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

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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

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

  1. 1. Role of Atosiban In ART Dr Jyoti Agarwal Dr. Sharda Jain
  2. 2. Over 200 ppts are available on slideshare.net www.slideshare.net / Lifecarecentre
  3. 3. Exponential increase in IVF Procedures in India
  4. 4. India performs approx 1 Lac IVF cycles annually & 55% of the IVF cycles performed across the top eight metro cities
  5. 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. 6. Improvements to increase success in IVF • Better culture conditions • Better selection criteria for best embyro • Extending embyro to blastocyst stage
  7. 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. 8. Embryo Transfer Final & most crucial step of IVF cycle Success of IVF
  9. 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. 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. 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. 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. 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. 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. 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. 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. 17. Published Clinical Studies
  18. 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. 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. 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. 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. 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. 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. 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. 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. 26. Atosiban improves implantation & Pregnancy rates in patients with repeated implantation failure
  27. 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. 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. 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. 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. 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. 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. 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. 34. Packaging & Storage Store at 20c to 80c. Do not Freeze Store in the original packet in order to protect from light
  35. 35. To conclude Atosiban improves uterine receptivity during ET and thus may increase success rates of advanced infertility procedures
  36. 36. Thank you
  37. 37. ADDRESS 11 Gagan Vihar, Near Karkari Morh Flyover, Delhi - 51 CONTACT US 9650588339 011-22414049 9599044257 WEBSITE : www.lifecareivf.in www.lifecarecentre.in ISO 14001:2004 (EMS) …..Caring hearts, healing hands ISO 9001:2008 Web.www.lifecareivf.in Helpline : 9910081484

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