Cigarette smoking and infertility de Mouzon Jacques MD

Cigarette smoking and infertility de Mouzon Jacques, MD, MPH, INSERM U 822, Le Kremlin-Bicêtre, France

Introduction Cigarette n n n Cancer : Lung, Stomach, Bladder, etc. Cardiovascular disease, lung insufficiency, etc. First cause of preventable mortality in France (65000 deaths) Among n n smoking associated to many pathologies women, well established role in pregnancy Pre-eclampsia, , Placenta praevia, Abruptio placentae Fetus : birth weight (150 -200 g), small for gestational age Increasing concern in human reproduction For natural fertility (woman and man) For ART Several hypotheses for action mode

I / Natural fertility

Normal fertility n n On average, 85% of couples conceive within 12 months 90 % within 18 months What about cigarette smokers ?

Diminution of probability to conceive French study (Gefco) 1887 couples, planned pregnancies de Mouzon J, Spira A, Schwartz D. Int J Epidemiol 1988, 17: 378 -384

Increase in TTP European study (7 countries) % * * * TTP > 9, 5 months Cigarettes / day General population : 3187 planned pregnancies Maternity hospitals : 2587 planned pregnancies Infertility duration multiplied by : 1. 2 pour 1 - 10 cigarettes (1. 1 -1. 4) 1. 5 pour > 10 (1. 3 -1. 8) Bolumar F, Olsen J, Boldsen J et al. Am J Epidemiol 1996, 143: 578 -587

Increase in TTP (2) England (Avon county) % 8515 planned pregnancies Hull MGR, North K, Taylor H et al. Fertil Steril 2000, 74: 725 -733

Increased risk of TTP≥ 12 months Male and female smoking cigarettes English study Hull MGR, North K, Taylor H et al. Fertil Steril 2000, 74: 725 -733 8515 planned pregnancies

Male and female smoking Canadian study OR for fecundibility Woman’s smoking Man’s smoking No Yes No 1. 00 0. 95 (0. 84 - 1. 07) Yes 0. 91 (0. 83 - 1. 00) 0. 77 (0. 68 - 0. 85) Ontario Farm Family Health Study: 2607 planned pregnancies Woman +, Man +, Both man and woman ++ Curtis KM, Savitz DA, Arbuckle TE Am J Epidemiol 1997, 146: 32 -41

In utero exposition to smoking Odds-ratios for fecundibility Woman’s mother OR CI 95% 1. 00 --- Smoking 0. 70 0. 48 -1. 03 Non smoking 0. 67 0. 42 -1. 06 Smoking 0. 53 0. 31 -0. 91 Non smoking Smoking Prospective study, CO stopping, 423 couples, multivariate analysis Jensen TK, Henriksen TB, Hjollund. NHI et al. Am J Epidemiol 1998, 148: 992 -997

In utero exposition to smoking Danish study (2) n n Jensen et al, Int J Androl. 2006 National cohort of twins born 1931 - 1952 n n n Fecundibility Odds Ratios, whole cohort n n n 1653 women / 1598 men, with TTP Exposition in utero to cigarette smoking Women : FOR = 0. 81; 95% CI 0. 67 -0. 99 Men : FOR = 1. 12; 95% CI 0. 89 -1. 40 NS Selection of twins of opposite sex n n Women : FOR = 0. 65; 95% CI 0. 47 -0. 91 Men : FOR = 0. 97; 95% CI 0. 60 -1. 55

Cigarette smoking and female fertility Other aspects n n n Increase in short / irregular cycles Younger menopausal age (2 years) Increase % of early menopauses (<40 yrs) n n n Related to level and duration of smoking Multiplied by 3 fo 20 cig / day, 20 years ± reversible Willett W, Stampfer MJ & Bain C et al. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983, 117: 651 -8

Cigarette smoking and male fertility Semen n Künzle 2003, infertile smokers Non smokers n n 655 1131 n Concentration : 68 (66) 80 (75) n Motility A : 37. 1 (18. 6) 38. 7 (17. 7) n Normal forms: 21. 2 (14. 6) 23. 7 (15. 5) n Trummer 2002, infertile: n=478 n Round cells (106) : 3. 5 (5. 3) n Saleh 2002 12 Infert S 21 Infert NS Leucocytes (106) 1. 8 (0. 6 -4. 4) 0. 0 (0. 0 -0. 4) p 0. 001 0. 07 0. 001 517 109 Ex. S 2. 7 (3. 4) 2. 6 (3. 4) 0. 01 13 Donors NS 0. 1 (0. 0 -0. 2) 0. 01 S=Smokers; NS=Non Smokers; Ex. S= Ex Smokers

II / Assisted Reproduction

Woman cigarette Smoking and IVF. Retrospective cohort Age Non Smoker Ex Smoker (n=351) (n=111) (n=37) 32. 9 33. 8 31. 5 E 2 2297 2097 1728* oocytes 15. 4 15. 1 14. 0 Fertilization rate 54. 1 49. 9 Transf Embryos 3. 6 3. 5 3. 6 Implant R (%) 16. 4 15. 9 6. 7* Van Voorhis BJ, Dawson JD, Stovall DW et al. Obstet Gynecol 1996; 88: 785 -791

Woman cigarette Smoking and IVF. Tubal infertility Age E 2 Non Smoker Passive Smk Smoker ≤ 20 (n=351) 20 -50 (n=111) >50 (n=37) 32. 5 32. 7 32. 4 1658 1738 981* Oocytes 5. 4 5. 5 Fertilization rate 67. 6 57. 7 67. 9 Transf Embryos 2. 4 2. 5 2. 3 Pregnancy (%) 32. 6 33. 3 32. 9 Smoking classified according to follicular cotinine (ng/ml) Sterzik K, Abt M, Strehler E et al. Human Reprod 1995, 10: 3213 -3217

