Embryo transfer: factors involved in optimizing the success Doç. Dr. Erdal Aktan Özel Ege Tüp Bebek Merkezi, IVF Center- Izmir 20.4.2008 Çeşme

2nd v 3rd day ET 3rd day ET increased PR (OR 1.26 %95 CI 1.06-1.51) 10 RCT Groups are similar regarding OPR and LBR (OR 1.05 %95 CI 0.83-1.32 ve OR 1.07 %95 CI 0.84-137 ) 3 RCT Cochrane Database Syst Rev 2004; 2:CD004378

Blastocyst v Cleavage ET LBR per couple (OR 1.16, 95% CI 0.74 -1.44 ) 2/3 day 34.3% vs 5/6 day 35.4% 7 RCT PR per couple (OR 1.05, 95% CI 0.88 -1.26) 2/3 day 38.8% vs 5/6 day 40.3% 15 RCT Groups are similar regarding multiple pregnancy rate (OR 0.85, 95% CI 0.63 - 1.13) 12 RCT Cochrane Database Syst Rev 2005 Oct 19;(4):CD002118

Blastocyst v Cleavage ET n of Couples with spare embryos to freeze more in cleavage ET group ET cancellation: more in blastocyst ET group Subgroups with good prognostic criteria are similar regarding ET cancellation rate Cochrane Database Syst Rev 2005 Oct 19;(4):CD002118

n of embryos transferred: 2 v 3 embryos Retrospective cohort study 1448 women & 4004 embryos transferred Only 1st IVF cycles At least 6 embryos eligible for ET in every cycle Salha O et al, J Assist Reprod Genet. 2000 Jul;17(6):335-43

n of embryos transferred: 2 v 3 embryos Women <35 y with good quality spare embryos: PR are similar LBR (total) are similar Twins and triplets are more frequent in 3 ET group Salha O et al, J Assist Reprod Genet. 2000 Jul;17(6):335-43

n of embryos transferred: 2 v 3 embryos Women <35 y without good quality spare embryos: In 3 ET group PR (39.3 vs 28.8%; P = 0.04) Total LBR (32.7 vs 19.4%; P = 0.02) LBR (single) Multiple PR are similar Salha O et al, J Assist Reprod Genet. 2000 Jul;17(6):335-43

n of embryos transferred: 2 v 3 embryos Women >35 y with or without good quality spare embryos: Clinical results are better in 3 ET group Multiple PR are similar Salha O et al, J Assist Reprod Genet. 2000 Jul;17(6):335-43

n of embryos transferred: 2 v 3 embryos Conclusion: Optimal n of embryos for transfer depends on Quality of embryos Age of women Presence of good quality spare embryos Salha O et al, J Assist Reprod Genet. 2000 Jul;17(6):335-43

n of embryos transferred: 2 v 3 embryos Retrospective analysis ET policies during two different periods Morphologic scoring, best embryos for ET <36 y, 2ET v 3ET: PR 42.5% v 55.7% (p<0.01) Twin rates are similar Triplets 0 v 6.8% Setti PE et al, Reprod Biomed Online. 2005 Jul;11(1):64-70

eSET v DET 3 RCT Meta-analysis: (OR 9.97 %95 CI 2.61-38.19) PR per woman DET (OR 2.08 %95 CI 1.24-3.50) LBR per woman DET (OR 1.90 %95 CI 1.12-3.22) Multiple PR DET (OR 9.97 %95 CI 2.61-38.19) Cochrane Database Syst Rev 2004; 4:CD003416

eSET v DET 4 RCT meta-analysis (fresh cycles) eSET: LBR , MPR eSET + 1 FET (subsequent cycle): groups are similar regarding cumulative LBR and CPR Pandian Z et al. Hum Reprod 2005; 20:2681-2687 Single blast v single cleavage ET (<36 y) %32 v 26.1 RR 1.48 %95CI 1.04-2.11 RCT Papanikolau EG et al. N Engl J Med. 2006 Mar 16;354(11):1139-46

Economic evaluations of eSET v DET It can be concluded that DET is the most expensive strategy. DET is also most effective if performed in one fresh cycle. eSET is only preferred from a cost-effectiveness point of view when performed in good prognosis patients and when frozen/thawed cycles are included. If frozen/thawed cycles are excluded, the choice between eSET and DET depends on how much society is willing to pay for one extra successful pregnancy. Fiddelers AA et al. Hum Reprod Update. 2007 Jan-Feb;13(1):5-13.

