In IVF, clinician tend to use many adjuvants during stimulation : where is the evidence ? which to adopt?

1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

2. Adjuvant Therapy in IVF

3. Why!!!
• To improve results of IVF e.g LMWH
• To overcome Potential threats e.g antibiotics
• To prevent complications i.e Cabergoline

4. success
• pregnancy rates in ART.

6. Adjuvant medical therapies to improve
implantation
• Aspirin.
• Ascorbic acid .
• Vitamin E.
• Corticosteroids.
• Heparin.
• Luteal E2 supplementation.
• Nitric oxide donors.

7. Adjuvant interventions
• For hydrosalpinx
• For uterine cavity evaluation
• others

8. Hysdrosalpinx
• TVUS aspiration of hydrosalpinx (at time of
oocyte retrieval)(Hammadieh et al, 2008
• Salpingectomy or tubal disconnection has
been proved to improve pregnancy rate in
case of VISIBLE hydrosalpinx by U/S

9. Treatment with Hysteroscopy

10. HSC vs SonoHSG
• Very few studies
• Insufficient evidence

11. • The inSIGHT study: costs and effects of routine
hysteroscopy prior to a first IVF treatment
cycle. A randomised controlled trial.

12. Endometrial biopsy (Pipelle)
• EB vs. Local injury
• > Wound-healing effect
• > Decidualization
• > Cytokines
• > Growth factors
• > Uterine receptivity
• > Implantation
• > PR
– Animal studies
• Indications
• < Endometrial receptivity
• > Intrauterine adhesions
• > Endometrial iregularity (US)
• < Endometrial thickness (US)
– Raziel A, FS 2007; Basak S,
AJRI 2002

13. Back to Medical Adjuvant
• To improve results

14. High dose FSH at hCG triggering
• Novel concept
• Give four ampoules of FSH at time of hCG
injection
• Why??????

15. LH surge is associated with FSH surge to a lesser extent

16. Outcome??
•10%

17. To prevent Complications
• OHSS

18. OHSS is the most serious complication
of ovulation induction.

19. Protocols for IVF
GnRH Antagonist
Protocols
GnRH Agonist
Protocols
225 IU per day
(150 IU Europe)
Individualized Dosing of FSH/HMG
250 mg per day antagonist
Individualized Dosing of FSH/HMG
GnRHa 1.0 mg per day
up to 21 days
0.5 mg per day of GnRHa
225 IU per day
(150 IU Europe)
Day 6
of FSH/HMG
Day
of hCG
Day 1
of FSH/HMG
Day 6
of FSH/HMG
Day
of hCG
7 – 8 days
after estimated ovulation
Down regulation
Day 2 or 3
of menses
Day 1
FSH/HMG

20. (GnRH) antagonists: off label
indication
• unique Idea
• Administration during GnRH agonist cycle
• when follicle reach ~16mm and E2 level >
4000pmol
• Decrease but Continue hMG (step down
protocol)
• Monitor by E2
• Not more than 3 days

21. Long Protocol
GnRH agonist daily/depot
DAY 21
No Cyst
E2<200pmol/L
hCG
OPU
32-42h
6
FSH
1
≥3 follicles ≥16mm
and/or
E2 ≥1000 pmol/L / foll ≥16mm

22. Value
• allow continued stimulation while rapidly
decreasing the E2 level to a range that is
clinically acceptable.

23. 23
Why RCTs?
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

25. Our Results
Parameter Coasting (n = 96) Antagonist (n = 94) P-value
Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS
Duration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS
No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NS
Days of stimulation1 9.1 ± 1.5 9.4 ± 1.5 NS
Peak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NS
Oestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NS
Range of oestradiol on day of HCG (pg/ml) 1110–4136 1223–4093 NS
Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001
No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02
No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NS
No. of fertilized oocytes 7.97 ± 3.80 9.14 ± 4.70 NS
No. of high quality embryos 2.21 ± 1.10 2.87 ± 1.20 0.0001
No. of embryos transferred 2.83 ± 0.50 2.79 ± 0.40 NS
No. of cryopreserved embryos 4.50 ± 3.93 5.77 ± 4.87 NS
Clinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NS
Multiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS

26. Intravenous Albumin to Prevent OHSS
• Cochrane review update (Al-Inany et al., 2011)
7 randomized controlled trials
Clear evidence of beneficial effect

