Surgical Procedures that enhance Fertility?

Cleveland Clinic Tommaso Falcone,M.D.

Professor & Chair Obstetrics &Gynecology

Surgical Procedures that enhance Fertility?

Enhance Spontaneous Pregnancy Enhance IVF outcomes Fertility preserving surgery versus fertility enhancing surgery

The Most Common Causes:

in Western Society Tubal disease: Male factor: 15% 25% (40%) Ovulation disorders: Endometriosis: Unexplained: 20% 25% 10%

Multiple Gestation Epidemic

Changing IVF paradigm

Guidelines for number of embryos to transfer – Typically 1 embryo

Tubal Disease: Result of Treatment

Depends on severity of disease Distal tubal disease – Preserved mucosal folds – Microsurgical technique for repair CO 2 laser makes no difference

Salpingostomy: Result of Treatment

Dubuisson et al HR1994 Canis et al F&S 1991 Donnez et al J Gynecol Surg 1989 Taylor et al F&S 2001 Milingos et al J Am Assoc Gynecol Laparosc 2000 N=81 PR% 37 N=87 PR% 40 N=25 PR % 20 N=139 PR% 25 N=61 PR% 21

Fimbrioplasty: Results of Treatment:

Dubuisson et al F&S 1990 Saleh & Dlugi F&S 1997 N=31 PR% 35 N=88 PR 40%

Proximal Tubal obstruction

Hysteroscopic surgery 48% PR

Peri-tubal adhesions

No laparoscopic study One prospective study of open treatment – n-=69 Tulandi et al 1990 Am J Obstet Gynecol – Pregnancy rates at 12 and 24 months Treated 32 and 45% Control 11 and 16%

When is it feasible?

Importance of other pathologies Age of patient Patient preference Desire for “natural” procreation Insurance coverage Results of ART program

Treatment effect

Treatment effect large enough to be clinically relevant?

Number needed to treat (NNT): number of subjects that must be treated to achieve one more outcome with intervention than control NNT=1/Risk difference Risk difference: Event rate treated group- Event rate control

Stage 1 & 2 endometriosis

Canadian study – N=172 treated & N=169 untreated – PR% 29% treated & 17% untreated – NNT= 1/.12=8.3

– NNT=9, 95 % CI, 5,33 Italian study – N=54 treated & N=47 no treatment – PR% 22% & 28%

Treatment Effect

Canadian study PR for pregnancies more than 20 weeks of gestation, Italian study reported any pregnancies – Combine the studies for pregnancies over 20 weeks: 27% (treated) & 18% ( non treated): NNT=12 ( 95% CI 6,112) – 20% prevalence of endometriosis – 60 diagnostic laparoscopies to get an extra pregnancy

Endometriomas

Drainage has a high recurrence rate Need to excise the cyst – Cochrane database 2005 Hart R et al – Excision of cyst associated with a reduced rate of recurrence; reduced symptom recurrence and increased spontaneous pregnancy rates compared with ablative surgery

Endometriomas

Unresponsive to medical therapy – Surgery required to remove them Jones & Sutton 2002; Alborzi et al 2004 – Surgical removal 40-50 % young women spontaneously will conceive – Laparoscopic removal of endometrioma represents the first line treatment for infertile women

Stage III&IV Endometriosis: reoperation or IVF Pagidas, Falcone et al Fertility & Sterility 1996

Previously operated patients with infertility Reoperation PR were – 6% at 3 months – 18% at 7 months – 24 % at 9 months

Reoperation for Stage III&IV Endometriosis ?

Pagidas et al Fertility & Sterility 1996

Stage III&IV endometriosis

After initial unsuccessful operative procedure to restore fertility , IVF-ET appears to be a superior alternative to re operation In patients with chronic pain reoperation is a viable alternative

Endometrial Polyps

Afifi K et al Eur J Obstet Gynecol Reprod Biol- 2010 – Meta-analysis management of endometrial polyps in subfertile women: a systematic review – Significantly improved PR in women undergoing IUI

Leiomyomas & Infertility:

Submucosal fibroids – PR after hysteroscopic resection up to 43% Goldberg F&S 1995 Hart Br J Obstet & Gynecol 1999 Bernard Eur J Obstet Gynecol Reprod Biol 2000 Intramural fibroids distort the uterine cavity

Myomectomy: Indications

Shokeir et al 2010 Fertil Steril 2010 – Randomized matched trial; – Unexplained infertility – Type 0 and Type 1 myomas – Hysteroscopic surgery was performed – PR significantly improved ( 63 % vs 28 %)

Ideal Candidate for Hysteroscopic procedure Single intracavitary myoma or one involving less than 50 % of the myometrium (Type 0 or 1) and up to 3cm in diameter.

