Transcript Document

Dr Sohani Verma
Sr. Consultant Obstetrics & Gynaecology
Infertility & ART Specialist
Clinical & Academic Coordinator
Indraprastha Apollo Hospitals, New Delhi
Chairperson North Zone AICC RCOG
President Elect Indian Fertility Society
Introduction
 A woman of reproductive age who has not conceived
after 1 year of unprotected vaginal sexual intercourse, in
the absence of any known cause of infertility, should be
offered further clinical assessment and investigation
along with her partner.
 Offer an earlier referral for specialist consultation to
discuss the options for attempting conception, further
assessment and appropriate treatment where –
- the woman is aged 36 years or over
- there is a known clinical cause of infertility or a
history of predisposing factors for infertility
NICE Guidelines 2013
Main Causes of Infertility
Male
34%
Cervical
3%
Uterine
11%
Tubal
23%
Hormonal
29%
Multiple relatively minor abnormalities, either with 1 partner or both,
account for 30% of all causes
Assisted Reproductive Techniques (ART)
Any treatment that deals with “means of conception
other than vaginal intercourse” is termed as ART.
NICE guideline 2013
 IUI – Intra Uterine Insemination (Husband /
Donor)
 IVF + ET – In Vitro Fertilization + Embryo transfer
 ICSI – Intra Cytoplasmic Sperm Injection
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•
•
IUI
Injection of washed prepared sperms into
the uterine cavity through a fine catheter
during peri-ovulatory phase in a natural
or stimulated cycle.
Although pregnancy may not occur as quickly, a policy of
initial treatment by IUI will probably save 20% of couples
from moving onto IVF
After 3-4 cycles of failed IUI treatment, patients should
be encouraged to opt for IVF
IUI
The procedure may help in increasing the chances of
pregnancy in following ways –
1. Allowing sperm-ovum contact close to the date and time of
ovulation
2. By bringing the sperm very close to the site of fertilization
and by passing the cervical factors
3. Sperm preparation increases the sperm density and
removes all antigens on the surface of sperm and in seminal
plasma
- IUI is the simplest and the least expensive method of
ART
- IUI alone (natural cycle) does not improve pregnancy
chances, hence mild ovarian stimulation is usually
recommended.
Indications for Intra Uterine Insemination (IUI)
- At least one Fallopian tube must be normal and
patent
- Mild male infertility
- Unexplained infertility
- Ovulatory dysfunction, PCOS
- Mild endometriosis
- Cervical factors
- Coital problems
- Immunological factors
- HIV, HBs Ag infection
- Donor Sperm
Indications for Donor Sperm IUI
 Azoospermia (where ICSI
is not an option)
 Severely subnormal semen parameters (ICSI
not an option)
 Persistent failure of ICSI
 Rh Isoimmunization
 Hereditary disease in the male partners
Indication for ART – IUI or IVF
 The indications for IUI are often not
dissimilar to those for IVF (or even
for ICSI for moderate male factor)
and often interchangeable with
overlapping.
Common Indications for IUI
- Unexplained infertility
- Endometriosis (mild)
- Male factor infertility (mild)
- Ovulatory disorders
- Inability to have vaginal intercourse
- People with conditions that require
Indications for IVF
- Unexplained infertility
- Endometriosis (moderate to severe)
- Male factor infertility (moderate to
severe)
- Ovulatory disorders
- Tubal pathology
specific consideration (such as man HIV - Donor Oocyte
positive)
- Genetic Surrogacy
- People in same-sex relationship
- PGD (Possibility of genetically
- Donor Sperm
transmitted disease)
- Fertility preservation in cancer
patients
- Where ICSI is indicated
(Azoospermia)
Meta-Analysis of IUI in Male Factor
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Timed intercourse in natural cycle
Timed intercourse in COH cycle
IUI in natural cycle
IUI in COH cycles
Pregnancy Rate
2.4%
5.0%
6.5%
12.6%
Cohlen BJ et al Cochrane database Syst Rev 2003
Basic requirements for IUI success
1. Patient selection
- Age of female partner < 35 years
- Duration of infertility < 5 years
- Cause of infertility (at least one functional normal
-
fallopian tube and no uterine factors)
Adequate ovarian reserve (based on Serum AMH, antral
follicle count, Day 2 FSH, LH, E2 levels)
Semen parameters Post wash TMSC >5 million/ml
Best pregnancy rates with >10 million/ml
< 1 or 2 million/ml – do not waste time in IUI.