Woman cigarette Smoking and oocyte quality Smoking No (n=102) 33. 8 Passive (n=21) < 15 cig/D (n=37) 32. 1 32. 2 ≥ 15 cig/D (n=37) 32. 4 10. 2 9. 5 8. 0 7. 3* Fertilization rate 37 47 46 34 Fixed oocytes % 37. 8 27. 7 55. 0 54. 1 Diploid (%) 5. 1 13. 0 12. 1 21. 1 Age Oocytes Zenzes MT, Wang P, Casper RF (Human Reprod 1995, 10: 3213 -3217

Couple cigarette smoking and IVF failure OR Failure risk Smoking status Pregnancy Live birth Both no smoker 1. 00 Couple smoker 2. 41 (1. 07 -5. 45) 3, 76 (1. 40 -10. 0) Woman smoker 2. 71 (1. 37 -5. 35) 2. 51 (1. 11 -5. 67) Year of smoking 1. 09 (1. 01 -1. 16) N=221 Klonoff-Cohen H. , Natarajan L. , Marrs R. , Yee B. Human Reprod 2001, 16 : 1382 -1390

Woman cigarette smoking and Pregnancy rate Cigarette smoking No < 10 cig / D ≥ 10 cig / D OPU 842 133 206 Pregnancies (%) 21. 1 20. 3 15. 1* Belaisch-Allart J, El-Akoum. , Mayenga JM, et al. Fertil Steril 1996, 66: 679 -689

Woman passive cigarette smoking and Pregnancy rate Non Smoker Passive (146) smoker (40) Smoker (39) Age 34. 6 (4. 0) 33. 5 (3. 4) 33. 6 (3. 8) Ampoules 32. 4 (14. 9) 30. 2 (16. 2) 29. 2 (14. 2) E 2 (pmol/l) 7316 (3721) 7921 (4179) 7142 (3388) Oocytes 11. 1 (5. 7) 11. 5 (5. 6) 11. 3 (5. 3) M 2 oocytes (%) 77. 0 (17. 0) 78. 0 (18. 0) 80. 0 (1. 0) All NS Neal MS, Hughes EG, Holloway AC et al. Hum Reprod 2005, 20: 2531 -5

Woman passive cigarette smoking and Pregnancy rate (2) Non Smoker Passive Smoker (146) smoker (40) (39) Fertilization rate 63 58 57 Transf. embr 2. 3 (0. 9) 2. 2 (0. 5) 1. 9 (0. 8) CES* 12 (4) 10 (4) 12 (5) PR/OPU (%) 48. 3** 20. 0 19. 4 Implantation (%) 25. 0** 12. 6 • Cumulative embryo score • ** p<0. 05 Neal MS, Hughes EG, Holloway AC et al. Hum Reprod 2005, 20: 2531 -5 12. 0

Cigarette smoking and implantation: oocyte donation S. R. Soares, Human Reproduction 2006 785 oocyte donations, Valence, man no-smoker, transfer D 3 2. 1 embryos on average (identical in the groups) Pregnancy rate according to smoking No 1 - 10 cig/j >10 cig/j Donor (n) 49. 9 (401) 52. 6 (384) Recipient(n) 51. 6 (680) 59. 0 (n=61) 34. 1 (44)* *: p<0. 05 ---

Meta-analysis 1 (EG Hugues) 13 studies on natural fertility (n=55000) n All odds-ratios or relative risks of fertility lower than 1 except 1 : from 0. 3 to 1 7 studies on ART (n=1700) n All odds-ratios of fertility lower than 1 n Mean estimate, 0. 57 (0. 42 -0. 78) n Hugues EG, Brennan BG. Fertil Steril 1996, 66: 679 -689

Meta-analysis 2 (Augood) 13 studies on natural fertility Mean estimate of risk of infertility among smokers: Mean estimate of risk of TTP >1 yr among smokers OR =1. 60 (1. 34 -1. 91) OR = 1. 42 (1. 27 -1. 58) 9 studies on ART Mean estimate of risk pregnancy among smokers OR = 0. 66 (0. 49 -0. 88) Augood C, Duckitt K, Templeton. Human Reprod 1998, 13 : 1532 -1539

Cigarette smoking and infertility Hypotheses Nicotine n Hypothalamo-pituitary-ovarian axis n n Early menopause, Estradiol, oocytes number local : n cervical mucus, tubal motility, ciliary function Other compounds : Cadmium (diploid oocytes ? ) Hypoxia: oxydative stress on follicle Marker for tubal infertility n Van Voorhis BJ et al. Tubal infertility in IVF cohort : No smoker 34 %, Ex smoker 57 %, smoker 62 %. n Smoker more sexually active (ACSF)

Conclusion (1) Decreased fertility (natural and ART) Probable causal relationship Relation dose-effect, duration-effect Biological plausibility Reversibility at stopping (±) Some interesting points In utero exposure Probable maternal and paternal effect Passive exposition

Conclusion (2) n Methodological difficulties in measuring exposition n n Questionnaires, but concealed exposures Biological measurements (cotinine) , expensive Difficulties to measure duration, level Carbon monoxyde tester in expired air No study with large sample in ART

Conclusion (3) French epidemiological study n n n Objective: association smoking/ Result Large cohort study (3500 couples) 14 ART Centres Measurement of carbon monoxyde Both members of couples Criteria n n n Sperm quality Oocyte number and quality Cycle result and pregnancy outcome