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Physician’s Training Module

Dr. Sarwat JabeenMBBS, MBA Health Management & Pharmaceutical Marketing

Product Manager – Fertility

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

The procedure allows one to bypass the cervix to deposit spermcloser to tubal ostium, thereby facilitating a larger number of motilesperms to reach the fertilization site in the ampulla of fallopiantube.

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

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

Controlled ovarian stimulation is often used in conjunction with IUItreatment which also enhances the chance of pregnancy byinducing multiple ovulation.

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 usuallyreceives a course of daily fertility injections for 7 to 10 days.

However, the exact duration of stimulation will depend on whichday of the cycle it is started.

In both circumstances the treatment should be monitored byultrasound scan to assess the ovarian response.


When one to three follicles are seen to have developed to asuitable size, usually with one dominate follicle, then an injection ofhCG is given which triggers ovulation.

Insemination of prepared sperm will be undertaken 24 to 36 hourslater. However, in order to reduce the risk of multiple pregnancies ifmore than three follicles have developed or two or more maturefollicles are seen then insemination may not be undertaken.


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

Unexplained infertility

Mild endometriosis

Mild male factor infertility

Disability (physical or psychological) preventing vaginal sexualintercourse

Conditions that require specific consideration in relation tomethods of conception (such as after sperm washing in a couplewhere the male is HIV positive)

Fertility preservation

As part of donor insemination

IUI in stimulated cycles may be considered while waiting for IVF, orwhen 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

IUI is contraindicated in women with:

Cervical atresia

Cervicitis

Endometritis

Bilateral tubal obstruction

In 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

Female age <40 years

Minimum of 1.5 years of infertility

Patent fallopian tubes confirmed by laparoscopy /hysterosalpingogram

Presumptive proof of ovulatory cycle

Ultrasound evidence of mature follicles & ovulation

Luteal phase progesterone (P) cutoff >35 nmol/L

Male partner:

Two semen analysis revealing at least 10 million recovered motilesperm / whole sample

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

Unexplained infertility

Male factor

Immunological factors

Cervical factors

Proper indication

Satisfactory semen analysis

Patent, healthy fallopian tubes

Need to increase FSH threshold in early follicular phase with eitheroral ovulation inducing agent and / or injections of exogenousgonadotropin preparations (E.g. Puregon)

Identify or preempt the spontaneous LH surge

Detailed clinical history of both partners

Counseling for IUI procedure

Detail explanation of the technique, risk, complications and expectedoutcome.

Examination of the Female Patient

Physical examination and local

Transvaginal Sonography

Day-21 serum progesterone

Tubal assessment by laparoscopy / hysterosalpingogram

If the patient has got irregular menstruation – baseline hormonesshould be done

Poor results have been described when IUI was performed in natural cycles forunexplained and cervical factor.

The rationale behind the use of ovarian hyperstimulation in artificialinsemination is the increase of the number of oocytes available for fertilizationand to correct subtle unpredictable ovulatory dysfunction.

Drugs for OI in IUI:

Oral

Anti-estrogens (Clomiphene Citrate – Ovafin®) 50 – 100 mg for five days

Aromatase Inhibitors (Letrozole) 2.5 – 7.5 mg for five days

Injectables

hMG 75 – 150 mg / day from day 3 – 7 of cycle

FSH – uFSH or rFSH (E.g. Puregon®) 75 – 150 mg / day from day 3 – 7 of cycle

hCG (E.g. Pregnyl®) 5000 – 10,000 IU for follicle puncture and to timeinsemination

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.

The drugs for OI in IUI – A Comparison:

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

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

Antiestrogens Vs. Gonadotropins

In the 2007 Cochrane review of seven trials, the results demonstrated that in an IUIprogram, ovarian stimulation with gonadotrophins increases pregnancy rates percouple significantly, compared to anti-oestrogens, without effecting adverseoutcomes.

Antiestrogens Vs. Aromatase Inhibitors

In the 2007 Cochrane review of five studies, None of the trials solely or incombination 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.

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

Screening for anti-sperm antibodies should not be offered because there isno evidence of effective treatment to improve fertility.

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

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

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

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

NICE Guidelines 2013

The semen is a mixture of motile and dead spermatozoa with cells, cellulardebris and sometimes micro-organisms present.

Prior to IUI, it is necessary to remove seminal plasma to avoidprostaglandin-induced uterine contractions.

Insemination with unprocessed semen is also associated with pelvicinfection.A variety of methods have been developed to separate the motile spermsfrom the ejaculate. The most common methods are washing andcentrifugation 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 specialsperm 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

Simple Sperm Wash

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

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

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 ofculture medium.

The centrifugation is repeated at 250-300g for 5-7 min and the supernatantremoved. 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

Swim Up Method

This technique relies on the ability of the sperms to swim. This method issuitable 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 semenpellet beneath the media.

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

Carefully take up the top 0.5-0.6 ml without disturbing the lower layer andtransfer 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.


