role of atosiban in art dr. jyoti agarwal

Role of Atosiban

In ART

Dr Jyoti Agarwal

Exponential increase in IVF Procedures in India

India performs approx 1 Lac IVF cycles annually &55% of these IVF cycles are performed in the

top eight metro cities

The ART Boom

The IVF cycles are expected to grow at approx 20% p.a

Current 1 Lac cycles will increase to 2.6 Lac cycles by 2020

Improvements to increase success in IVF

• Better culture conditions

• Better selection criteria for best embyro

• Extending embyro to blastocyst stage

Success of IVF

80% women undergoing IVF reach Embryo Transfer

stage………………….

but Pregnancy Rates are Low

Implantation is still considered as

“ Black Box ” of IVF

Embryo TransferFinal & most

crucial step of IVF cycle

Success of IVF

Embryo Transfer should be Absolutely Gentle and Least Traumatic

• Procedure itself increases release of local oxytocin &

prostaglandins

• Any additional manipulation of the vagina or cervix, such

as the use of ellis \ tenaculum provides an additional

stimulus for oxytocin & prostaglandin release which

further increases uterine contractions. However the

pregnancy rates are same

Dorn C. Eur J Obstet Gynecol Reprod Biol. 1999 Nov;87(1):77-80.

The Embryo Transfer Procedure

• Uterine contractile activity in IVF cycles is

increased by approx 6-fold when

measured before embryo transfer as compared to ovulation in the natural cycle

• About 30% of patients undergoing embryo

transfer have pronounced uterine contractions

Cavagna M, Mantese JC. 2003 Oct;24 Suppl B:S39-47.

The embryo Transfer Procedure

• < 50% of transferred embryos remained in the uterus 1 hr after transfer (Menezo et al., 1985)

• About 15% of embryos could be found in the vagina after embryo transfer (Poindexter et al., 1986)

• Uterine contractile activity at the time of embryo transfer could expel embryos from the uterus

Ayoubi JM. Fertil Steril. 2003 May;79(5):1101-5

• IVF cycles induce an abundant increase in oestradiol

concentrations which are about 10–20 nmol/l at the end

of ovarian stimulation as compared to less then 2 nmol/l

in the natural cycle

• Supra-physiological concentrations of oestradiol induces

local endometrial production of oxytocin, formation of

oxytocin receptors, & formation & release of PGF2α

which is similar to the prelabour status

Novel target in fertility treatment

Pierzynski P. Reprod Biomed Online. 2011 Jan;22(1):9-16.

During the very last days of ovarian stimulation

in IVF the endocrine situation ,results in

oxytocin receptor status which resemble those seen before the onset of labor thus resulting in increased excitability of the uterus

Novel target in fertility treatment

Akerlund M. Prog Brain Res. 2002;139:359-65.

Measures at the time of embryo transfer to reduce uterine contractions

• Use of a soft catheter

• Avoid touching the uterine fundus

• Use of ultrasound to guide embryo

transfer

• Use of drugs to reduce

uterine contractionsLan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

Atosiban: Application in Embyo-Transfer

• Inhibition of oxytocin & vasopressin receptors by

Atosiban improves uterine receptivity by

1. Reducing uterine contractions

2. Reduction in intrauterine PGF2α production &

3. Improving uterine blood supply: Atosiban

preferentially relaxes uterine arteries which in turn

increases uterine perfusion

• These potential benefit are useful for implantation

during embryo transfer Pierzynski P. Reprod Biomed Online. 2011 Jan;22(1):9-16.

Effect of atosiban on uterine contractionwaves during embryo transfer

A) Four-minute recording of uterine contractions before the atosiban infusion

B) Recording of uterine contractions after 1 h of infusion

Dotted circles mark uterine contractions.

Published

Clinical Studies

Atosiban Treatment before embryo transfer increases implantation rates in IVF

• RCT (2010 )enrolled

• 180 infertile women undergoing IVF /ICSI who had top-

quality embryos were randomly allocated into treatment and control groups

• The treatment group received IV administration of atosiban before embryo transfer with a total dose of 37.5 mg.

