Strategy for Myomas Associated with Infertility: Surgery Versus ART?

1

G. I. Serour, FRCOG, FRCS, FACOG, FSOGC, FJSOG (Hon.)

Professor of Obstetrics and Gynaecology, Director, International Islamic Center for Population

Studies and Research, Al-Azhar University Clinical Director, The Egyptian IVF-ET Center,

Maadi, Cairo, Egypt

FIGO Immediate Past President 1st congress of the Society of Endometriosis and Uterine Disorders

(SEUD) Paris - France

7-9 May 2015

Conflict of interest

I declare I have no conflict of interest in this

presentation.

2

Items Addressed

1- Myomas and fertility. 1.1. Natural conception. 1.2. ART. 2- Strategy for Myomas, associated with infertility. 2.1. Myomectomy. 2.2. Myomectomy followed by ART. 2.3. ART. 2.4. ART followed by Myomectomy. 3- Conclusion.

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4

Mean age of women at the birth of the first child (2008) UN Statistics, July 2011

This recent trends of women to delay childbirth to their 30th and 40th ,when the

incidence of fibroids is significantly increased, resulted in an increasing number of infertile patients seeking

treatment and have myomas; not uncommonly multiple and large myomas.

5

Pundir J et al 2015 J Obstet and Gynecol, 35:37-41

Other Main Risk Factors for Development of Myomas

• African- American ethnicity (almost three times as likely as white women).

• Nulliparity. • Obesity. • Cigarette smoking.

6 Chen C R et al 2001. Am. J. Epidemiol. 153, 27-29

* Stewart E A 2001. Lancet: 357:293-298. * Baird DD et al 2003. American J Obstet & Gynecol 188:100-107. * Guo XC and Segars H, 2012. Obstet & Gynecol Clinics of North America: 39:521-533. ** Donnez J and Jadoul P 2002 Hum. Reprod 17:1424-1430. ** Mayonda I et al 2004, BJOG 111: 95-102. ** Benecke C et al 2005, Gynecol Obstet Invest. 59:225-230. ** Rackow BW, Arici A, 2005. Curr. Opin. Obst. Gynecol, 17:225-231

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Though uterine fibroids occur in up to 77% of women in reproductive

age*, yet as a sole cause of infertility they may be responsible for only 2-3% of infertility cases**.

How Fibroids cause Infertility? 1- Physical location impending egg or sperm transport. 2- Impaired uterine peristalsis. 3- Vascular changes. 4- Chronic inflammatory response by the endometrium to underlying fibroid. 5- disruption of the uterine intracavitary biochemical milieu.

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-  Deligdish L and Reiter RC, 1970. J. Clini. Path. 23, 676-680. -  Casini MI et al 2006. Gynecol. Endocrinol. 22, 106-109. -  Richards PA et al 1998. Hum. Reprod. Update 4, 520-525. -  Rackow BW and Taylor HS, 2010. Fertil & Steril 93. 2027-2034. -  Ben-Nagi J et al 2010. Reprod. Biomed. Online. 21(5), 610-615.

Submucosal & Intramural fibroids/ Natural conception

Several studies had shown that Infertility could be attributed to

submucosal fibroids and intramural fibroids distorting the endometrial

cavity and impeding sperm transportation or normal implantation.

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-  Verkauf BS, 1992. Fertil & Steril 58:1-15

-  klatsky et al 2008. American J. Obst,. And Gynecol 198:357-366.

-  Pritts et al 2009. Fertil & Steril 91: 1215-1223.

-  Saravelos et al 2011. Hum. Reprod. 26: 3274-3279

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TWO SYSTEMATIC REVIEWS Leiomyomas that distort the uterine

cavity (submucosal or intramural with an intracavitary component) result in difficulty conceiving a

pregnancy and an increased risk of miscarriage.

- Klatsky, PC. 2008. Am J Obstet Gynecol; 198:357. - Pritts, EA, Parker, WH, Olive, DL. 2009Fertil Steril; 91:1215.

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Women with cavity-distorting fibroids who did versus did not

undergo myomectomy had a significant increase in

conception rate (RR 2.03, 95% CI 1.08–3.83).

- Pritts, EA, et al. 2009. Fertil Steril; 91:1215.

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-  Pritts E A et al 2009. Fertil-Steril 91 (4) 1215-22. -  Olive DL et al (2010). Semin reprod. Med. 28, (3) 218-227.

Updated Systematic Review of the Evidence had shown that by

removing SM fibroids women had comparable pregnancy rates to controls with no fibroids (RR:

1.545 nonsignificant) .

Patients undergoing IVF have a decreased pregnancy rate and an increased miscarriage rate if they have submucosal or intramural

fibroids distorting the endometrial cavity.

