Fertility Blaze
Fertility Blaze 2018 › Fertility Blaze Vol-5, No-1, 2018

Improving Intrauterine Insemination (IUI) Outcomes

INTRODUCTION

Infertility is the failure of a couple to conceive after one year of regular, unprotected intercourse. The process is complex in both men and women. About a third of infertility problems are due to female infertility, and another third are due to male infertility.1Infertility in women. Available from: http://www.umm.edu/health/medical/reports/articles/infertility-in-women [Accessed on 21st October 2017]  Infertility is a global health issue and affects relatively large number of couples. According to the World Health Organisation (WHO), worldwide around 60 to 80 million couples are currently suffering from infertility.2Mahanta P. A clinico-epidemiological study of infertile couples among the suburban/rural population of Bokakhat, Assam. J. Evolution Med. Dent. Sci. 2016;5(24):1296-1299. DOI: 10.14260/jemds/2016/303   By using the “Age but no birth” definition, WHO estimates of primary infertility in India are 3.9% (Age-standardised to 25-49 year) and 16.8% (Age-standardised to 15-49 year).2Mahanta P. A clinico-epidemiological study of infertile couples among the suburban/rural population of Bokakhat, Assam. J. Evolution Med. Dent. Sci. 2016;5(24):1296- 1299. DOI: 10.14260/jemds/2016/303  Estimates of infertility vary widely among Indian states from 3.7% in Uttar Pradesh, Himachal Pradesh and Maharashtra to 5% in Andhra Pradesh and 15% in Kashmir.2Mahanta P. A clinico-epidemiological study of infertile couples among the suburban/rural population of Bokakhat, Assam. J. Evolution Med. Dent. Sci. 2016;5(24):1296- 1299. DOI: 10.14260/jemds/2016/303  Infertility is classified as primary and secondary infertility. According to WHO, primary infertility is the inability to conceive within one year of exposure to pregnancy (i.e. sexually active, non-contracepting and non-lactating) among women 15 to 49 year old and secondary infertility is to the inability to conceive following a previous pregnancy.2Mahanta P. A clinico-epidemiological study of infertile couples among the suburban/rural population of Bokakhat, Assam. J. Evolution Med. Dent. Sci. 2016;5(24):1296-1299. DOI: 10.14260/jemds/2016/303

 

 

Treatment plans are based on the diagnosis, duration of infertility and the woman’s age. Management of any female and/or male factors affecting fertility may include medical treatment (e.g., pharmacotherapy), surgical intervention, or both.3Puscheck EE. Infertility. Available from: https://emedicine.medscape.com/article/274143-overview?pa=jA8uukln%2FP%2BJ6jxgWsfVDe9nfRnSNOA8U7sjDh JG%2F3QD29cyVCeIMLq3AhbT4nu9s7CF3wx2Tu1U792SxywYLg%3D%3D#showall[Accessed on 21st October 2017]   Assisted reproductive techniques (ARTs) like; intrauterine insemination (IUI), in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) are now an established therapy for the treatment of infertility in a multitude of clinical conditions.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs.2013.01.001    IUI is defined as direct transfer of motile spermatozoa into the uterine cavity, after semen preparation and concentration in a small volume of medium.5Sathanandan SM, ‎Jacobs HS. Ovulation induction in patients with polycystic ovaries. In: Sathanandan SM, ‎Jacobs HS, editors. Practical guide to ovulation induction. London: Imperial College Press;2002.125    IUI is an effective treatment for sub-fertility, originally described in 1957 by Mastroianni.6Fong SA, Palta V, Oh C, et al. Multiple pregnancy after gonadotropin-intrauterine insemination: An unavoidable event? ISRN Obstetrics and Gynecology. 2011. http:// dx.doi.org/10.5402/2011/465483  IUI is the first therapeutic step in ARTs, and is especially appropriate for cases with mild male factor infertility, female infertility anovulation, endometriosis with at least one patent tube and unexplained infertility.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs.2013.01.001   Contrary to IVF/ICSI methods, IUI is easy to perform, inexpensive and offers particular advantages such as the minimal equipment required, an easy technique to learn, being less invasive with a reduced psychological burden on the couple. IUI also has a good couple compliancy (low drop-out rate), a low risk for ovarian hyperstimulation syndrome (OHSS) and a low multiple pregnancy rate in natural cycles and clomiphene citrate (CC) or low-dose human menopausal gonadotrophins (HMG) ovarian stimulation protocols.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs. 2013.01.001    Thus, among the ARTs, IUI is considered a first-line procedure due to its simplicity, easy management, low cost and absence of potentially serious complications.7. Soria M, Pradillo G, García J, et al. Pregnancy predictors after intrauterine insemination: Analysis of 3012 cycles in 1201 couples. J Reprod Infertil. 2012;13(3):158-166