ET Catheters

ET Catheters Tight Difficult Transfer (TDT) Catheter (Hard catheter), The Worst One

ET Catheters Soft Catheters: Cook v Wallace

ET Catheters Abou-Setta A et al. Hum Reprod 2005; 20:3114-3121

Mock embryo transfer During the luteal phase of previous cycle On the day of oocyte retrieval Just before the real transfer To choose the right catheter and determine the axis of the uterus

Mock embryo transfer Reduces the risk of difficult transfer, increases IR and PR Mansour R et al, Fertil Steril 1990; 54:678-681 Uterus at mock embryo transfer will often change position at real embryo transfer (RV AV) Henne MB, Milki AA, Human Reprod 2004; 19:570-572 Moulding the catheter according to the uterocervical angle measured by ultrasound increases CPR & IR Sallam HN et al, Human Reprod 2002; 17:1767-1772

Endometrial assessment Endometrial thickness in pregnant and nonpregnant groups are similar Rashidi BH et al. Eur J Obstet Gynecol Reprod Biol 2005 1;120(2):179-84 Schild RL et al. Hum Reprod 1999; 14:1255-1258 Laasch C, Puscheck E. Assist Reprod Genet 2004; 21:47-50

Endometrial assessment In oocyte recipients who shared oocytes from the same donor and showed discordant pregnancy outcome: Endometrial thickness in pregnant and non-pregnant groups are similar (Matched pair analysis) Garcia-Velasco JA et al. Fertil Steril 2003;80:54-60

Endometrial assessment Endometrial thickness predicts PR in IVF cycles McWilliams GD et al. Fertil Steril 2007;88:74-81 Kovacs P et al. Hum Reprod. 2003;18:2337-2341 In “<8 mm endometrial thickness group” PR is significantly decreased Noyes N et al. Fertil Steril 2001; 76:92-97 Zenke U et al. Fertil Steril 2004; 82:850-856 Ardaens Y et al. Gynecol Obstet Fertil 2002; 30:663-672

Endometrial assessment The chances of achieving a thick endometrium for patients >40 years of age are lower than for younger patients. A thicker endometrium is correlated with a higher PR only for patients >35 years of age Amir W et al. Fertil Steril 2007;87:799-804 Endometrial thickness is independently and significantly related to higher pregnancy rates in IVF cycles of women 40 y and older Tsafrir A et al. Reprod Biomed Online 2007 Mar;14(3):348-55

Endometrial assessment Endometrial pattern is similar in pregnant and non-pregnant groups Noyes N et al. Fertil Steril 2001; 76:92-97 Rashidi BH et al. Eur J Obstet Gynecol Reprod Biol 2005 1;120(2):179-84 Triple-line pattern group had significantly higher PR campared with homogenous pattern Jarvela IY et al. Ultrasound Obstet Gynecol. 2005;26:765-769 The effect of pattern on the day of OPU is more important than the one on hCG day Sharara FI et al. J Assist Reprod Genet. 1999;16:523-528

Effect of “provider at ET” 10 different providers had significantly different PRs during 854 fresh ETs. Hearns-Stokes RM et al. Fertil Steril 2000; 74:80-86 Appropriately trained nurses and doctors had similar IR/PR Barber D et al,Hum Reprod. 1996; 11:105-108 Sinclair L et al, Hum Reprod. 1998; 13:699-702 Bjuresten K et al, Acta Obstet Gynecol Scand 2003; 82:462-466 (RCT)

Effect of “provider at ET” Experienced (training completed) and inexperienced (training ongoing) nurses are compared: Nurses in a given group are similar regarding results Groups are significantly different regarding results (29.5% v 19.5%, p<0.02) Barber D et al, Hum Fertil (Camb) 2000; 3:181-185

Effect of “provider at ET” Learning curve: ET trainees can reach an acceptable PR after the first 25-30 ETs. Clinical pregnancy rates of fellows-in-training were indistinguishable statistically from those of experienced staff by 50 transfers. (45.5% v 47.3%) Papageorgiou TC et al. Hum Reprod 2001; 16:1415-1419

