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Centers for Disease Control and Prevention (US); National Center for Chronic Disease Prevention and Health Promotion (US); Office on Smoking and Health (US). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2010.

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How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General.

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8Reproductive and Developmental Effects

Introduction

Health professionals have long considered exposure to tobacco smoke harmful to reproduction, affecting aspects from fertility and pregnancy outcome to fetal and child development. Tobacco smoke contains thousands of compounds, some of which are known to have toxic effects on reproductive health, such as carbon monoxide (CO), nicotine, and metals. Along with more than four million births in the United States annually, 10 to 20 percent of pregnancies end in miscarriage or stillbirth before delivery, and another 10 percent of couples who want to conceive a child experience infertility or reduced fertility. In 2007, 17.4 percent of all women and approximately 19 percent of women of reproductive age (18 through 44 years) smoked cigarettes (Centers for Disease Control and Prevention [CDC] 2008). Smoking rates among women of reproductive age vary by other factors such as education, race, and geographic area, ranging from about 10 percent in Utah to nearly 30 percent in Kentucky and West Virginia (CDC 2005). From 2002 to 2005, 17.3 percent of pregnant women reported smoking cigarettes in the past month (NSDUH Report 2007). CDC’s Pregnancy Risk Assessment Monitoring System is an ongoing, population-based surveillance system designed to identify and monitor selected self-reported maternal behaviors and experiences that occur before, during, and after pregnancy among women who deliver a live infant. In 2002, the prevalence of smoking in the three months before pregnancy ranged from 13.6 percent (Utah) to 37.0 percent (West Virginia); in the last three months of pregnancy, from 6.8 percent (Utah) to 25.3 percent (West Virginia); and after pregnancy, from 9.0 percent (Utah) to 33.7 percent (West Virginia) (Williams et al. 2006). Prevalence of smoking is generally higher among men. In 2003, 24.1 percent reported smoking and prevalence was higher among younger men than among older men. This chapter examines reproductive and developmental outcomes, although the term “reproductive” may be used generally to describe both, in relation to smoking.

The reproductive endpoints include aspects affecting a person’s ability to conceive a child, such as menstrual cycle function, semen quality, fertility, and menopause, in addition to complications of pregnancy, such as miscarriage, ectopic pregnancy, and preterm delivery. Developmental endpoints that affect child health status include birth weight, congenital anomalies, and perinatal and infant deaths—especially sudden infant deaths and sudden unexplained infant deaths which have been associated with exposure to secondhand smoke—and they extend into childhood with neu-robehavioral endpoints and puberty. Previous Surgeon General’s reports have examined epidemiologic data for most of these endpoints. This chapter cites conclusions from those earlier reports, examines in more detail endpoints for which the evidence was not sufficient to establish causality, and provides an updated review of the epidemiologic literature for these endpoints. Other sections explore the possible biologic basis for an effect of smoking on reproduction and development from the pathophysiological levels to the cellular and genetic levels.

When studying the reproductive effects of smoking in humans, there are several exposure issues to bear in mind. Most studies have examined the effects of active smoking on fertility or pregnancy. For the past decade, interest has also increased in the effects of secondhand exposure to tobacco smoke, so these studies are mentioned when available (U.S. Department of Health and Human Services [USDHHS] 2006). Because smoking rates have declined, persons who are involuntarily exposed to tobacco smoke probably now outnumber active smokers. Thus, many nonsmokers are exposed to some of the same toxins to which smokers are exposed. The problem of involuntary exposure may be particularly pervasive for women who stop smoking during pregnancy. They may live with partners or family members who continue to smoke, so the potential still exists for exposure to tobacco smoke in the household. Such an exposure may also occur in the workplace. However, local, state, and federal laws against smoking in the workplace have led to a decline in this type of exposure. The critical exposure periods may be very specific for certain pregnancy outcomes or congenital anomalies, but most epidemiologic studies do not seek such detailed information about exposure to tobacco smoke. For endpoints of child development, postnatal exposure to tobacco smoke may also be important but difficult to separate from prenatal exposure, because the two are correlated.

