Chapter 36 Artificial Insemination

INTRODUCTION

Artificial insemination is an assisted conception method that can be used to alleviate infertility in selected couples. The rationale behind the use of artificial insemination is to increase the gamete density near the site of fertilization.¹ The effectiveness of artificial insemination has been clearly established in specific subsets of infertile patients such as those with idiopathic infertility, infertility related to a cervical factor, or a mild male factor infertility (Table 36-1).^2,³ An accepted advantage of artificial insemination is that it is generally less expensive and invasive than other assisted reproductive technology (ART) procedures.⁴

Table 36-1 Infertility Disorders with Proven Benefit from Partner Insemination

Idiopathic infertility

Cervical factor infertility

Mild male factor infertility

From Cohlen BJ: Should we continue performing intrauterine inseminations in the year 2004? Gynecol Obstet Invest 59:3–13, 2004.

This chapter provides a comprehensive description of indications for artificial insemination, issues to consider before donor insemination, complications associated with intrauterine insemination (IUI), factors affecting the success of artificial insemination, and the current evidence available on effectiveness of artificial insemination for different indications.

HISTORY

Artificial insemination has been used in clinical medicine for more than 200 years for the treatment of infertile couples. In 1785 John Hunter, a Scottish surgeon from London, advised a man with hypospadias to collect his semen and have his wife inject it into her vagina. This was the first documented case of successful artificial insemination in a human.

In the second half of the nineteenth century, numerous reports were published of human artificial insemination in France, England, Germany, and the United States. In 1909, the first account of successful donor artificial insemination was published in the United States. By 1949, improved methods of freezing and thawing sperm were being reported.

Today, artificial insemination is frequently used in the treatment of couples with various causes of infertility, including ovulatory dysfunction, cervical factor infertility, and unexplained infertility as well as those with infertility caused by endometriosis, male, and immunologic factors. Artificial insemination with donor semen has become a well-accepted method of conception.

GENERAL CONSIDERATIONS

Semen Sources

The source of semen for artificial insemination can be either from the woman’s male partner or from a donor, who usually remains anonymous. When donor insemination first became widely available, the terms homologous artificial insemination and heterologous artificial insemination were used to differentiate these two alternative sources. However, the use of these biomedical terms in this manner is at variance with their scientific meaning, where they denote different species or organisms (as in, e.g., homologous and heterologous tissue grafts).

In the latter half of the 20th century, the terms artificial insemination, donor (AID) and artificial insemination, husband (AIH) found common use. However, the widespread use of the acronym AIDS for acquired immunodeficiency syndrome resulted in the replacement of AID with therapeutic donor insemination (TDI). An analogous alternative term for AIH has not evolved, probably in part because of the increasingly common situation where the woman’s partner is not her legal husband. In this chapter, artificial insemination using these two standard sperm sources will be designated simply as partner and donor insemination.

Techniques

Several different techniques have been used for artificial insemination. The original technique used for over a century was intravaginal insemination, where an unprocessed semen sample is placed high in the vagina.

In the latter half of the 20th century, the cervical cap was developed to maintain the highest concentration of semen at the external os of the cervix. It was soon discovered that placing the semen sample into the endocervix (intracervical insemination) resulted in pregnancy rates similar to that obtainable using a cervical cap and superior to those seen with high vaginal insemination.⁵

Intrauterine Versus Intracervical Insemination

A major breakthrough came in the 1960s when methods were developed for extracting enriched samples of motile sperm from semen. These purified samples were free of proteins and prostaglandins, and thus could be placed within the uterus using a technique designated intrauterine insemination (IUI). This technique was found to result in pregnancy rates 2 to 3 times those of intracervical insemination. However, intracervical insemination is still utilized in some practices.⁵

In an effort to further improve pregnancy rates, techniques were developed to place washed sperm samples directly into the tubes via transcerival cannulation (intratubal insemination) or into the peritoneal cavity via a needle placed through the posterior cul-de-sac (intraperitoneal insemination). Another technique developed in Europe, termed fallopian tube sperm perfusion, involves pressure injection of a large volume (4mL) of washed sperm sample while the cervix is sealed to prevent reflux of the sample.⁶ This technique appears to have a higher pregnancy rate than IUI in couples with unexplained infertility. The remainder of these technically difficult approaches have never been shown to result in better pregnancy rates than IUI. One prospective, randomized study found that simultaneous intratubal insemination actually decreased the pregnancy rates associated with IUI.⁷ In modern clinical practice in the United States, IUI is the predominant technique used for artificial insemination.

