Is there evidence to support myomectomy to enhance fertility?

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Fibroids & Fertility: Not to operate
Tevfik Yoldemir MD BSc MA
Prof. Marmara University, School of Medicine,
Dept. of Obs Gyn, Istanbul, Turkey
Adjunct Prof. Eastern Mediterranean University, School of
Medicine, Dept. of Obs Gyn, Famagusta, North Cyprus
Photo
(compulsory)
I have no conflict of interest.
I have no financial relationships to disclose.
opening statements
Power Analysis
• Ideally this should precede the study
• The power analysis determines the sample size necessary to show either a
difference or similarity between groups.
• It depends on the assumption of the magnitude of the difference
• Usually a value of >80% is needed for validity
• A power analysis has become almost mandatory for all RCT’s

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Valueable research data
• In order for research data to be of value and of use, they must be
both reliable and valid.
• Reliability refers to the repeatability of findings. If the study were to be done a
second time, would it yield the same results?
• Validity refers to the credibility or believability of the research. Are the findings
genuine?
• Sample size determination is the act of choosing the number of observations or
replicates to include in a statistical sample.
• The sample size is an important feature of any empirical study in which the goal is
to make inferences about a population from a sample.
Critical review of sham surgery clinical trials
• A double-blinded randomized placebo-controlled trial is recognized as the gold
standard of clinical research.
• The clinical trial, in simplest form, involves the application of the experimental
variable (treatment to a person or group of persons) and follow-up observation of
the treatment to measure its effect.
• Trials are said to be controlled if the effect of the treatment is measured against a
comparison treatment administered over the same time period and under similar
conditions.
• The ideal of a clinical trial is that the researcher compares groups of patients who
differ only with respect their treatment.
Annals of Medicine and Surgery 12 (2016) 21-26
Critical review of sham surgery clinical trials
• If the groups differ by other characteristics then the comparison of treatments
can be biased.
• If these can be identified, their effects on the cause effect relation can be
avoided, but unknown or unexpected biases cannot be dealt with.
• Confounding is referred to as a ”mix of effects”. This determines that the causal
association mingles the effects of one or more factors that can change the
intensity or even reverse this association in an unpredictable way the real
association between exposure and outcome, in presence of confounding factors,
can be mistakenly shown or failed to avoid or to eliminate biases.
Annals of Medicine and Surgery 12 (2016) 21-26
Ten confounding factors
I) lack of homogeneity among inclusion/exclusion criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Annals of Medicine and Surgery 12 (2016) 21-26
Methodological
Statistical
Clinical
For a one sided hypothesis setting with 5% type 1 error,
80% power with allocation ratio 1:1
• For a 25% improvement
• 20% → 25% 862 / 862
• 30% → 37% 562 / 562
• 35% → 45% 296 / 296
• 40% → 50% 305 / 305
Calculated with G*Power 3.1.9.2

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For a one sided hypothesis setting with 5% type 1 error,
80% power with allocation ratio 1:1
• For a 30% improvement
• 15% → 20% 714 / 714
• 20% → 28% 352 / 352
• 23% → 30% 490 / 490
• 25% → 35% 259 / 259
• 30% → 40% 280 / 280
Calculated with G*Power 3.1.9.2
rebuttals
2015 Assisted Reproductive Technology National Summary Report 2015 Assisted Reproductive Technology National Summary Report
Fibroids and infertility: an updated systematic review of
the evidence
Fertil Steril 2009;91:1215–23.
Fibroids and infertility: an updated systematic review of
the evidence
Fertil Steril 2009;91:1215–23.