Uterine size less than 12-14 weeks Normal hemoglobin and normal electrolytes

General Assumptions

The pregnancy rate 1-2 years following laparosocpic or laparotomy myomectomy in an infertile woman ( with no other problems) is approximately – 40-60% Laparoscopic Surgery is superior to laparotomy – Challenges are

Reproductive Outcome: Pregnancy rates

Seracchioli et al 2000 – RCT ( only study Cochrane database) – Pregnancy rate: over 3 years AM:56% LM:54% – Spont Ab: AM 20% LM:12% – Preterm labor:AM:7% LM:5% – C/S: AM: 77% & LM:65% – No ruptures

EndoWrist

TM

Instrumentation

Modeled after the human wrist. Full range of motion High-strength cable system – Transpose fingers to instrument tips

Summary of Literature on Robotic Myomectomy Surgery Author Year Advincula 2004 AP et al Number of Robotic Cases 35 Type of Study Preliminary experience Mao SP et al 2007 Bocca S et al 2007 1 1 Case report Case report Removed Myomas Weight Results Mean = 223.2 + 244.1g

Not available Not available Robotic myomectomy is new promising approach Successful robotically-assisted excision of large uterine myoma measuring 9x8x7cm Achievement of uncomplicated full term pregnancy after robotic myomectomy

Summary of Literature on Robotic Myomectomy Surgery Author Advincula 2007 AP, et al Nezhat C et al Year Number of Robotic Cases 2009 29 15 Type of Study Removed Myomas Weight Results Retrospective case matched between robotic and open myomectomy Mean = 227.86 + 247.54g

Robotic myomectomy approach is comparable to open approach regarding short term surgical outcome and costs Retrospective case matched between robotic and laparoscopic myomectomy Mean = 116g Robotic myomectomy (min 25-max 350)g had significant longer surgical time without offering any major advantages

Cleveland Clinic Obstet Gynecol 2011 Abdominal (n=393) Laparoscopic (n=93) Robotic (n=89) p value Age years Weight Kg Height cm BMI kg/m2 36.93

( 5.61) 75.5

(62.8,90.7) 163.92

( 13.17) 27(23,32) 39.57

( 9.17) 64.8 (59.1, 76.66) 164.02

( 6.19) 36.62

( 5.18) 68.04

( 57.6, 82.5) < 0.001 163.63

(6.62) < 0.001 0.97 24.1 ( 22, 28.1) 25.1 ( 22.1, 29.4) < 0.001

Maximum Diameter of the Resected Myoma (in cm) by Surgical Approach

30 20 10 0 Abdominal Laparascopic Robotic

( P=0.036)

Weight of the Resected Myomas (in grams) by Surgical Approach

2,500 2,000 1,500 1,000 Overall P < 0.001

RM vs LM < 0.001

500 0 Abdominal Laparascopic Robotic

The Actual Operative Time (in minutes) by Surgical Approach

350 300 250 200 150 100 50 Overall P < 0.001

RM vs LM NS Abdominal Laparascopic Robotic

The Intra−operative Blood Loss (mL) by Surgical Approach

2,500 2,000 1,500 1,000 Overall P < 0.001

RM vs LM NS 500 0 Abdominal Laparascopic Robotic

The Postoperative Hemoglobin Drop (gm/dL) by Surgical Approach

7 6 5 Overall P < 0.001

4 3 2 1 RM vs LM NS 0 Abdominal Laparascopic Robotic

8-10 cm

45 °

Solution: Side Docking – 4 arm

Surgical Procedures that will improve IVF outcome

Hydrosalpinx: meta-analysis

Zeyneloglu et al Fert Steril 1998 – 13 published studies, 10 abstracts – Pregnancy rate decreased by half compared to controls (fresh & frozen cycles) – 50% lower implantation rate – Higher miscarriage rates Strandell et al HR 1999 – Prospective RCT – 204 patients – Salpingectomy group: 36.6% – No surgery: 24%

