How to advise the couple planning to conceive: Modifiable factors that may (or may not) impact fertility I have nothing to disclose Disclosures Heather Huddleston, MD Associate Professor of Clinical Medicine University of California-San Francisco LEARNING OBJECTIVES Evolution At the conclusion of this presentation, participants should be able to discuss the role of the following in impacting fertility: Obesity Common Vices: caffeine, smoking, alcohol Nutrition Exercise Stress OBESITY The human reproductive system evolved over millions years But its only recently that we look like this 1
Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) 1994 2000 Diabetes No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% 26.0% 1994 2000 2010 2010 No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics www.cdc.gov/diabetes/statistics SART DATA: The Role of Obesity in IVF Success Rates when using your own eggs Underweight 1.07 (.99-1.16) Normal (18.5-24.9) 1 REF Overweight (25-29.9) 1.07 (1.03-1.06) BMI 30.0-34.9 1.14 (1.09-1.29) BMI 35.0-39.9 1.26 (1.18-1.34) BMI 40.0-44.9 1.41 (1.27-1.57) BMI4 5-49.9 1.4 (1.7-1.67) BMI >50 1.53(1.13-2.06) AOR for NOT achieving clinical pregnancy AUTOLOGOUS eggs n=45,000 For example: A BMI of between 35-39 increases chance of a negative pregnancy test by 26% Model adjusted for age, race, fertility diagnosis, nulligravidity, height Adapted from Luke et al F and S 2011 SART DATA: Role of OBESTIY in Women using Donor Eggs >35 AOR for not achieving a clinical pregnancy for DONOR EGG CYCLES Underweight.96 Normal 1.00 Overweight 1.00 (.88-1.22) 30-34.9.92 (.72-1.16) 35-39.9 1.18 (.81-1.71) 40.0-44.9.91 (.55-1.50) 45.0-49.9.97 (.51-1.86) >50.76 (.22-2.64) No Significant Difference in Pregnancy Rates by BMI when using donor eggs Luke et all 2012 Fertility and Sterility Obesity Donor Cycle Outcomes: Bellver et al 9,587 first cycles of ovum donation with ova from normo-weight donors Recipients divided according to BMI In vitro fertilization lab parameters did not differ according to BMI Implantation, pregnancy, clinical pregnancy, twin and live birth rates were reduced as BMI increased Bellver et al Fertility and Sterility 2013 2
Obesity and Impact on Donor Egg Success Rates Racial And Ethnic Differences with BMI Adjusted odds of failure to achieve live birth relative to white This ethnic difference between White and Non- White are more pronounced in obese c/w non obese Adapted from Bellver et al F and S 2013 Amongst obese women, Asians, Hispanics and Blacks are roughly twice as likely to NOT get pregnant. Luke et al Fertility and Sterility 2011 Summary: Impact of obesity Role of obesity in reducing pregnancy rates is clear in women using their own eggs Data suggests possible impact on those using donor eggs. There is lack of clarity on whether obesity is related to egg or endometrium; though it is likely that there is impact on multiple systems. Impact on Non-whites appears to be more significant relative to White Audience Question: You are seeing a 39 year old infertile patient with BMI of 35, planning to proceed with IVF. You recommend: A. Proceeding with treatment B. Taking six months to work on weight loss with a diet C. Taking six months to increase exercise and healthy habits. 57% 15% 28% 3
Physical Activity: Wise et al Pregnancies Cycles Unadjusted model a Adjusted model b FR 95% CI FR 95% CI Vigorous physical activity, h/wk None 500 2,856 1.00 (ref.) 1.00 (ref.) <1 566 3,492 0.91 0.80 1.04 0.88 0.77 1.01 1 440 2,607 0.94 0.81 1.08 0.87 0.76 1.01 2 520 3,156 0.93 0.82 1.07 0.84 0.73 0.97 3 4 342 2,295 0.82 0.70 0.95 0.73 0.63 0.86 5 116 819 0.77 0.61 0.96 0.68 0.54 0.85 Moderate physical activity, h/wk <1 161 1,150 1.00 (ref.) 1.00 (ref.) 1 227 1,543 1.02 0.82 1.27 1.00 0.80 1.25 2 538 3,273 1.17 0.96 1.41 1.15 0.95 1.40 3 4 720 4,283 1.19 0.99 1.44 1.16 0.95 1.40 5 838 4,976 1.20 0.99 1.45 1.18 0.98 1.43 To Adverse impact seen with vigorous only Wise et al Fertility and Sterility 2012 Randomized Trial of a Lifestyle Program in Obese Infertile Women Women with BMI of 29 or higher were randomized to a six month life-style intervention preceding treatment for infertility 290 women were assigned to six month lifestyle intervention program preceding 18 months of infertility treatment 21% discontinued lifestyle after median of 2.8 month Mean weight loss after 6 months (if not pregnant) was 4.4 kg in intervention group and 1.1 in control group (p=.0001) 287 were assigned to prompt infertility treatment for 24 months In first six months: 37.7% ost 5% of original body weight. None of the women in control group did. Mutsaerts et al NEJM 2016 Lifestyle Intervention and Livebirth How do common vices impact fertility? Singleton live birth rate: Intervention: 27% versus Control: 35.3% Rate Ratio: 0.77 (95% CI.60-.99) Overall Livebirth rate: Intervention: 43.9% vs 53.9% 0.82 (.69-.97) Mutsaerts et al NEJM 2016 4