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• Stoval 1998
• IM/SS, 91:91, CPR & DR ↓
• Farhi 1995
• 46 cases, IR ↓
• Narayan 1994
• SM, 27: 73, PR ↑ aŌerwards
• Varasteh 1999
• 36 M, 23 P, 19 N, LBR ↑ aŌerwards
Fertil Steril 2009;91:1215–23.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
• Ramzy 1998
• 367 C, 39 M, uterine corporeal myomata,
not encroaching on the cavity and <7 cm in mean diameter,
IR =
• Bernard 2000
• 15 SM, 16 SM-IM, hysteroscopic myomectomy
• Buletti 1999
• LSM 106, M 106, N 106, Delivery ↑ after LSM
• Buletti 2004
• 84 Myomectomy before IVF, 84 IVF, delivery ↑ (21:10) after myomectomy
Fertil Steril 2009;91:1215–23.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
• Gianaroli 2005
• IM, SM, 1+, 75 M, 127 C, 2+ Ets, PR =
• Casini 2006
• 52 SM, 45 IM, 42 mixed SM-IM, 31 IM-SS, 11 SS, SM & SM-IM PR better after
myomectomy
• Seoud 1992
• Among 1415 IVF patients, 11 myomas and 47 prior myomectomies
• Ongoing PR =
Fertil Steril 2009;91:1215–23.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
• Vercellini 1998
• Conception rate 57% (138 subjects)
• UnEx Inf 61%, Inf+myoma 38%
• IM +/- SS 58-65%, SM 53-70%
Hum Reprod 1998; 13(4):873-9.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
• Vimercati 2007
• 51 M, 63 previous myomectomy, 106 N
• The data did not support pre-IVF myomectomy in women with small-to-
moderate uterine fibroids, regardless of their location
Reprod Biomed Online. 2007 Dec;15(6):686-91.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
intramural fibroids without uterine cavity involvement
the outcome of IVF treatment
• 19 observational studies
• 11 → LBR ( 4 ↓ & 7= )
Human Reproduction, Vol.25, No.2 pp. 418–429, 2010

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Human Reproduction, Vol.25, No.2 pp. 418–429, 2010 Human Reproduction, Vol.25, No.2 pp. 418–429, 2010
Human Reproduction, Vol.25, No.2 pp. 418–429, 2010
Uterine Leiomyomas and Their Effect
on In Vitro Fertilization Outcome
(Jun et al. 2001)
• Age difference
• 141 exposed vs 406 unexposed
• FSH, HMG
• Luteal support (IM, VG, VS)
• ET or BT
• ET number ↑↑
• LBR =
Journal of Assisted Reproduction and Genetics, Vol. 18, No. 3, 2001
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Pregnancy rate 30% → 40% 280 / 280
small intramural uterine fibroids
cumulative outcome of assisted conception
(Khalaf et al. 2006)
• Only patients with intramural fibroids
not encroaching on the endometrial cavity.
• 112/ 322
• embryos were replaced 2–3 days after oocyte retrieval
• Male factor, Tubal damage , Unexplained, Other reasons
• Ongoing pregnancy and Live birth rates different
Human Reproduction Vol.21, No.10 pp. 2640–2644, 2006
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Pregnancy rate
Ongoing pregnancy rate
Live birth rate
1:1 1:2 1:3
289/289 214/429 189/567
237/237 174/349 154/460
228/228 167/334 147/440
intramural, subserosal, and submucosal
uterine fibroids (Eldar-Geva et al. 1998)
• 88 patients / 106 cycles
• fibroids ranged between 1 and 7 per patient.
• Their size ranged between 6 mm and 51 mm
• long protocol or flare protocol
• SS, IM SM
• ET 2+
FERTILITY AND STERILITY VOL. 70, NO. 4, OCTOBER 1998
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
111/111 81/162 71/212 66/262