Gradient Systems

Gradient systems use solutions with a higher density than semen toseparate the debris, cells, micro-organisms and non-motile sperms from themotile 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 lessdense seminal fluid into a denser solution.

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

Select more normal sperms than swim up method.

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


Quality 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.

• The sperm suspension can be deposited in the cervix, the uterus, theperitoneum 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 theuterus with a small catheter, usually without imaging guidance.

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

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


• In two trials among patients with unexplained infertility, results with FSPwere 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 anybetter than IUI.


• Insemination can be done at various time points around ovulation and canbe done once or several times.

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

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

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


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IUI 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 trackingand of specialized IUI laboratory for sperm preparation.

In case of any complication, patients are transferred to a specializedhospital.

Good coordination between gynecologist, sonology lab and IUI lab isrequired to make this setup successful.

IUI within a General Hospital

IUI is done by gynecological consultants.

Laboratory and ultrasound services are available in respective departmentsfor follicular tracking and semen preparation.

Disadvantage is sonologist may not have adequate training in folliculartracking and semen preparation in a general laboratory may result insuboptimal results.

IUI 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 othertreatments of ART.

This should be kept in mind when planning IUI clinic so that space forexpansion to create a future ART center in same premises is available.

IUI within ART Center

This IUI setup is in a specialized ART laboratory.

The appropriate equipments, media, drugs and staff are already in placeand no separate requirements need to be filled.

Room 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 communicatewith lab personnel.

There must be suitable facilities for sperm preparation.

1. Semen Assessment & SpermPreparation

Meckler counting chambers

Microscope phase contrastmicroscope with resolving power4,10,40,100 with eye piece 10x.

Centrifuge machine with swing-outrotor, timer and RPM meter

5% CO2 incubator with 37C withgas cylinder

Laminar flow hood (horizontal /vertical)

Wide mouth sterile semencollecting jar

Integrated Laminar FlowIUI Workstation

2. Semen Assessment & Sperm Preparation

Sterile test tubes

Sterile conical / round bottom tubes

Pipette

Pipette pump

Test tube rack

Media

Good light source

CASA system

CASA System

3. Gynecological Equipment

Cusco’s speculum

IUI catheter

1 ml syringe

Uterine sound

Cervical dilator 5/6 mm

Tenaculum single toothed

OT light

Ultrasound machine with transvaginal probe

4. Media

Flushing media

Culture media

Sperm preparation media

Cryopreservation media

5. Record Keeping and Documentation

6. Maintenance of Equipment

Incubator should be checked daily in the morning for temperature

Internal water reservoir of the incubator should be cleaned regularly

Laminar flow should be cleaned periodically with 70% isopropylalcohol

Gas cylinder should be checked regularly to check for any leakage

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

Physical Structure & Floor Plan

1. 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

9. IUI Procedure Room

Patient bed

Cusco’s speculum

Disposable rubber sheet

Disposable per vaginal gloves

Swab holding forceps

Volsellum

10. Doctor’s Office

11. Transvaginal Ultrasonography Room

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.

Age of the female

Indication for IUI

Use of controlled ovarian stimulation

The processed total motile sperm count in the inseminate

Practical Issues Involved in Enhancing Pregnancy Outcome inIUI

Duration of subfertility

Parity

Pre-IUI semen report

Number of IUI cycles attempted

Practical Issues Involved in Enhancing Pregnancy Outcome inIUI (contd.)

Number and size of dominant follicle

Blood estradiol concentration on hCG day

Endometrial thickness at scan on hCG day

Doppler blood flow studies of follicles / endometrium

Practical issues at IUI:Type of IUI catheter

Fresh or frozen-thawed sperm

Post-processing sperm morphology / motility grade

Timing of IUI in relation to hCG administration

Practical Issues Involved in Enhancing Pregnancy Outcome inIUI (contd.)

Practical issues at IUI (contd.):Number of IUIs

Volume of inseminate used

Time to rest following IUI procedure

1. For people with unexplained infertility, mild endometriosis or mildmale factor infertility, who are having regular unprotected sexualintercourse:

– do not routinely offer intrauterine insemination, either with orwithout ovarian stimulation

– advise them to try to conceive for a total of 2 years (including up to 1year before investigation) before IVF will be considered.


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

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

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

– people in same-sex relationships.


3. For people in recommendation 2 who have not conceivedafter six cycles of donor or partner insemination, despiteevidence of normal ovulation, tubal patency and semenanalysis, offer a further six cycles of unstimulated intrauterineinsemination before IVF is considered.


• In good prognosis couples, the live birth rate is better withouttreatment.

• IUI is widely used with infertility diagnoses other thanbilateral tubal obstruction, severe male infertility and severeovulation defects.

• Differences in sperm preparation and IUI methodology do nothave profound effects on the success rate.

• Prior to using IVF, IUI with clomiphene ovarian stimulation isrelatively cheap and many couples will conceive and notrequire IVF.


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

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

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


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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