insemination and ovulation induction are used in these couples, the effect of each of these interventions must be examined when comparing pregnancy rates to those achieved by the couple practicing intercourse alone. It appears from the prior controlled studies of natural IUI that there is no consistent benefit compared with intercourse alone. When ovulation induction is added, any improvement in pregnancy rates may result from the combination of IUI with ovulation induction or ovulation induction alone. In an initial study, Cruz and coworkers in 1986⁷¹ compared IUI with ICI in couples undergoing ovulation induction. They report a 7.3% pregnancy rate per cycle in IUI cycles compared with a 1.1% rate in ICI cycles. Since ICI is not markedly different than intercourse in terms of sperm placement, this study strongly suggests that the improvement in pregnancy rates resulted from the combination of IUI with superovulation and not superovulation alone. Other studies report comparing IUI with the combination of intercourse and ovulation induction. Most these also demonstrate a significant improvement in pregnancy rates in IUI compared with intercourse. In one study, an 11.5% pregnancy rate per cycle was reported for IUI cycles with superovulation compared with a 3.9% pregnancy rate per cycle in intercourse superovulation cycles.⁷⁸ Further support for the synergistic benefit of combining IUI with superovulation was demonstrated by Nulsen and colleagues in 1993.⁷⁵ These investigators report a 13% pregnancy rate per cycle in IUI superovulation cycles compared with a 2.4% pregnancy rate in IUI natural cycles. It can be concluded from these studies that the baseline pregnancy rate in male factor couples through intercourse alone is approximately 2–3% per cycle, which is the same rate obtained with natural cycle IUI. Whereas the data with clomiphene citrate-stimulated cycles are not as clear, pregnancy rates in the range of 5–8% per cycle might be expected. Gonadotropin-stimulated IUI cycles generally result in pregnancy rates of 10–15% per cycle. In most studies, most pregnancies occur within the first three cycles, with few pregnancies occurring beyond that point.⁷⁵

As with pregnancy after intercourse, there is no minimum number of sperm that is required for pregnancy to occur after IUI.  A recent meta-analysis suggested that pregnancy rates dropped significantly with post-wash total motile sperm counts of less than 0.5–5 million sperm.⁸⁰ It is not clear that inseminating motile counts of greater than 10 to 20 million result in increasingly higher pregnancy rates.^{81, 82} The value of evaluating sperm morphologic features by rigid criteria is not clear. Reports demonstrate a correlation between morphologic features and pregnancy rates after IUI.^{83, 84} Similarly, there has been conflicting evidence on the use of sperm function tests such as the sperm penetration assay.^{72, 85} In view of the above results, it is our policy to offer IUI to couples with at least 1 million motile sperm after semen processing. For patients with rigid sperm morphologic features in the range of 0–1%, we usually recommend a sperm penetration assay. If the patient fails to fertilize on this functional test, we encourage the couple to proceed with IVF rather than IUI.

The role of IUI in the treatment of couples in which the male partner demonstrates antisperm antibodies has been controversial. IUI alone using standard semen processing generally has been unsuccessful in this group of patients.⁸⁶ Although there have been many attempts to remove surface-bound antibodies by semen processing, most attempts have been unsuccessful. In a randomized trial, semen was treated either by standard semen processing or with chymotrypsin. A 25% pregnancy rate per cycle was reported in the chymotrypsin group compared with only a 3% pregnancy rate in the standard processing group.¹¹ Whereas it has been clearly demonstrated that female fertility decreases with age, several reports demonstrate decreased pregnancy rates with increasing age in the man, particularly in those older than 35–40 years of age.^{87, 88}

Female Factor Infertility

Cervical factor infertility has commonly been treated with IUI. Uncontrolled studies report success with both nonstimulated and stimulated cycles.⁸⁹ In a large retrospective study, pregnancy rates for cervical factor infertility were higher when IUI was combined with superovulation compared with natural cycle IUI.⁹⁰ A review in 2005 concluded that studies were inadequate to perform a meta-analysis and suggested there was no data to support the use of IUI for cerfical factor infertility.⁹¹ However, a more recent 6 month randomized trial of IUI versus intercourse found a 51% pregnancy rate with IUI compared to a 31% rate with intercourse.⁹² Unfortunately, the study was underpowered and the difference was not statistically significant.  We recommend starting couples with pure cervical factor infertility with natural cycle IUI for three to four cycles. If no pregnancy ensues, ovulation induction is added.

