the impact of female obesity on in vitro fertilization outcomes evangelos makrakis md, phd director...

The impact of female obesity on in vitro

fertilization outcomes

Evangelos Makrakis MD, PhDDirector of EMBRYO A.R.T. Unit

Athens, Greece

obesity: epidemiology

obesity is the new worldwide epidemic

in USA and Europe 60% of all women are overweight (BMI>25 kg/m2)

- 30% of them are obese (BMI>30 kg/m2)- 6% of them are morbidly obese (BMI>40 kg/m2)

50% of women 25-44 years old are overweight- 20% of them are obese

definition of obesity Body Mass Index (BMI): 18.5 – 25 – 30 – 35 – 40 kg/m2

waist circumference to define truncal/abdominal obesity

OBESITY AND IVF - 2010

E. MAKRAKIS

obesity and infertility

obese women: x3 times at risk of infertility in the presence of irregular cycles

- associated with oligo-anovulation in the presence of regular cycles

- probability of pregnancy is reduced by 5% for every BMI unit that

exceeds 29 kg/m2

anovulation even with regular cycles release of oocytes with reduced fertilization potential endometrial abnormalities

underlying mechanisms insulin resistance hyperandrogenism elevated leptin levels and leptin resistance


E. MAKRAKIS

obesity and assisted reproductive technologies

(A.R.T.) obesity can be main, secondary or accompanying

infertility factor

high prevalence of OW or OB women who need A.R.T.

the impact of obesity on A.R.T. outcomes is debatable

British Fertility Society guidelinesinfertility treatment should be deferred until BMI<35 kg/m2

or even until BMI<30 kg/m2 in young women with good ovarian reserve


E. MAKRAKIS

obesity and IVF outcomesproblems with the studies

retrospective: nearly all

heterogeneity: clinical, methodological, statistical

-different cut-off values for BMI-analysis of overweight and obese women as one group-different stimulation protocols -different starting doses of gonadotropins-different metabolic and endocrine patterns in each woman

unable to adjust for confounders-age-PCOS-poor response-type of obesity (truncal)


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in vitro fertilization (IVF) controlled ovarian

stimulation oocyte retrieval in vitro fertilization embryo culture embryo-transfer support of luteal phase


E. MAKRAKIS

obesity and ovarian stimulation

total dose of gonadotropins: higher in OW

and OB

WMD: weighted mean difference

Maheshwari et al, 2007 : 37 papers for effects of obesity on ART- 12 papers actually included


E. MAKRAKIS


number of retrieved oocytes: fewer in OW

and OB

Maheshwari et al, 2007

WMD: weighted mean difference


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cancellation rates: higher in OW and OB


OR: odds ratio


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OHSS: higher in OW and OB


OR: odds ratio


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Bellver et al, 2009: the largest single center study

(6500 IVF cycles) total dose of gonadotropins: higher in OW and OB number of retrieved oocytes: similar in NW/OW/OB peak E2 levels: similar in NW/OW/OB

studies with opposite conclusions [number of studies] same response to gonadotropins in NW/OW/OB [4] lower dose of gonadotropins in OB [5] fewer days of stimulation in OB [3] similar peak E2 levels [8]



E. MAKRAKIS


conflicting results

may be due to confoundersPCOS

- Martinuzzi et al(2008): similar need for FSH but PCOS patients started with lower dose

- Dokras et al(2006): in BMI>40, PCOS patients had fewer cancellations and stimulation days compared to non-PCOS

age- Sneed at al (2008): high BMI has a more profound

negative effect in number of retrieved oocytes in younger patients

- Martinuzzi et al (2008): included only young patients and found no effect of BMI on ovarian response


E. MAKRAKIS


‘gonadotropin resistance’

exogenous FSH threshold increases with

BMIgreater amount of body surfacedifferences in absorption and metabolic

clearancealtered peripheral steroid metabolism and

decreased SHBG levels impaired absorption due to increased

subcutaneous fat (not likely)


E. MAKRAKIS


‘gonadotropin resistance’independent role of insulin and IGF-1

NW-IR-PCOS women are still gonadotropin resistant

role of leptin: high levels – resistance in OBhigh intra-follicular levels: associated with

gonadotropin resistance- inhibitory effect on developing follicles- inhibits FSH and LH stimulated steroidogenesis in

granulosa cells


E. MAKRAKIS

obesity and oocyte retrieval

number of retrieved oocytes in OW/OB

womenmetanalysis of Maheshwari et al(2007):

significantly decreased numberdecreased number: 9 studiessimilar number: 9 studies

mechanisms fewer growing folliclestechnically difficult retrievals

- there are no studies confirming more difficult retrievals


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obesity and pregnancy rates

BMI >25 vs <25: lower pregnancy rates

Maheshwari et al, 2007 : 37 papers for effects of obesity on ART- 12 papers actually included


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BMI >30 vs <30: lower pregnancy rates



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BMI >25 vs 20-25: lower pregnancy rates