CLINICAL USE OF IUI

The clinical use of IUI is based on the hypothesis that placing a large number of sperm high in the reproductive tract enhances the likelihood of conception. The minimum requirements for performing the procedure are ovulation in the IUI cycle, patency of at least one fallopian tube, inseminate with an adequate number of motile sperm, and absence of documented or suspected active cervical, intrauterine or pelvic infection.8Ginsburg ES. Procedure for intrauterine insemination (IUI) using processed sperm.Available from: http://www.uptodate.com/contents/procedure-for-intrauterineinsemination-iui-using-processed-sperm [Accessed on 27th October 2017]

INDICATIONS FOR IUI

The indications for IUI are as follows:

IUI CONTRAINDICATIONS

IUI is contraindicated in women with cervical atresia, cervicitis, endometritis or bilateral tubal obstruction and in most cases of amenorrhea or severe oligospermia.12Chimote N, Chimote N, Mehta B. Intrauterine insemination. In: Rao K, Carp H, Fischer R, editors. Principles and practice of assisted reproductive technology. Vol.1.New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2014. p.629-644

INTRAUTERINE INSEMINATION VS. TIMED INTERCOURSE/INTRACERVICAL INSEMINATION (IUI VS. TI/ICI)

Various studies has been documented that IUI is superior to TI in couples with male subfertility. IUI is slightly more beneficial than TI or ICI in couples with unexplained infertility, in natural cycles. IUI combined with controlled ovarian hyperstimulation (COH) in unexplained infertility has also been proven to be superior to TI.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs.2013.01.001

PRE-TESTING FOR IUI

Laboratory evaluation of the male partner includes the following:

Laboratory, radiologic and/or surgical assessment of the female includes the following areas3Puscheck EE. Infertility. Available from: https://emedicine.medscape.com/article/274143-overview?pa=jA8uukln%2FP%2BJ6jxgWsfVDe9nfRnSNOA8U7sjDhJG%2F3QD29cyVCeIMLq3AhbT4nu9s7CF3wx2Tu1U792SxywYLg%3D%3D#showall[Accessed on 21st October 2017]  :

  • Cervical: Postcoital test or Sims-Huhner test.
  • Uterine and Endometrial: Hysterosalpingogram—most frequently used diagnostic tool to assess endometrial cavity, pelvic ultrasonograms, saline infusion sonograms, pelvic magnetic resonance imaging, hysteroscopy and endometrial biopsy.
  • Tubal and Peritoneal:Laparoscopy and hysterosalpingogram.
  • Ovarian: Progesterone levels and/or serial ultrasonography to assess ovulation; FSH and estradiol levels (or antral follicle counts, ovarian volume, inhibin B level, and antimüllerian hormone level) to assess ovarian reserve; CC challenge test for dynamic ovarian reserve testing.

USING OVULATION MEDICATIONS(OVARIAN STIMULATION FOR FEMALE PATIENTS)

Unstimulated Cycles

The UK National Institute for Clinical Excellence (NICE) recommends offer of up to six cycles of unstimulated intrauterine insemination (U-IUI) for couples with unexplained or mild male factor subfertility.16. National Collaborating Centre for Women’s Children’s Health: Fertility: Assessment and treatment for people with fertility problems. Clinical Guideline. 2004, London:RCOG Press   A few days before the estimated ovulation and underwent an ultrasonography scan and assessment of urinary LH using an assay kit. When a follicle with a diameter of >18 mm was detected and the urinary LH was positive, IUI was performed the next day.17Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14:27–32. doi: 10.1007/s12522-014-0192-2

