Obesity and Reproduction

Obesity Awareness Symposium: 2102

October 26, 2012

Jane Nani, M.D.Fertility Centers of Illinois

Scope of the ProblemPercent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

Percent of Obese (BMI > 30) in US Adults

INTRODUCTION

Prevalence of Obesity

Nationally

Globally

Impact of Obesity

Natural fecundity

ART

Childhood obesity

Allocation of reproductive resources

Centers FOR Disease control

2005-2006: 34% of US adults older than 20 years had BMI higher than 30mg/kg.

Most common chronic condition in US– 31% non-Hispanic white– 38% Hispanics– 49% non-Hispanic blacks

Centers for disease control : 2010

No state had less that 20%

36 states: prevalence of 25% or greater

12 of these: prevalence of 30% or greater

Body mass index: 1998 NIH

THE MOST COMMON DISEASE IN THE U.S.

Global Obesity

World Health organization

PREVALENCE OF OBESITY IN 2010 HIGHEST: PACIFIC ISLANDS ~ 80% LOWEST: INDIA ~ 1%

Impact on health care

300,000 deaths in the US each year Diabetes Hypertension Obstructive Sleep Apnea Cancer: breast, endometrial, ovarian, colon Dyslipidemia Cardiovascular Disease

Why are we so fat?

“Human appetite is elastic: give us more and we’ll eat more”.

The New Yorker, July 20, 2009

Impact on Reproductive Health

Gynecology– Early puberty– DUB– Urinary incontinence– Breast cancer– Endometrial cancer

Fertility– ART– Increased Miscarriages– Adverse Obstetrical

Outcome

Menstrual cycle disturbances

30-50% of overweight & obese have cycle irregularity Correlation with increasing BMI and increased truncal obesity

Douchi t et al, Acta Obstet Gynecol Scand 2002

INFERTILITY

ANOVULATION: COMMON CAUSE INCREASE BMI: INCREASE RISK of ANOVULATION WEIGHT LOSS IMPROVES OVULATION

Shah DK, et al. Curr Opin Obstet Gynecol, 2010

Polycystic ovarian syndrome (PCOS)

MOST COMMON ENDOCRINOPATHY – Not all obese women have PCOS– Not all women with PCOS are obese

Fasting Insulin and Cycle frequency

Conway G. et al. JCEM, 1996

Obesity and PCOS

Insulin Resistance Hyperinsulinemia Decreased SHBG Increased free testosterone Increased peripheral aromatization Relative increased estrogen Altered negative pituitary feedback

Catalano PM, et al. Reproduction 2010

Insulin in lean & classic PCOS

Conway G, et al. JCEM 1996

Majority of women with PCOS regardless of weight have insulin resistance

20-year follow-up: PCOS Longitudinal Study 193 PCOS women Aged 20-25 Followed at 5 year intervals over 20 years Focus: metabolic changes with aging

Carmina E, et al. Obstet Gynecol, 2012

20-year follow-up: PCOS

0102030405060708090

100

InitialVisit

Year5

Year10

Year15

Year20

Testosterone

BMI

Insulin

WaistCircumference

Carmina E, et al. Obstet Gynecol 2012

**

**

OVULATORY OBESE WOMEN

LONGER TIME TO CONCEIVE 4% per kg/m2 decrease in natural conception in women with BMI > 29

kg/m2

H-P-O AXIS DYSREGULATION LONGER FOLLICULAR PHASAE SHORTENED LUTEAL PHASE

van der Steeg JR, et al. Hum Reprod, 2008

Impact of obesity on Male fertility

Case-Cohort 2,157 men Ages: 17-67 All SA parameters decreased in age 20-30 yr: Count negatively correlated in BMI

Paasch U, et al. Fertil Steril, 2010

Effect of obesity on Male fertility Incidence of oligospermia and asthenospermia increase with BMI:

– 5.3% and 4.5 % in normal men– 9.5% and 8.9% in overweight men– 15.6% and 13.3 % in obese men

Hammoud AO, et al. Feril Steril, 2008.

Etiology: BMI assoc. Infertility in men

Abnormal reproductive hormones Increased adipose-derived E2

Reduced total testosterone levels Gonadotropin suppression (negative E2 feedback) Increased Scrotal Temperature Erectile Dysfunction

Impact of obesity on Natural fecundityOutcome Type of Study Number of pts. Reference

Subfertile Prospective Cohort

4901 Nohr et al. 2009

Subfertile Large Case-Control

2527 subjects46,718 controls

Rich-Edwards et al. 1994

Subfertile Prospective 7327 Gesink-Law et al. 2007

Subfertile Prospective Cohort

500 Zaadstra BM et al. 1993

Subfertile Prospective Cohort

1651 Wise LA, et al. 2010

Subfertile Prospective Cohort

3029 Van der Steeg et al. 2008

Subfertile Prospective 12073 Jokela et al. 2008

RETROSPECTIVE DATA: FCI

Effect of BMI on IVF outcome 2167 cases: first cycle of IVF January, 2005 – March, 2006 Clinical pregnancy rate: main outcome BMI alone: no impact on IVF outcome

Sneed ML, et al. Hum Reprod, 2008

Clinical Pregnancy Rate

0

10

20

30

40

50

60

70

80

90

18 20 22 24 26 28 30 32 34 36 38 40

Cli

nic

al P

reg

na

nc

y R

ate

BMI

20 25 30 35 40

Conclusion

At younger ages, high BMI has a profound negative influence on IVF pregnancy rates but this effect diminished with increasing age.