Current smoking may be assessed for reproductive endpoints such as fertility, but this timing may not reflect exposure during the critical period when fertility began if the woman has stopped smoking as a result of ongoing fertility problems. Fertility may also be affected by her partner’s smoking, either directly or indirectly as exposure to secondhand smoke. Research shows the long-lasting effects of prenatal exposures on later health, even in adulthood. Thus, age at puberty, fertility, or even maintenance of a pregnancy may be affected by in utero exposure to tobacco smoke, but this relationship is rarely studied. For age at menopause, patterns of exposure to tobacco smoke over a lifetime may be important.

Review of Epidemiologic Literature on Smoking

Reproductive Endpoints

Menstrual Function, Menarche, and Menopause

Menstrual Cycling

The effects of exogenous exposures on menstrual function have become the focus of much research. Studies of these effects are hindered because cyclic patterns of menstruation vary and do not have one well-defined health endpoint. For example, some menstrual disturbances such as irregularity do not have standard definitions, and others, such as dysmenorrhea (painful menstruation), may be subjective. However, menstrual morbidity has a significant impact on women’s health and economics (e.g., physician visits and time lost from work) (Harlow and Ephross 1995). Furthermore, menstrual cycle patterns are a useful marker of ovarian function and reproductive health and may affect risks of chronic disease. The 2004 Surgeon General’s report on the health consequences of smoking did not examine menstrual function or menopause, but the 2001 report on women and smoking reached suggestive conclusions that are expanded upon here (USDHHS 2001, 2004).

Beginning in the 1960s, numerous studies have examined menstrual function in relation to smoking, but most were focused on dysmenorrhea or other self-reported symptoms. As summarized in the 2001 Surgeon General’s report on women and smoking (USDHHS 2001), the prevalence of dysmenorrhea was increased with current smoking, with intermediate effects among former smokers (Brown et al. 1988; Parazzini et al. 1994; Harlow and Park 1996; Mishra et al. 2000), but not in all studies (Andersch and Milsom 1982). A Chinese study of exposure to secondhand smoke in nonsmoking women reported an adjusted risk for dysmenorrhea that increased with higher exposure levels (Chen et al. 2000). In examining multiple endpoints or symptoms, a community survey in Los Angeles, California, revealed that the prevalence of physician-attended menstrual disorders (e.g., dysmenorrhea and oligomenorrhea) was higher among heavy smokers (≥15 cigarettes per day) than among nonsmokers (Sloss and Frerichs 1983). A postal survey in England found that compared with nonsmokers, smokers more frequently reported six of seven aspects of “abnormal” menstruation, including frequent, short, or irregular periods and prolonged and heavy bleeding (Brown et al. 1988).

Similarly, other worldwide studies have reported higher risks of multiple symptoms, including premen-strual tension, heavy periods, severe pain, and frequent and irregular periods among smokers, especially heavy smokers (Kritz-Silverstein et al. 1999; Mishra et al. 2000). Additional studies reported increased risks of short and/or irregular cycles among smokers, with some dose-response relationships observed (Kato et al. 1999; Rowland et al. 2002). Using prospective menstrual diaries to improve ascertainment, Hornsby and colleagues (1998) found more reporting of dysmenorrhea, an increased daily amount of bleeding, and a shorter duration of bleeding among smokers. The findings suggested that heavy smokers (>10 cigarettes per day) had irregularity or greater variability in cycle length than did nonsmokers. However, the study had limited power to examine higher smoking levels, and the study sample was selective in that the participants’ mothers had participated in a clinical trial of diethylstilbestrol while pregnant with them.