EVALUATION

Male Evaluation

Semen Analysis

The male partner is initially evaluated by obtaining a complete semen analysis and screen for sperm antibodies. A minimum of two samples provided over 1 to 2 months is analyzed. A third sample may be required if there is a discrepancy between the initial samples. All samples should be provided after 48 to 72 hours of sexual abstinence. Samples should be analyzed within 2 hours of collection.

Antisperm Antibodies

Male antisperm antibodies are found in approximately 10% of semen samples from infertile couples. Men with antisperm antibodies attached to their sperm are classified as having immunologic infertility. These antibodies are believed to decrease fertility by inducing agglutination or immobilization of the sperm. Studies have identified multiple antisperm antibodies that correspond to a variety of sperm components.

There are multiple known risk factors for the development of male antisperm antibodies.⁸ Vasectomy results in the development of antisperm antibodies in the majority of men. After successful vasovasostomy, more than half of these men will have detectable sperm-bound antibodies. The pregnancy rates will depend on many factors, including the titer and quantity of gross agglutination. Obstructive azospermia from any cause (e.g., congenital absence of the vas deferens, cystic fibrosis, infant hernia repair) increases the risk of antisperm antibodies. Reproductive infections (e.g., epididymitis, prostatitis, or orchitis) are also associated with antisperm antibodies.

Antisperm antibody tests are performed as a routine part of a complete semen analysis during the initial infertility evaluation. The most commonly used test in clinical practice is probably the immunobead assay.⁸ This quantitative assay evaluates live sperm and indicates percent bound, antibody isotype, and binding location. For routine screening, some andrology laboratories use a commercially available mixed antiglobulin reaction assay (SpermMar).

Male subfertility is significantly increased when the antisperm antibody level is greater than 50%.^9,¹⁰ Antisperm antibodies interfere with sperm–zona pellucida binding and prevent embryo cleavage and early development.

Complete Evaluation

In the presence of persistently abnormal results on semen analysis, a complete history, physical examination, and laboratory evaluation is performed to find and treat any potentially reversible abnormalities (see Chapter 35).

Female Evaluation

The female partner should undergo a basic infertility evaluation so that any correctable factors can be identified and treated before artificial insemination (see Chapter 34). In addition to a detailed history and physical examination, each woman considering partner or donor insemination should be evaluated with an imaging technique, usually a hysterosalpingogram, to document patent tubes. Unless oral or injectable medications are used to induce superovulation, ovulatory function should be evaluated with a urinary luteinizing hormone (LH) detection kit and midluteal serum progesterone level. Further evaluation is required in the event of detection of any clinical or laboratory abnormalities.

In the past, a great deal of time was spent investigating the possibility of cervical factor infertility by evaluating the character and sperm survivability in periovulatory cervical mucus, using what is termed a postcoital test. This test had many false-positive results, because it depended more on timing in the cycle and hormonal status than on static cervical characteristics. Except for exclusion of cervicitis during pelvic examination, timed evaluation of cervical mucus and sperm interaction is infrequently included in a fertility examination. This is because partner IUI is used as a basic fertility enhancement method for the majority of couples who have otherwise been unable to conceive regardless of diagnosis.

INDICATIONS

Partner Insemination

Partner insemination was originally developed as a treatment for male factor infertility. With the advent of IUI, partner insemination has been found to be an excellent treatment for a range of diagnoses, including cervical factor infertility, unexplained infertility, and subfertility, on the basis of other diagnoses or therapeutic measures (Table 36-2). This ability of partner insemination to increase pregnancy rates regardless of diagnosis has made this technique one of the fundamental approaches to infertility treatment today.