Stimulated Cycles

The level of ovarian reserve and the age of the female partner are the most important prognostic factors in the fertility workup. Two protocols are used for ovarian stimulation18Omar MH, Ong FB, Adeeb NN, et al. Assessing the status of intrauterine insemination before forming a medically assisted conception unit. Med J Malaysia.1999; 54(1); 65-71. :

Induction with Protocol A (CC only): CCC (50-200 mg) is given on days 2-6 of the cycle. A step up regime is used i.e. increasing the dosage of CC in subsequent cycles until a good follicular development is seen.18Omar MH, Ong FB, Adeeb NN, et al. Assessing the status of intrauterine insemination before forming a medically assisted conception unit. Med J Malaysia.1999; 54(1); 65-71.    CC is a weak oestrogen-like hormone that acts on the hypothalamus, pituitary gland and ovary to increase levels of FSH and LH, which results in growth of the dominant follicle and its subsequent maturation (Figure 1).19Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www.uptodate.com/contents/ovulationinduction-with-clomiphene-beyond-the-basics [Accessed on 31st October 2017]   20Thomas S, Sudharshini S. Polycystic ovarian syndrome: Treatment options for infertility. Curr Med Issues. 2016;14(4):87-93. DOI: 10.4103/0973-4651.194459

According to The American College of Obstetricians and Gynaecologists (ACOG) Practice Bulletin 2002, the maximum dose of CC is 250 mg/day, but a dose above 150 mg/day is avoided as there are adverse effects of the cumulative doses in the same cycle on the endometrium and has systemic side-effects.21Parihar M. Optimizing Ovulation Induction. Available from: http://www.fogsi.org/ optimizing-ovulation-induction/ [Accessed on 31st October 2017]

Traditional CC protocol for ovulation induction involves a starting dose of 50 mg per day for five days during the follicular phase. If ovulation does not occur, the dose is often increased by 50 mg in the next cycle after a progesterone-induced withdrawal period. A new protocol is the stair-step protocol in which the increasing daily CC dose is administered without intervening menses between the dosages.22Abd Elsalam WY, Mohammed EM, Safwat HI. Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome: A randomized controlled trial. NY Sci J. 2017;10(1):113-119. doi:10.7537/marsnys100117.19.   In this protocol, once failure to ovulate to a given dose is recognised by day 14–21, the higher dose of CC is started immediately without first inducing a withdrawal bleed with progestin. The advantage of this protocol is a shorter time to achieve ovulation when increasing doses of CC are required. In addition, inducing a menstrual bleed with progestins before CC therapy in anovulatory women has been associated with a lower conception and live birth rate compared with women in whom CC was started in the follicular phase remote from spontaneous or induced menses (Figure 2).13Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: A committee opinion. Fertil Steril. 2015;103(3):e18-25. doi: 10.1016/j.fertnstert.2014.12.103. Epub 2015 Jan 15.   23Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA. Is clomiphene citrate stair-step protocol a good alternative to gonadotrophins in clomiphene-resistant PCO patients? Prospective study. J. Obstet. Gynaecol. Res. 2016. doi:10.1111/jog.12940  

Induction with Protocol B (Clomiphene citrate – human menopausal gonadotrophin (CC-HMG)): CC (50-200 mg) is given on day 2-6 cycle followed by HMG (75 IU daily) on day 5-9. The ovarian response is monitored starting on day 9 or 10 by transvaginal ultrasound. The number of developing follicles and their diameters are measured every alternate day. The morphology of the endometrium and the thickness are also measured. Intramuscular (IM) human chorionic gonadotropin (hCG) (5000 IU) is administered when the leading follicle is 16-18 mm in diameter. In case of poor follicular response cycles are cancelled.17Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14:27–32. doi: 10.1007/s12522-014-0192-2   8Ginsburg ES. Procedure for intrauterine insemination (IUI) using processed sperm.Available from: http://www.uptodate.com/contents/procedure-for-intrauterineinsemination-iui-using-processed-sperm[Accessed on 27th October 2017]  