IUI has been used to treat couples in which the female partner has antisperm antibodies. Studies examining IUI often combine male and female antisperm antibody couples, making it difficult to interpret the results. In a study limited to couples with female antisperm antibodies, Gregoriou and associates treated 24 couples initially with three cycles of natural cycle IUI. A 1.4% pregnancy rate per cycle was achieved. After this, the remaining couples underwent IUI and clomiphene citrate-stimulated cycles. The pregnancy rate remained unchanged at 1.4% per cycle. Finally, the remaining 22 patients underwent three cycles of gonadotropin stimulation, resulting in a 6.1% pregnancy rate per cycle, which was significantly greater than the pregnancy rates in the prior two protocols. These limited data suggest that if IUI is to be done for female antisperm antibodies, it should be combined with gonadotropin ovulation induction.⁹³

Female age clearly has an effect on pregnancy rates after IUI. Beyond 35 years of age, pregnancy rates decrease more rapidly than in the years before age 35.⁹⁴ A recent study examines the results of IUI combined with ovulation induction in women aged 40 years and older, showing a pregnancy rate per cycle of 9.6% for women aged 40, 5.4% for women aged 41, 2.4% for women aged 42, and no pregnancies in women aged 43 and older.⁹⁵

IUI has been commonly used to treat couples with unexplained infertility. A recent meta-analysis found that IUI with ovulation induction was superior to timed intercourse with ovulation induction.⁹⁶ In addition, IUI with ovulation induction was superior to natural cycle IUI in these couples.

IUI also has been used to treat couples in which the female partner has mild to moderate endometriosis.^{97, 98} Pregnancy rates in the range of 13–18% per cycle have been reported in these retrospective and prospective studies.⁹⁹ In a prospective randomized study, IUI combined with superovulation was found superior to IUI alone in this group of patients.⁷⁵ Tummon and associates compared superovulation with IUI versus intercourse alone without superovulation in a prospective randomized trial. IUI combined with superovulation produced an 11% live birth rate per cycle compared with only 2% in the nontreatment group.¹⁰⁰ Notice that these studies report on women with mild to moderate endometriosis and exclude women with severe endometriosis. Patients with tubal disease also have been treated with IUI. Retrospective studies report pregnancy rates per cycle of 8–10%.^{90, 97} Similarly, success also has been reported for the treatment of ovulatory disorders.⁹⁷

Initial, uncontrolled studies of ITI suggest an improvement in pregnancy rates with this technique.^{38, 101, 102} Most of the subsequent controlled trials comparing IUI and ITI demonstrate no benefit of ITI over IUI^{37, 103, 104, 105, 106, 107, 108} (Table 3).

Table 3. Pregnancy rate per cycle in controlled trials of intrauterine and intratubal insemination

ITI = intratubal insemination; IUI = intrauterine insemination

Two controlled trials using two different variations of the ITI technique report a twofold higher pregnancy rate in ITI cycles compared with IUI cycles.^{107, 108} Further studies need to be performed to confirm this benefit. Controlled trials comparing DIPI with IUI consistently demonstrate no benefit of DIPI over IUI. Importantly, most of these studies have used ovulation induction. In the one study demonstrating the benefit of DIPI over IUI, no superovulation was used (Table 4).^{73, 109, 110, 111, 112}  It appears that DIPI offers no advantage over IUI combined with superovulation. The use of IFI has been examined in a series of 50 patients with normal tubal function. Only one pregnancy occurred in this series, suggesting that IFI offers no benefit for the infertile couple.⁴²

Table 4. Pregnancy rates per cycle in controlled studies comparing direct intraperitoneal and intrauterine insemination

DIPI = direct intraperitoneal insemination; IUI = intrauterine insemination.
*Reported as pregnancy rate per couple

Complications

Since IVI places sperm in the same position as with intercourse, it carries no more risk than intercourse. The complications after ICI also are low. ICI is commonly performed with unwashed semen, which usually carries microorganisms. Cervical mucus is believed to act as a barrier, preventing ascension of microorganisms into the upper female reproductive tract. Stone and coworkers found microorganisms present in the peritoneal fluid in 10% of patients after ICI.¹¹³ Interestingly, none of these patients developed clinical infections.

