Adjuvant therapy

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 : [email protected]