Cigarette smoking and infertility

1
Cigarette smoking and infertility

• de Mouzon Jacques, MD, MPH,
• INSERM U822, Le Kremlin-Bicêtre, France

2
Introduction

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

3
I / Natural fertility

4
Normal fertility

• On average,
• 85 of couples conceive within 12 months
• 90 within 18 months
• What about cigarette smokers ?

5
Diminution of probability to conceiveFrench
study (Gefco)
1887 couples, planned pregnancies
de Mouzon J, Spira A, Schwartz D. Int J Epidemiol
1988,17378-384
6
Increase in TTPEuropean study (7 countries)

TTP gt 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 gt 10
(1.3-1.8)
Bolumar F, Olsen J, Boldsen J et al. Am J
Epidemiol 1996,143578-587
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Increase in TTP (2)England (Avon county)

8515 planned pregnancies
Hull MGR, North K, Taylor H et al. Fertil Steril
2000,74725-733
8
Increased risk of TTP 12 months Male and female
smoking
cigarettes
8515 planned pregnancies
English study
Hull MGR, North K, Taylor H et al. Fertil Steril
2000,74725-733
9
Male and female smokingCanadian study
OR for fecundibility
Womans smoking Womans smoking
Mans smoking No Yes Yes
No 1.00 0.95 (0.84 - 1.07) 0.95 (0.84 - 1.07)
Yes 0.91 (0.83 - 1.00) 0.77 (0.68 - 0.85) 0.77 (0.68 - 0.85)
Ontario Farm Family Health Study2607 planned
pregnancies
Woman , Man , Both man and woman
Curtis KM, Savitz DA, Arbuckle TE Am J Epidemiol
1997,14632-41
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In utero exposition to smokingOdds-ratios for
fecundibility
Woman Womans mother OR CI 95
Non smoking Non smoking 1.00 ---
Smoking 0.70 0.48-1.03
Smoking Non smoking 0.67 0.42-1.06
Smoking 0.53 0.31-0.91
Prospective study, CO stopping, 423 couples,
multivariate analysis
Jensen TK, Henriksen TB, HjollundNHI et al. Am J
Epidemiol 1998,148992-997
11
In utero exposition to smoking Danish study (2)

• Jensen et al, Int J Androl. 2006
• National cohort of twins born 1931 - 1952
• 1653 women / 1598 men, with TTP
• Exposition in utero to cigarette smoking
• Fecundibility Odds Ratios, whole cohort
• 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
• Women FOR 0.65 95 CI 0.47-0.91
• Men FOR 0.97 95 CI 0.60-1.55

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Cigarette smoking and female fertilityOther
aspects

• Increase in short / irregular cycles
• Younger menopausal age (2 years)
• Increase of early menopauses (lt40 yrs)
• 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
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Cigarette smoking and male fertilitySemen

• Künzle 2003, infertile smokers Non smokers
  p
• n 655 1131
• Concentration 68 (66) 80 (75)
  0.001
• Motility A 37.1 (18.6) 38.7 (17.7)
  0.07
• Normal forms 21.2 (14.6) 23.7 (15.5)
  0.001
• Trummer 2002, infertile n478 517 109 ExS
• Round cells (106) 3.5 (5.3) 2.7 (3.4) 2.6
  (3.4) 0.01
• Saleh 2002 12 Infert S 21 Infert NS 13
  Donors NS
• Leucocytes (106) 1.8 (0.6-4.4) 0.0 (0.0-0.4) 0.1
  (0.0-0.2) 0.01

SSmokers NSNon Smokers ExS Ex Smokers
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II / Assisted Reproduction

