New Perspectives : Unexplained infertility 2018

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‘Infertility that is idiopathic
In the sense that
Its cause remains unknown
Even after Infertility workup’
Unexplained Infertility

Goals and Objectives
Understand
Unexplained Infertility
Evaluate Right
Diagnostic Approach
Management

Ovulatory disorders - 20 – 30 %
Tubal Damage - 20 - 35 %
Sperm dysfunction - 10 – 50 %
Endometriosis - 5 - 10 %
Cervical mucus problems - 5 %
Coital dysfunction - 5 %
Unexplained Infertility - 10 – 25 %
Sub fertility in both partners –
30 – 50 % couples
Main Causes
of Infertility

Diagnosis of unexplained
infertility
10-30% of couples seeking treatment
No etiology identified
Ovulatory function
Tubal patency &
SA
Most frequently made diagnosis
Diagnosis is one of exclusion

Is It ‘Unexplained’ Or
‘Undiagnosed’ ?
Reaching specific diagnoses can be difficult
Multifactorial Infertility
Failure to detect one or more presumed causes

Putative Causes (story of transport)
Sperm & egg
transport or
interaction
Embryonal
development
Implantation
failure
Post-implantation
pregnancy loss

Validity of Diagnostic Testing
According to ESHRE –
tests divided into 3 categories
Those with „established correlation‟ with the
occurrence of pregnancy
conventional semen analysis
tubal patency tests
tests of ovulation

Those „not consistently‟ showing correlation
Post coital test
Antisperm antibody tests
Zona free Hamster egg penetration test

Those „apparently not correlating‟ with the
occurrence of pregnancy at all
Endometrial biopsy
Varicocele assesment
Chlamydia testing

Unexplained Infertility-

Potential
Difficulties
Ordering correct tests
Performing tests
appropriately &
Correct interpretation
A specific cause of
infertility is never
certain
Initial diagnostic
work ups should
encompass both
partners

Potential contributing factors
The diagnosis is made by exclusion

Increased age of female partner
30 – 31 yrs.
37 – 38 yrs.
51 yrs.
Subfertility
Critical point
reached with approx
25,000 follicles
remaining
Follicular count
reaches 1000
Follicles continue to decline from birth

PAO
Normal Decline 25000
Accelerated
Decline
Early
Menopause
• 37 – 38 yrs –
25,000 follicles
• 51 yrs –
menopause,
1000 follicles
Accelerated
decline in
fertility at
age
• Approx
13.5yrs
Time period
between
accelerated
decline in fertility
is fixed at
Normal Decline
25000
Accelerated
Decline
Early
Menopause

Ovarian Reserve Markers
• AMH
 3 – 5 ng/ml (normal)
 More reliable
 No cyclical variation
• AFC
 > 5 – 2-6 mm follicles
 Good predictor,
 cost effective
• FSH
 > 10 m IU / ml - low
reserve
 Less reliable
 Rise when Function
deeply compromised

10 % women experience early menopause before
45 yrs of age & 1 % - before 40 yrs age.
Signs of PAO
Age atypical resistance to
ovarian stimulation
Elevated FSH
Low AMH
Low AFC
F/H of early menopause
IVF
Follicular output in IVF –
diagnostic test for
ovarian function
PAO

Fecundity in general –
85 – 90 % in 1yr

Tubal Function
Defects HSG
Less accurate in detecting
and evaluating tubal
disease than laparoscopy
Poorly suited to assess distal
tubal disease and peritubal
disease
Laparoscopy & Hysteroscopy
To evaluate for unexplained
tubal and uterine disease

Endometriosis
Prevalence remains controversial
As low as 5 – 10 %
As high as 30 – 50 %
Accurate diagnosis can be difficult
About 30 % of asymptomatic women-diagnosis with mild endometriosis if laparoscopy
undertaken
Mild endometriosis can affect normal function, as well as other reproductive processes

Endometriosis
No evidence that medical treatment
improves fertility,
Laparoscopic ablation-
improves live birth rate minimally
Debatable whether mild endometriosis is
responsible for sub-fertility in UI
Endometriosis affects IVF outcomes in
all aspects

Fibroids
Submucosal component –
Could be associated with reduced
conception
Insufficient evidence that
myomectomy for IM or SS
fibroids improve PR

Adenomyosis
Impact of adenomyosis or its
treatment on fertility remains
unsubstantialed because of
pancity of data

Fertilization Defects
Subtle defects in Oocyte and
sperm-leading to defective
fertilization
Introduction of ICSI

Implantation Defects
Alterations in Biochemical factors
Cytokines
Lenkaemia inhibiting factor
Interleukin-1
Chemokines