Smoking Audience Response Question: When taking a social history: Reduces IVF pregnancy rate by about one half Increases miscarriage by almost one fourth Reductions are also seen with donor eggs Second hand smoke has lesser but still significant effects A period of 3-6 months from smoking cessation is recommended Can be a powerful motivator to quit A. I never ask about caffeine B. I ask about caffeine and recommend discontinuing its use C. I ask about caffeine and recommend limited intake 40% 1% 59% Pineles et al Am J Epi 2014 Caffeine and IVF Outcomes Alcohol and IVF Outcomes Associations of live birth and caffeine consumption in 2,742 IVF Couples (female consumption) Unadjusted OR for Live Birth No Caffeine 1 1 Adjusted OR for Live Birth Odds of Live Birth for those drinking >4 drinks per week (n=2454 couples undergoing IVF) >0-800 mg per week >800-1400mg per week >1400 mg per week.99 (.83,1.18) 1.0(.83, 1.21) NS.80 (0.64,0.99).89 (0.71,1.12) NS.88 (.72,1.09) 1.07 (0.85,1.34) NS No Significant Effects Seen! Choi et al J of Caffeine Res 2011 Rossi et al Obset and Gynecol 2011 5
DIET Couples planning pregnancy visiting outpatient OBGYN clinic completed questionnaire. Six questions based on dietary recommendations of Netherlands Nutrition Centre covered the intake of six key nutrients fruits, vegetables, meat, fish, whole products and fats). Calculated PDR (preconception Dietary Risk Score) Selected 199 couples who underwent IVF/ICSI within six months of preconception visit Preconception Diet and IVF Outcomes What about Dairy? PDR: OR 1.65 (1.08-2.25). Logistic regression analysis shows association between PDR of woman and probability of ongoing pregnancy: Chance of pregnancy increased 65% with one unit increase PDR. Model controlling for: treatment indication, age of woman (squared), BMI and smoking status Twight et al Human Reproduction 2012 M.C. Afeiche et al. Hum. Reprod. 2016;31:563-571 6
Exercise Audience Question: You see a 39 year old infertile patient with BMI of 32, planning to start fertility treatment. She has increased her exercise over the past year to improve her health. She tells she runs 4-5 hours per week. You recommend: 93% A. Decreasing her exercise a little bit B. Stop exercising completely until IVF is completed C. Continue as she has been doing D. Taking six months to increase exercise and healthy habits. 4% 2% 2% Vigorous Exercise: Wise et al 2012 Internet based observational study of Danish women planning a pregnancy 2007-2009 Total of 3,628 women aged 18-40 at baseline Questionnaires regarding exercise Baseline Characteristics: Vigorous positively correlated with: education, higher frequency of intercourse, Vigorous inversely associated with: BMI Waist Caffeine Current smoking Parity Report of doing something to time intercourse. Women in highest category of PA tended to have longer and irregular cycles Wise et al Fertility and Sterility 2012 7
Exercise: Effect Modification by BMI Hours of Exercise per week BMI GROUP None 1 2 3 4-5 >5 <25 Fertility Ratio BMI 25 Fertility Ratio 1.00 0.79 (0.66 0.93) 1.00 (ref.) 1.12 (0.89 1.41) TAKE HOME: Moderate exercise is fine 0.79 (0.66 0.94) 1.15 (0.88 1.48) 0.76 (0.64 0.89) 1.16 (0.89 1.51) 0.72 (0.60 0.87) 0.76 (0.56 1.03) 0.58 (0.45 0.75) 1.22 (0.74 2.02) Vigorous may have adverse effect on thin, but not overweight women Adapted from Wise et al F and S 2012 A population based health survey HUNT 1 was conducted during 1984-1986 in Nord Trondelag county, Norway Followup from 1995-1997 (Hunt 2) 3887 women who completed two two assessments with data collected on diet, exercise, and fertility problems at the second followup. Gudmundsdottir et al Human Reproduction 2009 Exercise: North Trondelag Health Study Women with the highest levels of physical activity had the highest frequency of fertility problems. However exercise at the submaximal level did not show an association Physical activity prior to IVF in obese women Retrospective Review of all IVF ICSI between 2009-2012 Inclusion was obese women with Stable BMI between IVF scheduling and actual IVF procedure (generally six months) Data on exercise was derived from standardized questionnaire administered at scheduling and at IVF. Gudmundsdottir et al Human Reproduction 2009 Palomba et al Reproductive BioMedicine Online 2014 8
Physical activity prior IVF in infertile obese women Regular Physical Activity n 41 175 No Regular Physical Activity Age 37 37 NS BMI 33 33 NS Waist Hip.82.94.0001 M2 Oocytes 4.8 5.1 NS Fertilization rate 78.8 74.7 NS High quality embryos 36.5% 37.6% NS Total pregnancies 39% 15%.001 Miscarriage 16.7 18.8 NS Live births.004 P value Adapted from Palomba et al Reproductive BioMedicine Online 2014 Conclusions Obesity clearly has adverse effects on fertility. Smoking is detrimental to fertility efforts. There is no clear data suggesting adverse effects caffeine. A healthy and balanced diet, such as the Mediterranean is a prudent approach and may have benefit. Moderate exercise is fine for all women and possibly beneficial for overweight/obese Lean women with high levels of vigorous exercise can consider substituting moderate exercise. My Strategy Advanced End Glycation Products Stick to recommendations that would benefit patient s overall health (ie, things you would tell them even if they weren t trying to conceive). Patient s often experience increased stress and self blame, if they feel they are causing their own fertility. Exercise care in making recommendations that aren t backed by strong evidence. Jinno et al. Hum. Reprod. 2011 9
Advanced glycation end products in serum and follicular and IVF OUTCOMES Masao Jinno et al. Hum. Reprod. 2011;26:604-610 10