intrauterine insemination - physicians training module

Intra-uterine Insemination

Physician’s Training Module

Dr. Sarwat JabeenMBBS, MBA Health Management & Pharmaceutical Marketing

Product Manager – Fertility

What is IUI?Intrauterine insemination (IUI) is a form of treatment where

sperm are inserted into the uterine cavity around the time of ovulation.

IUI can be carried out in a natural cycle, without the use of drugs, or the 5 ovaries may be stimulated with oral anti-

estrogens or gonadotrophins.

1. NICE Guidelines - 2012

How does IUI work?The procedure allows one to bypass the cervix to deposit sperm closer to tubal ostium, thereby facilitating a larger number of motile sperms to reach the fertilization site in the ampulla of fallopian tube.

In addition, the sperm separation procedure would remove WBC, dead and moribund sperms generating free oxygen radicals which reduce the functional capacity of intact sperms.

Components in the media also induce gentle capacitation of sperm which is necessary to make them functionally ready for fertilization.

Controlled ovarian stimulation is often used in conjunction with IUI treatment which also enhances the chance of pregnancy by inducing multiple ovulation.

How does IUI work?Where drugs are used to stimulate a cycle, in the case of oral anti-estrogens a woman will take a course of tablets for 5 days.

With gonadotrophins (E.g. rFSH-Puregon) the woman usually receives a course of daily fertility injections for 7 to 10 days.

However, the exact duration of stimulation will depend 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.


How does IUI work?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 will be undertaken 24 to 36 hours later. However, in order to reduce the risk of multiple pregnancies if more than three follicles have developed or two or more mature follicles are seen then insemination may not be undertaken.


How does IUI work?

Go to following Youtube link for 3D animation on how IUI works:http://www.youtube.com/watch?v=qCdIiLLF0vw

Indications for IUIUnexplained infertility Mild endometriosis Mild male factor infertility Disability (physical or psychological) preventing vaginal sexual intercourse Conditions that require specific consideration in relation to methods of conception (such as after sperm washing in a couple where the male is HIV positive)Fertility preservationAs part of donor insemination IUI in stimulated cycles may be considered while waiting for IVF, or when in women with patent tubes IVF is not affordable.

1. NICE Guidelines – 2012. 2. Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009. IUI – The ESHRE Capri Workshop Group

Contraindications for IUIIUI is contraindicated in women with:

Cervical atresia CervicitisEndometritisBilateral tubal obstructionIn most cases of amenorrhea or severe oligospermia

1. Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009. IUI – The ESHRE Capri Workshop Group

Patient Selection Criteria for IUI

Female age <40 yearsMinimum of 1.5 years of infertilityPatent fallopian tubes confirmed by laparoscopy / hysterosalpingogramPresumptive proof of ovulatory cycleUltrasound evidence of mature follicles & ovulationLuteal phase progesterone (P) cutoff >35 nmol/L

Male partner:Two semen analysis revealing at least 10 million recovered motile sperm / whole sample

Patient with any of the following diagnosis could be considered for IUI treatment:

Unexplained infertilityMale factorImmunological factorsCervical factors

Patient Selection Criteria for IUI

Prerequisites for IUIProper indicationSatisfactory semen analysisPatent, healthy fallopian tubesNeed to increase FSH threshold in early follicular phase with either oral ovulation inducing agent and / or injections of exogenous gonadotropin preparations (E.g. Puregon)Identify or preempt the spontaneous LH surge

Patients’ Preparation (Male & Female)

Detailed clinical history of both partnersCounseling for IUI procedureDetail explanation of the technique, risk, complications and expected outcome.

Examination of the Female PatientPhysical examination and localTransvaginal SonographyDay-21 serum progesteroneTubal assessment by laparoscopy / hysterosalpingogramIf the patient has got irregular menstruation – baseline hormones should be done

Clinical Aspects of IUI

Ovulation Induction (OI) in IUIPoor results have been described when IUI was performed in natural cycles for unexplained and cervical factor. The rationale behind the use of ovarian hyperstimulation in artificial insemination is the increase of the number of oocytes available for fertilization and to correct subtle unpredictable ovulatory dysfunction.

