An Overview of Intrauterine InseminationCHAPTER 1

Inability to conceive though not a physically disabling disorder has far reaching psychological and social consequences. In many societies, it is still a stigma and invariably it is the woman who bears the social consequences of the couple's infertility. Since the advent of medical science treatments have been devised to overcome this condition but it is only in recent years that one has seen a great improvement in subfertility management. This is largely due to major advances that have taken place in reproductive research and technology.

Insemination of a raw semen sample into the uterus lead to severe cramping, infection and allergic reactions hence its popularity was limited. The introduction of sperm preparation methods for in vitro fertilization (IVF), which removed the seminal plasma and debris from the semen, led to a renewed interest in IUI. Consequently, many physicians started performing IUI with washed motile capacitated sperm with better results.⁴

Intrauterine insemination involves the deposition of a concentrated pellet of motile sperms into the uterine cavity close to the tubal ostia, around the time of ovulation. Reason for achieving pregnancy is presumably an increase in the number of highly motile spermatozoa with a high proportion of normal forms at the site of fertilization. Sperm preparation aids in removing leukocytes and dead sperms which generate free oxygen radicals that reduce the functional capacity of the intact sperm.⁵ The use of washed prepared sperm for IUI resulted in a significant reduction in the side effects associated with the earlier use of neat semen for IUI.

Intrauterine insemination was developed mainly as a treatment for male infertility and till date this remains the major indication. Over the years, IUI has been promoted as the first line treatment for unexplained infertility, mild to moderate endometriosis and immunological infertility with reasonable success. Though used in tubal factor patients, the success is compromised due to damage of the tubal cilia. The absolute indications for this procedure remain ejaculatory dysfunction, severe vaginismus and cervical hostility. The main indications for “donor insemination” are gross male subfertility (azoospermia or severe oligoasthenoteratozoospermia), familial or genetic disease such as Huntington's disease, hemophilia and also severe rhesus isoimmunization. The use of cryopreserved semen should be preferred for donor insemination to minimize the possibility of transmission of the human immunodeficiency virus to the recipients.3

The indications for IUI can be divided broadly into two groups: (1) IUI with husband's spermatozoa (Table 1); and (2) IUI using donor sperms (Table 2).

A comprehensive evaluation of the couple is mandatory before starting treatment. Clinical examination and the necessary investigations should be carried out. Discussion on procedure, pregnancy rates and complications 4should be a part of the treatment protocol. Counseling prior to starting treatment is important, especially when donor sperm is to be used. Couples should also be assured of complete confidentiality. Both partners should sign the consent form for AID. In India, it is very common for the husband or a member of the family to request that the wife not be told that donor semen is being used. This practice should be discouraged, as there can be repercussions later on in life, especially if there is marital discord.

Certain basic investigations must be carried out prior to IUI in all patients others are case and condition specific, e.g. polycystic ovarian syndrome, endometriosis, etc.

The basic investigations would include the following:

Since the success of IUI depends on insemination at the time of ovulation, determining follicular growth and rupture is basic to the procedure. The gold standard for detecting ovulation is serial ultrasound monitoring during the cycle, using a transvaginal probe. After a baseline scan on day 2 of the cycle the ovaries are checked for a dominant follicle on day 9 or 10 of the cycle. Subsequently, monitoring can be done more frequently and when the follicle reaches 18 mm or more an ovulation trigger is given. When the cycles are short, i.e. 24–26 days monitoring should start early. “Detection of the LH surge” can be done with urinary LH kits or by determining serum LH levels and IUI can be timed accordingly. Ovulation is considered to occur 28–36 hours after the beginning of the LH rise or 8–20 hours after the LH peak. For ease and accuracy of timing, an “ovulation trigger” is given with 5000 to 10,000 IU of human chorionic gonadotropin (hCG) which ensures ovulation at 36–40 hours.

The ideal sperm preparation technique is one, which allows recovery of the largest number of morphologically normal motile spermatozoa, free from seminal plasma, leukocytes and bacteria. The minimum concentration of motile sperms inseminated to achieve pregnancy is estimated to be 1 million/mL, though there is no threshold of sperm concentration below which pregnancy is impossible. The volume of media used to resuspend the final sperm pellet should be between 0.3–0.5 mL. Since the normal capacity of the uterus is between 0.2–0.4 mL using larger volumes may lead 6to a reflux of the inseminate through the cervical os. The two main sperm preparation techniques used are the “swim-up” and the “density gradient centrifugation” (DGC). The swim-up technique, is more widely used when sperm parameters are normal while the density gradient technique is preferred for a compromised sperm sample. Most of the published studies and systematic reviews show no difference in the IUI outcomes with the use of either technique,⁶ although a borderline benefit of DGC over swim-up technique was shown by a meta-analysis by Duran et al.⁷

It is very important that IUI be carried out using strict aseptic techniques to prevent infection being carried into the uterus. Additionally, take care to make the procedure as gentle and atraumatic as possible. Pelvic examination carried out beforehand to determine position of the uterus is very helpful. An acutely anteverted uterus needs a full bladder, but if the uterus is retroverted, a full bladder will push it back further. Prior knowledge of the direction and tortuosity of the cervical canal go a long way toward conducting a smooth procedure. Struggling with the catheter blindly causes bleeding from the cervical canal, blood and products of tissue injury are detrimental to sperm survival, fertilization and implantation.

The catheter used to perform IUI should be of nontoxic material with minimal dead space. A semi-rigid catheter like the Gynetics^® IUI cannula is easy to use. Makler's cannula is another interesting device, it is designed so that it blocks the external os, thus preventing backflow of the inseminate. Sometimes a metal cannula can be used to traverse a difficult cervical canal.