Other studies have assessed menstrual cycle parameters by measuring hormone levels to define lengths of phases in the cycle. A small study noted cycles of heavy smokers that were, on average, 1.6 days shorter than cycles of nonsmokers, and the mean follicular phase was shorter by 1.4 days (Zumoff et al. 1990). A study based on diaries and daily measurement of urinary levels of hormone metabolites reported that heavy smoking (≥20 cigarettes per day) was also associated with menstrual cycle lengths that were shorter by 2.6 days and more variable than those of nonsmokers (Windham et al. 1999b). The shortening of the cycle occurred primarily during the follicular phase. The findings also suggested an increased risk of a short luteal phase (<11 days) and anovulation, but the confidence intervals (CIs) for these endpoints were wide and not significant. The mean duration of bleeding in smokers was not different. Another study, based on diaries of workers in the semiconductor industry, as well as levels of hormone metabolites, found little difference in cycle length among smokers compared with nonsmokers (Liu et al. 2004a). However, this finding was modified by age: shorter follicular phases were associated with smoking only among women older than 35 years of age. The data also revealed a nonsignificant increase in risk of anovulation among smokers. Dose-response relationships were not examined (Liu et al. 2004b).

Alterations in menstrual cycle function may have several ramifications, including a burden on the health care system. Dysmenorrhea may lead to a loss of work productivity. Women with variable cycle lengths may have difficulty trying to conceive, because the timing of ovulation is less predictable. Anovulation has an obvious relevance for time to conception or fertility. Cycles that are shortened during the follicular phase might indicate abnormal folliculogenesis and ovum maturation. A short luteal phase may indicate a progesterone response that is inadequate for implantation and maintenance of the trophoblast. Studies have implicated a luteal phase defect as a cause of infertility as well as a cause of recurrent spontaneous abortion (SAB) (Regan et al. 1990; Tulppala et al. 1991). These effects are consistent with evidence for association of smoking with decreased fertility (see “Fertility” later in this chapter). Women with short menstrual cycles may also be at a higher risk of breast cancer (Kelsey et al. 1993).

Reproductive Life Span—Menarche to Menopause

Smoking may also affect the duration of menstrual cycling (reproductive life span). The 2001 Surgeon General’s report on women and smoking summarized numerous studies that consistently found a younger age at natural menopause among women who smoked than that for nonsmokers (USDHHS 2001). The studies also concluded that smokers may have more menopausal symptoms. In an earlier meta-analysis, the difference in the mean age at natural menopause ranged from 0.8 to 1.7 years (Midgette and Baron 1990). This same meta-analysis showed a prevalence ratio for being postmenopausal that was nearly doubled among current smokers versus lifetime nonsmokers, with dose-response trends by the number of cigarettes smoked. Later studies confirmed these findings (Cooper et al. 1999; Harlow and Signorello 2000; Meschia et al. 2000; Brett and Cooper 2003). One study reported a decrease in mean age at natural menopause with current active smoking but did not find an association among former smokers or with exposure to secondhand smoke (Cooper et al. 1999). However, two studies that were more briefly described found an earlier age at menopause with exposure to secondhand tobacco smoke (Everson et al. 1986; Tajtakova et al. 1990). In a population-based study in the United States, smoking was weakly associated with transition to menopausal status and strongly associated with postmenopausal status (Brett and Cooper 2003). This finding led the authors to suggest that the menopausal transition period may be shortened in smokers.

On the other end of the spectrum, some studies have examined age at menarche (start of menstrual periods) in relation to parental smoking. On the basis of data from a longitudinal birth cohort study, daughters whose mothers had smoked heavily during pregnancy had an earlier mean age at menarche by several months (Windham et al. 2004). This effect was greater among non-Whites than among Whites. Two studies from Poland reported a younger age at menarche for daughters of smoking mothers than that for daughters of nonsmoking mothers (Kolasa 1997; Kolasa et al. 1998). A retrospective study of teachers found a slightly higher risk of early menarche among women who reported that during their childhoods, their parents had smoked at home (Reynolds et al. 2004). These later studies primarily examined exposure to secondhand smoke, and the timing with respect to puberty was not established. However, mothers who smoked postnatally, especially before smoking was socially prohibited, may have smoked during pregnancy as well. Windham and colleagues (2004) showed that girls with high prenatal and childhood exposure to secondhand smoke had the earliest mean age at menarche. One study examined the effects of parental smoking on puberty in both boys and girls and reported earlier pubertal milestones in boys whose mothers had smoked during pregnancy, but not in girls. However, the study had such small numbers that the power to examine age at menarche was insufficient (Fried et al. 2001).