Drugs for OI in IUI:

Oral Anti-estrogens (Clomiphene Citrate – Ovafin®) 50 – 100 mg for five daysAromatase Inhibitors (Letrozole) 2.5 – 7.5 mg for five days

InjectableshMG 75 – 150 mg / day from day 3 – 7 of cycleFSH – uFSH or rFSH (E.g. Puregon®) 75 – 150 mg / day from day 3 – 7 of cyclehCG (E.g. Pregnyl®) 5000 – 10,000 IU for follicle puncture and to time insemination

1. Human Reproduction 2008. Intrauterine insemination (IUI) as a first-line treatment in developing countries and methodological aspects that might influence IUI success. 2. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility (Review). Copyright © 2011 The Cochrane Collaboration.

Ovulation Induction (OI) in IUIThe drugs for OI in IUI – A Comparison:

Intra-uterine insemination combined with OH has been proven effective for couples with unexplained and mild male factor subfertility.

Compared with IVF, IUI with OH is less invasive and more cost-effective .

Antiestrogens Vs. GonadotropinsIn the 2007 Cochrane review of seven trials, the results demonstrated that in an IUI program, ovarian stimulation with gonadotrophins increases pregnancy rates per couple significantly, compared to anti-oestrogens, without effecting adverse outcomes.

Antiestrogens Vs. Aromatase InhibitorsIn the 2007 Cochrane review of five studies, None of the trials solely or in combination provided convincing evidence of a significant difference.

1. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility (Review). Copyright © 2011 The Cochrane Collaboration.

Semen Analysis

1. WHO 2010 laboratory manual for the Examination and processing of human semen

WHO Reference Values Reference Limit

Semen volume (ml) 1.5

Sperm concentration (106/ml) 15

Total sperm number (106/ejaculate) 39

Progressive motility (PR, %) 32

Total motility (PR +NP, %) 40

Vitality (live sperms, %) = / > 58

Sperm morphology (NF, %) = / > 4

pH* = / > 7.2

Leucocyte* (106/ml) <1

MAR/Immunobead test* (%) <50

Semen AnalysisScreening for anti-sperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility.

If the result of the first semen analysis is abnormal, a repeat confirmatory test should be offered.

Repeat confirmatory tests should ideally be undertaken 3 months after the initial analysis to allow time for the cycle of spermatozoa formation to be completed. However, if a gross spermatozoa deficiency (azoospermia or severe oligozoospermia) has been detected the repeat test should be undertaken as soon as possible.

Concerning the insemination sample, the recommended lower limit ranges from 3 million motile sperm to 5 million to 10 million

The routine use of post-coital testing of cervical mucus in the investigation of fertility problems is not recommended because it has no predictive value on pregnancy rate.

NICE Guidelines 2013

Semen Preparation in IUIThe semen is a mixture of motile and dead spermatozoa with cells, cellular debris and sometimes micro-organisms present. Prior to IUI, it is necessary to remove seminal plasma to avoid prostaglandin-induced uterine contractions. Insemination with unprocessed semen is also associated with pelvic infection. A variety of methods have been developed to separate the motile sperms from the ejaculate. The most common methods are washing and centrifugation which has been shown to cause some damage to the sperm.

Simple sperm washSwim upGradient

All preparations should done in a laminar flow for sterility.The clean sperm suspension is used for IUI, IVF and ICSI and certain special sperm tests.

1. Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009. IUI – The ESHRE Capri Workshop Group. 2. WHO 2010 laboratory manual for the Examination and processing of human semen

Semen Preparation in IUISimple Sperm Wash

This method is used if the semen sample is very poor. It mainly removes seminal plasma from the sperms.

One volume of semen is placed in a 15 ml test tube and diluted with 2 volume of culture medium. The tube is gently inverted twice to mix the components.

The tube is then centrifuged at 250-300g for 5-7 min.

The supernatant is removed and the pellet is re-suspended in 2 ml of culture medium.

The centrifugation is repeated at 250-300g for 5-7 min and the supernatant removed. About 0.4 ml of media is added to the final sperm pellet for re-suspension.

The sample is suited for intra-cervical insemination

WHO 2010 laboratory manual for the Examination and processing of human semen

Semen Preparation in IUISwim Up Method

This technique relies on the ability of the sperms to swim. This method is suitable for semen with high to moderate motility.

Semen is diluted with 1:2 ratio of culture medium and centrifuged at 250-300g for 5-7 min.

The supernatant is removed leaving the pellet.

Pipette 0.8-1 ml of media into a new test tube. Carefully layer the semen pellet beneath the media.

Stand at 37o for 45-60 min. Placement of tube at 45oangle creates a larger surface area for sperms to swim-up.

Carefully take up the top 0.5-0.6 ml without disturbing the lower layer and transfer into a new test tube.

