Stress Urinary Incontinence (SUI) : Dr Sharda Jain
IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bhaskar Dr. Jyoti Agarwal Dr. Abhishek Parihar
1. IVF – ICSI
in PCOS
DIFFICULTIES AND SOLUTIONS
Dr. Sharda Jain
Dr. Jyoti Bhaskar
Dr. Jyoti Agarwal
Dr. Abhishek Parihar
2. ESHRE/ASRM-Sponsored PCOS Consensus Workshop
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Group March 2007, Thessaloniki, Greece.
Human Reproduction 2008
These INFERTILITY GUIDELINES FOLLOWED WORLD OVER
3. CHALLENGES IN IVF cycles in
PCOS
• Selection of patients of PCOS for IVF
• Pre IVF work-up
• Pre IVF Treatment
• Which Protocol to be used & Rationale
• Prevention of OHSS in PCOS patients
• Challenges in titrating Gonadotropin dose rationale
• Unpredictable & exaggerated ovarian response & OHSS
prevention.
• Early treatment of early and late OHSS
• Increased risk of cycle cancellation
• Increased risk of spontaneous pregnancy loss
4. OVERVIEW of PPT
• Selection of patients of PCOD for IVF
• Pre IVF work-up
• Pre IVF Treatment if any
• Which Protocol to be used & Rationale
• Challenges in titrating Gonadotropin dose
rationale
• Prevention of OHSS in our PCOS patients
5. CLASSIFICATION
WHO
• I - Hypothalamic pituitary failure
(Hypogonadotrophic hypogonadism)
Kallman’s, Sheehan’s, anorexia
• II - Hypothalamic pituitary dysfunction (PCOS)
• III – Ovulatory Failure – Hypergonadotrophic
hypogonadism, Turner’s, autoimmune, mumps, RT, CT
6. DIAGNOSIS OF PCOS
( Rotterdam’s Criteria)
Diagnosis of PCOS is made in the prsence of at least two of
the following three criteria, when congenital adrenal
hyperplasia (CAH), androgen- screening tumors, or Cushing
syndrome have been excluded.
• Oligo – Ovulation or Anovulation
• Clinical / biochemical evidence of hyperandrogenism
• Polycystic ovarian on ultrasonography (>12 small antral
follicle in an ovary)
7. Selection of PCOS Patients for IVF
Patients who fail to conceive following the use of
•First & second Line Ovulation Induction
Medications and / or
• Laparoscopic Ovarian diatheramy or
• THREE IUI in conjunction with ovulation
induction
8. It is Good to RULE OUT Diagnosis of
following before start of IVF
Treatment
Ensure good general health of women to ensure safe
pregnancy in case of success
BMI
Pre-Diabetes
Hypertension
Fatty Liver
Diabetes type II Hyperlipidemia
Insulin Resistance Hypo-Thyroidism
Metabolic Syndrome Vitamin-D Deficiency
10. Pre. IVF Considerations in
PCOS Patients
• Weight Loss In Overweight Women
* Structured weight loss
* Place of Orlistat
* Bariatric Surgery
• Metformin
• OCP Prior to IVF
• Hysteroscopy & EB to R/O TB
11. Obesity
60 – 65 % of our patients are over weight or obese
Over weight BMI > 24
Obese BMI > 27
Morbid Obesity is >32.5
Literature shows that patients of BMI > 29, they are
likely to take longer to conceive. So it is good to lose
weight by structured weight loss programme and not
be allowed to do on their own
It is our policy not to take patients over BMI 30
12. BMI Cutoff for INDIAN
-2.5 in Each Category
BMI Cutoff Weight Status Comments
<18.5 UNDERWEIGHT Being underweight also puts you at risk
for developing many health problems.
18.5 - 23.9 HEALTHY WEIGHT
RANGE
Your weight is within normal range. You can
continue to keep a healthy weight through physical
activity and healthy eating. Keep up with the good
work!
24 - 26.9 OVERWEIGHT Being overweight can put you at risk for
developing many chronic diseases
>27 OBESE
Obesity increases risks for developing many
chronic diseases such as heart disease and
diabetes, and decreases overall quality of
life.
13. FAT DISTRIBUTION
–CENTRAL OBESITY android,
APPLE SHAPE
Central Obesity is High Risk
For Co-Morbidities /
Complications PEAR SHAPE
Even if the BMI is the normal central
obesity judged by size of the waist is
detrimental to conception
15. Lifestyle Modifications
Before the initiation of IVF, importance of
lifestyle modification should be stressed,
particularly
• Weight loss (Structured weight loss programme is always better)
• Increase Exercise
• Smoking Cessation &
• Reduced Alcohol consumption
16. PHARMACOTHEREPY
for Weight Loss
All drugs are banned except Orlistat . This decreases
the absorption of fat by 30% but also decreases
absorption of fat – soluble vitamins, such as
vitamine D
We recommend multivite containing Vitamin – D
either before or after orlistat treatment.