Effect of difficult ET Sallam HN. Curr Opin Obstet Gynecol 2005; 17:289-298

Effect of difficult ET ETs in 584 IVF cycles, only GI, II or blastocysts transferred, 10 physicians Parameters Blood on catheter (10.3%) Mucus on catheter (20.7%) Retention of embryos in catheter (5%) Aborted first attempt at ET (8.9%) Difficult ET as judged by provider (10%) Need for mock embryo transfer immediately before the actual transfer (6.7%) Alvero R et al, Hum Reprod. 2003;18:1848-1852

Effect of difficult ET Presence of blood on or in the catheter negatively affected the IR and PR. (31.3% v 19.5% p=0.015) and (51.7% v 31.7% p=0.004) None of the other factors significantly affected PR. Alvero R et al, Hum Reprod. 2003;18:1848-1852

Tenaculum placement Tenaculum placement during ET increases oxytocin concentration and “junctional zone” contractions Dorn C et al, Eur J Obstet Gynecol Reprod Biol 1999; 87:77-80 Lesny P et al, Hum Reprod 1999; 14:2367-2370 Frequency of uterine contractions is negatively correlated to IR & PR (embryos are expelled ?) Fanchin R et al. Contracept Fertil Sex. 1998; 26:498-505

Tenaculum placement Tenaculum (volsellum) placement during ET did not have any significant effect on PR & IR Tenaculum placement ET v easy transfer (PR & IR) OR=0.71 (95% CI 0.31-1.63) & OR=0.97 (95% CI 0.53-1.77) Sallam HN et al. J Assist Reprod Genet. 2003 Apr;20(4):135-142

Ultrasound-guided embryo transfer: immediate withdrawal of the catheter versus a 30 second wait Does failing to withdraw catheter immidiately after ET causes uterine contractions which can lower PR? PR: %60.8 v 69.4% p>0.05 RCT Martinez F et al. Hum Reprod. 2001 May;16(5):871-4

Time interval between embryo catheter loading and discharging The longer the duration, the lower the PR and IR. The decrease in PR and IR is gradual until a duration of 120 s, and decreases sharply afterwards. Matorras R et al, Hum Reprod. 2004; 19:2027-2030

Impact of retained embryos on the outcome 2.8-3.9% of all transfers Retained embryos in the transfer catheter and immediate retransfer of them have no adverse impact on clinical pregnancy*, implantation**, and live birth rates*** Vicdan K et al. Eur J Obstet Gynecol Reprod Biol. 2007;134:79-82 */** Lee HC et al. Fertil Steril 2004;82:334-7*/**/*** Alvero R et al. Hum Reprod. 2003;18:1848-1852** Tur-Kaspa I et al. Hum Reprod. 1998;13:2452-5* Nabi A et al. Hum Reprod. 1997;12:1188-90*

Impact of retained embryos on the outcome Retained embryos in the transfer catheter and immediate retransfer of them have adverse effect on CPR. Visser DS et al, J Assist Reprod Genet. 1993 Jan;10(1):37-43

US Guided ET Observation of ET catether tip Observation of the embryo discharge site Observation of the air bubble Prevents touch to fundus (contractions ?) Discharge 1-2 cm to fundus

US guided v clinical touch 5968 ET in 20 RCT Meta-analysis Abou-Setta AM et al. Fertil Steril. 2007;88:333-41

US guided v clinical touch Abou-Setta AM et al. Fertil Steril. 2007;88:333-41

US guided v clinical touch

US guided v clinical touch

US guided v clinical touch

US guided v clinical touch In US guided ET group: IR OR = 1.35, 95% CI = 1.22-1.50 Difficult ETR OR = 0.68, 95% CI = 0.58-0.81 Similar for MPR, ectopic & miscarriage rates Abou-Setta AM et al. Fertil Steril. 2007;88:333-41

Influence of embryo transfer depth For every additional millimeter embryos are deposited away from the fundus, the odds of clinical pregnancy increased by 11% (OR=1.11 by multivariable logistic regression model) Pope et al, Fertil Steril 2004; 81:51-58 Better IR & PR are obtained when the catheter tip is positioned close to the middle area of the endometrial cavity Oliveira JB et al, Reprod Biomed Online 2004; 9:435-441