IUI bypasses the cervical mucus and thus may be expected to have a higher incidence of infections. Stone and colleagues found positive results from peritoneal cultures in five of nine women after IUI with washed sperm. However, again none of these women demonstrated clinical infection.¹¹³ Importantly, sperm washing only consisted of one centrifugation step in this study, whereas most centers perform two washings, which may be expected to reduce the bacterial contamination even further. The clinical incidence of infection after IUI is low. In a review of the literature, a prevalence of 1.83 per 1000 patients was reported. Because of the concern of infection, the administration of oral antibiotics to the woman around the time of insemination has been suggested.^{85, 90, 5} In addition, some centers advocate adding antibiotics to the semen processing solutions.¹¹⁴ Despite these concerns, the incidence of infection after IUI with no antibiotic treatment is 2.1 per 1000 patients as opposed to 1.35 per 1000 patients with antibiotics added to the semen processing, and 2.76 per 1000 patients when the woman was given oral antibiotics.¹¹⁵ Because of the low incidence of infections without antibiotics, routine use of antibiotics is unwarranted. On the other hand, if there is a clinical vaginal or cervical infection in the woman or a clinical cystitis, urethritis, or prostatitis in the man, insemination should not be performed until the patient is treated.

Mild uterine cramping may occur when the insemination catheter reaches the uterus; however, severe uterine cramping is uncommon with washed-sperm IUI. Anaphylaxis after IUI with washed sperm prepared with bovine serum albumin has been reported. Symptoms included asthma, vomiting, itching, generalized urticaria, severe uterine contractions, shortness of breath, chest tightness, and angioedema.^{116, 117} Notice that in both of these case reports, the patients were having their first IUI treatments. Despite these reports, the incidence of anaphylaxis after IUI with washed sperm is extremely low. The physician should be aware of this possibility, but it should not affect the recommendation for treatment. Anaphylaxis to seminal fluid after unwashed-sperm IUI also has been reported.¹¹⁸ There has been concern that the intrauterine placement of sperm may result in the development of antisperm antibodies in the woman. In the study of 41 patients, 2 (4.8%) developed antisperm antibodies, whereas the remaining 92.7% of patients remained antisperm antibody negative.¹¹⁹ This appears to be an uncommon occurrence in most patients.

Occasionally, women whose male partners are positive for human immunodeficiency virus (HIV) inquire as to whether HIV can be removed from the semen by processing. HIV has been found free in seminal plasma as well as in white blood cells in the semen from HIV-1-infected men. Studies suggest that HIV does not infect motile spermatozoa or immature germ cells.¹²⁰ Studies of sperm washing demonstrate the removal of detectable HIV RNA and proviral DNA to below-detectable limits after Percoll gradient processing.¹²¹ Semprini and associates performed insemination in 29 women after gradient centrifugation and swim-up in semen from HIV-infected partners. None of the inseminated women experienced seroconversion, and all of the 10 babies born to these mothers remained HIV negative.¹²² On the other hand, the Centers for Disease Control report on what appears to be the seroconversion of a HIV-negative woman after insemination with Percoll-processed sperm from her HIV-positive male partner.¹²³ We currently caution against the use of HIV-positive semen for insemination.

As with pregnancy after intercourse, spontaneous abortions occur after IUI. Whereas reports of small series show wide-ranging miscarriage rates, a review of multiple studies report a mean spontaneously abortion rate of 26%.¹²⁴ Although this rate is higher than the 10–15% incidence reported in the general population, the factors relating to infertility may account for this increase. In addition, these couples are watched more closely, and pregnancies may be picked up that otherwise would have gone undetected.

Whereas ovulation induction has increased pregnancy rates, it also has resulted in multiple gestations in approximately 15–30% of pregnancies. Approximately 80% of multiple gestations involve twins, with approximately 12% involving triplets and approximately 7% involving more than three gestational sacs.^{125, 126}

The potential complications from ITI are the same as with IUI. In addition, there is the possibility of damage to the fallopian tube; however, this complication has either been unreported, or patients have not been studied to access this type of damage. Tubal spasm has resulted in vasovagal reactions. Finally, ectopic pregnancies occur infrequently.

Whereas DIPI involves the intraperitoneal placement of a needle and the potential risk of bowel injury and bleeding, these have not been reported. Pelvic infections have been infrequent.¹²⁷ IFI has the same inherent risks as DIPI; however, there have been no complications reported. This may result from the low numbers of cases reported.