27. Administration of human albumin might result
in :-
1. restoration of intravascular volume
2. Inactivation of the vasoactive intermediates
responsible for the pathogenesis of OHSS
5/23

28. Another Colloid
• Hydroxyethyl starch (HES) is a plasma
expander
• it avoids any potential concern about viral
transmission that may be present with
albumin
7/23

29. Results Of Search
31 studies
10 RCTs (n= 2048)
7 RCTs : HA vs. P 1 RCT : HES vs. P 2 RCTs :HA vs. HES vs. P
9/23
No RCTs compared dextran or haemaccel vs placebo

30. IV fluids versus placebo, Severe OHSS
18/23

31. Cabergoline (Cb2) therapy
• Cb2 prevents VP in a dose dependent manner without affecting
angiogenesis and implantation in humans
• Cb2 reduced the amount of ascites, hemoconcentration and incidence of
moderate-severe OHSS5
• Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger
Alvarez, et al, Hum Reprod, 2007; 22: 3210-3214.

32. After OPU: Dopamine Agonist :
Youssef et al., 2010

33. Youssef et al., 2010

34. But it is expensive!!
• So is there any other drug???

35. Metformin Cochrane review, Tso et al., 2008

36. The Aromatase Inhibitors
• Letrozole (Fimara 2.5 mg)
• effective.
• It reduces E2 level.

37. To overcome Potential threats
Infection
Poor response

38. Poor responders: who are them ?
No standard definition or diagnostic criteria exist until now,
 Expected :-
Retrospectively :
history of low ovarian response in their first IVF cycle
Prospectively :
basal day 3 FSH level > 10 IU/mL,
antral follicular count < 5 follicles
advanced women age ≥ 35 years
 Unexpextantly :-
in young patient < 35 years with non elevated FSH level
which may reflect early ovarian aging .

39. Prediction
• age;
• FSH,
• estradiol,
• inhibin,
• anti-Müllerian hormone;
• AFC

40. Growth hormone
• Growth hormone may improve the number of
oocytes but no difference in pregnancy rate
• However, they are expensive and routine use
can not be justified

41. Growth Hormone

42. DHEA
• Rx DHEA 50 mg ½ tab BID (Belmar)
• Can decrease dose for SE, i.e. acne
• Optimal > 8 weeks prior to OPU
• stops med at hCG

43. Infection
• Vaginal antisepsis, negative effect
• < Quality of the oocytes and the embryos
• Bacterial contamination of the ET catheter tip
• But the problem:
• Which antibiotics: against gram –ve, or
anaerobic or gram +ve
• When to give : start of stimulation or around
OPU
• For how long???

44. Controversial role of antibiotics
• Ceftriaxone + metronidazole
• At oocyte recovery
– Reduction of bacteria on the
transfer catheter clip (78,4%)
– > CR
• 21,6 % vs. 9,3%
– > CPR
• 41,3% vs. 18,7%
– Egbase PE, Lancet 1999
• Amoxycillin + clavulanic acid
1g/1,25, RCT
• At oocyte recovery + 6 days
• > Pregnancy loss rate
– 33,3% vs. 20,8% (p=9,15)
• Not recommend this antibiotic
prescription *
• Ensure maximum catheter
sterility *
• Peikrishvili R, JGOBR 2004

45. To improve Implantation

46. Luteal E2
• No evidence of improvement in
pregnancy rates
Dragisic KG, et. al., Fertility and Sterility, Oct 05, 1023-6.

47. Assisted Hatching
• Routine assisted hatching is not
recommended because it has not been
shown to improve pregnancy rates

48. Sildenafil
– Vaginal sildenefil improves
uterine artey blood flow and
sonographic endometrial
appearence
• Sher G, HR 2000
• No evidence of effectiveness

49. Heparin
• Treatment of choice
– Recurrent pregnancy loss due to aPL antibodies
• Heparins are involved in activities anticoagulation and
adhesion of the blastocyst to the endometrial epithelium and
subsequent invasion
• aPL may be responsible
– < Phospholipid adhesion molecules of trophoblast
– < hCG release
– < Trophoblast invasiveness
– < Trophoblast differentiation in vitro
» Fiedler K, EJMR 2004, Di Sormone N, AR 2000