Immunological, metabolic and
genetic factors
Dysregulation of immune system and
ed production of antoantiboidies –
antithyroid
antiovarian
antinuclear
antiphospolipid &
antismooth muscle
Reduction of fertilization rate and interference with early implantation
Oxidative stress –
imbalance between reactive oxygen species and antioxidants caused
by factors
obesity, alocohol, smoking, drugs

Subclinical Autoimmune
Disease
Controversial
association
Preclinical stage of
autoimmune
disease
demonstrate
decreased
fecundity
Antiphosphatidyl choline
significantly increases
Statistically well
established association- to
ignore would appear
intellectually dishonest

Life style factors
role of obesity
 BMI > 30 - odds of subfertility
- ed risk of miscarriage and
adverse pregnancy outcome
 High risk of subfecundity
- with both members obese
 Treatments less successful & losing wt. increases
chances
 Aim for BMI of 20 – 25 % with balanced diet and
regular exercise

Bariatric Surgery

Timing Of Intercourse
0 – 6 days prior to ovulation-Higher
chances
Normal sperm densities with short
abstinence (2 d)
Highest sperm conc. In daily ejaculates –
even in oligospermia men
Frequent IC from 1 – 2 d encouraged

Use Of Lubricants
Water based
lubricants & olive
oil
Canola oil, mineral oil
& hydroxyethyl
cellulose based
lubricant
Inhibit sperm
viability
Do not inhibit
sperm
viability

Other life-style choices
Smoking (Active & Passive)
Can affect potential to conceive
Reducing ovarian reserve
Altering tubal function and uterine environment
In men, impairs fertilizing of sperm
Reducing mitochondrial activity and DNA damage
Excessive alcohol intake :-
In men; consumption over 5 units / wk.
Adverse affect on sperm quality
In women, decreasing implantation rate, Luteal phase dysfunction
OTHER FACTORS
Psychological stress
Exposure to pollutants

Treatment
• In absence of
specific medical
cause –
specific
treatment
lacking
• Treatment
empirical

Factors Influencing Treatment
Age
Duration of
Infertility
Treatment efficacy
Side effect profile
Cost
 Multiple pregnancy

Principal Treatment Options
Expectant observation with Timed
intercourse & Life style changes
CC + IUI
CC + HMG + IUI
IVF
‘although various treatment strategies are
available, evidence is lacking to confirm the
superiority of one over the other’.
Individualize treatment for a
successful outcome

Expectant Management
COUNSELLING
 Probability of Live-birth
Informed decision about
‘to pursue or not to’
 chances of sp.conception
remain high in UI –
Varying from 30 – 70 %
within 2 yrs

Tubal flushing during HSG
Possible benefit known for over ½ a century
Possible mechanism of action
Mechanical removal of tubal debris
Immunological
Affecting peritoneal cylokines
Effect on or endometrium to promote
implantation

Adjuvant effect of
preovulatory pertubation
Lignocaine 0.1
mg/ml in
balanced salt
solution
Reduces sperm
phagocytosis
preg. rates

Agents - OI
• Oral antiestrogens
 Clomiphene Citrate
 Tamoxifen
• Insulin sensitizing agents
 Metformin
• Aromatase inhibitors – Letrozole, Anastrozole
• Injectable Gonadotrophins
 Alone or
 In association with
GnRH-a
GnRH-antagonists

Clomiphene Citrate
C C + hMG
C C + FSH / Rec-FSH
hMG
FSH
hMG +FSH
Rec- FSH
Rec- FSH+Others
GnRHa + hMG
GnRHantagonist + hMG
Regimens Of Ovulation Induction

Aromatase inhibitors -
Women who might ‘benefit most’
Estrogen dependend disorders
 Endometriosis
 Breast ca.
 Inherent clotting abnormality

Luteinized unruptured
follicle vs ovulatory follicle
LUF
Follicles which fail to ovulate
Undergo Luteinization and
May become increasingly filled
with blood

LUF – U/s characteristics
Failure of follicle to rupture at expected phase
(follicular-Luteal transition)
Thicker follicle wall
Luteinization – showing Lutein tissue like
appearance
Presence of echogenic foci & fibrin – like
strands in follicle autrum –
suggesting haemorrhage

LUF – a subtle cause
Occurrence linked to
UI
Endometriosis
Pelvic adhesions
Use of NSAIDS
Exclude hyperprolactinaemia, Hypothyroidism
( ovarian reserve)
Ovulatory dysf. In POI
Consecutive stimulation with CC

LUF – ‘how common’
LUF syndrome „highly repeatable‟ (79 – 90 %)
across cycles resulting in rec. anovulation
Affects upto 23 % of women with normal
menstrual cycles and
Upto 73 % with endometriosis

CC with or without IUI
CC alone
CC + IUI
Options
Cost
Female
partners
age
Duration of
infertility
Factors
to
Consider
A cochrane review (1159 participants) found no clinical benefit of CC for UI