13 -  Farhi J et al 1995. Hum. Reprod. 10:2576-2578. -  Somigliana A et al 2007. Hum. Repord. Update . 13:465-476

Cavitary distorting Myomas/ART

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In contrast, subserosal fibroids do not impair fertility.

The role of non-cavitary distorting intramural fibroids in infertility is controversial .

- Klatsky, PC. 2008. Am J Obstet Gynecol; 198:357. - Pritts, EA, et al 2009. Fertil Steril; 91:1215.

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Women with non-cavitary distorting intramural myomas/ Natural

conception

Pitts EA 2009. Fertil & Steril. 91:1215

RR 0.81, 95% CI 0.70–0.94

Less likely to become pregnant

RR 1.7, 95% CI 1.2–2.5

More likely to have a spontaneous abortion

Non- Cavitary distorting Intramural myomas & ART

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In a prospective study by our group of 406 infertile patients including 39 patients with non-cavitary distorting myomas undergoing

ART it was found that uterine myomas <7cm and not encroaching on the cavity did not affect implantation or miscarriage rates.

Ramzy A M, Sattar M, Amin Y, Mansour R, Serour GI, Aboulghar M. 1998. Hum. Reprod. Jan, 13 (1):198-202.

17

- Oliveira FG et al (2004). Fertil & Steril, 81 (3), 582-587. - Vimercati A et al (2007). Reprod. Biomed Online, 15 (6), 686-691.

More recently Oliveira et al (2004) and Vimercati et al (2007) indicated that

interstitial myoma <4cm, not distorting the uterine cavity, do not pause threat to the pregnancy and live birth rates

following IVF.

18 -Khalaf Y et al (2006). Hum. Reprod. 21 (10), 2640-2644.

However, Khalaf et al (2006) found that even the small myomas significantly reduced the ongoing pregnancy rate at each IVF/ICSI cycle by 40% and the Live birth rate at each IVF/ICSI cycle by

45%.

A recent systematic review and meta – analysis compiling >6000 patients reported a significant reduction in

the clinical pregnancy and live-birth rates following IVF treatment in

women with non-cavitary distorting intramural fibroids, compared with

controls. 19 Sunkara SK et al 2010. Hum. Reprod. 25:418-429

Negative Effect of Non-Cavitary Distorting Intamural Fibroids/ Patient without Fibroids

Meta-analysis 19 Observational studies

6,087 IVF cycles

LBR RR=0.79;95% C1=0.7-0.88; P<0.0001

CPR RR= 0.85;95% C1= 0.77-0.94; P=0.002

20 Sunkara SK, et al, 2010. Hum. Reprod. 25(2):418-29

A recent meta- analysis has highlighted a number of study design issues with

suboptimal localization of fibroid position being a common problem in interpreting the

exact role of intramural fibroids. Since fibroid location was determined by imaging methods,

less reliable than hysteroscopic documentation, thus biasing the results.

21

Knox A and McClure N. 2012. Fibroid and infertility: a review of evidence.

Expert Review of obstet & Gynecology Informa Health care. Com. Downloaded 12/2014. www.expert-reviews.com. 10.1586/EOG.11.70

A word of caution

Myomas associated with other confounding

factors of infertility

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More commonly myomas are associated with other confounding factors of infertility as:

- Tubal or ♂ factor infertility, - Advanced maternal age - Long duration of infertility - Failure of previous management (IVF/ART). All these must be taken into consideration when outlining strategy for myomas associated infertility.

What is the strategy for Myomas? - Mymectomy - Myomectomy followed by ART - ART - ART followed by myomectomy

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Before counselling the couple the RM physician should ask his/herself: 1- Is myoma/s the sole possible cause of infertility? 2- What is site, size and number of myoma/s? 3- Is myoma/s associated with other confounding factors of infertility? 4- Age of the patient. 5- duration of infertility

If Myoma/s is/are the sole possible cause of

infertility, the Answer is Surgery.

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Although myomectomy remains the preferred treatment method for women who wish to preserve

fertility, sufficient evidence that myomectomy improves fertility is

lacking due to absence of well designed randomised trials.

27

-  Metwally M et al 2012. Cochrane Database of systematic reviews (11): CD003857. -  Pundir J et al 2015. J Obstet. Gynecol, 35:37-41

28

Casini MI et al 2006. Gynecol. Endocrinol. 22, 106-109

The only prospective controlled trial on 181 women had shown that in

women with IM myomas there was no significant difference in pregnancy

rates between those who had myomectomy (56.5%) and those who

did not (41%).

In a review of 27 studies by Vercellini et al 1998, prospective data revealed a pregnancy rate of

57% after abdominal myomectomy.

29 Vercellini P et al 1998. Hum. Reprod. 13:873-879.

Existing literature suggests that the pregnancy rates after

abdominal myomectomy ranges between 24-72%.