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Woman cigarette Smoking and IVF. Retrospective
cohort
Non Smoker (n351) Ex Smoker (n111) Smoker (n37)
Age 32.9 33.8 31.5
E2 2297 2097 1728
oocytes 15.4 15.1 14.0
Fertilization rate 54.1 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 199688785-791
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Woman cigarette Smoking and IVF. Tubal
infertility
Non Smoker 20 (n351) Passive Smk 20-50 (n111) Smoker gt50 (n37)
Age 32.5 32.7 32.4
E2 1658 1738 981
Oocytes 5.4 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 1995,103213-3217
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Woman cigarette Smoking and oocyte quality
Smoking Smoking Smoking Smoking
No (n102) Passive (n21) lt 15 cig/D (n37) 15 cig/D (n37) 15 cig/D (n37) 15 cig/D (n37) 15 cig/D (n37)
Age 33.8 32.1 32.2 32.4 32.4 32.4 32.4
Oocytes 10.2 9.5 8.0 7.3 7.3 7.3 7.3
Fertilization rate 37 47 46 34 34 34 34
Fixed oocytes 37.8 27.7 55.0 54.1 54.1 54.1 54.1
Diploid () 5.1 13.0 12.1 21.1 21.1 21.1 21.1
Zenzes MT, Wang P, Casper RF (Human Reprod
1995,103213-3217
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Couple cigarette smoking and IVF failure OR
Failure risk Failure risk
Smoking status Pregnancy Live birth Live birth
Both no smoker 1.00 1.00 1.00
Couple smoker 2.41 (1.07-5.45) 3,76 (1.40-10.0) 3,76 (1.40-10.0)
Woman smoker 2.71 (1.37-5.35) 2.51 (1.11-5.67) 2.51 (1.11-5.67)
Year of smoking 1.09 (1.01-1.16)
N221
Klonoff-Cohen H., Natarajan L., Marrs R., Yee B.
Human Reprod 2001,16 1382-1390
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Woman cigarette smoking and Pregnancy rate
Cigarette smoking Cigarette smoking Cigarette smoking
No lt 10 cig / D 10 cig / D 10 cig / D 10 cig / D
OPU 842 133 206 206 206
Pregnancies () 21.1 20.3 15.1 15.1 15.1
Belaisch-Allart J, El-Akoum ., Mayenga JM, et al.
Fertil Steril 1996,66679-689
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Woman passive cigarette smoking and Pregnancy
rate
Non Smoker (146) Passive 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)
E2 (pmol/l) 7316 (3721) 7921 (4179) 7142 (3388)
Oocytes 11.1 (5.7) 11.5 (5.6) 11.3 (5.3)
M2 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
2005,202531-5
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Woman passive cigarette smoking and Pregnancy
rate (2)
Non Smoker (146) Passive smoker (40) Smoker (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 12.0

• Cumulative embryo score
• plt0.05

Neal MS, Hughes EG, Holloway AC et al. Hum Reprod
2005,202531-5
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Cigarette smoking and implantation oocyte
donation
S.R.Soares, Human Reproduction 2006 785 oocyte
donations, Valence, man no-smoker, transfer
D3 2.1 embryos on average (identical in the
groups)
Pregnancy rate according to smoking Pregnancy rate according to smoking Pregnancy rate according to smoking
No 1 - 10 cig/j gt10 cig/j gt10 cig/j gt10 cig/j
Donor (n) 49.9 (401) 52.6 (384) --- --- ---
Recipient(n) 51.6 (680) 59.0 (n61) 34.1 (44) 34.1 (44) 34.1 (44)
plt0.05
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Meta-analysis 1 (EG Hugues)

• 13 studies on natural fertility (n55000)
• All odds-ratios or relative risks of fertility
  lower than 1 except 1 from 0.3 to 1
• 7 studies on ART (n1700)
• All odds-ratios of fertility lower than 1
• Mean estimate, 0.57 (0.42-0.78)
• Hugues EG, Brennan BG. Fertil Steril
  1996,66679-689

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Meta-analysis 2 (Augood)

• 13 studies on natural fertility
• Mean estimate of risk of infertility among
  smokers OR 1.60 (1.34-1.91)
• Mean estimate of risk of TTP gt1yr among smokers
• 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
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Cigarette smoking and infertility Hypotheses

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

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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

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Conclusion (2)

• Methodological difficulties in measuring
  exposition
• 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

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Conclusion (3)French epidemiological study

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