Advice IVF / ICSI straight away
Basic requirements for IUI success
contd…
2. Choice of ovarian stimulation used
3. Number of dominant follicles – 1 to 3 follicles
4. Use of “transvaginal ultrasound follicle monitoring”
5. Timing of IUI
- Between day 12 to 16 of the cycle usually highest
pregnancy rates
- Interval from hCG injection 32-42 Hours usually
recommended (range 12-60 hours)
- Single IUI 36 hours after hCG is usually the
preferred option.
Basic requirements for IUI success
contd…
6. Semen preparation technique – Quality and
expertize of lab personnel
7. Procedure of IUI & type of catheter used
8. Luteal support is recommended
9. How many IUI cycles- 3-6 cycles usually
recommended
INTRAUTERINE INSEMINATION – ESHRE Guidelines
 There is general agreement in the literature that chances of
success are better after mild ovarian stimulation and the
maturation of a maximum of two or three follicles.
 However, the cycle must be monitored by ultrasound and
hormonal analysis; if there are more than three mature follicles,
the attempt should be cancelled.
 While the concurrent use of ovarian stimulation may
increase pregnancy rates, it may be at the expense of a
high chance of multiple pregnancy.
 The majority of pregnancies occur during the first six
cycles. In any case, the number of attempts should not exceed
nine cycles.
 When assessing the duration of an IUI programme, the age of
the woman must be taken into account, to ensure timely
transfer to more complex treatments if indicated.
• The world's first "test-tube
baby", Louise Brown, has
spoken of her joy at giving
birth to her first child.
• Baby Cameron was born on
20 December’06 in Bristol,
where his 28-year-old mother
lives with husband Wesley
Mullinder.
Well over two million "test-tube" babies have been born globally
since Louise's 1978 birth after IVF
IVF and ET
•
In Vitro Fertilization (IVF) and Embryo Transfer (ET) are the basic ART
for all related technology. These include:
-
Intra Cytoplasmic Sperm Injection (ICSI)
-
Assisted hatching
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Pre-implantation Genetic Diagnosis (PGD)
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Cryopreservation
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Donor oocyte IVF programs
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Donor embryo (genetic surrogacy)
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Intracytoplasmic Morphologically selected
Sperm Injection (IMSI)
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And many more
Various steps of an IVF treatment cycle
Pre IVF work-up
Ovarian stimulation
Monitoring
Preparation of
sperms
Oocyte retrieval
Ovulation induction
In Vitro Fertilization
Embryo transfer
Luteal Support
IVF & ET
Procedure
 Picture
In vitro embryo development
COC at the time of
retrieval
4 cell embryo
M II oocyte with a PB
(Mature)
8 cell embryo
2 PN embryo
Fully grown blastocyst
Indication for IVF
I. IVF as first line infertility treatment
- Tubal pathology (severe, non-repairable)
- Donor Oocyte
- Genetic Surrogacy
- PGD (Possibility of genetically transmitted disease)
- Fertility preservation in cancer patients
- Where ICSI is indicated (Azoospermia)
II. IVF following failed cycles of IUI
- Usually up to six cycles of IUI with controlled ovarian
stimulation are recommended, but there are situations
where couples should move to IVF earlier.
Indicators for early referral
I. Female age
- The biological clock is the major adversary to human
reproduction
Woman’s age is the initial predictor of her
overall chance of success
Live birth rates per Embryo
transfer by age (HFEA postOctober 2007 data)
NICE Guideline 2013
II. Diminished Ovarian Reserve at any age
- AMH- anti-Mullerian hormone of less than or equal to
5.4pmol/l
- Antral Follicle Count (AFC) – Less than or equal to 4
- Day 2/3 FSH >8.9 IU/L
III. Endometriosis
IV. Moderate (more than slightly abnormal) degree of semen
quality abnormalities.