Changes that affect the reproductive life span can have an impact on other aspects of a woman’s health. Shorter cycles may lead to a more rapid depletion of oocytes, shortening the reproductive life span and leading to earlier menopause (Whelan et al. 1990; Bromberger et al. 1997). Early menopause is associated with other hormone-related health problems such as osteoporosis and cardiovascular disease (Harlow and Ephross 1995; Sowers and La Pietra 1995; Cooper and Sandler 1998). Early menarche or puberty may lead to psychosocial problems, adolescent pregnancy and attendant risks, other adverse reproductive outcomes, and breast cancer (Hardy et al. 1978; Liestol 1980; MacMahon et al. 1982a; Martin et al. 1983; Sandler et al. 1984; Wilson et al. 1994; Ge et al. 1996; He and Karlberg 2001).

Fertility

Fertility is an endpoint that is difficult to compare across studies, because no standard definition exists. Fecundity refers to the biologic ability to conceive, given unprotected intercourse, and depends on the reproductive capacity of both sexual partners. The clinical definition of infertility in the United States usually connotes lack of conception after one year of unprotected intercourse during the fertile phase. However, couples who delay childbearing may seek treatment before one year, which further complicates studies. Subfertility refers to any form of reduced fertility in couples trying to conceive, and one way to study it is by measuring time to conception or pregnancy. One commentary indicated that about 20 percent of couples experience subfertility, defined as the inability to conceive within six months (Gnoth et al. 2005). About 50 percent of these couples conceive in the next six months, leaving 10 percent of couples that match the clinical definition of infertility. Another 50 percent will likely conceive spontaneously in the next three years, leaving 5 percent infertile. Smoking affects fertility in men and women, as well as the success of in vitro fertilization (IVF).

Fertility in Females

Numerous studies have found associations of smoking with reduced fertility. The 2001 Surgeon General’s report concluded that “women who smoke have increased risks for conception delay and for both primary and secondary infertility” (USDHHS 2001, p. 14). The 2004 Surgeon General’s report also reviewed the literature and concluded that “the evidence is sufficient to infer a causal relationship between smoking and reduced fertility in women” (USDHHS 2004, p. 7). Other reviews have found consistent decrements in fertility associated with smoking, as well as evidence for dose-response trends. In a meta-analysis of data from 12 studies, the odds ratio (OR) was 1.6 (95 percent CI, 1.3–1.9) for infertility among smokers (Augood et al. 1998). Furthermore, meta-analyses of data on IVF treatment indicated a reduction in fecundity (conception rate per cycle) among women smokers ranging from 0.57 (95 percent CI, 0.42–0.78) to 0.66 (95 percent CI, 0.49–0.88) (Hughes and Brennan 1996; Augood et al. 1998). In a later qualitative review of 22 studies, all but 3 of the studies indicated a detrimental effect of smoking on female fecundity (Wilks and Hay 2004). The Practice Committee of the American Society for Reproductive Medicine (PCASRM) also issued a statement strongly supporting evidence for an association between smoking and infertility, estimating that 13 percent of infertility may be attributable to smoking (PCASRM 2004).

Several studies also examined the effects of exposure to secondhand tobacco smoke on fertility, but these effects may be difficult to separate from the direct effects of smoking on the partner’s fecundity. Researchers have reviewed these studies and found suggestive but inconsistent results (National Cancer Institute [NCI] 1999; USDHHS 2001, 2006), so there are insufficient data to reach conclusions. A study published since two of those reviews examined the effects of exposure to mainstream and sidestream smoke on IVF outcomes. The researchers found that implantation and pregnancy rates were reduced by about one-half from both types of exposure to tobacco smoke among smokers compared with nonsmokers (Neal et al. 2005). The investigators noted that the association of exposure to sidestream smoke may reflect some direct effect of smoking on the male partners. However, they claimed that this could not explain the entire effect in that they observed no difference in implantation and pregnancy rates by the partner’s smoking level.