IVF outcomes in obese patientsDegree of Difference

Number of Patients

Study Type Main outcome Reference

No difference 1293 Retrospective Clinical Pregnancy Rate

Dokras et al 2006

Decreased 3586 Retrospective Clinical Pregnancy Rate

Wang et al. 2000

Decreased 5019 Retrospective Live Birth Rate Fedorcsak et al. 2004

No difference 2167 Retrospective Clinical Pregnancy Rate

Sneed et al. 2008

Decreased 8457 Retrospective Live Birth Rate Lintsen et al. 2005

Decreased 516 Retrospective Clinical Pregnancy Rate

Orvieto et al. 2009

No Difference 113 PCOS Retrospective cohort

Clinical Pregnancy Rate

Shalom-Paz et al. 2011

IVF outcomes in Obese patients

Higher cycle cancellation rate More days of gonadotropins Higher doses of gonadotropins Lower peak estradiol levels Lower oocyte yield Lower fertilization rate

EFFECTS OF OBESITY IN REPRODUCTIVE DEVELOPMENT

Stage of Development

Proposed mechanism

Possible effects on reproduction

Evidence References

OOCYTE Abnormal GnRHpulsatility, follicular development

Poor oocyte quality, impaired ovulation

Human IVF specimens, serum samples

Jain A, et al. 2007Robker RL, et al. 2009

Preimplanta-tion Embryo

Impaired embryonic metabolism

Impaired implantation, miscarriage

Human IVF specimens

Metwally M, et al. 2007Carrell DT, et al. 2001

Implantation Abnormal endometrium

Impaired implantation, miscarriage

Human endometrial biopsies

Mozzanega B, et al. 2004

Obstetrical complications

PREECLAMPSIA GESTATIONAL DIABETES MACROSOMIA SHOULDER DYSTOCIA CESAREAN DELIVERY BIRTH DEFECTS

NEONATAL ACIDOSIS NEONATAL RESP.

COMPLICATIONS ANESTHETIC

COMPLICATIONS VBAC FAILURE MISCARRIAGE

WHO Consultants on Obesity. June, 1997

Adverse Pregnancy outcomes

Gestational Diabetes: 20% of pregnancies in women who are obese 4-fold increased Hypertension: 2- to 3-fold increased odds of preeclampsia

Weiss JL, et al. Am J Obstet Gynecol,2004.

Maternal obesity & Pregnancy complications

Population-based cohort All Danish women with singleton birth Danish Medical Birth Registry 2004- June 2010 N = 369,347 Overweight: 20.9% Obese: 7.7% Severe Obesity: 4%

Per Ovesen, et al. Obstet Gynecol, 2011

Adjusted odds ratios (OR)

Overweight Obese Severe ObesityGestational DM 3.5 7.7 11.0Preeclampsia 1.9 3.0 4.4Macrosomia 1.6 2.2 2.7Low Apgars 1.3 1.4 1.9Stillborn 1.4 1.6 1.9

Per Ovesen, et al. Obstet Gynecol, 2011

Position of the American Dietetic association & the American society for nutrition

All overweight and obese women of reproductive age should receive counseling on the roles of diet and physical activity in reproductive health prior to pregnancy, during pregnancy, and in the inter conceptional period, in order to ameliorate adverse outcomes.

Is Maternal Obesity a risk factor for childhood obesity?

The offspring of obese women face an increased risk of obesity and other chronic metabolic diseases.

Even normal birth weight offspring of obese mothers are more likely to be obese than normal weight mothers.

Oken E, et al Obese Res, 2003

Childhood Obesity

2007—2009 County Obesity Prevalence Among Low-Income Children Aged 2 to 4

2009 State Prevalence AmongLow-Income Children Aged 2 to 4 Years

Should fertility services be conditional on BMI?

Treatment decisions/restrictions are made at the provider/clinic level Ongoing discussion among REIs Differences in use of fertility services according to female body mass

Vahratian A, et al. Hum Reprod, 2009

Resource allocations for Obese pts.

Extensive debate in countries where fertility treatment is publicly funded

Analysis of cost-effectiveness Risks & benefits Poor success rates and obstetrical outcomes Calls for restricting fertility treatment for obese women

Pandey S, et al. Hum Reprod, 2010

Management of obesity

Diet and exercise Medical Treatment

– Anti-absorptive drugs• Orlistat

– Appetite suppressants• Phentermine• Sibutramine

Insulin-sensitizing agents– Metformin

Cannabinoid receptor antagonists– Rimonabant

Bariatric Surgery

Several Case Series Compare outcomes in women pre- and postoperatively Lower rates of gestational diabetes Lower hypertensive complications

Fewer children born with size and metabolic abnormalities

Smith J, et al. JCEM 2009

Bennett WL, et al. BMJ 2010

Conclusions

Obesity prevalence has reached epidemic proportion Prospective studies are needed to better understand ART success in

the obese