UNEXPLAINED INFERTILITY &INTRAUTERINE INSEMINATION Dr. Sharda jain Lifecare Centre

UNEXPLAINED INFERTILITY &
INTRAUTERINE INSEMINATION
DR. SHARDA JAIN
DR. JYOTI AGARWAL
DR. JYOTI BHASKAR

Over 300 ppts are available on
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WHY THIS PPT !!!
2013….NICE GUIDELINES ON
INFERTILITY
UNEXPLAINED INFERTILITY
NO IUI
STRAIGHT I.V.F.
BOMBSHELL

DEFINITION
• Unexplained infertility means that couple
does not conceive after 1year of unprotected
vaginal sexual intercourse, with basic
infertility evaluation showing no obvious
abnormality.
• INCIDENCE
15%to 20% of infertile couples
UNEXPLAINED IS PRIMARILY A
DIAGNOSIS OF EXCLUSION

ESHERE 2000
Categorized investigation of infertility in to 3
*Direct relation with pregnancy rate
**Non consistent Relation with PR eg PCT
anti- sperm anti-bodies
***No Association with PR eg EB, Varicele

3 BASIC INVESTIGATIONS FOR
DIAGNOSIS OF UNEXPLAINED INFERTILITY
• Normal basic semen
analysis according to WHO
criteria (WHO,2010)
+ semen culture
• Patent fallopian tube
confirmed by HSG / SSG
Role of Diagnostic Laparoscopy is debated
• Ovulation confirmed by
mid –luteal serum
Progesterone level
• +follicle monitoring

*To be abandoned.
**Missed diagnosis ( bad investigation ,
bad interpretation )
MANY OPINIONS about UI

It is essential to understand that
though these tests do assist us in
planning treatment, but
they have their limitations.

• Processed total motile sperm count >10million
• 24 h survival >70%,and
• Normal sperm morphology of>4%(according
to kruger’s criteria)
• Predict good pregnancy outcome with
(94%sensitivity , 86%specificity)
SPERM PARAMETERS & PR

SEMEN ANALYSIS : HAS LIMITATIONS
IN TERMS OF PREGNANCY RATE
Despite the many advanced tests available for
sperm function we still cannot assess the
fertilizing ability of the sperm in vivo.
Fertilization failures have been observed with
semen showing absolutely normal characteristics
as defined by WHO standards (1999 & 2010)
WHO laboratory manual for the examination of human semen & sperm cervical mucus
Interaction, 4th edn. Cambridge university press, cambridge 1999
WHO manual 2010

Tubal Patency /
Day 21 Serum Progesterone
• Tubal patency does not necessarily indicate
normal tubal function
** a rise in progesterone in the luteal phase
can occur even if the oocyte remains trapped in
the follicle (luteinised un-ruptured follicle).
***In addition couples with no fertility
problems may show abnormal results.

CAUSES OF INFERTILITY
• Routine infertility assessment reveals that
in approximately 30% of couples the reason
for infertility lies with the male partner.
• In 35% cases female factors are responsible
• In 20% couple it is a combination of both
• In 15 – 20 % cases the cause of infertility is
unexplained.

THE FEMALE FACTOR
The female factor includes
*ovulatory dysfunction 20 to 30 %,
**tubal damage 20 to 30 % ,
***endometriosis 5 to 10 % &
****cervical mucus problems 5 %.
In another 5% of patients infertility is
related to coital problems
Br Med j 291:1693-97, 1985

SOME HIDDEN SUBTLE , PUTATIVE
ISSUES underlying UI
• Poor ovarian reserve
• Poor Oocyte quality: chromosomal abnormalities contribute
to oocyte disorders & impaired embryonic development.
• Increased chromosomal anomalies (Aneuploidies) are also
found in the oocytes of older women.
• Oocyte maturation arrest ( failure to complete meiosis) :
it may be the cause of infertility in some couples previously
classified as having unexplained infertility.

POSSIBLE FACTORS FERTILIZATION
Problems with fertilization are
identified during conventional IVF
only like defective sperm – poor zona
binding & zona penetration,
failure of oocyte activation
may result in failure of fertilization.

POSSIBLE ENDOMETRIAL FACTOR
• The endometrium has been extensively studied
in the implantation phase to try & identify
molecular & biochemical marker of implantation
key adhesion molecules, certain biochemical
marker & gene expression which are Not near
normal
OR
• Endometrial Vascular Changes
OR
• Genetic Factor

MANAGEMENT OF UI
Unexplained subfertility creates some
complexity in management
mainly because of the lack of a specific ,
& potentially treatable abnormality.
The treatment is generally Empirical.