Intriguingly, some studies have also examined the effects of in utero exposure to maternal smoking on later fertility or fecundability. One study found a significantly reduced likelihood of conception in smokers versus non-smokers (fecundability ratio [FR]) of 0.5 (Weinberg et al. 1989); another study found a slightly reduced FR of 0.9 (Wilcox et al. 1989); and a third study found a slightly increased FR of 1.1 but also observed no effect of active smoking among the women (Schwingl 1992). In the range of these studies, a Danish study reported FRs for in utero exposure to cigarette smoking of 0.70 among adult nonsmokers and 0.53 among smokers, as well as 0.67 for female smokers with no in utero exposure, all compared with that for nonsmokers who had no in utero exposure (Jensen et al. 1998b). This study also found a similarly decreased fecundability in males exposed to smoking in utero.

Effects on Semen Quality and Male Fertility

For decades, epidemiologic studies have investigated the effects of cigarette smoking on semen quality, because of its relationship to male fertility (Campana et al. 1996; Eggert-Kruse et al. 1996; Bonde et al. 1998; Chia et al. 2000), although this relationship is not always predictive (Polansky and Lamb 1988; Guzick et al. 2001). Semen quality is measured by seminal plasma constituents and sperm cell characteristics such as ejaculate volume, sperm count, sperm motility, and sperm morphology. The World Health Organization (WHO) Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction (WHO 1980, 1987, 1992, 1999b) provides reference values for many semen parameters associated with fertility. A number of epidemiologic studies of smoking effects have used WHO reference values to categorize participants by their fertility status. Reproductive hormones are important determinants of normal sperm production and male sexual function and have thus also been studied in relation to exposure to cigarette smoking (see “Endocrine System” later in this chapter).

The 2004 Surgeon General’s report reviewed the published epidemiologic literature evaluating semen quality and fertility and concluded that “the evidence is inadequate to infer the presence or absence of a causal relationship between active smoking and sperm quality” (USDHHS 2004, p. 28). However, “the evidence suggests that smokers may have decreased semen volume and sperm number and increased abnormal [morphologic] forms, although any clinical relevance of these findings is not clear” (USDHHS 2004, p. 534). A stronger causal statement could not be made at that time because of variability in published findings across studies. Reviews on this topic (Mattison 1982; Stillman et al. 1986; Little and Vainio 1994; Vine 1996; Marinelli et al. 2004; PCASRM 2004) and one meta-analysis of data from 20 studies covering 1966–1992 (Vine et al. 1994) attribute this variation in the findings across studies to weaknesses in study designs. These weaknesses include a failure to adjust for potential confounders, small sample sizes, inadequate exposure assessments, and the use of fertility clinic populations.

Subsequent to the 2004 Surgeon General’s report (USDHHS 2004), the PCASRM review (2004), and the review by Marinelli and colleagues (2004), some publications have strengthened the evidence for decrements in adult semen quality and fertility associated with exposure to tobacco smoke either prenatally or in adulthood (Table 8.1). Both studies in Table 8.1 that evaluated adult semen quality after in utero exposure found decrements in sperm concentration (Storgaard et al. 2003; Jensen et al. 2004). Studies conducted in clinical settings using assisted reproductive technology with extremely sensitive measures of fertilization and very early pregnancy loss also reported adverse effects from paternal smoking. Some studies had low power for detecting effects, but one of the largest studies, which was based on a retrospective review of records, did not find independent effects of cigarette smoking. However, the researchers reported a reduction in seminal volume, sperm concentration, and the percentage of motile sperm in men who smoked and consumed alcohol, behaviors that tend to be correlated (Martini et al. 2004). Another study based on a retrospective review of medical records for exposure assessments could not include more than 46 percent of the medical records initially reviewed, because of insufficient data, particularly data related to smoking (Ozgur et al. 2005). Although the study found no significant differences in sperm density, normal sperm tail morphology decreased or abnormal forms increased.

Table 8.1. Association of adult cigarette smoking and in utero exposure to cigarette smoke with semen parameters and fertility in adults.

