Maternal Tobacco Use and Its Preimplantation Effects on Fertility: More Reasons to Stop Smoking

Amber R. Cooper, M.D.; Kelle H. Moley, M.D.


Semin Reprod Med. 2008;26(2):204-212. 

In This Article

Abstract and Introduction

There are numerous health concerns regarding tobacco smoke. Yet, only recently have researchers extensively explored the association between tobacco smoke and a woman's inability to conceive. Whether exposure occurs in utero, during pregnancy, or throughout the reproductive years, it can affect all facets of fertility and lead to diminished ovarian function and earlier menopause. This review analyzes the literature concerning the delay or absence of conception in some women exposed to cigarette smoke and provides a detailed examination of the potential reproductive targets of the mutagenic and toxic components of tobacco. A negative influence on ovarian steroidogenesis and gameto-genesis, oocyte maturity, ovulation, oocyte cumulus complex pick-up, gamete and embryo transport by the oviduct, fertilization, and implantation could all play a role. Assisted reproductive technology, or more specifically, in vitro fertilization, has allowed us to more thoroughly analyze successful pregnancy cycles and the negative consequences of smoking. Objective measurements of tobacco compounds and their metabolites in follicular fluid correlate with subjective measures of ovarian, gamete, and embryo quality in smokers and in those exposed to passive smoke. Regardless, there is an abundance of literature accumulating and more than enough reasons to tell patients to stop smoking.

Tobacco smoke is composed of more than 4000 chemicals, including many dangerous toxins and carcinogens.[1] Nicotine, tar, polycyclic aromatic hydro-carbons (PAHs), metals (cadmium, lead), carbon mon-oxide, arsenic, and hydrogen cyanide are just a few of the major components linked to many disease states. Active smoking tends to be the primary target for intervention by health care professionals. Secondhand, or passive, smoke is a term used for both sidestream smoke, from the burning end of a cigarette, and mainstream smoke, what is exhaled from a smoker. In fact, there are higher levels of some toxins in sidestream smoke, though it dilutes quickly as it passes through the air. The Environmental Protection Agency (EPA) has now classified secondhand smoke as a carcinogen because of concerns regarding the deleterious health effects on both adults and the children of smokers.[2] Furthermore, there are undoubtedly numerous toxic substances in tobacco smoke that we have not yet identified.

Both active and passive smoking have the potential to harm almost every organ in the body and are associated with the leading causes of mortality: cardiovascular disease, cancer, stroke, and chronic lung disease.[3] The public health impact is huge, not only because of increased mortality and the significant nature of the addiction but also because of the enormous economic burden from medical expenditures and other indirect costs. Finally, the projected deceleration of population aging is thought in part to be due to mortality and fertility rates affected by smoking.[4] According to a 2004 Centers for Disease Control and Prevention (CDC) report, 44.5 million U.S. adults, more than 1 of every 5 people, were current smokers, nearly just as many women as men.

Women who smoke have the same health concerns as men but also many less advertised health consequences unique to females. When 388 women working in a health care setting, the majority of which had at least some college education, were surveyed about their knowledge regarding the negative health impact of smoking, 95 to 99% of those surveyed were aware of lung cancer, heart disease, and respiratory disease. Yet, only 39% of women associated smoking with miscarriage, and even less with osteoporosis (30%), ectopic pregnancy (27%), infertility (22%), and early menopause (17%), risks that have been supported repeatedly in the literature.[5] A secondary analysis of the 1995 National Survey of Family Growth (NSFG) was performed to identify lifestyle factors associated with infertility. Using logistic regression analysis, Kelly-Weeder and Cox found the following factors directly related to infertility in 824 women: increasing age, previous ectopic pregnancy, current smoking, obesity, and self-reported health status.[6] Others have shown that active smoking by either partner delays conception, and women smokers are 54% more likely to have a delay greater than 12 months. Whereas it would behoove smokers to quit, this number only minimally decreases for those women whose husbands still expose them to passive smoke.[7]

The surgeon general's pregnancy warning on every cigarette box has existed for years because smoking has been consistently linked to adverse pregnancy outcomes. Yet, many pregnant women still continue to smoke. Increased miscarriage, lower birth weight infants, premature rupture of membranes, placental abruption, perinatal mortality, risk of sudden infant death syndrome, and possibly behavioral disorders in childhood are seen more in pregnancies and offspring born to women who smoke.[8,9,10,11,12,13]

While causal associations between smoking and untoward pregnancy outcomes are being solidified, researchers are discovering more about the influences of tobacco smoke on couples who cannot “get pregnant.” It is estimated that at least 10% of U.S. couples are infertile, which has increased significantly in the past few decades in all age groups, and this number will only continue to rise.[14] There has been a significant amount of epidemiologic data published associating female cigarette smoking with subfecundity. Yet, there is some conflicting literature and significant heterogeneity in studies. One must be aware of the importance of study design in assessing an exposure often based on self-reported smoking patterns. Furthermore, studies vary with regard to the populations studied, statistical analyses, definitions of infertility and subfecundity, and social influences/confounding factors.[15] Smokers are more apt to be of lower socioeconomic status, have more sexual partners, and have intercourse at an earlier age so it may be difficult to control for the confounding risks of sexually transmitted diseases and their effect on infertility.[16,17] Although it may be hard to draw conclusions from various studies, there are two well-done reviews that reach the same conclusion. In the first, Hughes and Brennan[18] reviewed 13 observational studies of natural conception, and all but one revealed a negative association between smoking and live birth rates. In the other review, Augood and colleagues[19] performed a meta-analysis of similar studies, 12 of which met strict inclusion criteria, and found an odds ratio (OR) for infertility in women smokers versus nonsmokers of 1.60 (95% CI, 1.34 to 1.91). The dose-dependent relationship between number of cigarettes smoked and infertility adds strength to the possibility of a causal relationship. Although one may argue that some studies have weak methodological design, the abundance of literature and consistency in the results is more convincing.

Since the advent and rapid advancement in the field of in vitro fertilization (IVF), as well as improved laboratory assays and technology, more detailed information has been discovered regarding the complex process of conception. Objective data collected on heavy metals, PAHs, and cotinine (the longer-acting metabolite of nicotine) in follicular fluid as well as serum and urine to compare with self-reported smoking status is important to diminish questionnaire bias. We are able to more closely analyze conception through ovarian follicular development and steroidogenesis, oocyte quality and quantity, fertilization, embryo quality, and implantation because of the continued monitoring and analysis of gametes and embryos during the IVF process. Each of these areas is a potential target for the toxic and mutagenic compounds in tobacco smoke. Neal et al more recently published data to show that exposure to passive smoke had just as detrimental of consequences to pregnancy rates as active smoking does in patients undergoing IVF, even with similar fertilization rates and embryo quality.[20] Some of these toxic compounds can also alter gene expression in embryo development. Finally, there is even some data to suggest that a female fetus exposed in utero to tobacco smoke could have an increased risk of future infertility. Each of these areas will be discussed below in further detail. Nonetheless, there are so many known and unknown harmful substances in tobacco smoke that it is not surprising that we keep discovering more reasons to encourage smoking cessation.


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