LUTEAL SUPPORT

Luteal phase deficiency (LPD) is associated with insufficient production of progesterone, which is essential for embryo implantation and maintenance of early pregnancy.24Rashidi BH, Tanha FD, Rahmanpour H, et al. Luteal phase support in the intrauterine insemination (IUI) cycles: A randomized double blind, placebo controlled study.Journal of Family and Reproductive Health. 2014;8(4):149-153.   Therefore, for luteal support 5000 IU of IM hCG was given on days 2 and 7 after insemination or 300 mg of micronised progesterone.18Omar MH, Ong FB, Adeeb NN, et al. Assessing the status of intrauterine insemination before forming a medically assisted conception unit. Med J Malaysia.1999; 54(1); 65-71.    A prospective randomised study was conducted by Mahaer MA, to determine the impact of luteal phase support with progesterone on pregnancy outcomes in infertile couples undergoing IUI when recombinant follicle-stimulating hormone used for ovulation induction. A total of 71 patients were randomised to start with a supported cycle (n = 37) and an unsupported cycle (n = 34). The clinical pregnancy rate per patient was higher for supported cycles than unsupported cycles (54.92% vs. 35.21%, respectively; p = 0.016). Live birth rate was also higher for supported cycles than unsupported cycles (25 vs.7, respectively). Thus, luteal phase support with progesterone improved the success of IUI cycles when recombinant follicle-stimulating hormone was used for ovulation induction.25Maher MA. Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):57-62. doi: 10.1016/j.ejogrb.2011.03.022.

SPERM PREPARATION TECHNIQUES (SPT) FOR THE MALE PARTNER

Sperm Collection

A semen specimen collection should be performed following an abstinence period of 2 to 3 days.26Semen Analysis – An overview. ScienceDirect Topics. Available from: http://www.sciencedirect.com/topics/medicine-and-dentistry/semen-analysis [Accessed on 30thOctober 2017]

Sperm Processing (Semen Quality)

Liquefaction is done by keeping the collected sample in an incubator at 37°c for 20 minutes. The sample is then investigated for various sperm parameters.27Kumar S, Azgaonkar H, Awasthimed RT, et al. Role of intra-uterine insemination and sperm preparation techniques in treatment of unexplained infertility and male infertility. J Armed Forces India. 2000;56(3):209–212   The semen parameters are determined by using Makler counting chamber according to WHO criteria (2000) of semen analysis. Current techniques of sperm preparation for IUI are swim-up and density gradient. These techniques require the use of centrifugation to separate the sperm from the seminal plasma which provides better sperm quality regarding concentration and motility leading to higher success rates after IUI.28Selvaraj P, Selvaraj K, Kalaichelvi S, et al. Semen preparation techniques in intrauterine insemination: A comparison of non-temperature and temperature controlled centrifugation in cases of unexplained infertility. J Hum Reprod Sci.2013;6(4): 241–244. doi: 10.4103/0974-1208.126289    Sperms prepared by density-gradient centrifugation (DGC) were superior to the swim-up and simple wash technique.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs.2013.01.001

IUI PROCEDURE

Timing of ovulation appears to be one of the crucial factors to determine the success of IUI therapy. It is the major goal of treatment to provide sperm that are capable of fertilising the oocyte at the site of fertilisation during a narrow time window, the so-called peri-ovulatory period. Urinary LH peak monitoring, hCG injection to stimulate ovulation and scheduling IUI with different frequencies at different time points are some of the strategies developed to achieve the goal.29Duran HE, Morshedi M, Kruger T, et al. Intrauterine insemination: A systematic review on determinants of success. Human Reproduction Update. 2002;8(4):373-384.    The insemination at 34-36 hours after hCG may give a better timing for the sperms to meet the oocyte(s). Finally, the injection of highly motile sperms into the uterine cavity may also be a contributory factor.30Akhlaghi F, Hamedi A. Intrauterine insemination after ovarian stimulation as a treatment for subfertility because of subnormal semen. The Internet Journal of Gynecology and Obstetrics. 2003;3(1).