E. MAKRAKIS


BMI >30 vs 20-30: lower pregnancy rates



E. MAKRAKIS

obesity and pregnancy ratesMaheshwari et al, 2007

•OW and OB women face a reduced likelihood of pregnancy•theory of inverted U: low BMI has similar detrimental effect on pregnancy rates

Metwally et al, 2007 •no effect of BMI on clinical pregnancy rates

Martinuzzi et al, 2008 •trend to lower implantation and ongoing pregnancy rates in PCOS patients with high BMI

Sneed et al, 2008 •analysis of the interaction BMIxAGE effect on pregnancy rates•in younger ages (<35 years) BMI has a significant negative impact on implantation, pregnancy, and livebirth rates•it may be reasonable to delay treatment in younger women and recommend weight loss


E. MAKRAKIS

obesity and pregnancy ratesin obese: lower implantation, pregnancy, livebirth rates

Bellver et al, 2009

in overweight: lower implantation, pregnancy, livebirth rates

raising BMI by 1 unit: odds for pregnancy decrease by 0.98

reducing BMI by 1 unit: odds for pregnancy increase by 1.19


E. MAKRAKIS

difficult embryotransfers (ET)?ET under ultrasound guidance improves pregnancy rates

-proven [Cochrane Review, 2007]the quality of visualization correlates with pregnancy rates

-if excellent/good: 41.5% - if fair/poor: 16.7% [Wood et al,2000]in obese: difficulty to see the air-bubble of the catheter and tendency for blood in the catheter tip [Martinuzzi et al, 2008]

impaired oocyte-embryo quality?impaired endometrial receptivity?

mechanisms for reduced pregnancy rates

tip of external catheter sheath

placement of embryos


E. MAKRAKIS

obesity and oocyte quality

Carrel et al, 2001 •fewer metaphase II (MII) oocytes in BMI≥30 vs. BMI 20-30

Whittemer et al, 2000 •fewer metaphase II (MII) oocytes in BMI≥25 vs. BMI 20-25

•fewer mature oocytes by nuclear assessment in BMI≥40 Dokras et al, 2006

Balaban et al, 2006 •negative impact of increased BMI

•negative impact of increased BMIEsinler et al, 2008

Metwally et al, 2007

Bellver et al, 2009

•no effect of increased BMI


Cano et al, 1997 •PCOS women with recurrent failures who were also donors•Group I: no own pregnancy, no recipient pregnancy Group II: no own pregnancy, no recipient pregnancy Group III: non-PCOS controls doing IVF •impaired oocyte quality and increased BMI in group I


E. MAKRAKIS

obesity and fertilization ratesSalha et al, 2001 •reduced FR in BMI >26(26.6%) vs. BMI 18-25(37.1%)

van Swieten et al, 2006

•reduced (by 45%) FR in BMI≥30

•reduced FR in BMI >24(51.7%) vs. BMI <24(58.9%)Matalliotakis et al, 2008

Fedorcsak et al, 2004



Dokras et al, 2006

Esinler et al, 2006

Dechaud et al, 2006



Whittemer et al, 2000


Lashen et al, 1999

Martinuzzi et al, 2008

Bellver et al, 2009







E. MAKRAKIS

obesity and embryo qualitySpandorf et al, 2004 •impaired embryo quality in BMI >30

Dechaud et al, 2006 •impaired embryo quality in BMI >30

•impaired embryo quality, fewer cryopreserved embryos, more discarded embryos in obese women younger than 35 years


Fedorcsak et al, 2004



Carrell et al, 2001

Arce et al, 2006

Bendus et al, 2006



Bellver et al, 2009 •no effect of increased BMI

Esinler et al, 2008 •no effect of increased BMI


E. MAKRAKIS

high doses of gonadotropins due to ‘resistance’ impair embryo quality

- abnormal embryonic development- reduced invasional capacity of blastocyst

induce defects in embryos and oocytes induce chromosomal defects in oocytes

inverse correlation between BMI and intra-follicular HCG concentrations low concentrations affect embryo quality becomes significant in obese women

mechanisms for impaired oocyte/embryo quality


E. MAKRAKIS

obesity and endometrium

Wattanakumtornkul et al, 2003

•no effect of increased BMI on pregnancy rates•BUT very small sample (7 lean, 12 obese, 97 cycles)

Styne-Gross et al, 2005

•trend towards reduced implantation and pregnancy rates•x4 increase in miscarriages•BUT small sample and not only the 1st cycles included

Bellver et al, 2003

oocyte donation models•use of oocytes from young donors with normal weight•transfer to recipient and analysis according to their BMI•effects on pregnancy rates (if any) should be attributed to endometrial factors

•no effect of increased BMI on pregnancy rates•BUT very high miscarriage rate for unknown reasons