It is not advised in patients with cholestasis and
malabsorption syndrome
17. Bariatric Surgery
A serious approach to serious problem
We try to motivate patients once the BMI is 32 +
LAP Adjustable Gastric Banding
Given - up procedure in India
SLEEVE Gastrectomy &
Gastric Bypass surgery
are the only alternative &
done routinely
Weight Loss of 40-50 kg is Expected
18. Pre - Pregnancy
counseling
after Bariatric surgery
When ever possible, pregnancy should be delayed TILL
WEIGHT LOSS STABILIZES for 12-24 months, use active
contraception
19. Nutrient Supplements After Bariatric
Sx
(In Non-Pregnant)
Supplement Dose per day
Multivit 1-2
Calcium Citrate 1200-2000 mg
Vit-D 400-800 IU
Folic Acid 400 ug
Elemental Iron 40-65 mg
Vit-B12 350 ug orally or 1000 ug IM/month
20. Role of Metformin in IVF
ADVANTAGES
ESHRE and ASRM international workshop concluded that
metformin should no longer be considered as a first – line
medication in PCOS,anovulatory infertility and should be
restricted to those women with demonstrable glucose
intolerance.
We also use It in patients with BMI > 30
The use of Metformin to decrease Incidence of OHSS in
high responders
is known to be beneficial, so it should be started a month
or two prior to IVF
21. DOSE OF METFORMIN
• DOSE :
1500 mg in divided doses
• GI Side-effects are known
• Risk of Lactic acidosis is minimum in non-diabetic
women
• However serum creatinine, SGOT/SGPT must
be done
22. Laparoscopic Ovarian Drilling as an
Adjunct to I.V.F.
• May decrease the frequency and severity of
OHSS in women with a previous episode of
OHSS
• May facilitate ovarian stimulation in the
brittle PCOS patient
(Ferraretti, Fertil Steril 2001)
23. OCP
We continue to use it as it gives rise to :
• Similar size of cohort follicles
• Decreases LH levels
24. Our Aim & Which Protocol Should Be
AIM - Optimal Ovarian Stimulation for
Used in PCOS Patients
IVF
AIM :
• Avoid understimulation
• Avoid overstimulation
• Minimize cycle cancellation
• Minimize if not avoid altogether OHSS
OOVVEERR SSTTIIMMUULLAATTIIOONN
OOPPTTIIMMAALL SSTTIIMMUULLAATTIIOONN
UUNNDDEERR SSTTIIMMUULLAATTIIOONN
150 187.5
112.5
25. WHICH PROTOCOL
LITERATURE NOW SHOWS
Pregnancy Rate Same
in Agonist Long Protocol &
Antagonist Protocol
26. CDC Report also shows 2008
Pregnancy Rate same
in FRESH / FROZEN – thawed cycles
28. INCIDENCE of OHSS
MILD – 33% Now Omitted in IVF Cycles
MODERATE – 3-6%
SEVERE – 2%
Critical – 0.1 – 0.2%
WE SHOULD ALL AIM FOR OHSS FREE IVF PREGNANCY
Dr Razia S 28
29. We have to be careful….
PRIMARY RISK FACTORS for OHSS
WHO are AT HIGH RISK BEFORE OI – in IVF
Young patients
Lean women
Polycystic Ovarian
PCOS
Previous OHSS
Easily
Recognized
SENSITIVE OVARIES
AFC over 16 (Both Ovaries)
(>- 10 follicle of 4-10mm in each ovary)
• Raised AMH
25.0 pmol/l for a high response
( >6 ng/ml
30. Optimal IVF Cycle Management in the
PCOS Patient
• Careful titration of the gonadotropin dose
• Measures to prevent OHSS
– GnRHa for triggering final oocyte maturation
– Cabergoline before ovulation trigger
– Single Blasto cysts transfer vs Cryopreservation of
all embryos
– Coasting ???