Table 8.1

Association of adult cigarette smoking and in utero exposure to cigarette smoke with semen parameters and fertility in adults.

Spermatogenesis in the adult testes depends on a hormonal milieu that is temporally and compartmentally specific (e.g., seminiferous tubule, interstitial space, and epididymis). Thus, factors likely to be responsible for the decrements seen in semen quality and male fertility are constituents of cigarette smoke that influence the normal development and adult function of the hypothalamus and pituitary gland or that influence the differentiation, development, and adult function of Leydig and/or Sertoli cells that secrete hormones (see “Endocrine System” later in this chapter). Support for the contribution of smoking effects on hormonal factors to male fertility is still evolving (Meikle et al. 1989; Michnovicz et al. 1989; Sofikitis et al. 1995; Chapin et al. 2004). Other potential mechanisms of smoking for male infertility include effects on the sperm plasma membrane (Belcheva et al. 2004) and tobacco-related damage to DNA and/or chromosomes in gametes (PCASRM 2004) (see “Genetic Damage to Sperm” later in this chapter). Studies have associated in utero exposure to polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke with adverse effects on male fertility and on testes (see “Polycyclic Aromatic Hydrocarbons” later in this chapter). Additional targeted research in human populations with use of molecular laboratory tools will help to elucidate the mechanisms underlying these observations.

Study designs have not addressed the timing of exposures in relation to sperm cell maturation in the testes, the formation and secretion of fluids contributed by accessory organs outside the testes, and events during fertilization. This information is critical to unraveling mechanisms of the toxic effects of tobacco smoke, determining whether these exposures result in long-term risks to male reproductive health, and documenting the benefits of smoking cessation. For example, if spermatogonial stem cells prove to be the cells most sensitive to exposure to tobacco smoke, then long-term consequences might be observed even after smoking cessation. However, if mechanisms of toxic effects relate primarily to effects on epididymal sperm or to direct effects on mature sperm in the ejaculate from seminal plasma constituents, then smoking cessation could result in immediate benefits.

Pregnancy Complications

This section addresses a variety of complications that may occur during pregnancy. These complications primarily represent difficulties the pregnant mother may experience trying to maintain a healthy pregnancy, but there also may be wide-ranging effects on the health of the fetus or the offspring. In general, these conditions may be influenced by maternal age, reproductive history, and medical history or conditions affecting the maternal endocrine or immune systems, uterine structure, and cardiovascular system, among others. Exogenous exposures may also play a role in causing or exacerbating these conditions. This section briefly presents the etiology of these complications and puts potential smoking-induced mechanisms into context. (For details on the mechanisms of these complications, see “Pathophysiological and Cellular and Molecular Mechanisms of Smoking” later in this chapter.)

Spontaneous Abortion

SAB is typically defined as the involuntary termination of an intrauterine pregnancy before 20 weeks of gestation. Studies have reported recognized SABs in approximately 12 percent of pregnancies, and most occur before 12 weeks of gestation (Regan et al. 1989). However, very early pregnancy loss may go unrecognized and/or unreported. An estimated 30 to 45 percent of conceptions actually end in pregnancy loss (Wilcox et al. 1988; Eskenazi et al. 1995). Studies of tissue from SABs suggest that 50 to 80 percent of losses have an abnormal karyotype, depending on the mother’s age and the gestational age at the time of the loss; a higher proportion of abnormalities is found in losses at earlier gestational ages (Kajii et al. 1980; Hogge et al. 2003; Philipp et al. 2003). In addition to fetal abnormalities, other factors that likely contribute to SAB include maternal anatomical abnormalities of the uterus, immunologic disturbances, thrombotic disorders, and endocrine abnormalities (Christianson 1979; Cramer and Wise 2000; Regan and Rai 2000). Infections may also play a role, but data are limited and inconsistent (Cramer and Wise 2000; McDonald and Chambers 2000; Matovina et al. 2004).

