Role of Atosiban In ART Dr, Jyoti Agarwal presentre on 27th November 2016 Exponential increase in IVF Procedures in India

1. Role of
Atosiban
In ART
Dr Jyoti Agarwal

2. Exponential increase in IVF
Procedures in India

3. India performs approx 1 Lac IVF cycles annually &
55% of these IVF cycles are performed in the
top eight metro cities

4. 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

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

6. 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

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

8. 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.

9. 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.

10. 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

11. • 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.

12. 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.

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

14. 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.

15. 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.

16. Published
Clinical Studies

17. 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.

18. 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

19. 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

20. 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

21. • 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.

22. 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.

23. 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.

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

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

26. 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
Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

27. 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
4.1 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

28. 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.

29. 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.

30. Atosiban
Early 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.

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

32. 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.

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

34. 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

35. Thank you