• In the control group, the same number of cycles was performed with placebo medication.

Moraloglu O. Reprod Biomed Online. 2010 Sep;21(3):338-43.

Atosiban Treatment before embryo transfer increases implantation rates

Uterine contractions

decreased from 11contractions per 4 min

to 7 contractions per

4 min as well as decrease in their amplitude

Atosibangroup

Control group

P-value

Implantation rate % 20.4 (57/279) 12.6(34/270)

0.01

Clinical pregnancy rate % 46.7 (42/90) 28.9 (26/90) 0.01

Miscarriage rate (%) 16.7 24.4 0.01

Outcomes of IVF–Embryo transfers in the control & Atosiban groups

P < 0.05 is considered to be statistically significant

These results suggest that Atosiban treatment before embryo transfer is effective in priming of

the uterus for implantation

Effect of Atosiban : Human EndometriumIn IVF program using USG

Atosiban Group - 13 pts

Echogenic endometrium in 1 case (7.7%), triple line endometrium in 12 cases (92.3%),

Endometrial thickness >7 mm in all cases,

Endometrial volume >2.31 cm3 in 11 cases (84.6%),

Abnormal sub-endometrial halo in 3 cases (23.1%),

Endometrial blood flow in 11 cases (84.6%) &

Complex vessel’s architecture in 6 cases (46.2%).

The Control Group - 13 pts

Echogenic endometrium in all cases,

Endometrial thickness >7 mm in all cases (84.6%),

Endometrial volume >2.31 cm3 in 5 cases (38.5%),

Abnormal sub-endometrial halo in 3 cases (23.1%),

Endometrial blood flow in 6 cases (46.2%) and

Complex vessel’s architecture in 2 cases (15.4%).

Women who have taken Atosiban presented anendometrium with characteristics more predictive of implantation

Kalmantis K. Arch Gynecol Obstet. 2012 Jan;285(1):265-70.

26 pts

• 52 women with repeated failure of implantation after IVF/ICSI were included in this study.

• The ongoing pregnancy rate was 12 out of 52 (23.1%)

Results indicated that with good quality embryos Atosiban might offer a significant better implantation rate

in women with repeated implantation failure

Role of Atosiban in Repeated Implantation Failure

Decleer W. Facts Views Vis Obgyn. 2012;4(4):227-9.

Atosiban improves implantation & pregnancyrates in patients with RIF

• Study enrolled 71 women with repeated implantation

failure using cryopreserved embryos

• The implantation rate per transfer was 13.9% &

clinical pregnancy rate per cycle were 43.7%.

Pregnancy rate went from 0 % to 43.7%

Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

Parameter Sample population

Frequency of uterine contractions≥16 contractions per 4 min 10/71 (14.1 %)

<16 contractions per 4 min 61/71 (85.9 %)

Total No. of contractions per 4 min

Before atosiban 6.0 ± 5.7 (0 to 20)

After atosiban 2.6 ± 2.1 (0 to 9)

Cycles with 16 uterine contractions per 4 min

Before atosiban 18.8 ± 1.6 (1–20)

After atosiban 5.1 ± 2.6 (2–9)

Cycles with <16 uterine contractions per 4 min

Before atosiban 3.9 ± 2.4 (0–8)

After atosiban 2.2 ± 1.7 (0–6)

The frequency of uterine contractions was significantly reduced after atosiban in all cycles


Outcome Sample population

No. of embryos transferred 3.4 ± 0.7 (2–5)

Clinical pregnancy per cycle 31/71 (43.7) Type of pregnancySingletonTwinsTriplets

29/31 (93.5) 1/31 (3.2)1/31 (3.2)

Implantation per embryo transferred

34/245 (13.9)

Miscarriage per cycle 3/71 (4.2)

Ectopic pregnancy per cycle 1/71 (<1.0)

Ongoing pregnancy per cycle 26/70 (37.1)

Pregnancy outcomes of embryo transfer cycles after Atosiban administration


Atosiban improves implantation & Pregnancy rates in patients with

repeated implantation failure

Dose of Atosiban in IVF

• Atosiban is administered as an i.v. bolus of 6.75 mg , 30 min prior to embryo transfer

• Followed by i.v. infusion at a rate of 18 mg/ hr for 1 hr and then reduce to

• 6 mg/ hr for next 2 hr.