Table 36-2 Indications and Contraindications for Partner Insemination

Indications	Contraindications
Male Factor Infertility Disorders of semen density, motility, and morphology (mild oligospermia, asthenozoospermia, teratozoospermia) Immunologic factors Ejaculatory failure Mechanical factors (malformed urethra, hypospadias)	Absolute Contraindications Rh blood factor incompatibility Medical conditions that could endanger the patient’s life A partner with hereditable disease Cervical neoplasia Blocked tubes Active genital tract infection in either partner
Female Factor Infertility Cervical factor Vaginismus Mild endometriosis Ovulatory dysfunction	Relative Contraindications Severely abnormal semen parameters Multiple failures at previous partner insemination attempts Recent chemotherapy or radiotherapy Coexisting multiple infertility etiologies Pelvic surgery Older age woman
Unexplained Fertility

Male Factor Infertility

Partner insemination appears to be of clear benefit when the couple’s infertility is the result of any condition that makes it difficult to place semen high in the vagina during coitus. Male conditions resulting in this situation are termed ejaculatory failure. The most common causes of ejaculatory failure are impotence, severe hypospadias, and retrograde ejaculation. A unique condition that has been found to be treatable with artificial insemination is impotence secondary to spinal cord injury.¹¹

Partner insemination is also commonly used as a treatment for male factor infertility documented by repeated abnormal results on semen analysis. In couples where there is mild male factor infertility, defined as a progressive sperm motility of at least 20% to 30%, the prognosis appears to be good with partner insemination. Theoretically, increasing the number of motile sperm reaching the egg should improve fertility whenever decreased numbers and motility of normally functioning sperm is the primary problem.

Unfortunately, the pregnancy rates after partner IUI for the treatment of severe male factor infertility have been disappointing.¹² This is probably because markedly abnormal parameters on routine semen analysis often reflect a sperm defect that decreases the ability to fertilize eggs. This type of defect is unlikely to be overcome by increasing the number of sperm to which the egg is exposed at the site of fertilization. In patients with severely abnormal parameters on semen analysis and those with male factor infertility not amenable to partner insemination, more effective treatment will be either donor insemination or in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI).

Female Factor Infertility

Female reproductive conditions can also make it difficult to place semen high in the vagina during coitus. Such conditions that can benefit from partner insemination include severe vaginismus and other psychological problems, and less common anatomic conditions. Little data exists documenting the success of partner insemination for these conditions.

Women with cervical factor infertility will benefit from IUI, because this approach bypasses the cervical abnormalities that decrease fertility. This includes women with abnormal cervical mucus secondary to noninfectious chronic cervicitis and women with scant mucus or cervical stenosis, usually the result of cervical surgery. However, even women with a normal cervix and mucus appear to benefit from IUI, because the cervix appears to be the limiting factor in sperm reaching the site of fertilization in the tube.

An Adjunct to Other Infertility Treatments

Partner IUI appears to be of value for increasing per cycle fecundity when inducing ovulation in women with ovulatory dysfunction.¹³ After ovulation induction with clomiphene citrate, partner IUI might work by overcoming the decreased cervical mucus associated with the use of clomiphene.¹⁴ With gonadotropins, partner IUI might compensate for subtle changes in sperm transport within the uterus or tubes related to marked alterations in circulating estrogen and progesterone levels associated with their use.

Partner IUI also appears to be of some benefit when women with mild and minimal endometriosis are trying to achieve pregnancy. After appropriate surgical treatment, the monthly improvement in fecundity with partner IUI appears to be similar to that seen in patients with idiopathic infertility.¹⁵

Women with severe endometriosis or tubal disease have a far lower fecundity rate and often an increased rate of ectopic pregnancies. For this reason, these patients appear to benefit more from IVF than from partner IUI combined with superovulation.

Unexplained Infertility

Unexplained (i.e., idiopathic) infertility is diagnosed after all known etiologies of infertility have been excluded. In these cases, semen analyses are normal and there is no evidence of any female causes of infertility, such as ovulation defects, tubal factor, endometriosis, and cervical factor. The average incidence of unexplained infertility is approximately 15% among infertile couples.