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intramural leiomyomata with
a normal endometrial cavity
(Surrey et al. 2001)
• 399 IVF cycles (<40 y : 51+/257-; ≥40 y : 22+/59-)
• Long protocol / microdose flare regime
• D3 / D5 transfer
• ET 3+
• LBR =
Fertil Steril 2001;75:405–10.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
376/376 283/565 251/754 236/942
subserosal and intramural uterine fibroids
not distorting the endometrial cavity
(Oliveira et al. 2004)
• 245 / 245
• Number (1-4), SS / IM, fundal / corpus, <2 / <4 / <7cm
• LBR =
Fertil Steril 2004;81:582–7.
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
fibroids without cavity involvement
(Klatsky et al. 2007)
• 275 controls / 95 cases
• Midluteal lupron or late follicular GnRH antagonist treatment.
• Intramural , Mixed subserosal and intramural, Subserosal,
Greater than 4-cm diameter, Single fibroid, Multiple fibroids
• ET 2+
• oocyte donor recipient transfer cycles with fresh embryos
• powered to detect a 33% difference in PR
• Clinical pregnancy =
Human Reproduction Vol.22, No.2 pp. 521–526, 2007
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
630/630 472/945 420/1259
Endometrial Receptivity and Implantation Are Not
Affected by the Presence of Uterine Intramural
Leiomyomas (Horcajadas et al. 2008)
• 1 (532), 2 (128), 3+ (125) myomas less than 5 cm,
22 single myoma more than 5 cm
• Control groups 93 women with previous myomecytomy &
135 women without uterine pathology
• Donor cycles 2+ ETs
• Ongoing/term pregnancy =
Clin Endocrinol Metab. September 2008, 93(9):3490–3498
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Fibroids not encroaching
the endometrial cavity
(Somigliana et al. 2011)
• Previous pregnancies (29% vs 24%)
• Previous gynecological Surgery (29% vs 23%)
• 119 cases/ 119 controls
• Male factor , Tubo-peritoneal factor, Unexplained/reduced ovarian reserve
• Long protocol / GnRH antagonist
• ET 1 / 2/ 3
• DR =
Human Reproduction, Vol.26, No.4 pp. 834–839, 2011
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
fibroids not distorting the endometrial cavity
the outcome of in vitro fertilization treatment
(Yan et al 2014)
• 51 SS, 198 IM, 198 C
• D3 FSH different
• Male factor , Tubal factor, Combination
• Short agonist , Long agonist, Ultralong GnRH agonists, GnRH antagonist
• ET 2+
• Myom diameter cut-off 2.85 cm and 2.95 cm
• CPR, DR similar
Fertil Steril 2014;101:716–21
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
CPR 48.1% vs 44.2% 2020/2020
DR 33.7% vs 30.5% 2631/2631

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Fibroids that do not distort the uterine cavity
IVF success rates
( Christopoulos et al 2016)
BJOG 2016; DOI: 10.1111/1471-0528.14362
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Christopoulos et al 2016
1:1 1:2 1:3 power
284/284 214/427 190/571 0.699
244/244 184/369 164/493 0.755
89/89 68/135 60/181 0.904
126/126 96/191 85/256 0.839
72/72 55/109 49/147 0.809
82/82 63/125 56/168 0.758
173/173 260/130 116/347 0.738
179/179 135/269 120/359 0.726
Uterine Fibroids and Pregnancy Outcomes
Following Ovarian Stimulation-
Intrauterine Insemination for
Unexplained Infertility (Styer et al 2017)
• 102/798
• D3 FSH, AMH, AFC different
• CC, Let, HMG
• LBR = (56.8% vs 68.2%)
Fertil Steril. 2017 March ; 107(3): 756–762.e3.
1:1 1:2 1:3 power
222/222 168/335 448/597 0.404
I) lack of homogeneity among inclusion/exclusion
criteria.
II) false double blind.
III) lack of post-surgery double blind.
IV) power of the study.
V) sample characteristics.
VI) lost patients to follow-up.
VII) gender distribution.
VIII) age equilibrium.
IX) lack of psychological patient evaluation.
X) lack of psychiatric patient evaluation.
Intramural Myomas – Pregnancy rates
1:1 1:2 1:3 1:4
208/208 153/307 135/406
119/119 89/177 78/235
111/111 81/162 71/212 66/262
311/311 230/460 203/610 190/949
Calculated with G*Power 3.1.9.2
Intramural Myomas – Pregnancy rates
1:1 1:2 1:3 1:4
376/376 283/565 251/754 236/942
152/152 113/226 100/300 93/374
1780/1780 1338/2676 1191/3572
3417/3417 2564/7691 2279/6838
630/630 472/945 420/1259
Calculated with G*Power 3.1.9.2
Post- myomectomy - Fertility
Dubuisson et al, Hum Reprod Update, 2000.

