Smoking and infertility: a committee opinion

Smoking and infertility:a committee opinion The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama Approximately 30% of women of reproductive age and 35% of men of reproductive age in theUnited States smoke cigarettes. Substantial harmful effects of cigarette smoke on fecundity andreproduction have become apparent but are not generally appreciated. This document replaces the 2008 ASRM Practice Committee document of the same name. (Fertil SterilÒ 2012;-:-–-.
Ó2012 by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
ent but are not generally appreciated.
medical subject headings ‘‘smoking,’’ tobacco,’’ ‘‘oocyte,’’ ‘‘sperm,’’ ‘‘fertil- ity,’’ ‘‘pregnancy,’’ ‘‘complications,’’ and ‘‘conception.’’ The reference lists was restricted to published articles. Re- tive hazards for both females and males.
jority of the studies were case series and increase the likelihood that their patients discussion of additions and deletions.
Overall, the literature strongly supports Received July 30, 2012; accepted July 31, 2012.
Correspondence: Practice Committee, American Society for Reproductive Medicine, 1209 Montgom- ery, Hwy., Birmingham, AL 35216 (E-mail: and also provides an importanteducational and motivational Fertility and Sterility® Vol. -, No. -, - 2012 0015-0282/$36.00 Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
study yielded an overall OR and 95% confidence interval (CI) for infertility in smoking compared with nonsmokingwomen across all studies designs of 1.60 (CI 1.34–1.91). In co- Public knowledge of the risks of smoking.
hort studies, the OR for conception delay over one year in smoking versus nonsmoking women was 1.42 (CI 1.27– 1.58), and in case-control studies, the OR for infertility versus fertility in smokers compared with nonsmokers was 2.27 (CI 1.28–4.02). The narrow CI suggests that the summary OR is a reasonably accurate estimate of the effect and that the results are unlikely to have arisen by chance. Most of the stud- ies excluded from the meta-analysis also support the findings that the prevalence of infertility is higher, fecundity is lower, Practice Committee. Smoking and infertility. Fertil Steril 2012.
and the time to conception is increased in smokers comparedwith nonsmokers. In some studies, the effects on fertility wereseen only in women smoking more than 20 cigarettes per day, Specificity: The specificity of the association between but a trend for all levels of smoking was identified.
smoking and infertility is not strong. The possibility Furthermore, a large scale population-based study dem- remains that other confounding variables are in- onstrated that smoking negatively affects fecundity, indepen- volved, as suggested by the relationship between dent of other factors The investigators studied data from cigarette smoking and tubal factor infertility.
nearly 15,000 pregnancies to determine time to conception. In Temporal Sequence: Most studies that have examined the addition to smoking, factors such as parental age, ethnicity, relationship between smoking and infertility have education, employment, housing, pre-pregnancy body mass been retrospective and therefore unable to assess any index, and alcohol consumption were assessed for their pos- sible confounding influences. Active smoking was associated with increased failure to conceive within both 6- and 12- month durations of study. Increasing delay to conception cor- biological plausibility for an adverse effect of smoking related with increasing daily numbers of cigarettes smoked.
on the ovary, oocytes, and the reproductive tract .
The percentage of women experiencing conception delay Various known toxins have been identified in the for over 12 months was 54% higher for smokers than for non- ovary and/or follicular fluid of smokers .
smokers. Active smoking by either partner had adverse ef- Smoking has been associated with short menstrual fects, and the impact of passive cigarette smoke exposure cycle length (%24 days), which could result in alone was only slightly smaller than for active smoking by reduced fecundity The evidence cited earlier suggesting accelerated follicular depletion and anearlier age of menopause further supports thebiological plausibility of an adverse impact of Menopause occurs one to four years earlier in smoking If a causal relationship between cigarette smoking and fe- women than in nonsmokers The dose-dependent male infertility is accepted, up to 13% of female infertil- nature of the effect supports the contention that smoking ity may be caused by smoking, based on the 1.6 odds may accelerate ovarian follicular depletion. Chemicals in cig- ratio (OR) from meta-analysis and assuming a 25% arette smoke appear to accelerate follicular depletion and the prevalence of smoking in women of reproductive age .
loss of reproductive function Mean basal follicle-stimu-lating hormone (FSH) levels are significantly higher in young smokers than in nonsmokers In one study, basal FSHlevels were 66% higher in active smokers than in nonsmokers and 39% higher in passive smokers than in nonsmokers .