Sex Ratio

The percentage of male infants at birth in the general population is 51.4%.¹²⁸ There is no clear evidence that THI alters this ratio. A large European study found a ratio of 51.2%.¹²⁹ On the other hand, other reports suggest a 7–10% increase in the male-to-female sex ratio after THI. Interestingly, ovulation induction seems to lower the sex ratio; thus, when it is combined with THI, the ratio remains unaltered.¹³⁰

Indications

The most common indication for donor insemination is male factor infertility. Azoospermia is the most frequent male factor diagnosis for which couples elect TDI. Couples with other seminal defects such as oligospermia, asthenospermia, teratazoospermia, or antisperm antibodies in the man also are candidates for TDI. Many of these couples may have already failed THI combined with superovulation or IVF. In addition, some couples with these diagnoses, being candidates for assisted reproductive techniques (ART), are not comfortable with the superovulation aspect and the risks of multiple gestation common with these procedures. Interestingly, with the success of ICSI, many couples who would not be candidates for regular IVF or IUI, and who would have proceeded with TDI, are undergoing ICSI.

In some couples, the decision to proceed with TDI results from the presence of autosomal dominant hereditary disorders in the man such as polycystic kidney disease, hemophilia, chromosomal abnormalities, or Huntington's chorea. In some cases, however, these conditions may be detected through prenatal testing. Some couples prefer TDI to the prospect of pregnancy termination if the fetus is affected. TDI also may be used when both partners carry a recessive disorder such as the cystic fibrosis trait.

In the past, Rh incompatibility has been an indication for TDI. The availability of RhoGAM (Ortho, Raritan, NJ) has resulted in this being an uncommon indication for the use of donor sperm. Whereas the Rh status of donors is commonly listed on the donor profile sheets, couples are able to select donors regardless of the Rh status. In some cases when the female partner is Rh negative and severely Rh-isoimmunized and the male partner is Rh-positive, the couple may elect to proceed with TDI. Sexual dysfunction in the man is an uncommon indication for TDI. Dysfunction from impotence, whether organic or psychological, is more commonly managed by treating the underlying erectile dysfunction. Ejaculatory failure often may be treated or sperm may be retrieved for use in IUI or IVF. Some couples may not wish to proceed with these procedures and elect TDI. TDI has become commonly used for women without male partners. This includes single women not in relationships and women in lesbian relationships.

Counseling Before Insemination

For many couples, the decision to proceed with donor insemination is difficult. In some cases, the couple may request the mixing of donor sperm with the male partner's sperm. This practice should be discouraged, since suboptimal semen specimens may contain compounds such as superoxide radicals, which may impair normal sperm. Most couples undergoing TDI are comfortable with their decision. Kremer and coworkers found that 98% of couples in a TDI program believed they had made the right decision, whereas 2% were uncertain, and no couples regretted the decision to proceed with TDI.¹³⁰ The discussions between the couple and the physician before the start of TDI are important in addressing couple's concerns about proceeding with this technique. Although this setting may be adequate for most couples, some may require additional psychological counseling. The decision whether to disclose the use of TDI to any subsequent children should be discussed before initiating therapy. Studies of couples undergoing TDI have found that only approximately 20% plan on informing the child about the means of conception.^{131, 132, 133} Of significance, in one study, after 6 months of inseminations, only 10–12% of couples planned on disclosing the method of conception with the child.¹³¹ In a study of families that have conceived by TDI, only 6% had informed the child of the method of conception.¹³³ In most couples, the husband and wife agreed about how to handle disclosure.¹³⁴ One study found that younger age, azoospermia, and having more than one donor insemination was correlated with a higher likelihood of disclosure. The decision to disclose was not linked to parental bonding with the child and did not seem to affect the quality of the couple's relationship.¹³⁵ Interestingly, whereas most couples do not discuss the method of conception with the child, one study reports that 71% of families discussed the origin with others.¹³³