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Fertil Steril 2008;89:1247–53 Fertil Steril 2008;89:1247–53
Expert Adhesion Working Party of the European
Society of Gynaecological Endoscopy (ESGE)
2007
1. Adhesions need to be recognised as the most frequent complicationmost frequent complication of
abdominal surgery
2. Surgeons, other healthcare workers, budget holders and policy makers need to
increase their awareness and understanding of adhesions and the associated
healthcare burden and costshealthcare burden and costs and take active steps to reduce this
3. Patients need to be informed of the risk of adhesionsrisk of adhesions, given that adhesions are
now the most frequent complication of abdominal surgery
4. Surgeons who do not advise of the risk of adhesions may put themselves at risk
of claims for medical negligencemedical negligence
Expert consens pos Gynecol Surg 2007;4(4):243–253.
Expert Adhesion Working Party of the ESGE 2007
5. Surgeons have a duty of care to protect patients by providing the best possiblebest possible
standards of carestandards of care—which should include taking steps to reduce adhesion
formation
6. Surgeons should adopt a routine adhesion reduction strategy, at least in surgery
associated with a high risk of adhesions, such as:
• Ovarian surgery
• Endometriosis surgery
• Tubal surgery
• Myomectomy
• Adhesiolysis
Expert consens pos Gynecol Surg 2007;4(4):243–253.
Expert Adhesion Working Party of the ESGE 2007
7. Good surgical techniqueGood surgical technique is fundamental to any adhesion reduction strategy
8. Surgeons should consider the use of adhesion-reduction agents as part of their
adhesionadhesion--reduction strategyreduction strategy, giving special consideration to agents with data to
support safety in routine abdominopelvic surgery and efficacy in reducing
adhesions. The practicality and ease of use of agents, as well as the cost of any
agent, will influence their acceptability in routine practice
9. Further research to understand the impact that adhesion reduction agents have
on clinical outcomes will be important
Expert consens pos Gynecol Surg 2007;4(4):243–253.
An overview of Cochrane reviews
• No reviews identified any studies that investigated the effect of solid, gel or
pharmacological agents on pelvic pain, pregnancy rate, live birth rate or QoL,
which were our primary outcomes.
• There was no conclusive evidence of a difference between liquid agents and
control with regard to pelvic pain (moderate quality evidence), pregnancy rate
(moderate quality evidence) or live birth rate (moderate quality evidence).
• No reviews identified any studies that investigated the effect of liquid agents on
QoL.
Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD011254.

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effect of aromatase inhibitor (letrozole) + cabergoline
(Dostinex) and letrozole alone on uterine myoma
regression
European Journal of Obstetrics & Gynecology and Reproductive Biology 210 (2017) 257–264
2.5 mg letrozole once daily and cabergoline 0.5 mg/week from the first day of the menstrual cycle for 12 weeks
SPRM – fibroid
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Esmya_20/
Under_evaluation/WC500243545.pdf
Fertility after uterine artery embolization for symptomatic
multiple fibroids with no other infertility factors
Eur Radiol (2017) 27:2850–2859 DOI 10.1007/s00330-016-4681-z
cross-examinations
Q and As
closing statements
The early history of Canada's apple industry
(Canadian Geographical Journal 1938
by M. B. Davis and R. L. Wheeler)
• Deemed the "king of fruits," apples were first cultivated in Canada by early
French settlers, with the first planted trees appearing in Nova Scotia's Annapolis
Valley around 1633.
• For a while, only one variety – the Fameuse, also known as the Snow apple –
reached commercial importance. But when varieties from south of the
border started seeping into the market, they were met with mixed feelings.
• The 1886 annual report of the Nova Scotia Fruit Growers' Association stated that
"American tree peddlers began to infest the country and though they are a fraud
and a deception in many cases, yet on the whole, they have been a benefit to the
country."
https://www.canadiangeographic.ca/article/canadas-long-history-apple-growing

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The early history of Canada's apple industry
• The biggest obstacle to cultivating new apples, as is often the case in Canada, was
climate.
• The federal government launched a breeding campaign, and today close to 20
different varieties of apple are grown in Ontario alone.
• While Nova Scotia can claim much of Canada's early apple-related history, New
Brunswick, Quebec, Ontario and British Columbia have since become players in
the industry (with the creation of the Crimson Beauty, Fameuse, McIntosh Red,
and Spartan apples under their belts, respectively).
https://www.canadiangeographic.ca/article/canadas-long-history-apple-growing
http://seattlegardenfruit.blogspot.com.tr/2016/02/top-10-apple-varieties.html
https://www.allrecipes.com/recipe/234035/canadian-apple-pie/
Recipe
Standard ??
Thank you for your attention
Tevfik Yoldemir MD BSc MA
tevfik.yoldemir@marmara.edu.tr
Photo
(compulsory)