31. Clinics providing ovarian stimulation with
Gonadotrophins for IUI/IVF -
Protocol should be in place for preventing,
diagnosing and managing
Ovarian Hyperstimulation Syndrome
Nice Guideline 2004
32. Proposed Protocol of
Zero% OHSS
STEPS 3 Steps
• The use of the GnRH antagonist protocol
for OI instead of long protocol
• Ovulation Triggering with GnRH agonist
Instead of HCG trigger
• Cryopreservation of all oocytes and embryos
↓
ET in frozen – thawed cycle
I
II
III
33. STEP III
CRYO PRESERVATION
of oocytes & embryo
A valuable modality…
But Skill - is the key
Oocyte / embryo vitrification –
↑ P.R. (40% - 80%)
↓ Severe OHSS to 0%
Results better than COASTING
Ethical Issue of freezing embryo
34. GnRH Antagonist Flexible Protocol
Day 2
Follicle size 14 mm
Or 6th Day HCG OPU
GnRH antagonist Follicle size
18-20 mm &
endometrium 08
mm+
Day 1
REC FSH / HMG
Blood Test – LH, E2
Progesterone
TVS Injection Rec FSH / HMG
34 and half
hrs later
35. Protocols Used at
Lifecare IVF & Surrogacy Centre
• Gonadotrophin of choice …. FSH at least for first
four days
• Dose: Varies between 150-300units
Depends on BMI, AFC, AMH
• Change over to HMG after 4-6 days of FSH
36. ANTAGONIST PROTOCOL
We have given up Agonist protocol in PCOD patients
• All PCOD patients are taken for antagonist
protocol to minimise risk of OHSS
• We freeze all embryos & do ET in next cycle
or do blastocyst transfer
Fragmentation of IVF
37. Predictors of Ovarian Reserve Before
Starting IVF Protocol
CHARACTERISTICS FOR A GOOD
MARKER
AGE AMH FSH AFC
PREDICTION OF POOR
RESPONSE
+ +++ ++ ++
+
PREDICTION OF HYPER –
RESPONSE
+ +++ _ ++
COST +++ _ _ _
*FSH and antral follicle count (AFC) are not informative in patients on OCP or GnRH
agonist treatment. Moreover the count of antral follicle may be difficult in women
with ovarian cysts or with previous pelvic surgeries
38. How we modify FSH dose according to
AMH nmol/L
Negligible < 1 Low 1 - 2 Normal 2 - 6 High (over 6)
Very poor
responder
High cycle
cancellation
Treatment Donor
Egg IVF
Poor/ average
responder
High dose FSH –
300 IU
Good
Responder
FSH dose 225
Hyper –
responder/ OHSS
Low dose FSH
150 IU
Significance of AMH levels prior to IVF
40. ANTAGONIST PROTOCOL
• Flexible Protocol
Antagonist added when lead follicle is
14mm.
• Monitoring is done by Transvaginal
Sonography Alone
• Trigger is given when at least 4 -5 follicles are
18-20mm.
41. TRIGGER
• In our experience, minimum of 10 days of
stimulation is essential to get mature oocytes.
• Trigger used is
1. Agonist trigger
2. Recombinant HCG trigger
3. HCG: 5000 -10000 units
• OPU done 34 ½ hours after trigger
42. Adjuvant Therapy to Prevent OHSS
• Metformin
• Cabergolin 0.5gm OD
(to be started before giving the HCG trigger)
43. METFORMIN AND OHSS
• Two meta-analyses found that metformin co-administration
in PCOS women undergoing IVF
decreased the incidence of OHSS
• The beneficial effect was observed in all RCTs
regardless of duration and dosage of metformin
• Number of oocytes collected and peak E2 levels were
unaffected by metformin
Costello et al. 2006 Hum. Rep. 21(6);1387 – 1399
Moll et al. 2007 Hum. Reprod. Update 13(6); 527 - 537
44. GGnnRRHHaa TTrriiggggeerriinngg ooff OOooccyyttee
MMaattuurraattiioonn--hhiinnttss aanndd ttiippss
• Lower implantation rates reported in some
studies may be attributed to the luteolytic
effect of the GnRHa
• Titration of the luteal phase support is
important
Both these issues are irrelevant as we do
not do ET in stimulation Cycle
47. FET PROTOCOL
ET
Follicle size 14 mm
Or 6th Day HCG OPU
GnRH
antagonist
Follicle size
18-20 mm &
endometrium
08 mm+
OPU
Rec FSH / HMG
Blood Test – LH, E2 Progesterone
TVS
Injection Rec FSH / HMG
34 and half
hrs later
48. FET Protocol
Day 2
Day12 -14
B HCG
ET
ET 8- 12 mm
Oestiadiol Valerable 2mg TDS
Ultrasound , ET , Dopplers
Injection Progesterone
100 mg i/m daily
According to
embryo dating
S. Prg >0.5 ng/ml
Cycle cacel
49. Hormonally Manipulated Cycles in Frozen ET
( Non GnRH-a Programmed)
• D2 P (prog > 0.9 ng/ml cycle cancellation) 6mg E2 Valerate
• Ultrasound Monitoring of endometrium.
• D12-14 .. When ET > 8mm, Triple line, Doppler assessment… P
measurement (for spontaneous ovulation) (prog>0.9 ng/ml cycle
cancellation)
• And Injectable Progesterone 100 mg daily till ET( LPS )
• ET according to Embryo dating
• β-hCG after 15 days of ET
• If pregnancy is present, E2 and P dose x2 is maintained until placental
autonomy.