To concentrate the sperms, pooled several tubes and centrifuged at 250-300g for 5-7 min. The supernatant is removed and the resultant pellet re-suspended in 0.4 ml of media.


Semen Preparation in IUIGradient Systems

Gradient systems use solutions with a higher density than semen to separate the debris, cells, micro-organisms and non-motile sperms from the motile ones.

Commercially available dense solutions used are colloidal silica (Percoll, Puresperm), poly-sucrose (Ficoll, Ixaprep) and other dense solutions (Optiprep, Nycodenz).

Centrifugal force is applied to enable the motile sperms to swim from a less dense seminal fluid into a denser solution.

Cellular debris and non-motile microorganisms will be trapped at the interphase between the two solutions

Select more normal sperms than swim up method.

Recovery may be poor in viscous semen and severe teratozoospermia (small heads but good swimmers)


Semen Preparation in IUIQuality of the Specimen

• There is no consensus on a lower limit of semen quality at which one would advocate ICSI rather than IUI.

• It has been reported that pregnancy rates are lower if the semen sample contains ,10 million sperm in total.

• Concerning the insemination sample, the recommended lower limit ranges from 3 million motile sperm to 5 million to 10 million.

Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009. Intrauterine insemination. The ESHRE Capri Workshop Group.

Mode of Insemination• The sperm suspension can be deposited in the cervix, the uterus, the

peritoneum or the Fallopian tube.

• IUI is by far the most common method.

• It is performed by introducing a 0.2–0.5 ml sperm suspension into the uterus with a small catheter, usually without imaging guidance.

• With Fallopian tube sperm perfusion (FSP), the inseminate is 4 ml, so that with this large volume of fluid the inseminate may fill not only the uterine cavity and Fallopian tubes, but also some of the volume may even end up inside the peritoneal cavity.

• For frozen semen, IUI is better than intracervical insemination (ICI): the likelihood of live birth after six insemination cycles is 2-fold higher (OR: 1.98; 95% CI: 1.02–3.86) (Besselink et al., 2008).


Mode of Insemination• In two trials among patients with unexplained infertility, results with FSP

were better than with IUI (Kahn et al., 1993; Cantineau et al., 2003).

• For other indications, there is not sufficient data to suggest that FSP is any better than IUI.


Timing of Insemination• Insemination can be done at various time points around ovulation and can

be done once or several times.

• In the majority of the published studies, the insemination is done 32–36 h following hCG administration.

• It is assumed that the timing of insemination relative to ovulation is critical for an optimal success rate.

• A systematic review found no difference in the pregnancy rate per couple with two inseminations compared with one (Cantineau et al., 2003).


Overview of an IUI Laboratory

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IUI in Various ScenariosIUI in an Office Setting

IUI is done as an office procedure by gynecologists in private practice.They use the services of the nearby ultrasound centers for follicular tracking and of specialized IUI laboratory for sperm preparation. In case of any complication, patients are transferred to a specialized hospital.Good coordination between gynecologist, sonology lab and IUI lab is required to make this setup successful.

IUI within a General HospitalIUI is done by gynecological consultants.Laboratory and ultrasound services are available in respective departments for follicular tracking and semen preparation. Disadvantage is sonologist may not have adequate training in follicular tracking and semen preparation in a general laboratory may result in suboptimal results.

IUI in Various ScenariosIUI within an IUI Clinic

All IUI services re provided under one roof.Initially the unit may start only as IUI clinic but may later commence other treatments of ART.This should be kept in mind when planning IUI clinic so that space for expansion to create a future ART center in same premises is available.

IUI within ART CenterThis IUI setup is in a specialized ART laboratory.The appropriate equipments, media, drugs and staff are already in place and no separate requirements need to be filled.

IUI LaboratoryRoom for IUI Laboratory

The room should be as close as possible to procedure room.The room must have its own air conditioning.There must not be any free access to any toxic fumes.Sufficient space to accommodate necessary equipments.During insemination it is vital that clinician is able to communicate with lab personnel.There must be suitable facilities for sperm preparation.