For most couples, the donor's characteristics generally are matched to that of the male partner. Characteristics that are commonly reported for donors include height, weight, eye color, hair color, curly hair, straight hair, big boned, little boned, ethnic background, educational level, and blood type. Some centers prefer to choose the donor based on these characteristics, whereas other centers, including ours, prefer to give the couple the donor list and let them choose. We prefer the same approach with single women. Both partners should sign an informed consent, which should be designed with the help of legal counsel. The requirements may vary by state. The woman should undergo an evaluation before initiation of TDI. This should include a routine medical and reproductive history and a physical examination. These requirements should be no different than those used in women attempting conception without TDI. The American Society of Reproductive Medicine (ASRM) has published guidelines for donor insemination.¹³⁶ It is recommended that the female recipient be tested for blood type, Rh factor, Rubella and varicella titers, gonorrhea, Chlamydia, HIV-1, HIV-2, serologic test for syphilis, hepatitis B surface antigen, Hepatitis B core antibody (IgG and IgM), hepatitis C antibody, cytomegalovirus (CMV) antibody (IgG and IgM).  Testing for human T-cell lyimphotropic virus (HTLV) type I and II is concerdered optional. In addition, recipients should be asked about possible exposure to transmissible spongiform encephalopathies.  Women that do not conceive after four to six cycles may require further studies, including hysterosalpingogram (HSG) and laparoscopy. In women without risk factors for infertility, it is uncommon to find a HSG abnormality that affects fecundity.¹³⁷ Women with specific abnormalities found in the history or physical examination should have appropriate testing performed. Generally, the male partner in a couple requesting TDI also should have completed an appropriate evaluation. In some couples, the request for TDI is based on the faulty assumption that the man has untreatable sterility. The ASRM guidelines also recommend screening of both partners for HIV.

Selection of Donors

The process of sperm donor selection attempts to recruit donors in good health, without genetic abnormalities, and with sperm of high fertilizing capacity.¹³⁸ Evidence supports that the incidence of birth defects, particularly new nonstructural autosomal mutations, increases with paternal age.¹³⁹ In view of this, the ASRM recommends that donors be younger than 40 years of age. Donors of proven fertility are desirable but not required.  In practice, many centers recruit students from universities who usually are of unproven fertility. There is no clear evidence that limiting the donor pool to those with proven fertility results in higher pregnancy rates than pools that include screened donors of unproven fertility.  A full medical history, including the history of genetic diseases and a complete sexual history, should be obtained. Recently the United States Food and Drug Administration (FDA) produced rules for determining donor eligibility.¹⁴⁰ The purpose is to prevent the transmission of communicable diseases.  The categorized couples into sexually intimate partners, those utilizing a known donor (directed donors), and those utilizing anonomous donors.  A process of screening (history and physical examination) and laboratory testing is outlined.  Although sexually intimate partners undergoing IUI with the male parterner’s sperm are exempt from screening and testing, the ASRM recommends viral testing of both parteners.The FDA lists specific required items to be included in the history and physical exam.  These items are designed to identify donors at increased risk of harboring communicable diseases.  Following the screening process, a variety of laboratory testing is also mandated.  The current list of communicable diseases for which testing is mandated include HIV-1, HIV-2, Hepatitis C and B, syphilis, HTLV-1, Chlamydia trachomatis, Neisseria gonorrhoeae, and CMV.  Testing must be performed by FDA approved methods.  While CMV testing is mandated, donors that test positive for CMV antibodies but that do not have active CMV infection may still serve as donors.  The types of mandated testing may change over time, current requirements may be obtained from the FDA web site (www.fda.gov/cber).  Other countries may have other requirements for evaluaton of potential sperm donors.  The ASRM recommends that the donor semen samples meet the reference ranges of the World Health Organization.¹⁴¹ Whereas these criteria are likely to exclude samples with poor fertilizing capacity, they do not guarantee that samples exceeding these criteria have high fertilizing capacity. The quality of the semen sample has not always correlated with fertility potential.^{142, 143, 144, 145} Despite having adequate parameters, donors whose samples result in low pregnancy rates in recipients should be removed from the donor pool.  For donors that pass screening and testing, semen samples should be collected, cryopreserved, and quarantined for 180 days. At that point, the prospective donors should be retested for HIV and the sample released only if the results are negative. The FDA requires the 180 quarantine for anonymous donation but not directed donation.  In contrast the ASRM recommends quarantine for both types of samples.  In additions the FDA allows the use of directed donor sperm even if the donor fails sceening and/or testing.  The ASRM recommends against the use of such donors.  It is common to pay donors; however, the ASRM recommends that the compensation should not be such that it is the primary incentive for donating sperm. Records should be maintained so that the number of pregnancies from a given donor is recorded. Keeping the pregnancy limit to 25 or fewer in a population of 800,000 results in an inconsequential chance of consanguinity. Permanent confidential records should be maintained. Most centers release anonymous medical information about the donors to recipients.

