This chapter should be cited as follows:
Dhillon Pai R, Kundnani MT, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421083

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 15

Reproductive medicine for the obstetrician and gynecologist

Volume Editors: Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS

Published in association with the
International Federation of
Fertility Societies

Chapter

Artificial Insemination

First published: November 2024

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INTRODUCTION

Artificial insemination means the introduction of a semen sample into the female reproductive tract for the purpose of accomplishing pregnancy through in vivo fertilization. The rationale behind the procedure is to increase the density of gametes at the site of fertilization. The procedure can either be done with the partner’s semen sample (homologous artificial insemination – AIH) or donor semen (AID) and is often offered as first line of treatment to many infertile couples worldwide and those seeking pregnancy who may not have a male partner. Artificial insemination can be done intravaginal, intracervical or intrauterine, amongst these intrauterine inseminations or IUI is the most commonly practiced worldwide and is discussed in detail in this chapter.

INTRAUTERINE INSEMINATION 

Intrauterine insemination (IUI) is a simple, easy and cost-effective assisted reproductive technique which involves introduction of a washed semen sample into the uterine cavity around the time of ovulation. The treatment requires minimal equipment, is easy to perform, is less invasive and is associated with less psychological and financial burden compared to in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The treatment is thus associated with good couple compliance and lower drop-out rates compared to other more complex assisted reproductive technologies (ART) treatments. Though the treatment was first described centuries ago, it gained popularity in 1980s. The past four decades have witnessed multiple researches evaluating different aspects of this treatment including indications, optimal ovarian stimulation, semen preparation techniques, ovulation trigger (choice of drug to achieve final oocyte maturation and trigger ovulation), timing and luteal phase support.

RATIONALE FOR INTRAUTERINE INSEMINATION

The rationale behind the procedure is to increase the quality and quantity of gametes at the site of fertilization, thereby increasing the probability of fertilization and achieving pregnancy. Additionally, the procedure helps to overcome sperm and cervical mucus abnormalities, if any.

INDICATIONS FOR INTRAUTERINE INSEMINATION

IUI with or without ovarian stimulation is widely advised for different infertility indications including male factor, unexplained infertility, cervical factor, and sexual disorders. Whether or not IUI is effective in these situations especially in relation to IVF/ICSI is debatable as there is lack of good quality randomized controlled trials and prospective studies evaluating the efficacy of IUI individually for these indications. Table 1 lists the common indications of IUI as used by different clinicians.¹

Male factor infertility – IUI is routinely advised for couples with mild (sperm count between 5 and 14 million sperm/ml) to moderate male factor (sperm count between 1 and 5 million sperm/ml) infertility.^2,3 However, according to a Cochrane database systematic review of the evidence of the usefulness of IUI in mild to moderate male factor infertility is insufficient.⁴ However, a randomized controlled trial conducted by Bensdorp et al. showed that IUI with ovarian stimulation is not inferior to IVF in mild to moderate male factor infertility.⁵

Unexplained infertility – The effectiveness of IUI in women with unexplained infertility was analyzed by Veltman-Verhulst et al. in a Cochrane systematic review.⁶ They observed that IUI in natural cycle does not benefit women with unexplained infertility. However, IUI with ovarian stimulation can significantly improve the pregnancy rates in these women.

Cervical factor – The role of IUI with or without ovarian stimulation in women with cervical factor infertility is debatable. A systematic review by Helmerhorst et al. did not find IUI to be beneficial these women.⁷ Also, postcoital testing as a part of an infertility workup to diagnose cervical factor is now not recommended as it is subjective, poorly reproducible, inconvenient, rarely changes the clinical management; further discouraging the use of IUI for this indication.^8,9

Sexual disorders – IUI is beneficial in sexual disorders like hypospadias, vaginismus, retrograde ejaculation and impotence. However, intravaginal or intracervical insemination can also be performed in such cases. In males with retrograde ejaculation, where the semen parameters are also compromised, IUI should be the preferred choice.

Prerequisites before IUI:

• At least one patent Fallopian tube;
• Good ovarian reserve:
• Minimal semen parameters – total motile sperm count (TMSC) ≥5 million/ml or a total count of ≥10 million,¹⁰ motility >30%, morphology >4% normal forms.

