fibroids and fertility - gksgks.fi/.../2019/07/suvitie-fibroids-and-fertility.pdffibroids and time...

11.6.19

Fibroids and fertility Pia Suvitie, MD, PhD Turku University Hospital NCGE 2019, Helsinki

What is the impact of fibroids on • Spontaneous pregnancy rate • Miscarriage rate •  IVF outcome • Obstetric outcome

• Fertility sparing treatment options •  Impact of myomectomy on fertility

NCGE2019 Pia Suvitie

Fibroids and fertility

•  Do not overestimate the impact of fibroids!

•  Is there a problem? •  Symptoms or not?

•  Severity of symptoms (heavy bleeding, pain, pressure)

•  Location (FIGO type), size and number

•  Patients age matters

Donnez and Dolmans 2016 Human Reproduction: FIGO classification of uterine fibroids according to Munro et al. (2011)


Type 2 fibroid Type 2–5 fibroid (white arrow) and type 5 fibroids (black arrows)

Donnez and Dolmans 2016, Human Reproduction Update NCGE2019 Pia Suvitie

Age matters

Heffner 2014 N Engl J Med

Cum

ulat

ive

inci

denc

e of

fibr

oids

1.0

0.8

0.6

0.4

0.2

0.0 36 38 40 42 44 46 48

Age (years)

Black

White

Estimated cumulative incidence of fibroids

Day Baird et al 2003 Am J Obstet Gynecol NCGE2019 Pia Suvitie

Impact of fibroids on fertility

• Distor(on of the uterine cavity • Occlusion of the Fallobian tubes Anatomy • Endometrial altera(ons •  Increased uterine contrac(lity •  Impaired blood supply to the endometrium or the myometrium

• Hormonal and paracrine changes

Implanta(on

• Above changes may impair placenta(on and increase the risk of miscarriage and obstetrical complica(ons Placenta(on

Somigliana et al 2007, Donnez and Jadoul 2002, Sinclair et al 2011, Galliano et al 2015 NCGE2019 Pia Suvitie

Fibroids and time to spontaneous pregnancy Johnson et al. 2012 Human Reproduction: Right from the Start Study

•  3000 women enrolled in early pregnancy or when planning to get pregnant

•  Women with infertility treatments excluded->underestimation of impact of fibroids?

•  Incidence of fibroids 11% (n=324) •  In 95% small <3 cm fibroids (4mm – 12cm) •  Single fibroids in 72%

•  Fibroids did not effect the time to pregnancy •  Median 2 cycles in controls and 3 cycles in women with

fibroids •  * Adjusted by maternal age, race/ethnicity, education,

employment, smoking and body mass index. Mostly small <3cm and single fibroids


Myomectomy – Spontaneous pregnancy rate Casini et al. 2006, RCT, n=181

N Pregnancy rate With surgery

Without surgery

P-value

Submucous 52 43% 27% <0.05

Submucous-intramural 42 36% 15% <0.05

Intramural 45 57% 41% NS

Intramural-subserous 31 37% 21% NS

•  Surgery vs. no surgery •  Infertile women aged ≤35, no other causes for infertility •  Single fibroid of any location with size ≤4cm •  Follow-up 12 months


•  Hysteroscopic myomectomy vs. diagnostic hysteroscopy •  One (90%) or more submucous fibroids 1-5 cm •  Age 21-35, primary NUD-infertility, normal laparoscopy •  No other type of fibroids •  Follow-up 12 months, no infertility treatments

•  Significant difference only in women with type 0 and 1 fibroids (p<.001)

•  Only 14% had type 2 fibroids, lack of power? •  No association to fibroid size and number

Myomectomy (n=101) Controls (n=103)

Pregnancy rate 63% (64) 28% (28) RR 2.1 (CI 1.5–2.9)

Time to pregnancy 3.8 ± 2.1 months 7.5 ± 2.6 months P<0.05

Hysteroscopic myomectomy – Spontaneous pregnancy rate Shokeir et al. 2009, a randomised matched control study, n=215


Laparoscopic myomectomy – Spontaneous pregnancy rate Bulletti et al. 1999, case-control study

•  Myomectomy vs. fibroids in situ •  Infertility or recurrent miscarriages •  At least one fibroid >6 cm •  73% had 3 or more fibroids

•  Follow-up 9 months

Myomectomy n=106

No myomectomy n=106

NUD infertility, no fibroids n=106

Pregnancy rate 42% 11%*,+ 25%*

*p<0.001 compared to myomectomy + p<0.002 compared to NUD infertility


Fibroids and miscarriage Sunderman et al. 2017, Obstet Gynecol, A systematic review and meta-analysis, n=21829

Fibroids n=1394

No fibroids n=20435

Adjusted RR (95% CI)

Miscarriage rate 11.5% 8.0% 0.83 (0.68-0.98)

No association between location, size or number of fibroids and miscarriage rate

Older meta-analyses have reported that submucous fibroids increase the risk of miscarriage but conflicting data in women with intramural fibroids. Data have not been adjusted with age.