IUI Laboratory Equipment1. Semen Assessment & Sperm Preparation

Meckler counting chambersMicroscope phase contrast microscope with resolving power 4,10,40,100 with eye piece 10x.Centrifuge machine with swing-out rotor, timer and RPM meter5% CO2 incubator with 37C with gas cylinderLaminar flow hood (horizontal / vertical)Wide mouth sterile semen collecting jar

Integrated Laminar FlowIUI Workstation

IUI Laboratory Equipment2. Semen Assessment & Sperm Preparation

Sterile test tubesSterile conical / round bottom tubesPipettePipette pumpTest tube rackMediaGood light sourceCASA system

CASA System

IUI Laboratory Equipment3. Gynecological Equipment

Cusco’s speculumIUI catheter1 ml syringeUterine soundCervical dilator 5/6 mmTenaculum single toothedOT lightUltrasound machine with transvaginal probe

IUI Laboratory Equipment4. Media

Flushing mediaCulture mediaSperm preparation mediaCryopreservation media

5. Record Keeping and Documentation

6. Maintenance of EquipmentIncubator should be checked daily in the morning for temperatureInternal water reservoir of the incubator should be cleaned regularly Laminar flow should be cleaned periodically with 70% isopropyl alcoholGas cylinder should be checked regularly to check for any leakage

7. Quality Control Methods & Laboratory Asepsis should be in place

IUI Laboratory Floor Plan

Physical Structure & Floor Plan

IUI Laboratory Floor Plan1. Reception Enlistment Area

2. Waiting Area

3. Subfertility Clinic Area

4. Male clinic Area

5. Sperm Collection Room

6. Andrology Laboratory

7. Receiving area

8. Main laboratory

IUI Laboratory Floor Plan9. IUI Procedure Room

Patient bedCusco’s speculumDisposable rubber sheetDisposable per vaginal glovesSwab holding forcepsVolsellum

10. Doctor’s Office

11. Transvaginal Ultrasonography Room

How to Improve Success in IUI

Diagram showing the many different variables

influencing success rates in IUI programs (AIH,

artificial insemination with homologous semen).

1. Human Reproduction 2008. Intrauterine insemination (IUI) as a first-line treatment in developing countries and methodological aspects that might influence IUI success.

Improving Success of IUI

Age of the femaleIndication for IUIUse of controlled ovarian stimulationThe processed total motile sperm count in the inseminate

Practical Issues Involved in Enhancing Pregnancy Outcome in IUIDuration of subfertilityParityPre-IUI semen reportNumber of IUI cycles attempted


Practical Issues Involved in Enhancing Pregnancy Outcome in IUI (contd.)Number and size of dominant follicleBlood estradiol concentration on hCG dayEndometrial thickness at scan on hCG dayDoppler blood flow studies of follicles / endometriumPractical issues at IUI:

Type of IUI catheterFresh or frozen-thawed spermPost-processing sperm morphology / motility gradeTiming of IUI in relation to hCG administration


Practical Issues Involved in Enhancing Pregnancy Outcome in IUI (contd.)Practical issues at IUI (contd.):

Number of IUIsVolume of inseminate usedTime to rest following IUI procedure

NICE Recommendations for IUI

1. For people with unexplained infertility, mild endometriosis or mild male factor infertility, who are having regular unprotected sexual intercourse: – do not routinely offer intrauterine insemination, either with or

without ovarian stimulation – advise them to try to conceive for a total of 2 years (including up to 1

year before investigation) before IVF will be considered.



2. Consider unstimulated intrauterine insemination as a treatment option in the following groups as an alternative to vaginal sexual intercourse: – people who are unable to, or would find it very difficult to have vaginal

intercourse because of a clinically diagnosed physical disability or psychosexual problem who are using partner or donor sperm;

– people with conditions that require specific consideration in relation to methods of conception (for example, after sperm washing where the man is HIV positive)

– people in same-sex relationships.



3. For people in recommendation 2 who have not conceived after six cycles of donor or partner insemination, despite evidence of normal ovulation, tubal patency and semen analysis, offer a further six cycles of unstimulated intrauterine insemination before IVF is considered.


Some Concluding Points

• In good prognosis couples, the live birth rate is better without treatment.

• IUI is widely used with infertility diagnoses other than bilateral tubal obstruction, severe male infertility and severe ovulation defects.

• Differences in sperm preparation and IUI methodology do not have profound effects on the success rate.

• Prior to using IVF, IUI with clomiphene ovarian stimulation is relatively cheap and many couples will conceive and not require IVF.


Some Concluding Points

• IUI in stimulated cycles was effective only in patients with more than 3 years duration of infertility but is associated with a significant rate of higher-order multiple births.

• Prevention of premature LH surges and luteal phase support do not appear major requirements in IUI cycles.

• Although IUI treatment is cheaper and less demanding on the patient, IVF is the most effective treatment for infertility.


Adapted from:NICE Guidelines 2012, 2013

Intrauterine insemination. The ESHRE Capri Workshop Group.Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009.


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intrauterine insemination - physicians training module

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