Management of UI
*CONSERVATIVE T T*
Technically a couple is said to have UI if they have not
conceived within a year of trying & investigations.
• It has been observed that about 40 – 65% of
couple with UI conceive within three year
without active management.
• After 39 months the chances of conception fall by 2%
every month, a decrease of about 10% for additional
year of infertility.

*EXPERTS…..PLEA FOR
CONSERVATIVE TREATMENT IF YOUNG*
It has been suggested that
treatment should be deferred
for 3 years if the
woman’s age is below 35 years.

Age & duration of infertility are the two
most important prognostic factor
The rate at which treatment progresses,
depends on the
*Age of the patient,
**The duration of infertility &
***The level of anxiety of the couple the
couple can become TOP spoiling game

PREGNANCY RATES
IN UNEXPLAINED INFERTILITY
Method Pregnancy rate (%)
INTERCOURSE (TIMED) 4 (follicular monitoring)
Iui 6 ----------do---------
Cc 6 ----------do---------
CC+IUI 8
FSH / HMG 7.7
CC/FSH/IUI 9-12
FSH / HMG / IUI 17-20%
IN-VITRO- FERTILIZATION 20 to maximum 30

CONCLUSIONS :
In stimulated cycles PR was higher with
IUI compared to timed intercourse.
&
COH + IUI is far better than IUI alone

THE TREATMENT CARRIED OUT for UI ARE AS
FOLLOWS:
• Ovulation induction
• Ovulation induction with intrauterine
insemination (IUI)
• IVF ( in-vitro fertilization) & IVF / ICSI

Ovulation induction
The rationale behind using ovulation induction as
a treatment for UI is , that it
A. increases the number of oocytes available for fertilization
B. Allow correction of luteal phase defect ,&
C. Corrects subtle defects on ovarian function
Drugs used for ovulation induction include
*Clomiphene citrate (CC),
*Letrozole &
*Gonadotrophins

CLOMIPHENE CITRATE (CC)
although the absolute treatment effect is
small, given the low cost & ease of
administration … clomiphene citrate appears
to be a sensible first choice treatment for
women with unexplained infertility.
Treatment with CC should not be extended
beyond six cycles because of endometrial
receptor depletion , concern about risk of
ovarian cancer & multiple pregnancy

GONADOTROPINS
Controlled ovarian stimulation (COS) with
gonadotropins +IUI has shown to increase the
pregnancy rate significantly in women with more
that 3 years of UI.
The therapy also resulted in a significant increase in
multiple pregnancy rate 18%
Good pregnancy rates of approximately 20%
have been reported with this regime + IUI

Atahulla et al 2002
Last word on which agent for OI is far away
conducted a study to assess the efficacy of oral
versus injectable ovulation induction agents for
unexplained subfertility.
They concluded that there was insufficient
evidence to suggest that oral agents were
either inferior or superior to injectable agents
in the treatment of unexplained subfertility &
recommended larger trials.
COCHRANE.. Data base 2002

Intrauterine Insemination (IUI) is used both in
stimulation & un-stimulation cycles. The
rationale of IUI being that an enhanced
preparation of motile sperms is deposited as
close to the oocyte as possible.
The cervical mucus barrier is bypassed & there is
an additional psychological benefits that the
infertility is being treated.

•Factors related to couples
• Factors related to therapy
FAVOURABLE PREDICTORS OF IUI
OUTCOME

A. COUPLE :
• Female age < 35y , Male < 40 yrs
• Shorter duration of infertility (< 5 yrs)
****************************************
• Type of Infertility Pregnancy Rate
• Primary inf. 7.9%
• Secondary 21.4

Higher PR with :
• Unexplained infertility (12%-22%)
• Ovulatory dysfunction (19-20%)
***************************************************
Modest PR- cervical factor (16.4%)
**********************************
Poor PR:
• Endometriosis(11.9%)
• Immunological infertility (10%)
• with ejaculatory disorders (13.3%)
(bourn hall clinic.1999:tay et al 2007: Wang al 2oo8)
Cause of infertility & Pregnancy
Rate/cycle :

Effectiveness of IUI in
treatment of
unexplained infertility
12..22%

GONADOTROPIN THERAPY WITH IUI
No doubt that
Gonadotropin therapy with IUI
is superior to no treatment in UI
But has so far not been proven
to be superior to CC + IUI in UI

UNEXPLAINED INFERTILITY &
Ovarian Stimulation + IUI has “grade A evidence
to confirm its effective use in
UI.

Meta – Analysis , Published in
‘Human Reproduction’
In a meta – analysis conducted by Hughes it
was concluded that COS or IUI alone increased
the possibility of pregnancy two – fold
but when both were combined the
fecundity increase FIVE – FOLD .
Pregnancy rates are around 20% & the
risk of multiple pregnancy is
also around 20%.