Klatsky et al. 2008, Pritts at al. 2009, Sunkara et al. 2010, Metwally et al. 2012

Forest plot for the association between uterine leiomyomas and risk of spontaneous abortion with crude point estimates adjusted using external estimate of confounding.


Myomectomy – Miscarriage rate Metwally 2012 Cochrane review

Casini et al. 2006, RCT, n=181 •  Infertile women aged ≤35 •  No other causes for infertility •  Single fibroid of any location with size ≤4cm

NS

Too small sample size


Do fibroids cause infertility?

Fibroids are the sole cause of infertility in 1-2.4%

Guo and Segars 2012, Obstet Gynecol Clin North Am


Submucous fibroids – IVF outcomes Pritts et al. 2009 Fertil Steril: Fibroids and infertility: an updated systematic review of the evidence

Outcome Studies (n) Rela3ve Risk (95% CI) Significance

Clinical pregnancy rate 4 0.4 (0.2–0.8) 0.005

Implanta(on rate 2 0.3 (0.1–0.6) 0.003

Miscarriage rate 2 1.7 (1.4–2.1) 0.022

Live birth rate 2 0.3 (0.1–0.9) <0.001


Removal of submucous fibroids and IVF outcome – Live birth rate Pritts et al. 2009 Fertil Steril: Fibroids and infertility: an updated systematic review of the evidence

Submucous fibroids Studies (n) Relative Risk (95% CI) Significance

A: Controls fibroids in situ 1 2.7 (0.9–7.7) NS

B: Controls infertile women without fibroids

3 1.3 (1.0–1.3) NS

Bosteel et al. 2018 Cochrane review: More studies are needed before hysteroscopy can be proposed as fertility-enhancing procedure


Intramural fibroids and IVF outcome – Live birth rate

Meta-analysis Studies (n) Live birth rate (%) OR/RR (95% CI)

Somigliana et al. 2007 7 0.7 (0.5-0.8)

Pritts et al. 2009 16 0.8 (0.7-0.9)

Sunkara et al. 2010* 11 31.7% vs. 32.4% 0.8 (0.7-0.9)

•  First IVF 29% vs. 36% OR 0.8 (0.6-1.0)

•  Women <37 25% vs. 31% OR 0.8 (0.6-0.9)

Metwally et al 2012* 3 30% vs. 31% 1.0 (0.5-1.9) •  *Cochrane review, controls women without fibroids

•  Differences not clinically relevant •  IVF results are good in women with fibroids •  No evidence that myomectomy improves results (Pritts et al. 2009) •  Treatment if first IVF fails?


Obstetrical complications

“It is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes”

National Institute of Health (NIH), USA Human Reproduction Update 2014

- Additional research is warranted

Fibroids and obstetric outcomes Klatsky et al. 2008 AJOG, Systematic review

Outcome Incidence (%) Fibroids No fibroids

Unadjusted OR (95% CI)*

Peripartum hysterectomy 3.3 0.2 13.4 (9.3–19.3) Cesarean 48.8 13.3 3.7 (3.5–3.9) Placental abruption 3.0 0.9 3.2 (2.6–4.0) Malpresentation 13.0 4.5 2.9 (2.6–3.2) Labor dystocia 7.5 3.1 2.4 (2.1–2.7) Placenta previa 1.4 0.6 2.3 (1.7–3.1) Retained placenta 1.4 0.6 2.3 (1.3–3.7) Postpartum hemorrhage 2.5 1.4 1.8 (1.4–2.2) Preterm labor 16.0 10.8 1.5 (1.3–1.7) IUGR 11.2 8.6 1.4 (1.1–1.7)

No evidence that treatment improves obstetric outcome NCGE2019 Pia Suvitie

Fertility sparing treatment of symptomatic fibroids in women with desire for pregnancy

•  Choice is guided by the symptoms, size, number and location of fibroids

1Dolmans et al. 2019, J Obstet Gynaecol Res, Singh et al. 2018 AJOG, 2Donnez and Dolmans 2016 Human reproduction Update, 3Cheung 2018 Best Practice & Research Clinical Obstetrics and Gynecology

Method Suitable if wish for pregnancy Myomectomy1 ✔ Ulipristal acetate (UPA)2 ✔(more data needed) MRIgFU3 ✔(more data needed) Uterine artery embolization (UAE) ✖, if no other options are possible?


In conclusion

•  Fibroids are common in women of reproductive age •  Majority of women with fibroids have normal fertility and pregnancy outcome •  Woman’s age matters – Think twice before you blame fibroids for miscarriage or infertility

•  Fibroids are rarely the sole reason for infertility •  Fibroids increase the risk of many obstetrical complications •  Submucous fibroids affect fertility and IVF outcomes – more evidence is needed

•  Removal of type 0 or type 1 fibroids is likely beneficial •  Insufficient evidence to suggest that:

•  Intramural fibroids impact fertility •  Treatment of any type of fibroids improves fertility or obstetric outcome

•  Myomectomy should not be performed without a clear indication •  Consider UPA as sole treatment or before surgery in women with symptomatic fibroids


fibroids and fertility - gksgks.fi/.../2019/07/suvitie-fibroids-and-fertility.pdffibroids and time...

Documents