OUTCOMES EVALUATION

“Outcome” or “Pregnancy” is defined as clinical pregnancies, including an intrauterine pregnancies in which a gestational sac was confirmed on ultrasonography, and ectopic pregnancies that required surgical/medical intervention.17Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14:27–32. doi: 10.1007/s12522-014-0192-2

MULTIPLE PREGNANCIES

A multiple pregnancy rate of 14-39% was reported in this high-risk group of couples. Major factors identified to predict multiple pregnancy outcomes include peak estradiol level and number of pre-ovulatory follicles on the day of hCG, which are basically indirect indicators of COH. Aspiration of supernumerary follicles before IUI has been associated with a multiple pregnancy rate of 10.4% without decreasing the overall pregnancy rate.29Duran HE, Morshedi M, Kruger T, et al. Intrauterine insemination: A systematic review on determinants of success. Human Reproduction Update. 2002;8(4):373-384.   It is recommended that secondary preventive measures to prevent multiple pregnancies are needed when four or more follicles ≥14 mm are present at the time of hCG injection, although evidence-based data are lacking. These measures include cancelation of the cycle, the aspiration of supernumerary follicles and/or escape IVF.4Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs.2013.01.001

FACTORS IMPROVING INTRAUTERINE INSEMINATION (IUI) OUTCOMES

Increasing the gamete density at the time and site of potential fertilisation is the principle behind IUI.31Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14: 27–32. doi: 10.1007/s12522-014-0192-2   Several prognostic factors like; patient profile, cause and duration of infertility, stimulation protocol, follicular response, endometrial thickness, timing and number of IUI, percentage of sperm with normal morphology, type and percentage of sperm motility and total number of motile sperms inseminated result in success rates of IUI.31Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14: 27–32. doi: 10.1007/s12522-014-0192-2  A prospective analytical study was conducted by Jayakrishnan K et al., to identify the most important IUI variables with regard to successful outcome. The analysis found four significant variables like (Table 2)31Honda T, Tsutsumi M, Komoda F, et al. Acceptable pregnancy rate of unstimulated intrauterine insemination: A retrospective analysis of 17,830 cycles. Reprod Med Biol. 2015;14: 27–32. doi: 10.1007/s12522-014-0192-2;

CONCLUSION

Infertility is the failure to conceive (regardless of cause) after one year of unprotected intercourse. IUI is the first therapeutic step in ARTs and many factors, including male and female infertility and technique-dependent factors. IUI is a common therapeutic method to treat couples with subnormal sperm quantity and motility, cervical mucus hostility, antisperm antibodies, and unexplained infertility. IUI is the therapeutic process of placing washed spermatozoa transcervically into the uterine cavity for the treatment of infertility. The pregnancy rates per IUI cycle are variable due to differences in cause and duration of infertility, type of ovarian stimulation, sperm preparation techniques, treatment cycles and number of times IUI is performed during a cycle (single or double). IUI can be carried out in a natural cycle, without the use of drugs, or the ovaries may be stimulated with oral anti-oestrogens (CC) or gonadotrophins. Where oral anti-oestrogens are used to stimulate a cycle, a course of tablets for five days is given to women. When gonadotrophins are used to stimulate a cycle, the woman usually receives a course of daily fertility injections for 7 to 10 days. However, the exact duration of stimulation depends on which day of the cycle it is started. In both circumstances the treatment should be monitored by ultrasound scan to assess the ovarian response. When one to three follicles are seen to have developed to a suitable size, usually with one dominate follicle, then an injection of hCG is given which triggers ovulation. Insemination of prepared sperm is undertaken 34-36 hours after ovulation induction in stimulated cycles. Thus, IUI after ovarian stimulation with CC gives a better pregnancy rate than natural intercourse in couples with sub fertility.

REFERENCES

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  3. Puscheck EE. Infertility. Available from: https://emedicine.medscape.com/article/274143-overview?pa=jA8uukln%2FP%2BJ6jxgWsfVDe9nfRnSNOA8U7sjDhJG%2F3QD29cyVCeIMLq3AhbT4nu9s7CF3wx2Tu1U792SxywYLg%3D%3D#showall [Accessed on 21st October 2017]
  4. Ombelet W. Evidence-based recommendations for IUI in daily practice. Middle East Fertility Society Journal. 2013;18(2):74-77. https://doi.org/10.1016/j.mefs. 2013.01.001
  5. Sathanandan SM, ‎Jacobs HS. Ovulation induction in patients with polycystic ovaries. In: Sathanandan SM, ‎Jacobs HS, editors. Practical guide to ovulation induction. London: Imperial College Press;2002.125
  6. Fong SA, Palta V, Oh C, et al. Multiple pregnancy after gonadotropin-intrauterine insemination: An unavoidable event? ISRN Obstetrics and Gynecology. 2011. http://dx.doi.org/10.5402/2011/465483
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