Urinary estrogen excretion during the luteal phase in smokers Several comprehensive reviews have summarized the cumu- is only about one-third that observed in nonsmokers , lative data on cigarette smoking and female fecundity and possibly because constituents of tobacco smoke inhibit all support the conclusion that smoking has an adverse granulosa cell aromatase Current smoking is also studies are largely observational and include diverse in late reproductive age and perimenopausal women populations, there is considerable potential for bias from Mean gonadotropin dose requirements for smokers receiving stimulation for in vitro fertilization (IVF) are higher A meta-analysis identified the pertinent literature avail- when compared with those of nonsmoking women The able from Medline and Embase databases from 1966 through higher prevalence of abnormal clomiphene citrate challenge late 1997 and included 12 studies meeting strict inclusion test (CCCT) results in smokers than in age-matched non- criteria . Data from 10,928 exposed women and 19,179 smokers further provides evidence that smoking has adverse unexposed women were entered into these analyses. The Five of seven heterogeneous studies (includingthe only prospective study) of natural conception in female The effect of smoking on male fertility is more difficult to dis- smokers have found an increased miscarriage risk . In cern. The effects of smoking and passive smoke on various one study of inner-city women 14–39 years of age, smoking semen parameters have been evaluated .
accounted for 16% of miscarriages . Mechanisms have Reductions in sperm density, motility, antioxidant activity, not been completely elucidated. There are few data investigat- and a possible adverse effect on morphology have been ing chromosomal effects of smoking within abortus tissue, demonstrated The decrease in sperm concentration but the vasoconstrictive and antimetabolic properties of averaged 22% and was dose-dependent. Use of smokeless some components of cigarette smoke such as nicotine, carbon tobacco also has a dose-dependent negative effect on multiple monoxide, and cyanide may lead to placental insufficiency semen parameters . Although sperm concentrations, motil- and embryonic and fetal growth restriction and demise. How- ity, and/or morphology often are reduced compared with results ever, smokeless tobacco also is associated with increased risk observed in nonsmokers, they often remain within the normal of pregnancy loss , suggesting that nicotine alone is range. However, the available evidence suggests that smoking may have adverse effects on sperm function based on a study Smoking also has been associated with bacterial vagino- involving the zona-free hamster egg penetration test The sis (which in turn is associated with second-trimester miscar- available data do not demonstrate conclusively that smoking riage) and with preterm labor . The risk of multiple decreases male fertility . Few studies have or gestations also may be increased in smokers .
can address the question, because of the confounding effects Although it is difficult to control for involvement of other of partner smoking habits and fecundity.
lifestyle factors, an association between ectopic pregnancy and smoking also has been reported A case-controlstudy identified a dose-related risk for ectopic pregnancy Gametogenesis appears to be vulnerable to damage from among smokers Women who smoked more than 20 cig- tobacco smoke . Both chromosomal and DNA damage to arettes daily had an OR for ectopic pregnancy of 3.5 (95% CI human germ cells may result from tobacco smoke exposure 1.4–8.6) compared with nonsmokers.
The proportion of diploid oocytes in the ovary increases Pickup of the oocyte cumulus complex and ciliary beat with the number of cigarettes smoked per day (P<0.001), an frequency were found to be inhibited in hamster oviduct sub- observation suggesting that smoking may disrupt function jected to cigarette smoke in a perfusion chamber . These of the meiotic spindle in humans . Moreover, smoking abnormalities may contribute to increased incidences of in pregnant women is associated with an increased risk of tri- ectopic pregnancy and tubal infertility in smoking women.
somy 21 offspring resulting from maternal meiotic nondis-junction . The prevalence of Y chromosome disomy (twohomologous Y chromosomes) in sperm correlates with uri- Effects of Maternal Smoking on Male Progeny nary cotinine concentrations, a marker of recent exposure An epidemiologic study to identify the cause of decreasing sperm counts in Danish versus Finnish men has suggested Evidence suggests that gene damage in sperm may relate an effect of maternal smoking After adjusting for con- to direct binding of tobacco smoke constituents or their inter- founding factors, men whose mothers had smoked more mediates to DNA When bound to DNA, some of these than 10 cigarettes per day had lower sperm densities than ‘‘adducts’’ represent premutational lesions.
men with nonsmoking mothers. Paternal smoking was unre- Cigarette smoke contains toxic oxygen reactive species that lated to semen parameters of the offspring. It is possible that help produce adducts and are mutagenic in their own right.
these effects on male offspring could be mediated by cad- Nuclear DNA damage and mitochondrial and cytoskeletal mium or other contaminants of cigarette smoke. Together aberrations have been shown to result directly from with a reduction in fecundity and early pregnancy effects, oxidative stress in gametes, likely in part via adduct these effects on progeny may add substantially to the overall formation. These mechanisms are supported by the finding adverse reproductive burden from smoking.
of increased chemical adducts in embryos from smokerscompared with nonsmokers, indicating transmission ofmodified DNA originating from parental smoking .