ESHRE CAPRI WORKSHOP GROUP
• COH/IUI is indicated as empiric
treatment for all categories of
unexplained infertility
• 20% of couple after initial work –up.
• Couple with mild male subfertility (20-
40%)
• 50% of those in whom conventional
treatments have failed.

NICE GUIDELINE 2013
For people with :
•Unexplained infertility,
•Mild endometriosis or
•Mild male factor infertility ,
Who are having regular unprotected sexual :
Advise them to try to conceive for a total of 2
years before IVF will be considered.

UNEXPLAINED INFERTILITY &INTRAUTERINE INSEMINATION Dr. Sharda jain Lifecare Centre

Opinions & Practices
• Pregnancy resulting from IUI occur during the first 3-4
treatment cycles (88-95%; respectively)
• Aboughar et al 2001 suggested maximum of 3
COH/IUI cycles for treatment of unexplained
infertility.
• However ,others recommended up to 6 cycles

IUI & IVF FOR

IUI & IVF FOR
• Starting treatment with IUI
rather than IVF was either
cheaper or more cost –effective
than IVF in unexplained infertility
(goverde et al ..2000)

IN- VITRO FERTILIZATION
In vitro fertilization is now a widely accepted
treatment for unexplained infertility after NICE
GUIDELINES 2013
Since live birth rates per cycle is low , varying
between 13 & 30% & the
cost of treatment very high,
one needs to evaluate it in comparison
with other treatment in UI

IUI & IVF FOR
Cochrane, 2012
• IVF may be more effective than IUI+COH.
(pandian et al 2012)
Due to lack of data from RCT s the effectiveness of
IVF for unexplained infertility relative to expectant
management ,clomiphene citrate and IUI alone
remains unproven.

PLACE OF IVF & ICSI IN UI
Studies indicate that IVF is superior to FSH &
IUI but this benefits is achieved at a
considerable cost .
IVF being at least 10 times more expensive
than OI+IUI (in India)
in couples with unexplained infertility a higher
fertilization rate was achieved through ICSI
compared with conventional IVF
fertility steril 77(2):229-32,2002

USE OF BROMOCRIPTINE for UI
Bromocriptine improves
hyperprolactinaemic
amenorrhoea & so could also be
helpful in the treatment of
unexplained sub-fertility
in woman.

TAKE HOME MASSAGES FOR
STRATEGY FOR TREATMENT OF UI
To plan a strategy one has to balance
effectiveness as opposed to
invasiveness & cost – effectiveness
of the various therapeutic options.

“Proceed from Low – tech to high – tech
treatment”,
but it is not convincing enough to support a rigid
management protocol
Hum reprod 18(5) : 907-12,2003
MASSAGE 1

It is essential to give the couple a realistic
appraisal of their chances of pregnancy with &
without treatment & also to counsel them fully
about the risk & side effects of various
therapies.
MASSAGE 2

In conclusion expectant treatment is the option
of choice for young patients with short period
of infertility.
MASSAGE 3
The spontaneous pregnancy rate
is very high in this group of
patients.

MASSAGE 4
Evidence suggests that active treatment should be
deferred till the couple has tried for THREE YEARS.
It is virtually impossible to enforce this in practice
when faced with a distressed couple seeking help.
THE AGE OF THE FEMALE should be a
major factor in decision making & more
aggressive treatment may be warranted
after the age of 35.

• Evidence shows that treatment with
clomiphene is better than no treatment at all.
• Gonadotropins & IUI should be used by
experts even though it has not proven
superior to CC/ IUI.
MASSAGE 5

According to the available data , this procedure could be limited
to 3 to 4 COH+ IUI.
There is evidence that both COH & IUI are important
independent positive factor in achieving better pregnancy rate in
unexplained infertility.
• The treatment effects optimize in 4 IUI cycles & therefore if a
couple has not conceived , IVF should be considered next.
MASSAGE 6

Whether IVF improve the chances of conception over
other treatment has still not been established
conclusively but it has an additional advantage of
acting as a Diagnostic Tool.
MASSAGE 7
Couples with UI may have sperm, oocyte or fertilization
defects that will only be discovered during IVF.

IVF/ICSI should be performed in unexplained
infertility as it yields a high pregnancy rate as
compared to IVF .
GIFT is too invasive a procedure & since the results
are poorer than IVF it is rarely used
Arch gynecol obstet 267(4):177-88,2003,
MASSAGE 8

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UNEXPLAINED INFERTILITY &INTRAUTERINE INSEMINATION Dr. Sharda jain Lifecare Centre

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