Several studies have demonstrated a moderate association between smoking and SAB (DiFranza and Lew 1995). The 2004 Surgeon General’s report on the health consequences of smoking found the evidence suggestive but not sufficient to infer a causal relationship between smoking and SAB (USDHHS 2004). However, numerous studies are available since the handful reviewed at that time (Table 8.2), and most show positive associations. These results represent both retrospective and prospective study designs from a number of different countries, with adjustment for various confounders. One study found an association with amount smoked before pregnancy (Nielsen et al. 2006), and another reported an association among former smokers (Mishra et al. 2000), but others did not observe these associations (Chatenoud et al. 1998; Wisborg et al. 2003). The later study had a very low SAB rate of approximately 1 percent, so many SABs were likely missed, particularly early in pregnancy. Two studies used a measurement of cotinine to verify exposure to tobacco smoke and found relatively high risks of SAB (Ness et al. 1999; George et al. 2006). Estimates of the increase in risk of SAB from smoking are 30 to 100 percent, some in a dose-response pattern (Kline et al. 1977; Chatenoud et al. 1998; USDHHS 2004; George et al. 2006; Nielsen et al. 2006). In a meta-analysis of data from 13 studies, the pooled ORs for SAB in smokers were 1.24 (95 percent CI, 1.19–1.30) for cohort studies and 1.32 (95 percent CI, 1.18–1.48) for case-control studies (DiFranza and Lew 1995). In one study, the association with smoking appeared stronger in chromosomally normal SABs (Kline et al. 1995), but another study did not find a differential effect by chromosomal abnormality (George et al. 2006).

Table 8.2. Association between maternal smoking and spontaneous abortion (SAB), 1998–2006.

Table 8.2

Association between maternal smoking and spontaneous abortion (SAB), 1998–2006.

In examining exposure to secondhand smoke, the 2006 Surgeon General’s report on the health consequences of involuntary exposure to tobacco smoke concluded that the evidence was “inadequate to infer the presence or absence of a causal relationship” with SAB, on the basis of a few studies with inconsistent results (USDHHS 2006, p. 13). Since then, two studies have found an association with secondhand smoke on the order of 60 to 80 percent, one with a biomarker of cotinine (George et al. 2006) and one that examined very early fetal loss (Venners et al. 2004). Another study did not find an association in examining only paternal smoking (Chatenoud et al. 1998), and one found an effect of exposure to secondhand smoke at either home or work only among women who also consumed alcohol or high amounts of caffeine (Windham et al. 1999c).

Proposed mechanisms for an effect from tobacco smoke include fetal hypoxia from exposure to CO, vaso-constrictive and antimetabolic effects resulting in placental insufficiency and the subsequent death of the embryo or fetus (PCASRM 2004), and direct toxic effects of constituents of cigarette smoke.

Ectopic Pregnancy

Ectopic pregnancy occurs when a fertilized egg is implanted outside the uterus, usually within the fallopian tube. It is estimated to occur in 1 to 2 percent of pregnancies (Chow et al. 1987; Goldner et al. 1993; Van Den Eeden et al. 2005) and accounts for approximately 6 percent of pregnancy-related deaths in the United States (Berg et al. 2003; Chang et al. 2003). Factors associated with ectopic pregnancy include a history of sexually transmitted diseases and pelvic inflammatory disease, increased number of sexual partners, maternal age, history of SAB, history of surgical procedures affecting the fallopian tubes, previous use of an intrauterine device, and vaginal douching (Kendrick et al. 1997; Pisarska et al. 1998; Bouyer et al. 2003). Affected women are at increased risk of infertility and recurrent ectopic pregnancy in subsequent pregnancies (Chow et al. 1987; Coste et al. 1991; Washington and Katz 1993; Skjeldestad et al. 1998), as would be expected among women with tubal damage.