50. Hormonally Manipulated Cycles in Frozen ET
( GnRH-a Programmed)
D21(Luteal) GnRH-a 10-14 days
Day 2 ... Confirm Down regulation
(P‹ 0.5ng, E2 ‹50pg, LH ‹ 5 mIU) did not occur, treatment is
maintained for one more week and values are repeated
After down regulation, the duration of proliferative phase
which will last until the commencement of progesteron is
approximately 12-20 days.
51. Hormonally Manipulated Cycles in Frozen ET
( GnRH-a Programmed)
HRT is initiated after down regulation.
D1-D8 E2 Valerate 2 mg
D9-D12 4-6 mg
D12-14 .. When ET > 8mm, Triple line, Doppler assessment…
P measurement (for spontaneous ovulation)
Injectable Progesterone 100 mg daily till ET
ET according to Embryo dating
Luteal Phase support with progesterones to continue
β-hCG after 15 days of ET
If pregnancy is present, E2 and P dose x2 is maintained until
placental autonomy.
53. PROGESTERONE
• Micronised Progesterone started on day of OPU
• Mode of administration;
-- Intramuscular for 14 days
-- Vaginal Pessary 400 mg BD or TDS
• Beta HCG estimation is done of day 15 of ET to
confirm pregnancy
• NO HCG TO BE GIVEN
55. • The outcome in terms of pregnancy and implantation rates is
similar for patients with PCOS when compared with patients
undergoing IVF for other indications.
• There are some questions regarding oocyte and embryo
quality in women with PCOS. This manifests itself in lower
fertilization rate and decreased embryo quality in some
studies. However, increased numbers of oocytes available for
insemination or ICSI compensate for decreased fertilization
rates and embryo quality.
• More recent studies suggest higher cumulative conception
rates in women with PCOS when
compared with controls.
56. Pirinen et al’s study was designed to evaluate cumulative
live birth rates after an in vitro fertilisation (IVF) programme
in polycystic ovary syndrome (PCOS) women.
Despite a lower pregnancy rate among women with PCOS
versus controls, the cumulative baby take-home rate did not
differ between the groups . The first cycle was the most
successful cycle for living birth rate in PCOS group. One-third
of PCOS women, who did not continue after unsuccessful
treatment, had more miscarriage but not more OHSS
compared to those who continued.
They concluded - Although the baby take-home rate was
similar among women with PCOS, and controls, the
outcomes of consecutive cycles were not equal.
Cumulative data give more realistic information than
pooled cycles.
58. OUR RESULTS
1. OHSS in PCOS has made us give - up long protocol.
2. We use antagonist cycles in all PCOS
3. Lately we freeze all embryos & transfer in next cycle.
4. Blastocyst if formed is transferred in the same cycle
5. Our pregnancy rate are much better in frozen cycle than
fresh cycle in PCOS cases.
6. Success has improved from 25 – 30% to 50%
59. IN VITRO MATURATION (IVM)
• IVM of the oocytes has evolved as an alternative in PCO
patients, since it entails no stimulation.
• Germinal vesicle stage oocytes are retrieved from antral
follicles 2–10 mm diameter and IVM is performed until the
M-II stage.
• Advantages of IVM include simplification of treatment,
avoidance of the side-effects associated with the use of
gonadotrophins and thus reduction in treatment costs due
to minimal amount of medication that is used.
• IVM gives reasonable pregnancy rates in women with PCO,
and should be considered as a treatment option in this
group of women if they require treatment with IVF.
62. IVM vs IVF in PCOS
• Randomized trials do not exist
• Comparative studies, non-comparative case series
and randomized trials comparing different
protocols of IVM show:
– Favorable maturation, fertilization, pregnancy and live
birth rates with IVM compared to IVF
– The rate of congenital anomalies appear to be similar
– Urgent randomized trials are needed
63. CONCLUSIONS
• PCOS patient is the most difficult to treat with IVF
• Cycle cancellation rates and risk of OHSS are higher
• Fine tailoring of ovarian stimulation is necessary to
avoid major complication like OHSS.
• It is good to use antagonist protocol, give agonist
trigger & freeze all embryos.
• Treating IVF experts should be aware of the
difficulties (OHSS & multiple pregnancies) and their
remedies and solutions.
64. Conclusion
PCOS infertile women have a better change of
Conception today then they did a decade ago.
To optimise results, however it is important
that patients taken in IVF programme selected
properly & counselled
65. ADDRESS
11 Gagan Vihar, Near Karkari
Morh Flyover, Delhi - 51
CONTACT US
9650588339, 011-22414049,
WEBSITE :
www.lifecarecentre.in
www.drshardajain.com
www.lifecareivf.com
E-MAIL ID
Sharda.lifecare@gmail.com
Lifecarecentre21@gmail.com
info@lifecareivf.com
&
Thank You