Influence of embryo transfer depth PR in 1 cm depth group was significantly lower than in 1.5 cm and 2 cm depth groups Coroleu B et al. Hum Reprod. 2002;17:341-6 The IR & PR were similar whether the embryos were deposited in the upper or lower half of the endometrial cavity Franco JG Jr et al. Hum Reprod. 2004 ;19:1785-90

Influence of embryo transfer depth PR, OPR, and IR are higher when the air bubble is at the upper half of the endometrial length Schats R et al. Hum Reprod 2006; 21(Supp 1):i82 ESHRE 2006 Abstracts Book (O-210)

Bed rest versus free mobilisation following ET Immediate ambulation following the ET procedure has no adverse influence on the ability to conceive. Bar-Hava I et al. Fertil Steril. 2005 Mar;83(3):594-7 Sharif K et al. Fertil Steril 1998; 69:478-481 One-hour*/20’** and 24-hour rest post-embryo transfer result in comparable rates of clinical pregnancy. Amarin ZO, Obeidat BR. BJOG 2004; 111:1273-1276* RCT Botta G, Grudzinskas G. Hum Reprod 1997; 12:2489-2492** RCT

The effect of peri-transfer intercourse on pregnancy rates Multicenter RCT There was no significant difference between the intercourse and abstain groups in relation to PR Hence exposure to semen around the time of embryo transfer increases IR OR 1.48, %95 CI 1.01-2.19 Tremellen KP et al. Hum Reprod 2000; 15:2653-2658

PIROXICAM RCT 10 mg Piroxicam v placebo 1-2 h before ET IR (18.7% v 8.6% ) and PR (46.8% v 27.6% ) <40 y, fresh and frozen ET Moon HS et al, Fertil Steril. 2004 Oct;82(4):816-20

Antibiotic prophylaxis & IVF/ET Amoxicilline + clavulanic acid prophylaxis Only RCT on AB prophylaxis & IVF/ET IR (36.9% v 36.5%; p>0.95) Peikrishvili R et al. J Gynecol Obstet Biol Reprod (Paris). 2004;33:713-719 Failure to conceive in ART is significantly associated with bacterial colonization of the uterine cervix Salim R et al. Hum Reprod 2002; 17:337-340. Positive microbiology cultures of embryo catheter tip is accociated with PR and IR Prophylactic antibiotics are associated with a reduction in positive microbiology cultures of embryo catheter tips Egbase PE et al. Lancet 1999; 354:651-652

Aspirin & IVF/ET Currently available evidence does not support the use of aspirin in IVF or ICSI treatment.* (PR & LBR) However, the noted trend of improvement in clinical pregnancy, and the lack of power even when the studies were pooled highlight the need for a definitive trial.** Khairy M et al. Fertil Steril. 2007 Oct;88(4):822-31. Review/ Meta-analysis*/** Gelbaya TA et al. Hum Reprod Update. 2007 Jul-Aug;13(4):357-64. Review/ Meta-analysis*

Prednisolone Does not have any significant effect on IR & CPR Lee KA et al. Hum Reprod 1994; 9:1832-1835 Moffitt D et al. Fertil Steril 1995; 63:571-577 (RCT) Motta GL et al. J Reprod Med 1996; 41:889-891 (RCT) Fridstrom M et al. Hum Reprod 1999; 14:1440-1444 (RCT) Ubaldi F et al. Hum Reprod 2002; 17:1544-1547 (RCT)

Adjuvant therapy with Sildenafil in IVF for endometrial development While the use of adjuvant therapy did not significantly improve ultrasonographic endometrial thickness, it did improve outcome rates (PR&LBR). Fratterelli JL et al. Reprod Biomed Online. 2006 Jun;12(6):722-9. Vaginal administration of sildenafil enhanced endometrial development in 70% of patients with previous poor (<9mm) endometrial development High IR & OPR were achieved in group with enhanced development. Previous endometritis may decrease the response to sildenafil. Sher G and Fisch JD. Fertil Steril. 2002 Nov;78(5):1073-6.

Thanks for your attention