Adjuvant therapy
Post on 22-Aug-2014
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حمن الر الله بسمحيم الر
Adjuvant Therapy in IVF
Why!!!
• To improve results of IVF e.g LMWH• To overcome Potential threats e.g antibiotics • To prevent complications i.e Cabergoline
success• pregnancy rates in ART.
Adjuvant medical therapies to improve implantation
• Aspirin.• Ascorbic acid .• Vitamin E.• Corticosteroids.• Heparin.• Luteal E2 supplementation.• Nitric oxide donors.
Adjuvant interventions
• For hydrosalpinx• For uterine cavity evaluation• others
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
Treatment with Hysteroscopy
HSC vs SonoHSG
• Very few studies • Insufficient evidence
• The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial.
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
Back to Medical Adjuvant
• To improve results
High dose FSH at hCG triggering
• Novel concept• Give four ampoules of FSH at time of hCG
injection• Why??????
LH surge is associated with FSH surge to a lesser extent
Outcome??
•10%
To prevent Complications
• OHSS
OHSS is the most serious complication
of ovulation induction.
Protocols for IVF GnRH AntagonistProtocols
GnRH AgonistProtocols
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 6of FSH/HMG
Dayof hCG
Day 1 of FSH/HMG
Day 6of FSH/HMG
Dayof hCG
7 – 8 daysafter estimated ovulation
Down regulation
Day 2 or 3of menses
Day 1 FSH/HMG
(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
Long Protocol
GnRH agonist daily/depot
DAY 21
No CystE2<200pmol/L
hCG
OPU
32-42h
6
FSH
1
≥3 follicles ≥16mmand/orE2 ≥1000 pmol/L / foll ≥16mm
Value
• allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.
23Why RCTs?
Participants
R a
n d
o m
l y
A
s s
i g
n e
d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
Our ResultsParameter Coasting (n = 96) Antagonist (n = 94) P-value
Age (years) 30.0 ± 4.9 29.6 ± 4.6 NSDuration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS
No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NSDays of stimulation1 9.1 ± 1.5 9.4 ± 1.5 NSPeak 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 <0.0001No. 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 0.0001No. 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
Intravenous Albumin to Prevent OHSS
• Cochrane review update (Al-Inany et al., 2011)
7 randomized controlled trials
Clear evidence of beneficial effect
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
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
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
IV fluids versus placebo, Severe OHSS
18/23
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.
After OPU: Dopamine Agonist : Youssef et al., 2010
Youssef et al., 2010
But it is expensive!!
• So is there any other drug???
Metformin Cochrane review, Tso et al., 2008
The Aromatase Inhibitors
• Letrozole (Fimara 2.5 mg)• effective. • It reduces E2 level.
To overcome Potential threats
InfectionPoor response
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 .
Prediction
• age; • FSH,• estradiol, • inhibin, • anti-Müllerian hormone; • AFC
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
Growth Hormone
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
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???
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
To improve Implantation
Luteal E2
• No evidence of improvement in pregnancy rates
Dragisic KG, et. al., Fertility and Sterility, Oct 05, 1023-6.
Assisted Hatching
• Routine assisted hatching is not recommended because it has not been shown to improve pregnancy rates
Sildenafil
– Vaginal sildenefil improves uterine artey blood flow and sonographic endometrial appearence
• Sher G, HR 2000
• No evidence of effectiveness
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
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
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
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
Acupuncture
• 3 potential mechanisms– > Neurotransmiters, GnRH,
FSH, E2, “O”– > Uterine blood flow– < Endogenous opioids
• Cho ZS, PNAC 1998
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
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
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
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
Thank youDr. Hesham Al-Inany MD, PhDe-mail : Kaainih@yahoo.com
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