Contraindications for IUI:

• Bilateral tubal blockage;
• Severe tubal damage;
• Severe pelvic infection;
• Poor egg reserve;
• Severe male factor infertility (<1 million sperm/ml).

OVARIAN STIMULATION BEFORE INTRAUTERINE INSEMINATION

Controlled ovarian stimulation (COS) is known to have an independent positive effect on pregnancy rate when combined with IUI. A study by van Rumste et al. showed that, compared to monofollicular growth, pregnancy rates increase by 5, 8 and 8%, respectively, when two, three or four dominant follicles are present before IUI.¹¹ Another study by Huttenten et al. showed that the highest pregnancy rates are seen with three preovulatory follicles.¹² The risk of multiple pregnancy increases tenfold with four or more follicles with no further increase in pregnancy rates.

Different stimulation agents and protocols have been used for ovarian stimulation for IUI. These include oral agents (clomiphene citrate and letrozole), gonadotropins, and combination of oral agents and gonadotropins. Oral drugs (clomiphene citrate/letrozole) are economical, require less monitoring and are associated with a lower risk of ovarian hyperstimulation syndrome (OHSS) and, thus, seem to be most cost-effective. Gonadotropin protocols are shown to have highest success rates but are more expensive, require stringent monitoring, and are associated with higher incidences of OHSS and multiple pregnancy. Gonadotropin releasing hormone (GnRH) analogs have also been used in IUI cycles; however, these have not been found to be cost-effective and have not resulted in significant increases in pregnancy rates.^13,14 However, a select group of patients with a history of premature LH surge or premature follicle rupture may benefit by addition of a GnRH antagonist in subsequent cycles.

A randomized controlled trial by Cohlen et al. compared IUI with or without ovarian stimulation (OS) in couples with male infertility.¹⁵ They observed that OS results in increased pregnancy rates only when TMSC is >10 million. No significant improvement in pregnancy rates was seen with OS when TMSC was <10 million. OS and IUI significantly increase live birth rates in women with unexplained infertility (Cochrane database systematic review).¹³

Ovarian stimulation should be mild and should aim to result in 2–3 dominant follicles. Strict ultrasound monitoring is mandatory for all cycles. All preventive measures should be taken to avoid multiple gestations. It is advisable to cancel the cycle or convert to IVF in case of 4 or more dominant follicles are present on the day of triggering ovulation.

Ovulation is triggered when one or two dominant follicles reach the size of 18 mm. Different drugs (human chorionic gonadotropin (hCG), recombinant hCG or GnRH agonists) can be used to trigger ovulation. In a randomized controlled trial by Le et al., it was observed that hCG trigger was associated with significantly higher clinical pregnancy rates compared to GnRH agonist trigger.¹⁶ As women undergoing IUI are at low risk of OHSS, hCG trigger should be more beneficial in terms of pregnancy outcomes.

TIMING OF INTRAUTERINE INSEMINATION

Oocytes and spermatozoa are known to survive for a limited time period. Therefore, appropriate timing of IUI seems to be essential.¹⁷ IUI can be timed according to the LH surge (in natural cycles) or according to the hCG trigger. Most clinicians prefer to do IUI just before or within 10 hours of ovulation. A randomized controlled trial by Blockeel et al. showed that IUI in natural cycles should be performed 1 day after detection of the LH surge.¹⁸

In hCG triggered IUI cycles, IUI is usually performed 36 hours after the trigger. However, no significant difference in ongoing pregnancy or live birth rates was observed when IUI was performed in different time frames between 20 and 48 hours after hCG trigger.^19,20 It is thus concluded that undertaking IUI between 20 and 48 hours after hCG trigger does not compromise success rates.