The proper timing of IUI after hCG trigger and the frequency of IUI are still under debate. Majority of published studies define the ideal time for IUI to be 32–36 hours following hCG administration. Regarding the impact of single versus double insemination most studies find no significant difference between the two while some find an improved pregnancy rate with double IUI.⁷ Ghanem et al.⁸ (2011) aimed to examine the association between the cycle pregnancy rate (CPR) and: (a) single IUI timed at 36 ± 2 hour post-hCG (pre- or postovulation); (b) the number of IUI (single or double) for preovulatory cases and compared them in different infertility etiologies, i.e. male, anovulatory and unexplained infertility. They concluded that “a single IUI timed post-ovulation” gives a better CPR when compared with single preovulation IUI “for nonmale infertility.” The overall CPR was significantly higher when ovulation occurred before IUI (11.7%) than when it did not (6.7%) OR [95% confidence interval (CI)] 1.85 (1.12–3.06) (P = 0.015). “For male factor infertility, a preovulation, double IUI gives a better CPR when compared with single IUI.” A Cochrane meta-analysis in 2010⁹ found no difference among different techniques for timing IUI [detection of LH in urine or blood, hCG administration, combination of LH detection and hCG administration, basal body temperature chart, ultrasound detection of ovulation and gonadotropin-releasing hormone (GnRH) agonist administration].

Around 97% of the pregnancies occur in the first four treatment cycles. The National Institute for Health and Care Excellence fertility guidelines advocate for up to six IUI cycles for patients with unexplained infertility, male subfertility, cervical factor and minimal to mild endometriosis.¹⁰ If no pregnancy is achieved by the end of the fourth to sixth cycle, patients should be offered IVF.8

Intrauterine insemination is often combined with superovulation (SO) in women with ovulatory cycles and with ovulation induction (OI) in women with anovulatory cycles, to increase the effectiveness of treatment. The reason most cited for combining SO with IUI is to maximize the possibility of pregnancy by increasing the number of preovulatory follicles. Other reasons include correction of luteal phase defect and other subtle defects in ovarian function.

An accepted practice in infertility treatment is that therapy is initiated with clomiphene and IUI, if unsuccessful couples move in a stepwise fashion to gonadotropin and IUI treatments and then to IVF. This progression appears logical as a review of literature report success rates of 1.3–4% for no treatment, 8.3% for CC/IUI, 17.1% for hMG/IUI and 20.7% for IVF.¹²

Human menopausal gonadotropin/IUI is more effective than IUI alone for the treatment of endometriosis.¹⁷

In case of a severe semen defect, but more than 1 million motile sperm available after semen preparation and no morphological defects; IUI in a natural cycle should be the treatment of choice.¹⁸ With less severe semen defects, i.e. average total motile sperm concentration greater than 10 million, mild ovarian hyperstimulation with hMG has been suggested. COH should be reserved for patients with moderate semen defects. The maximum effect of IUI and the least effect of COH is seen in patients with the most severe semen abnormalities.

Age is the most important predictor factor of IUI success among other female factors. This is due to the negative impact of age on ovarian reserve, oocyte quality, and also the higher probability of fibroids, tubal pathology and pelvic inflammatory disease (PID) which can develop over time. In a retrospective analysis of the outcomes of 9,963 consecutive IUI cycles, Stone et al. showed that the pregnancy rates were 18.9%, 13.9%, 12.4%, 11.4%, 4.7% and 0.5% in the age groups of less than 26, 26–30, 31–35, 36–40, 41–45 and greater than 45, respectively.²⁰ In older couples, there may be a further compromise in fertility due to a higher rate of sperm aneuploidies.

In general, it seems that the best pregnancy rates after IUI were reported in patients with unexplained infertility and with anovulation. The per cycle PRs reported in anovulatory patients is 13%, unexplained infertility is 10%, tubal factor is 9%, male factor infertility (MF) is 7% and endometriosis is 12%.²¹ Dickey et al.²² reported cumulative PRs of 46% for ovulatory dysfunction; 38% for cervical factor, male factor and unexplained infertility; 34% for endometriosis; and 26% for tubal factor after four cycles of CC/IUI. After six cycles, CPRs were 65% for ovulation dysfunction, 35% for endometriosis, and unchanged for other diagnoses. Among patients with male subfertility, ejaculatory dysfunction had the highest pregnancy rates. Other factors that have been shown to negatively affect the pregnancy rates include endometriosis and history of pelvic infection, even if they do not cause obvious tubal damage.

Prognosis becomes poorer for patients with duration of infertility more than 3 years. After 39 months, chances of conception fall by 2% every month. However, 40–65% couples will conceive spontaneously within the first 3 years.

Patients with secondary infertility fare better than those with primary infertility.11

Though, controversial gonadotropin stimulation has an edge over oral agents in terms of IUI success.

Intrauterine insemination with three follicles almost tripled the PR with respect to only one, OR equal to 2.89 (95% CI: 1.54–5.41).²³

Pregnancy rates decrease progressively with decrease in the motile sperm count ranging from 15.3% in the highest category (30 million/mL) to 3.6% in the lowest (< 5 million/mL) [OR lowest/highest = 0.20 (95% CI: 0.09–0.45)], with a statistically significant dose-response trend.²³

Intrauterine insemination is a simple noninvasive, relatively inexpensive and a moderately effective first line of treatment in the subfertile patient. Careful selection and evaluation of patients is important to give good results. The maximum benefit can be expected in young women with patent fallopian tubes, mild degree of male factor infertility and no PID. Not much benefit is to be expected beyond three to four IUIs and the couple should be moved on to IVF after that.