30

-  Sirjusingh A et al 1994. West Indian Medical J. 43:138-139. -  Maddalena S et al 1999. Fertil Steril 72:109-114. -  Govai M et al 2006. Orvosi Hetilays, 147:971 -978. -  Somigliana E et al 2007. Hum. Reprod. Update 13:465-476. -  Obed JY et al 2011. Nigerian MJ 52:158-162. -  Metwally M et al 2012. Cochrane Database of systematic reviews (11): CD003857 -  Yoshino O et al 2012. J Minimally Invasive Gynecol. 19:63-67.

The live-birth rate after abdominal myomectomy for a large fibroid uterus or a greater number and

deeper localization of myomas is likely to be low.

31

Buttram VC, 1981, Fertil and Steril. 36: 433-445. Kasum M, 2009. Acta Clinico Croitica. 48: 137-143

In a recent retrospective study of abdominal myomectomy for subfertile women with a large fibroid uterus of > 16 weeks in size, LBR was 20% and miscarriage rate was 32% after 3-7

years follow up.

32

J Pundir J et al, 2015. J. Obstet. And Gynecology; 35:37-41

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The most important factor that influences the odds of achieving a live birth after abdominal myomectomy is the age of the woman at the

time of surgery.

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Significantly higher chances of successful pregnancy were

reported in women younger than 30 years of age and a very low

chance of pregnancy in women > 38 years at the time of surgery.

- Berkeley AS et al 1983. Surgery, Gynecology and Obstetrics 156: 319-322. -  Kasum M 2009. Acta Clinica Croatica 48:137-143. -  Roux I et al 2011. J. de Gynecologie et Obstetrique et Biologie de la Reproduction 40:

123-129. -  Obed JY et al 2011. Nigerian Med. J. 52: 158-162.

- Hysteroscopic myomectomy (HM) - Abdominal myomectomy (AM) - Laparoscopic myomectomy (LM)

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Surgical modalities for Myomectomy

- The location of the myoma/s. - Number and size of myomas. - Size of the uterus. - The expertise of the surgeon and supportive endoscopic equipment. 36

Choice of type of surgery

Depends upon:

Current evidence from two randomized controlled trials suggests there is no evidence for a significant effect of AM or LM on: - The live birth rate (OR 0.80, 95% CI 0.42 to 1.50), - Clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78), - Ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04)or - Miscarriage rate (OR 1.31, 95% CI 0.40 to 4.27)

37

AM/LM Cochrane review, 2012

Cochrane review, 2012. Metwally M et al, issue 11. http://www.thecochranelibrary.com

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Cochrane review, 2012. Metwally M et al, issue 11. http://www.thecochranelibrary.com

Laparoscopy Laparotomy Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M.H, Fixed, 95%CI M.H, Fixed, 95%CI

Cochrane review, 2014 concluded LM compared with all types of AM is a procedure associated with: - less subjectively reported postoperative pain, - lower post operative fever and - shorter hospital stay. More studies are needed to assess rates of uterine rupture, occurrence of thrombo-embolism, need for repeat myomectomy.

39

Cochrane review, 2014, Issue 10. Bhave Chittawar P et al http://www.thecochranelibrary.com

LM/AM

However, uterine size, number, size, and sites of

fibroids to be removed, and the level of expertise of the surgeon are limiting factors

for LM. 40

Mymectomy followed by

ART.

Indications

-  Associated infertility factors as male or tubal factor infertility.

-  Failure to get pregnant after myomectomy particularly in elderly women.

-  Young women with long duration of infertility and previously subjected to myomectomy.

Surrey ES et al 2005. Effect of myomectomy on the outcome of ART. Fertil & Steril, 83:1473-1479

A high clinical pregnancy rate (52%) was reported in women

undergoing IVF following abdominal myomectomy for different sizes of fibroid uteri.

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When ART is a first choice for infertile

couples with myoma/s?

ART first choice. -  Subserous myomas. -  Some interstitial myomas (<4 cm) not

distorting the uterine cavity. -  Other confounding factors as tubal or

male factor infertility in the absence of distortion of uterine cavity.

-  Advanced maternal age with small myomas.

ART followed by myomectomy

A woman in her late thirties with a small fibroid (<4cm) not distorting the uterine cavity deserves a trial

of ART to get pregnant without myomectomy

If this trial fails or ends in a miscarriage, she may

be counselled for sugary before repeat trial.

In women with myoma/s associated infertility myomectomy or ART can be an appropriate

first line of treatment or complimentary to each other depending upon site, size and

number of myomas, other confounding factors, age of the woman, duration of

infertility and outcome of previous treatment whether myomectomy or ART.

Conclusion