Influence on Assisted Reproduction Outcomes Gamete DNA damage may cause many of the recognized Ten retrospective and four prospective studies have been adverse reproductive effects of smoking such as increased included in one or more of three meta-analyses that have ex- miscarriages, accelerated onset of menopause, and reduced fe- amined the effects of smoking on the outcome of pregnancies cundity. Increases in birth defects veriably have been reported achieved via in vitro fertilization (IVF) or gamete intrafallo- among the offspring of smoking parents, but the teratogenic pian transfer (GIFT) . Most of these studies of effects of cigarette smoke during pregnancy confound assisted reproduction have low power and failed to adjust whether DNA damage in gametes may play a role .
for confounders. Meta-analysis of nine of the studies identi-fied an OR of 0.66 (95% CI 0.49–0.88) for conception among smokers undergoing IVF . Another meta-analysis of seven Smoking is associated with an increase in spontaneous relevant studies in addition to the authors' own prospective miscarriage in both natural and assisted-conception cycles data yielded an OR of 1.79 (95% CI 1.24–2.59) for the quotient of successful first IVF cycles for nonsmokers over smokers smoking cessation in infertile women found that a relatively the result suggested that smokers require nearly twice simple and inexpensive approach based on individualized the number of IVF cycles to conceive as nonsmokers.
counseling regarding the risks of smoking was reasonably ef- The specific adverse effects of smoking on reproductive fective, increasing the proportion of women who quit smok- processes cannot be defined precisely because reported out- ing from 4% at baseline to 24% after 12 months of comes have been heterogeneous. Yet studies of IVF and intervention This study method involved several minutes GIFT have variously reported an increased gonadotropin of counseling, education, and encouragement during each requirement for ovarian stimulation, lower peak E2 levels, el- clinic visit, according to the patient's individual stage of read- evated testosterone, fewer oocytes retrieved, higher numbers iness to quit. This method was more successful than just pro- of canceled cycles, thicker zona pellucida, lower implantation viding educational materials and website addresses alone .
rates, and more cycles with failed fertilization in smokers In general populations, various interventions including behavior modification, group counseling, feedback, advice, examined specifically the effects of cigarette smoking on and nicotine weaning with patches and gum have proven ef- ovulation induction outcomes. The detrimental effect of fective. However, only 5% of women referred to a specialty smoking cessation clinic actually attended. Regularly sched- undergoing treatment . The effects of smoking uled office visits and use of multiple interventions are more ef- and advancing age may therefore synergize to accelerate fective, albeit resource-intensive. In infertile women, carbon monoxide (CO) monitoring using an inexpensive hand-held Possible mechanisms of compromised oocyte quality spirometer also may be of benefit. Results correlate well include the presence of toxins derived from tobacco smoke with the self-reported number of cigarettes smoked and offer in follicular fluid. The follicular fluid concentrations of the feedback to patients. Serum and urine cotinine concentrations heavy metal cadmium a known ovarian toxin, are higher also have been used effectively for the same purpose .
in smokers than in nonsmokers. Likewise, the concentrations The Public Health Service and National Cancer Institute of cotinine (a major metabolite of nicotine) in the follicular offer validated office-based intervention guidelines for smok- fluid aspirated from women at time of egg retrieval in IVF cy- ing cessation that incorporate and extend the above- cles relate directly to the number of cigarettes smoked . All described recommendations . A five-step approach is women known to be exposed to passive smoke in the home suggested: 1) Ask about smoking at every opportunity; 2) also had detectable follicular fluid cotinine levels, albeit at Advise all smokers to stop; 3) Assess willingness to stop; 4) lower concentrations. Also concerning was the finding that Assist patients in stopping (including the use of pharmaceu- 84% of women who reported themselves as nonsmokers ticals and CO monitoring); and 5) Arrange followup visits with nonsmoking partners had detectable levels of cotinine Specific smoking-cessation protocols for pregnant in their follicular fluids These women were exposed en- women have been outlined in several recent reviews vironmentally, with all but one working outside the home.
Other helpful resources for smoking cessation for These data emphasize the potential hazards from passive health-care providers and patients are available from A more recent study not included in the meta-analyses American Cancer Association) via their websites.
also concluded that smoking has adverse effects on concep- Although medical adjunctive therapy for smoking cessa- tion rates in assisted reproduction treatment (ART) cycles tion has not been studied in infertile women, it may be justi- Uniquely, this was a five-year prospective study that fied for some. When behavioral approaches fail, the use of controlled for potential confounders to the effects of smoking nicotine replacement therapy (NRT) and/or bupropion has and analyzed the quantity, frequency, and duration of smok- resulted in a two-fold increase in the proportion of non- ing exposure among 221 couples. A dose-response effect for pregnant women able to quit smoking .