E. MAKRAKIS

obesity and endometriumBellver et al, 2007

2656 first oocyte donation cycles

•lower implantation and pregnancy rates as BMI increases

•higher miscarriage rate as BMI increases•lower ongoing pregnancy rate in OW and OB

ongoing PRin BMI<25: 45.5%in BMI>25: 38.3%


E. MAKRAKIS

obesity and endometriumBellver et al, 2007

2656 first oocyte donation cycles

excess weight may exert an extra-ovarian detrimental effect

the effect on the endometrium seems subtle but should be taken into account

being overweight implies negative impact as being obese

underweight women do not experience poorer outcomes in donation models the theory of inverted U is applied only to native oocyte

conceptions, based on the ovarian effect of underweight


E. MAKRAKIS

hyper-estrogenic state due to

- high activity of aromatase system: increased E production- decreased SHBG: increased free E2 delivered to target

tissues- increased estrone – decreased inactive metabolites

results in - extremely thick endometrium: if>14mm is associated with

lower PR (controversial)- more endometrial polyps and more multiple polyps

defective endometrium due to inverse correlation between BMI and

- E and PG receptors in endometrium- LIF in endometrial glands- leukocyte subpopulations

mechanisms for impaired endometrium


E. MAKRAKIS

other effects leptin resistance in peripheral tissues

insulin resistance and hyperinsulinemia- reduced glycodelin in endometrium: associated with

recurrent pregnancy loss - reduced IGF-binding protein (facilitates adhesion at

maternal-fetal surface)

increased acute phase proteins & pro-inflammatory cytokines (IL6, PAI-1, TNFa)

- negative effect on endometrium and early embryonic development

mechanisms for impaired endometrium


E. MAKRAKIS

obesity and miscarriages

BMI >25 vs <25: higher miscarriage rates



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Metwally et al, 2008: 25 studies(1964-2006) – 16 studies included – 16696 patients


E. MAKRAKIS


Metwally et al, 2008BUT problem with inclusion criteria (old age, PCOS) and publication bias (negative studies)

Odds ratio of miscarriage after IVF/ICSI: BMI>25 vs. <25: higher miscarriage rates

OR 1.52, 95%CI 0.88-2.61

Odds ratio of miscarriage after ovulation induction: BMI>25 vs. <25: higher miscarriage rates


E. MAKRAKIS

obesity and miscarriagesVeleva et al, 2008

•U-shaped effect of BMI on miscarriage rates after IVF (p=0.01)•in fresh cycles: 13.4%•in natural thaw cycles 11.4%•in hormonal thaw cycles: 23% (risk x 1.7, p= 0.002)

Bellver et al, 2009•no effect of BMI on miscarriage rates

• perhaps because no differences to embryo quality were noted


E. MAKRAKIS

hormonal alterationsendometrial receptivitytrophoblast functionearly embryo development

insulin resistance impaired progesterone release: inhibits normal corpus luteum functionreduced IGF binding proteinreduced aνb3 integrinreduced adhesion moleculesreduced glycodelin in endometrium

leptinwhen high or resistance: leads to insulin resistance statewhen low: detrimental to early embryo development and trophoblast invasion

mechanisms for increased miscarriages


E. MAKRAKIS

obesity and IVF: most recent studies

Kupka et al, 2010•retrospective analysis of 706360 cycles from German registry dataset•inclusion of female and male weights•the combination of obese male and normal-weight female is positively related to increased implantation rates after IVF/ICSI•this combination is more likely in couples with higher social status: the result may be related to lifestyle factors Keltz et al, 2010•retrospective analysis of 290 cycles•male overweight status was associated with significantly lower clinical pregnancy rate after IVF (53.2% vs 33.6%), but not after ICSI•ICSI may overcome some obesity-related impairement of sperm-egg interaction


E. MAKRAKIS

obesity and IVF: most recent studies

Zhang et al, 2010•retrospective analysis of 2628 cycles in Chinese couples•obese women

•higher FSH dose – more stimulation days – fewer oocytes – lower fertilization rates

•overweight women•fewer oocytes – lower fertilization rates – fewer cleavaged, high-grade and cryopreserved embryos

•no differences in pregnancy/miscarriage/live birth ratesVilarino et al, 2010•retrospective analysis of 208 cycles•no differences in

•FSH dose-number of oocytes-fertilization rate-embryo quality- frozen embryos•clinical pregnancy/miscarriage/live birth rates


E. MAKRAKIS

even though no evidence-based consensus obesity may have negative effects on

ovarian stimulation parameters

oocyte and embryo quality

fertilization rates

embryo transfer

implantation rates

pregnancy rates

miscarriage rates

obesity and IVF: conclusions


E. MAKRAKIS

fewer growing follicles

difficult retrievalsfewer retrieved

oocytes

poor quality of oocytes

low fertilization rates

impaired embryotransfer due to technical problems

impairment of endometrium and its receptivity

reducedimplantation

andpregnancy

rates

increasedmiscarriage

rates

poor outcom

e

obesity and IVF: conclusions


E. MAKRAKIS

poor quality of embryos

thank you

Evangelos Makrakis MD, PhDDirector of EMBRYO A.R.T. Unit

Athens, Greece

the impact of female obesity on in vitro fertilization outcomes evangelos makrakis md, phd director...

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