Total dose administered 36.75 mg in 3 hrs


Method of administrationAvailable in 2 different packs

Stage Regimen Atosiban

dose in

ml

Atosiban

dose in

mg

With 100 ml

infusion bottle

Time

1 30 minutes prior to

embryo transfer

give 0.9 ml iv bolus

over 1 min

0.9 ml 6.75 mg Bolus IV

injection

1

minute

2 followed by

continuous

intravenous

infusion for 1 hour

4.1 ml

In 100 cc

NS

18 mg /

hr

20 drops/min 1 hour

3 Subsequent

intravenous

infusion for 2 hours

6 mg/hr 6 drops/min 2 hours

Moraloglu O. Reprod Biomed Online. 2010 Sep;21(3):338-43.

4.1 ml

Lower dose of Atosiban may also improve pregnancy outcomes of patients with RIF

• Total 150 infertile couples with RIF undergoing IVF-ET were

divided into three groups

– (Group 1) 80 Patients who did not receive atosiban were

used as controls

– (Group 2) 40 patients received a single bolus dose (6.75mg,

0.9mL/vial) of atosiban before ET

– (Group 3) 30 patients received a bolus dose of 6.75mg

atosiban followed by infusion at 18mg/hr for 3 hours

immediately after ETChou PY. Taiwan J Obstet Gynecol. 2011 Jun;50(2):136-40.

Parameters Group 1(n=80)

(control group)

Group 2(n = 40)(single bolus

dose of Tractocile)

Group 3 (n =30)(infusion dose of

Tractocile)

p

Number of embryos transferred (mean)

2.23 ± 1.10 2.35 ± 0.99 2.37 ± 1.14 0.85

Implantation ratea 11.8 (21/178) 30.21 (29/96) 15.9 (11/69) 0.0006*

Clinical pregnancy rate

12.5 (10/80) 37.5 (15/40) 20 (6/30) 0.0057*

Miscarriage rate 20 (2/10) 6.67 (1/15) 16.6 (1/6) 0.62

Live birth rate 10 (8/80) 35 (14/40) 16.67 (5/30) 0.0031*

Multiple pregnancy rate

10 (1/10) 40 (6/15) 16.67 (1/6) 0.22

Study revealed that …..

Chou PY. Taiwan J Obstet Gynecol. 2011 Jun;50(2):136-40.

AtosibanEarly Pregnancies & Threatened Abortions

• First & second-trimester bleeding is more common in ART than in spontaneous pregnancies.

• From 2004 to 2010, 33 first-trimester pregnancies with vaginal bleeding & with evident uterine contractions after ART were treated using atosiban, and

• Concluded that there was no abortion and there was no preterm delivery before 30 weeks.

Wu MY. J Formos Med Assoc. 2011 Dec;110(12):800.

Pharmacovigilance

No important safety issues since

launch of Atosiban in 2000

Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

Embryonic safety of Atosiban

Rabbit Embryo Bioassay

Human sperm motility bioassay

• Atosiban did not: affect the survival of one-cell rabbit embryos

• Atosiban did not affect human sperm motility in

concentrations, 10 times the human mean plasma concn

• Both studies failed to detect an embryotoxic effect of

atosiban in concentrations up to 50-times the

therapeutic blood concn

Pierzynski P. Fertil Steril. 2007 May;87(5):1147-52.

Packaging & Storage

Store at 20c to 80c , Do not FreezeStore in the original packet in order to protect from light

To conclude

Atosiban improves uterine receptivity during ET and thus may increase success rates of advanced infertility procedures in fresh cycles, frozen cycles and also in pts with RIF

Thank you

role of atosiban in art dr. jyoti agarwal

Health & Medicine