Fresh or Frozen Specimens

Before the advent of AIDS, it was common for inseminations to be performed with fresh semen specimens. Because of reports of women contracting HIV from donor insemination, the use of fresh semen is no longer warranted.^{146, 147, 148} With current treatment strategies, the risk of HIV transmission from a screened donor is estimated to be approximately 1 in 5 × 10⁸.¹⁴⁹ Since HIV-infected donors may not be seropositive for 3–6 months, the quarantine period is essential to pick up these cases. The freeze-thaw process results in a degradation of semen parameters, specifically the number of motile sperm.¹⁵⁰ Although there may be some degradation of sperm quality once sperm are frozen, it is the actual freeze-thaw process that results in most of the injury.¹⁵¹ Thawed sperm do not survive as well as fresh sperm and tend to loose their fertilizing capacity more rapidly.¹⁵²

Semen Processing

Before cryopreservation, semen is mixed with a cryoprotectant. Most centers use either glycerol or, more commonly, a mixture of glycerol and buffered egg yolk solution. The egg yolk may prevent membrane damage to the sperm as well as yield higher pregnancy rates compared with glycerol alone.¹⁵³ Specimens may be frozen in plastic straws or plastic cryovials with screw-on caps. Although dry ice may be used, most centers use liquid nitrogen at -196°C. Specimens are thawed, followed by semen processing. This may involve any of the techniques that are used for THI, including sperm washing and Percoll processing.

Insemination Techniques

Donor insemination may be performed through IVI, ICI, or IUI. The technique is identical for that used with THI. Using a cervical cap, cervical reservoir, tampon, or recumbency results in no improvement in pregnancy rates.^{154, 155, 156, 157, 158}

Timing of Insemination

The same methods used to time THI may be used with donor insemination. Whereas some believe that timing is more critical with cryopreserved sperm as opposed to fresh because of the decreased survival of frozen thawed sperm, the benefit of more accurate timing remains unclear. When ovulation timing has been based on BBT charts, protocols using either one or two inseminations per cycle have been followed. In a retrospective study of TDI using BBT charts, no pregnancies occurred when inseminations were performed before day 11 of the cycle or 2 or more days after the temperature elevation.¹⁵⁹ In another retrospective review, Schwartz and colleagues¹⁶⁰ found the highest fecundity rates when single inseminations were performed on day 14. Finally, Corson reports that when using two inseminations per cycle, the highest pregnancy rates were obtained when inseminations were performed on days 13 and 15.¹⁶¹ LH kits are commonly used for the timing of TDI cycles. In a prospective, randomized, controlled trial, no difference was found in the cycle fecundities in cycles timed with urine LH dipsticks or BBT charts.¹⁶² Similar findings have been reported in retrospective studies.¹⁶³ Others have tried to determine if one insemination more accurately timed through LH testing may result in higher pregnancy rates than two inseminations timed with BBT monitoring. Federman and coworkers in a prospective randomized study report no statistical difference between these two approaches. The authors found a 12.3% fecundity rate for single inseminations in LH kit timed cycles and a 5.3% fecundity rate for non-LH method cycles.¹⁶⁴ Despite the improved accuracy with LH kit timing, this approach has not proved to result in higher pregnancy rates than BBT timed cycles. Because of the improved timing with urine LH measurements, investigators have examined whether one insemination yields as high a fecundity rate as two inseminations per cycle with LH timing of all cycles. Some retrospective studies report no difference between the approaches,^{165, 166} whereas others found a benefit to this approach.¹⁶⁷ In a prospective randomized study, Byrd and colleagues found a higher pregnancy rate with IUI compared with ICI with donor sperm. In the same study, they found a higher pregnancy rate in IUI cycles when two inseminations were performed compared with one, although there was no such benefit in ICI cycles.¹⁶⁸ These data suggest that if frozen sperm are used with LH timed cycles, two inseminations may offer higher pregnancy rates than one insemination per cycle. With LH kit timing, women often test in the morning, in which case the first insemination is performed the day of the LH surge, with the second insemination performed the following day. Some centers have the women test in the afternoon with the first insemination performed the following morning. There are no data comparing these two approaches.