number of cigarettes smoked could not be demonstrated but Available medical therapies include NRT in the form of was apparent for the duration of smoking. If a woman ever gum and patches (both available over the counter) as well smoked during her lifetime, her risk of failing to conceive as nasal sprays and inhalers. Because the latter two have via ART more than doubled (relative risk ¼ 2.5, 95% CI not been studied in pregnancy and are classified as category 1.38–4.55, P<0.01). Each year that a woman smoked was as- D agents (there is positive evidence of human fetal risk based sociated with a 9% increase in the risk of unsuccessful ART on adverse reaction data from investigational or marketing cycles (95% CI 1.02–1.15, P<0.01).
experience or studies in humans), NRT via nasal inhalers Overall, it appears that ART may not necessarily be able to and sprays are best avoided in pregnant women and women overcome the reduction in natural fecundity associated with attempting to conceive. Nicotine gum carries a category C classification and the nicotine patch is a category D agent,despite its reported safety in the limited clinical studies involving pregnant women that have been conducted to date.
Unfortunately, even among pregnant women who may The only non-nicotine Food and Drug Administration understand the risks of smoking, concerted efforts to help (FDA)-approved smoking cessation agent is the aminoketone them quit smoking have been only modestly effective .
bupropion (Zybanª, GlaxoSmithKline) Bupropion is also Smoking cessation rates generally are better for infertile available for use as an antidepressant (Wellbutrinª, Glaxo- women than for pregnant women. The only study to examine SmithKline) but is marketed differently (Zybanª) for smoking cessation with a category B classification. The efficacy of bu- have reproductive consequences as great as those observed propion appears similar to that of NRT strategies. Although studies of both bupropion and NRT in pregnant women  Clinicians can facilitate smoking cessation by providing have been limited, no adverse effects for pregnant women education, monitoring, and consistent individualized or their fetuses have been reported thus far. Ideally, however, pharmacological smoking cessation therapies are best usedprior to conception.
When the likelihood of achieving smoking cessation is The accumulated evidence supports the value of taking a pre- high and its benefits appear to outweigh the combined risks ventive approach to infertility by discouraging smoking and of smoking and NRT in pregnant or potentially pregnant helping to eliminate exposure to tobacco smoke in both women, NRT may be reasonable. The nicotine levels that result from daily inhalation of 10 or more cigarettes are higherthan those associated with recommended doses of nicotine gum and patches Eliminating the exposure to the direction of the Practice Committee of the American Society many other chemicals contained in cigarette smoke is one for Reproductive Medicine as a service to its members and clear advantage of NRT No studies have directly compared other practicing clinicians. Although this document reflects bupropion and NRT in infertile or pregnant women. However, appropriate management of a problem encountered in the given the relative safety and generally good compliance with practice of reproductive medicine, it is not intended to be prescribed bupropion treatment, it would appear to be an the only approved standard of practice or to dictate an exclu- acceptable initial medical intervention, when needed.
sive course of treatment. Other plans of management may be On average, female smokers referred for evaluation and appropriate, taking into account the needs of the individual treatment of infertility have tried to quit smoking three times patient, available resources, and institutional or clinical prac- previously. Sadly, only 18% of such women have received ad- tice limitations. The Practice Committee and the Board of vice on smoking cessation from their referring physicians .
Directors of the American Society for Reproductive Medicine The likelihood of achieving smoking cessation appears to in- crease with each attempt and physicians who care for The following members of the ASRM Practice Committee infertile women have another opportunity to help them quit participated in the development of this document. All Com- smoking, beginning with their initial visit.
mittee members disclosed commercial and financial relation- The substantial reproductive risks associated with smok- ships with manufacturers or distributors of goods or services ing and the revelation that much of the reduced fecundity used to treat patients. Members of the Committee who were associated with smoking may be reversed within a year of ces- found to have conflicts of interest based on the relationships sation can be powerful incentives when included disclosed did not participate in the discussion or development in physician counseling. When successful, smoking cessation of this document. Samantha Pfeifer, M.D.; Marc Fritz, M.D.; represents an important part of effective treatment for Jeffrey Goldberg, M.D.; R. Dale McClure, M.D.; Michael Thomas, M.D.; Eric Widra, M.D.; Glenn Schattman, M.D.;Mark Licht, M.D.; John Collins, M.D.; Marcelle Cedars, M.D.; Catherine Racowsky, Ph.D.; Owen Davis, M.D.; KurtBarnhart, M.D., M.S.C.E.; Clarisa Gracia, M.D., M.S.C.E.;  Available biologic, experimental, and epidemiological data William Catherino, M.D., Ph.D.; Robert Rebar, M.D.; Andrew indicate that up to 13% of infertility may be attributable to  Smoking appears to accelerate the loss of reproductive function and may advance the time of menopause by 1 to Roth L, Taylor HS. Risks of smoking to reproductive health: assessment of women's knowledge. Am J Obstet Gynecol 2001;184:934–9.
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