50. Heparin and success rates
• Assumption
– < Immunological status
– < Embryo implantation
• Seropositive women in IVF
– at least one aPL
• Heparin 5000 IU, Aspirin 100
mg daily
• NO significant difference in PR
those treated and those
receiving placebo
– Quenby S, FS 2005,
Stern C, FS 2003
• Seropositive women
– > 3 IVF failures
– at least 1 thrombophilic
defect
• Enoxaparin (Low molecular
weight heparin), 40 mg daily
• > CR,> PR, > LBR/ placebo
• 20,9% vs. 6,1%
• 31% vs. 9,6%
• 23,8% vs. 2,8%
» Qublasn H, HF 2008

51. Immunoglobulin (IgG)
• Indications
– > Embryo failure
– > Recurrent miscarriage
• > Inappropriate
immune response
• > Proinflammatory
cytokines
• Preparations of IgG contain
– All humoral IgG antibodies
– Normally in the plasma of
blood donors
• Effects of IgG:
– < Proinflammatory citokynes
– > Antinflammatory cytokines
– < NK cells
– < Pathological antibodies
• Dose:
– 500 mg iv / kg before ET
• Carp HJ, CRAI 2005
• Coulam CB, EP 2000

52. IgG before ET
• No improve in PR
• Stephenson MD, FS 2000
• No benefit
• Balasch J, FS 1996
• > LBR (SS), meta analysis,
3 RCT
• Clark DA, JARG 2006
• > PR (56% vs. 9%)
• Coulam CB, EP 2000
• > Outcomes in specific
group of IVF patients with
positive APA
• Sher G, AJRI 1996

53. Acupuncture
• 3 potential mechanisms
– > Neurotransmiters, GnRH,
FSH, E2, “O”
– > Uterine blood flow
– < Endogenous opioids
• Cho ZS, PNAC 1998

54. Beneficial effects of acupuncture
• Timing of administration:
– During ovarian stimulation
– At oocyte recovery
– At ET and afterward
• A number of systemic reviews
and meta-analysis have been
conducted on its efectiveness
as an adjuvant treatment
• > CPR, > LBR
• Manheimer E, BMJ 2008
• > PR
– Ng EH, BJOG 2008
• > CPR, > LBR
• El-Toukhy T, BJOG 2008
• > LBR
• Placebo effect and small sample
size cannot be excluded *
• Not recommended as a routine
use procedure *
• Cheong YC, Cochrane database
Syst Rev 2008

55. Aspirin following ET
• Aspirin 75 mg
– Alternate days from
the day of ETuntil 18
days after retrieval
• Evaluation:
– Ovarian blood flow
– Folliculogenesis
– Ovarian
responsiveness
– Uterine vascularity
and receptiveness
• RCT of 1380 women
– LBR
• 27% (with aspirin)
• 23% (without aspirin)
– Waldenstroem U, FS 2004
• Low-dose aspirin does not
improve IVF outcome and it
cannot be recommended for
routine clinical use
– Revelli A, FS 2008; Duvan CL, JARG
2006; Fratarelli JL, FS 2008;
Gelbaya TA, HRU 2007

56. Glucocorticoids
• Immunomodulators
– > Intra uterine environment
– > Implantation rate
– < NK cells
– < Cytokines
– < Endometrial inflammation
– Boomsma CM,
Cochrane Database Syst
Rev 2007
– Tetsuka M, JCEM 1997
– Miell JP, JE 1993
• > Ovarian response to
gonadotrophins
• Dexametasone
– => enzyme 11-beta
hydroxysteroid dehxdrogenase
type 1
– => Directly influence follicular
development
– => Indirectly by increasing
serum GH, IGF-1, and
consequently follicular fluid
IGF-1 levels

57. Glucocorticoids and success rates
• 1 mg dexamethone
• 10 mg prednisolone
• > Implantation rate
– 16.3 vs. 11.6% (NS)
• > Pregnancy rate
– 26.9 vs. 17.2% (NS)
• < Cancellation rate
– 2,8 vs. 12,4% (SS)
– Keay SD, HR 2001
• > Pregnancy rate
– Borderline (SS)
– Boomsma CM, Cochrane
Database Syst Rev 2007

58. Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : Kaainih@yahoo.com