SPERM PREPARATION TECHNIQUES

Different sperm preparation techniques are used for washing semen samples before IUI. The sperm preparation aims to separate viable sperm from non-viable sperm and other cells in the seminal fluid including epithelial cells and leucocytes. Also, the seminal plasma is known to have some decapacitating factors which need to be removed for complete capacitation of sperm.²¹ The ideal technique for sperm preparation should be simple, low-cost, safe and reliable, and can isolate the sperm with intact genetic and functional properties without causing DNA damage.²²

The commonly used sperm preparation techniques are simple wash, swim-up and density gradient. Although the density gradient technique is shown to be superior to simple wash and swim up in terms of better postwash semen parameters (greater number of morphologically normal sperm with better motility), no significant difference in pregnancy rates is observed with any of the techniques. A Cochrane systematic review concluded that there is insufficient evidence to recommend any one technique of semen preparation over another in terms of clinical outcomes after IUI.²³

Newer sperm preparation techniques, e.g., MACS (magnetic activated cell sorting) and microfluidics, are also being increasingly used for sperm preparation. MACS specifically separates apoptotic from non-apoptotic sperm. Microfluidic devices are apt for developing automated sperm preparation instruments. These devices avoid the harmful effects of centrifugation on sperm quality and sperm with better motility can be extracted. Although some studies have shown that these advanced sperm selection methods can improve ART outcomes, larger studies are needed to validate their efficacy in clinical practice.²⁴

SEMEN PARAMETERS AND INTRAUTERINE INSEMINATION

Various semen parameters have been evaluated as prognostic factors for the success of IUI. These include inseminating motile count after washing (IMC), sperm morphology using strict criteria, total motile sperm count (TMSC) and sperm motility. However, a clear definition of pre- and post-wash sperm parameters below which IUI is no longer cost-efficient and should be withheld, is lacking. In a review by Ombelet et al., it was observed that inseminated motile count >1 million and morphology >4% normal forms are the cut offs below which IUI should be withheld.²⁵ Another meta-analysis by Van Weert et al. suggested that inseminated motile count should at least be between 0.8 and 5 million for IUI to be performed with acceptable pregnancy rates.²⁶ Various other researchers have reported a cut off value of 5–10 million and 30% for TMSC and TM, respectively.^27,28 However, more prospective cohort studies are needed to find out the cut offs above which IUI can be recommended as first-line treatment.

SINGLE VERSUS DOUBLE INSEMINATION

The number of inseminations in one cycle is not well defined in terms of pregnancy rates. Theoretically, increasing the number of inseminations might increase the number of sperm present at the time of ovulation and this may increase the probability of fertilization and pregnancy. However, double inseminations have not been found to improve pregnancy rates in all IUI cycles.

A Cochrane database systematic review found that double inseminations can be beneficial in couples with unexplained and male factor infertility.⁹ Another systematic review by Zavos et al. found significant benefit of double IUI in male infertility.²⁹ However, a systematic review by Polyzos et al. and a randomized control trial by Rahman et al. did not observe benefit of double insemination in couples with unexplained infertility.^30,31 As the current evidence does not prove superiority of double IUI to single IUI in most cases, double IUI should be advised only when proven effective, as it increases the cost of treatment and psychological burden. More prospective cohort studies or randomized controlled trials for each indication separately can help to decide number of inseminations per cycle.

BED REST AFTER INTRAUTERINE INSEMINATION

It has been observed that sperm reach the Fallopian tube within 5–10 minutes after IUI.³² Thus, it can be assumed that resting in the supine position after the procedure may prevent losing a large fraction of inseminated sperm by ‘back flow’ and may improve treatment outcomes.

Randomized control trials conducted by Custers et al. and Salah et al. observed significant improvement in pregnancy rates after immobilization in the supine position (15 and 10 minutes, respectively) compared to immediate mobilization after IUI.^33,34 In both studies after three cycles, pregnancy rates per couple were significantly higher in the immobilization group. However, a randomized controlled trial conducted by van Rijsvik et al. did not find any significant difference in pregnancy rates after immobilization for 15 minutes versus direct mobilization.³⁵

LUTEAL PHASE SUPPORT AFTER INTRAUTERINE INSEMINATION

Whether luteal phase progesterone supplementation is needed in IUI cycles is still a matter of debate and there is no consensus. A systematic review and meta-analysis conducted by Green et al. observed that progesterone supplementation in the luteal phase after IUI is beneficial in women who underwent ovarian stimulation with gonadotropins.³⁶ However, no benefit was observed in women undergoing natural cycle IUI or IUI with ovarian stimulation with clomiphene.