Hydrosalpinx: effect of salpingectomy

Subgroup analysis: Hydrosalpinges visible at ultrasound appeared to benefit the most (Strandell et al)

Hydrosalpinx: alternative treatment

Proximal tubal cauterization Surrey & Schoolcraft F&S 2001 – Salpingectomy: 57% – Bipolar proximal tubal occlusion: 46%; P=NS

Impact of Fibroids on IVF

General observations – Submucosal fibroids & intramural leiomyoma that distort the cavity have an impact IVF outcome – Subserosal leiomyomas do not affect the on IVF fertility parameters – Although less clear, there is some evidence to support the concept that intramural leiomyomas without cavity distortion may affect IVF parameters such as pregnancy rates or implantation rates. However PR & delivery rates are still high.

Effect of intramural fibroids on IVF outcome Sunkara et al HR 2010 – Meta-analysis – Intramural fibroids without cavity distortion – 19 studies-6087 cycles – Significant decrease in live birth and clinical pregnancy rates – This does not mean that removal will restor PR to the levels expected in women without fibroids

Impact of Fibroids on IVF

Generally if there is a distortion of the uterine cavity: remove the fibroids Because of the lack of consistent or well designed studies, & high reported PR, prophylactic myomectomy pre-IVF if the cavity is normal should be individualized & not routine. No data for fibroids >5-7cm.

Impact of endometriosis on IVF outcome: Meta-analysis

22 studies ( 2377 with endometriosis & 4383 without endometriosis); Barnhart et al F&S 2002 Stage I & II- 21 % per cycle ( control 27.7%) – Decrease in implantation & fertilization rates Stage III & IV –13.8 % per cycle ( control 27.7%) – Decrease in the number of oocytes retrieved

Oocytes retrieved: previously operated endometriomas adapted from review Somigliana et al 2006 Endometriosis Controls-No endo Al-Azemi et al 2000 6.9+0.7

7.1+0.5

Canis et al 2001 Donnez et al 2001 Marconi et al 2002 Geber et al 2002 Pabucco et al 2004 Esinler et al 2006 9.4+6.2

10.6+4.2

7.5+3.9

9.8+5.4** 5.7+1.3** Uni (10.8) Bi (7.1)** 10.9+6.5

8.6+6.3

8.7+5.1

12.0+5.9

7.2+1.5

11.1+6.1

Oocytes retrieved: previously operated endometriomas

Endometrioma size >3cm but no upper limit given or mean diameter; others 2-5cm Pregnancy rates : – Not different in most studies – Geber et al (in women over 35) & Pabucco decreased PR Signs of decreased ovarian reserve – Marconi et al total dose of gonadotropin was higher – Esinler et al decreased antral follicle count & total dose of gonadotropin was higher

Oocytes retrieved: operated vs. non operated normal ovary Control ovary Nargund et al 1996 8.9+5.1

Loh et al 1999 Donnez et al 2001 3.6

6.6+3.5

Ho et al 2002 Somigliana et al 2003 Wong et al 2004 6.1+4.1

4.2+2.5

5.2+0.8

Operated ovary 6.3+5.2* 4.6

5.2+3.0

2.9+2.6* 2.0+1.5* 5.6+0.9

Bilateral Endometriomas

Somigliana et al HR 2008 Endometrioma group=68 patients Control group ( no ovarian surgery)=136 patients Day 3 FSH of cases> controls Number follicles/oocytes/embryos decreased/Implantation rate-lower PR/DR cases per transfer ( 14%/8%) vs. controls (28 %/25%)

General Consensus

Reduced responsiveness in operated patients Pregnancy rate not significantly affected-if unilateral but reduced if bilateral Large number of variables that determine outcome ( size, age, duration of infertility etc) CAUSE- surgical technique ?

Actual presence of the cyst?

Endometrioma surgery

Outcome is dependent on technique Minimize damage to the surrounding tissue

Will surgery improve IVF outcome?

Surgery within 6 months of IVF vs. 6 months to 5 years No effect of the time interval between surgery & oocyte retrieval Surrey & Schoolcraft

Endometriosis surgery prior to IVF: Conclusions If patient symptomatic, there does not appear to be a deleterious affect on outcome if surgery performed If patient asymptomatic: Case by Case