Exponential increase in IVF Procedures in India India performs approx 1 Lac IVF cycles annually & 55% of the IVF cycles performed across the top eight metro cities

1. Role of
Atosiban
In ART
Dr Jyoti Agarwal
Dr. Sharda Jain

2. Over 200 ppts are available on
slideshare.net
www.slideshare.net / Lifecarecentre

3. Exponential increase in IVF
Procedures in India

4. India performs approx 1 Lac IVF cycles annually &
55% of the IVF cycles performed across the top eight metro cities

5. The ART Boom
The IVF cycles are expected to grow at approx 20%
Current 1 Lac cycles will increase to 2.6 Lac cycles by 2020

6. Improvements to increase success in IVF
• Better culture conditions
• Better selection criteria for best embyro
• Extending embyro to blastocyst stage

7. 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

8. Embryo Transfer
Final & most
crucial step of
IVF cycle
Success of IVF

9. The Embryo Transfer Procedure
itself increases Uterine Contractions
• Procedure itself increases release of local oxytocin &
prostaglandins
• Any additional manipulation of the vagina or cervix, such
as the use of ellis tenaculum theoretically provides an
additional stimulus for oxytocin & prostaglandin release
which further increases uterine contractions. However
studies have not shown any difference in pregnancy rates
Dorn C. Eur J Obstet Gynecol Reprod Biol. 1999 Nov;87(1):77-80.

10. The Embryo Transfer Procedure
• Uterine contractile activity in IVF cycles is
increased by approx 6-fold when
measured before embryo transfer as
compared to situation before 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.

11. 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

12. • 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
before the ovulation 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.

13. • 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 labour thus resulting
in increased excitability of the uterus
Novel target in fertility treatment
Akerlund M. Prog Brain Res. 2002;139:359-65.

14. Measures at the time of embryo transfer
to reduce uterine contractions
• Use of a soft catheter without
touching the uterine fundus
• Use of ultrasound to guide
embryo transfer.
• Use of drugs to reduce uterine
contractions. Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

15. 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.

16. Effect of atosiban on uterine contraction
waves 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.

17. Published
Clinical Studies

18. Atosiban Treatment before embryo transfer
increases implantation rates in IVF
• RCT enrolled
• 180 women undergoing IVF /ICSI who had top-quality embryos
were randomly allocated into treatment and control groups.
• All the patients had infertility due to tubal factor, hormonal-
anovulatory disorders, male factor or unexplained reasons.
• The treatment group received IV administration of
atosiban before embryo transfer with a total
administered 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.

19. Atosiban Treatment before embryo transfer
increases implantation rates
Uterine contractions
decreased from 11
contractions per 4 min
to 7 contractions per
4 min as well as
decrease in their
amplitude

20. Atosiban
group
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

21. Effect of Atosiban : Human Endometrium
In 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 an
endometrium with characteristics more predictive of implantation
Kalmantis K. Arch Gynecol Obstet. 2012 Jan;285(1):265-70.
26 pts

22. • 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 when good quality embryos
obtained, the use of Atosiban at the occasion of embryo
transfer might offer a significant better implantation rate
in women with repeated implantation failure after
IVF/ICSI.
Role of Atosiban in
repeated implantation failure
Decleer W. Facts Views Vis Obgyn. 2012;4(4):227-9.

23. Atosiban improves implantation & pregnancy
rates 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.

24. 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
Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

25. Outcome Sample population
No. of embryos transferred 3.4 ± 0.7 (2–5)
Clinical pregnancy per cycle 31/71 (43.7)
Type of pregnancy
Singleton
Twins
Triplets
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
cyclesafter Atosiban administration
Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

26. Atosiban improves implantation &
Pregnancy rates in patients with
repeated implantation failure

27. 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.
• The total dose administered 36.75 mg in 3 hrs
Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

28. Method of administration
Available 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 ml 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 ml

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

30. 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
Clinical outcome of the Study
Chou PY. Taiwan J Obstet Gynecol. 2011 Jun;50(2):136-40.

31. Atosiban in Uterine Contractions
of Early Pregnancies after Assisted reproduction
• First & second-trimester bleeding is more prevalent 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.

32. Pharmacovigilance
No important safety issues since
launch of Atosiban in 2000
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

33. 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.

34. Packaging & Storage
Store at 20c to 80c. Do not Freeze
Store in the original packet in order to protect from light

35. To conclude
Atosiban improves
uterine receptivity during
ET and thus may increase
success rates of advanced
infertility procedures

36. Thank you

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