V. Tubal Compromise
NICE Guideline 2013
ICSI
• Unprecedented
successful development
of ART which has
revolutionized the
management of severe
male infertility (Van
Steirte-ghen 1992)
• The procedure
involves the direct
injection of a single
sperm into the egg
cytoplasm
Indications for ICSI
- Severe alterations of semen characteristics
- History of fertilization failure in conventional IVF
attempts
- Testicular or epidydimal sperm
- Other relative indications
Success rates following IVF / ICSI
 24.7 percent clinical pregnancies of
all women
who undergo IVF treatment (HFEA 2011).
 50% of
all embryos cultured in vitro reach
blastocysts stage by day 6.
 About 15% of
into a baby
transferred embryos will develop
Basics requirements for IVF/ICSI success
1. Pre – IVF work up of the infertile couple
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Clinical history
Examination
Investigations
Counseling
Why necessary?
 To identify the cause of infertility and thereby prognosis
 To identify and correct associated adverse factors before treating
primary disorder
 To decide most appropriate treatment protocol
- Type of drug
- starting dosage
- expected response and problems
 To assess reproductive ageing and plan early access / resort to ART
treatments
Basic requirements for IVF/ICSI success
2. To get adequate number of good quality oocytes
A. Predictors of COHS response
- Age, AMH, AFC
- Response to earlier COHS
- Basal FSH, LH, E2
- BMI, Smoking, Alcohol
- Previous Ovarian Surgery
B. Selection of COHS protocol
- Agonist versus Antagonist protocols
- Mild stimulation protocols
Normal responders
Hyper responders
Hypo- responders
contd…
Basic requirements for IVF/ICSI success
2.
3.
4.
5.
6.
7.
8.
9.
C. Ultrasound monitoring with power and colour
Doppler
D. Biochemical Monitoring
Ovulation induction
- hCG - urinary / recombinant
- GnRh agonist
Technique of Oocyte retrieval
Embryology lab quality and expertize
IVF or ICSI
Selecting best embryo (s) for transfer
Number of embryos transferred
Embryo transfer technique
Luteal Support
contd…
Luteal Support
Luteal Support

The transformation of mature follicle into corpus Luteum
(CL) after the release of ovum is triggered by an optimal
LH surge.

The function of CL is dependent upon continued LH
stimulation in luteal phase.

CL is an essential source of pro-fertility hormones ie
Progesterone (P), Estrogen (E) and other vasoactive and
growth factors.
Luteal Support
 It is well established that the ovarian stimulation
regimens used in assisted reproduction cycles
alter the luteal phase.
Edwards et al 1980, Kolibianakis et al 2003
 Ovarian stimulation causes
- an inadequate development of the endometrium
- an asynchrony between the endometrium and the
transferred embryo and
- adverse effects on endometrial receptivity
Macklon & Fraser 2000, Devroey et al 2004
Luteal Support
contd…
 The luteal phase defect in IVF is present whether
GnRH agonist or antagonist is used (Friedlers et al
2006).
 The possible mechanism responsible may be –
- Continuation of pituitary down regulation effect
- Duration of luteal phase is shortened
- Formation of multiple CL leading to inhibition of
pulsatile LH release
- Loss of granulosa cells during oocyte retrieval
Luteal Phase Support
I. Endometrial support – complements production by CL
(i) Progesterone preparation
(ii) Estrogen preparation
II. Agents which support CL
(i) hCG
(ii) GnRH-analogue
(iii) LH
III. Newer agents which promote angiogenesis and
vascular supply
Progesterone preparations available
(i) Micronized
(a) Oral / vaginal
(b) Vaginal Gel (8%)
(c) Vaginal Pessary
- 200-400 mg BD
- 90 mg daily
- 100-400 mg daily
(ii) Intramuscular (oil based)
- 100-400 mg daily
(iii) Subcutaneous (aqueous preparation) - 25 mg daily
(iv) Synthetic – Dydrogesterone
- 10 mg BD or TDS
Estrogen as an adjuvant to LPS
 Estradiol valerate. Hemihydrate
- Oral (intravaginal)
- 2-6 mg/day
 Micronized Estradiol
- Oral or intravaginal
- 2-6 mg/day
 Transdermal Estradiol
- Patches (2 per week)
- 50-100 ugm/day
GnRH agonist as an adjuvent to LPS
Luteal Phase Support for assisted reproduction cycles
(Cochrane Review 2011)
- Tesarik J et al 2006 published their result on 600 women
randomly assigned to receive a single injection of GnRH agonist
(0.1 mg of triptorelin) or placebo on Day 6 after ICSI. The
results showed improvement of implantation and live
birth rates.