Results

When fresh sperm were used for insemination, ICI was the most commonly used technique. In a prospective randomized controlled trial, frozen and fresh sperm were compared in ICI cycles.¹⁶⁹ With ICI, a fecundity rate of 20.3% for fresh sperm versus a 7.8% fecundity rate for frozen sperm was reported. Most reviews find a pregnancy rate of approximately 15% for fresh sperm versus 5–11% for frozen sperm.^{170, 171, 172, 173, 174, 175} Because of the reduced fecundity rates when using frozen sperm in ICI cycles, the benefit of IUI over ICI has been examined both in natural cycle and superovulatory cycles (see Table 4).^{168, 176, 177, 178, 179, 180}

Most studies show a clear benefit of IUI over ICI for insemination with cryopreserved sperm. Cumulative pregnancy rates with frozen sperm insemination range from 45–73% for a 1-year period.^{153, 170, 181, 182} Of the women who conceive, approximately 86% will do so within 6 months. Other techniques such as ITI and DIPI have not been widely used with donor sperm.¹⁷⁹ Similarly, the benefit of ovulation induction with donor insemination has not been well studied.¹⁸³ However, because of the benefit demonstrated in THI, it is reasonable to add ovulation induction if conception has not occurred after six cycles of donor insemination.

The success of donor insemination depends greatly on the quality of the semen and any infertility factors that may be present in the female partner. The total number of motile sperm inseminated has a direct bearing on pregnancy rates. Kang and Wu report a 5% fecundity rate when 5 million or fewer motile sperm were inseminated, an 11% fecundity rate when 5–10 million motile sperm were inseminated, a 16% pregnancy rate when greater than 10–20 million sperm were inseminated, and a 20% pregnancy rate when over 20 million motile sperm were inseminated.¹⁸⁴ Most centers try to inseminate at least 20 million motile sperm.

Female fertility disorders also result in decreased fecundity rates. The highest pregnancy rates occur in couples in which the man is azoospermic and the woman has no known infertility factors.^{168, 185} Lower fecundity rates have been reported in couples in which the woman has no infertility factors but the man is not azoospermic. Additional female factors resulting in lower fecundity rates include endometriosis and other pelvic abnormalities. Whereas ovulatory dysfunction may lower fecundity rates, appropriate treatment seems to mitigate this effect.¹⁸⁶ As has been found with THI, fecundity rates decrease with increasing female age.^{184, 187, 188}

Complications

As with husband insemination, complications such as pelvic infection and uterine cramping also may occur after donor insemination. The incidence of pelvic infection is low. Reported spontaneous abortion rates average approximately 15% and on average are no different between fresh and frozen donor insemination cycles.^{156, 189, 190, 191, 192, 193, 194, 195, 196} The incidence of congenital anomalies generally has been found to be the same as that in the general population. Whereas one study found a small increase in trisomy 21 and trisomy 12, this has not been confirmed and may have resulted from recruitment bias.^{132, 150, 197} In a large retrospective review, the trisomy 21 rate was found to increase with both maternal and donor age.¹⁹⁸ Studies evaluating the sex ratio after donor insemination suggest a slight lowering of the percentage of male births, although different studies report ratios from 0.72–1.6.^{199, 200, 201} Multiple gestations also may occur after donor insemination, particularly after ovulation induction. In gonadotropin-stimulated cycles, a 32% multiple gestation rate after IUI was reported compared with a 21% rate after ICI.²⁰²

Known Donor Insemination

It is common for couples to want to use a friend or relative as the sperm donor. A brother of the male partner often is identified as a potential donor. Known donors must undergo the same screening and testing criteria as unknown donors. In a study of couples who have conceived after known donor insemination, 75% report that they had developed a closer relationship with the donor, whereas 25% report a deterioration in the relationship. Approximately 70% of recipients and donors planned on identifying the donor to the offspring. Finally, men placed more importance on having a genetically related donor than did women.²⁰³

Alternative Insemination Arrangements

Donor insemination has become increasingly requested by single women and women involved in lesbian relationships. Single women requesting donor insemination generally are older than women involved in lesbian relationships. Common reasons for requesting insemination included concern about running out of time for fertility in relation to their biological clock.²⁰⁴ Most studies find that single and lesbian women are more likely to disclose the use of donor insemination to the offspring than heterosexual couples.^{205, 206} A recent study of 4- to 8-year-old children compared those born to lesbian couples with those born to heterosexual couples using donor insemination and to heterosexual couples with naturally conceived children. Various parameters of family development were found to be similar between the groups. Both boys and girls appeared to be well adjusted with no change in their gender roles compared with heterosexual couples.²⁰⁷ As with heterosexual donor insemination, it is important to have an appropriate consent form between all parties before initiation of insemination.