FACTORS AFFECTING INTRAUTERINE INSEMINATION SUCCESS

The results of IUI in terms of pregnancy rates per treatment cycle vary considerably in different studies. This is mainly due to variability in study populations, different etiologies of infertility, and different stimulation protocols. Different factors can influence the success after IUI treatment. Table 2 lists the positive predictive factors for IUI success.

Age of the female partner – Female age is the most important predictor of IUI success. A sharp decline in success is observed in women more than 40 years of age, mainly related to decrease in oocyte quality.³⁷

Age of the male partner – The effect of male age on IUI success is not very clear. A study by Bellver et al. did not observe any impact of advancing paternal age on IUI outcomes.³⁸ However, another study conducted by Mathieu et al. observed a decrease in pregnancy rates in men >35 years compared to men <30 years after controlling for maternal age, ovulatory status, duration of infertility, and presence of asthenozoospermia and/or teratozoospermia.³⁹

Cause of infertility – Couples with unexplained infertility and mild male factor infertility, cervical factor or ovulatory dysfunctions have better success rates compared to those with endometriosis and tubal factor.^40,41,42

Sperm parameters – Various sperm parameters have been evaluated for predicting success after IUI treatment. The most important are sperm morphology with a cut off of 4% and total motile sperm count in the ejaculate ≥10 million or inseminating motile count of 0.5–5 million. The success of IUI treatment is very limited below these thresholds (see above).

Ovarian stimulation – Controlled ovarian stimulation (COS) plus IUI is known to give better success rates than IUI in a natural cycle. Ovarian stimulation with gonadotropins gives better success rates compared to COS with oral agents, although it increases the risk of multiple pregnancy.¹⁴

Time interval to semen collection to insemination – It has been observed that IUI performed within 90 minutes of semen collection gives better results compared to late insemination.⁴³

Pre-washing the catheter with culture medium seems to increase the success rates per cycle.⁴⁴

COMPLICATIONS 

The complications which can be encountered during IUI treatment include:

• Ovarian hyperstimulation – mild stimulation with strict monitoring should be done to avoid OHSS;
• Pain – improper processing of semen sample can release prostaglandins causing pain;
• Trauma and bleeding – gentle atraumatic technique should be used;
• Vasovagal syncope – rare;
• Accidental mismatch of sample – this can be avoided by proper labeling of containers and all disposables, and by processing one sample at a time.

HOW MANY CYCLES OF INTRAUTERINE INSEMINATION?

There is no clear-cut guideline as to how many cycles of IUI should be offered to a couple undergoing fertility treatment. A common practice amongst clinicians worldwide is to offer 3–6 cycles of IUI before pursuing other treatment approaches. Bensdorp et al. in a randomized controlled trial concluded that it is cost-effective to offer 6 cycles of OS-IUI in couples with unexplained infertility or mild male factor infertility compared to going directly to IVF.⁵ A prospective study by Aboulghar et al. in women with unexplained infertility showed that clinical pregnancy rates were significantly higher in the first 3 cycles compared to next 3 cycles. Based on this observation, they suggested that at least 3 cycles of IUI should be offered.⁴⁵ However, there is insufficient evidence to recommend a maximum number of cycles.

FALLOPIAN SPERM PERFUSION

Fallopian sperm perfusion (FSP) involves insemination of larger volume of semen sample (4 ml) into the uterine cavity transcervically compared to 0.5 ml in regular IUI. FSP aims to flush the tubes with sperm and to have a increased number of spermatozoa in the tube around the time of ovulation. However, a Cochrane systematic review by Cantineau et al. did not show benefit of FSP compared to IUI in terms of live birth rates, thus IUI is recommended as the treatment of choice.⁴⁶

CONCLUSION

Artificial insemination is a valuable first line of treatment for many infertile couples. It is a simple, non-invasive yet cost-effective technique which requires minimal expertise and infrastructure. COS-IUI has better pregnancy rates compared to natural cycle IUI. However, ovarian stimulation should be mild and all precautions should be taken to avoid multiple gestation. Inseminating motile count >1 million, morphology >4% normal forms are good predictors for IUI success. IUI can be performed within 20–48 hours of hCG trigger. Double inseminations can be beneficial in case of male factor infertility. Immobilization for 10–15 minutes after IUI improves the success rates.

PRACTICE RECOMMENDATIONS

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