- Van der Linder et al investigated progesterone versus prog +
GnRHagonist
- Six studies (1646 women)
- There were significant results showing a benefit from
addition to GnRH agonist to progesterone for the
outcomes of live birth, clinical pregnancy and ongoing
pregnancy.
Luteal Phase Support for ART Cycles
Cochrane Review 2011
Authors' conclusions
 Cochrane review 2011 showed a significant effect in favour of
progesterone for luteal phase support, favouring synthetic progesterone
over micronized progesterone. Overall, the addition of other substances
such as estrogen or hCG did not seem to improve outcomes.
 They found no evidence favouring a specific route or duration of
administration of progesterone.
 It was found that hCG, or hCG plus progesterone, was associated with a
higher risk of OHSS.
 The use of hCG should therefore be avoided.
 There were significant results showing a benefit from addition of GnRH
agonist to progesterone for the outcomes of live birth, clinical
pregnancy and on-going pregnancy.
 For now, progesterone seems to be the best option as luteal phase
support, with better pregnancy results when synthetic progesterone is
used.
Nutritional Supplements and ART outcome
No definite conclusive evidence
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Anti-oxidants – Vit C, E, selenium, zinc, taurine,
carotene, lycopene
Vitamins – Folate, Vit B 12
Myoinositol and D-chiro-inositol (vit B complex)
L – Arginine
DHEA
Dehydroepiandrosterone (DHEA)
supplementation
 Cason and associates (2000) were first to suggest therapeutic benefits from
the supplementation of DHEA in women with diminished ovarian reserve
and suggested it may improve oocyte yields via IGF-1.
 It was left to a 43 year old infertility patient in US (advised donor oocytes)
to discover their paper and self administer DHEA while undergoing
subsequent IVF cycles.
The patient underwent nine
consecutive IVF cycles and
increased oocytes and embryo
yields from cycle to cycle,
starting with one egg and
embryo, respectively, and
ending up with 17 oocytes and
16 embryos in her ninth cycle.
(Gleicher et al 2009)
Dehydroepiandrosterone (DHEA)
supplementation
 While all other pharmacological agents affect follicle
maturation only during the final stage – gonadotropin –
sensitive last 2 weeks, DHEA in contrast appears to affect
folliculogenesis at much earlier stages of in-vivo follicle
maturation
(Gleicher N etal 2011)
 DHEA has been shown to increase the number of primary,
preantral and antral follicles.
 DHEA supplementation is reported to improve ovarian
response, IVF parameters and pregnancy chances. Younger
patients with POA appears to have a slight pregnancy
advantage.
Cumulative pregnancy rates in women with DOR with and without DHEA
supplementation. POA patients appear to have a slight pregnancy advantage,
Barad et al 2007
DHEA supplementation is also shown to significantly
(50-80%) reduce the miscarriage risks in patients with
poor ovarian reserve
(Gleicher etal 2007)
Age-stratified miscarriage rates in DHEA supplemented DOR patient in
comparison to national U.S. IVF pregnancies. Gleicher et al 2009
Treatment protocols, side effects and complications
 Micronized DHEA at a dosage of 25mg TID
 Effects occur relatively quickly (6-8 weeks) but peak
only after 5-6 months of supplementation.
 Side effects are small and rare and primarily relate to
androgen effects – oily skin, acne vulgaris and hair loss.
 Even long-term therapy of DHEA in suggested dosages
have been demonstrated safe (Panjari M etal 2009).
 However, before declaring DHEA as a wonder
drug, larger RCTs are urgently needed to confirm
the benefits.
Sohani Verma