In couples with unexplained infertility, partner IUI has been demonstrated to improve pregnancy rates when used in conjunction with superovulation.¹³ In a meta-analysis of almost 1000 superovulation cycles for unexplained infertility, partner IUI was found to almost double pregnancy rates (20%) compared to timed intercourse alone (11%).

Partner IUI appears to overcome one or more unknown fertility deficiencies that we cannot currently detect. Theoretically, this might be decreased sperm transport from the vagina to the tube secondary to either a sperm defect or an abnormality in sperm transport mechanisms in the female reproductive tract. In other cases, a subtle sperm fertilization defect might exist that is surmounted by increasing the absolute number of sperm reaching the egg.

Donor Insemination

In the past, the only available options for couples with severe male factor infertility (e.g., severe oligospermia, or failure to conceive using partner insemination) desiring children were either donor insemination or adoption. Since the widespread availability of IVF using ICSI, many couples with severe male factor infertility have chosen to procreate their own genetic children using these techniques. However, donor insemination remains an option when IVF/ICSI has been unsuccessful. Alternatively, many candidates for IVF/ICSI initially choose donor insemination because it is less invasive and ultimately more likely to achieve pregnancy for couples with limited resources.

Some women choose donor insemination because they are not candidates for IVF/ICSI. Perhaps the most obvious situation is women without male partners who seek pregnancy. The use of donor insemination is also indicated when the male partner has no viable sperm (i.e., azoospermia) or when IVF/ICSI fails to achieve fertilization. Finally, men with a known genetic disorder often choose donor insemination to avoid transmission to their children.

Donor Selection

Couples choose a donor from profiles of nonidentifiable information. This information usually includes racial or ethnic background, blood type, physical characteristics, and certain social characteristics. Many women who become pregnant as a result of donor insemination desire to use the same donor for further pregnancies.

Donor Evaluation

Thorough evaluation of all potential sperm donors (other than sexually intimate partners) is necessary to avoid inadvertent transmission of sexually transmitted diseases or known genetic syndromes.¹⁶ All donors undergo a review of relevant medical records, personal and family history, and a physical examination. Determination of normal semen characteristics is extremely important. In addition, blood grouping and karyotyping is performed.

Each donor must be screened for risk factors and clinical evidence of communicable diseases, including:

• human immunodeficiency virus types 1 and 2

• human T-lymphotropic virus types I and II

• hepatitis B and C

• cytomegalovirus

• human transmissible spongiform encephalopathy (including Creutzfeldt-Jakob disease)

• Treponema pallidum

• Chlamydia trachomatis

• Neisseria gonorrheae

If the donor is deemed acceptable and is aware of the ethical and legal implications, semen can be collected. All donor semen samples are cryopreserved and quarantined for 6 months. Before a donor sample is used for insemination, the donor is retested and determined if eligible.

Success Rate

The actual per cycle fecundity rate with donor IUI is dependent on multiple factors. A meta-analysis of seven studies demonstrated that IUI yielded a higher pregnancy rate per cycle than intracervical insemination with donor frozen sperm.¹⁷ Overall, the average live birth rate per cycle of donor IUI is approximately 10%.¹⁸

IUI TIMING, COST, AND FREQUENCY

Timing

Timing of insemination in relationship to ovulation is one of the crucial factors in the success of IUI. Although viable sperm remain in the female reproductive tract for up to 120 hours after coitus, the best pregnancy rates are obtained when IUI is performed as close as possible to ovulation.^19,²⁰

In the past, IUI was performed on the estimated day of ovulation based on basal body temperature rises during previous cycles. However, to optimize fecundity, modern prospective timing strategies are based on either detection of a urinary LH surge or administration of an ultrasound-timed dose of human chorionic gonadotropin (hCG) to trigger ovulation.

LH Surge

A commonly used method for timing of IUI is based on urinary LH measurement. Ovulation occurs 40 to 45 hours after the onset of the LH surge.²¹ Insemination is thus planned for the day after detection of a rise in urinary LH. This approach offers the simplest and most cost-effective of the indirect methods for predicting ovulation and is just as effective in achieving pregnancy as more complex ones.^22,²³

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