CC + IUI
• Superior to spontaneous
attempts in UI > 2yrs
duration
• Increasing female age and
poor semen
parameters - Lower
success rates More
aggressive treatment
warranted

IUI + COH
Widely used before resorting to more
invasive options like, IVF
COH may correct subtle ovulation
problems slightly no. of oocytes
available for fertilization
Cochrane review (2012) –
IUI + COH increases LBR more than
2 fold compared with IUI in natural
cycle

COH-concerns
MULTIPLE FOLLICLE DEVELOPMENT
 Multiple pregnancies
 OHSS
RISK FACTORS
 High initial Gonadotrophin dose
 Large no. of mature follicles (>15 mm) &
 1st stimulation cycle
TO REDUCE RISKS
 1 Stimulated follicle should be the goal &
 2 Follicles may be accepted after careful patient counseling
 By using mild ovarian hyperstimulation
 Strict cancellation policies

Ectopic & Heterotopic Pregnancies
Incidence of ectopic – 1.5 - 2 %
 With Ovulation Induction - 3 %
 With ART - 5 %
Incidence of Heterotopic Pregnancies – 1 in 30,000
 With Ovulation Induction & ART – 1 %
Surgical treatment – viable option
 1/3rd spontaneous miscarriages
A high index of suspicion required

Ovarian Hyperstimulation Syndrome

Aspiration of Follicles
Prevention Of OHSS

AGE FACTOR
Older women – “don‟t have
unexplained infertility”
Spontaneous pregnancy rates –
much lower

*
• 38 – 39 yrs –
6.1 % live
birthrate /
cycle
• No live births
after 2nd cycle *
*
• ≥ 40 yrs –
2 % per
cycle
• No live
births after
1st cycle
Success Rates in HMG + IUI
cycles:- 38 – 40 yrs.
Women over 40 yrs should be considered for IVF
after 1 failed IUI cycle

Can ART overcome Age
ART success rate linearly declined with
women‟s age
This treatment is unable to adequately
overcome the detrimental effect of age
IVF in particular can be viewed as a kind of
„multiple natural cycle‟

IUI / IVF
NICE GUIDELINES, 2013 :
recommends not routinely offering IUI to couples
with unexplained sub-fertility but proceeding
directly to IVF after 2 yrs of sub-fertility
• However, „success of IUI depends on multiple factors
and many clinicians continue to provide IUI plus
COH for UI despite Nice recommendations
ASRM GUIDELINES :
suggest a progressive approach starting with IUI
and then IVF

Laparoscopy first or
ART directly - UI
Laparoscopy in UI provides diagnosis, enables
significant no of patients to have
spontaneous pregnancy comparable to
preg. Rate with ART
Ectopic pregnancy rate higher in cases treated
with Lap. surgery
If ART needed in cases treated with Lap.
Surgery, chances of success are not
affected, but even facilitated

CONVENTIONAL VS
ACCELERATED TREATMENT
CONVENTIONAL
TREATMENT
3 cycles of CC with IUI
3 cycles of
Gonadotrophin
with IUI
≤ 6 cycles of IVF
ACCELERATED OR FAST
TRACK TREATMENT
3 cycles of CC + IUI
IVF
Median time to preg.
3m. faster
Couples in accelerated arm conceived more quickly and PR were
higher than those in conventional arm

IUI / IVF – effectiveness in UI
Multicentre RCT (Bensdorp et al, 2015)
Indicates per-cycle success rate of IUI lower
than that of IVF
Cumulative IUI SR comparable to those of
IVF
IUI remains less invasive, less stressful, less
time consuming
IUI + COH remainsa very realistic option

‘Indication – creep’
That is – once a technology has been
accepted and adopted for use in one
clinical area or patient group, the
door is often open for its use to
spread to other patient groups,
without formal consideration of
cost-effectiveness
Overutilization of treatments serves
neither patients nor society

Cost Analysis

Conclusions
‘Absence of evidence is not an evidence of absence’
Thorough and time efficient investigations
Treatments to be individualized
Factors to be considered –
age of female partner,duration of subfertility and previous pregnancies
Expectant management
Low cost
Lowest cycle fecundity rate
*Option in young women and with good ovarian reserve
*Impatience on the part of practitioners and couples frequently leads to overtreatment
CC with or without IUI-is not suitable for UI
3 – 4 cycles of IUI & OI with Gonadotrophins
Benefinicial for suitable couples
IVF – should remain 1st choice only for those with
Long duration of subfertility
Ov. Reserve deteriorating or
When conservative treatment failed
Treatment of choice when less expensive and simple modalities failed

Summary
 Progress from low tech to high
tech options
 Definite need for multicenter trials
to identify best treatment option
in Unexplained infertility

New Perspectives : Unexplained infertility 2018

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