The 2004 Surgeon General’s report found the evidence suggestive but not sufficient to infer a causal relationship between smoking and ectopic pregnancy (USDHHS 2004). A number of studies have associated smoking with ectopic pregnancy, and in a meta-analysis of data from nine studies, the OR from pooled data on ectopic pregnancy from smoking was 1.77 (95 percent CI, 1.31–2.22) (Castles et al. 1999). In addition, two other studies also reported significant associations between smoking and ectopic pregnancy (Bouyer et al. 2003; Karaer et al. 2006). Both found evidence of a dose-response relationship, even after adjustment for important potential confounders, such as a history of sexually transmitted diseases and infertility. In one study, the magnitude of the association of ectopic pregnancy and smoking was similar to that seen with infectious causes (Bouyer et al. 2003). In addition, plausible mechanisms for a relationship between smoking and ectopic pregnancy exist. The oviduct plays a critical role in the pickup and transport of the oocyte, and failure of this function can result in ectopic pregnancy. Both in vivo and in vitro studies showed that smoking impairs mammalian oviduct function (Talbot and Riveles 2005).

Preeclampsia

Preeclampsia is a syndrome of reduced organ perfusion attributable to vasospasm and endothelial activation with an onset after 20 weeks of gestation that is marked by proteinuria, hypertension, and dysfunction of the endothelial cells lining the uterus (National High Blood Pressure Education Program 2000; Sibai et al. 2005). The disease can be mild or severe. When accompanied by seizures that cannot be attributed to other causes, the diagnosis is established as eclampsia by exclusion. Preeclampsia affects approximately 2 to 8 percent of pregnancies (American Journal of Obstetrics and Gynecology 1988; Duley 2003; Zhang et al. 2003; Villar et al. 2004), and the incidence is highest in nulliparous women. The reported incidence varies widely, likely because of variation in population characteristics such as parity, race and/or ethnicity, and environmental factors (Zhang et al. 1997), as well as heterogeneity in classification systems (American Journal of Obstetrics and Gynecology 1988; Villar et al. 2004). Preeclampsia is a leading cause of pregnancy-related mortality in the United States (Berg et al. 2003). Morbidity and mortality are particularly high with early-onset disease (<33 weeks of gestation) (Sibai 2003; von Dadelszen et al. 2003). Preeclampsia is also associated with fetal growth restriction, placental abruption, and perinatal death (Sibai et al. 2005).

Risk factors for preeclampsia include preexisting medical conditions, multifetal gestation, an elevated body mass index (BMI), and older maternal age (Sibai et al. 2005). Immunologic factors have also been implicated (Zhang et al. 1997; Dekker and Robillard 2003; Einarsson et al. 2003), as have infectious and/or inflammatory conditions (Sibai et al. 2005). Evidence from epidemiologic and physiological studies has led to several hypotheses on the cause of preeclampsia. First, preeclampsia seems to be characterized by poor formation of the placenta (placentation) with a shallow invasion of the decidua and myometrium by trophoblast cells, resulting in an incomplete transformation of maternal spiral arteries that then retain their muscular characteristics (Brosens et al. 1972; Naicker et al. 2003). This process leads to placental ischemia and reperfusion and results in increased oxidative stress and vascular disease. Poor placentation in preeclamptic pregnancies could be the result of maternal-fetal immune maladaptation (Sibai et al. 2005). Researchers think that the clinical manifestations of preeclampsia result from the release of placental factors in response to ischemic conditions, resulting in the endothelial dysfunction of maternal circulation (Roberts and Redman 1993). Endothelial dysfunction is characterized by a disruption in regulatory functions of vasomotor tone through coagulation, by platelet activity, and by fibrinolysis in the vascular endothelium (Roberts et al. 1989, 1991). It is unclear which placental factors may be involved, but one hypothesis is that an imbalance between proangiogenic and anti-angiogenic factors may contribute. Animal and human studies support the hypothesis that angiogenic proteins may play a role in the etiology of preeclampsia (Maynard et al. 2003; Levine et al. 2004).

Smoking is inversely associated with preeclampsia; the pooled risk reduction is 32 percent (Conde-Agudelo et al. 1999). The 2004 Surgeon General’s report found the evidence sufficient to infer a causal relationship between smoking and a reduced risk of preeclampsia (USDHHS 2004). Whether a dose-response relationship exists is unclear because study results are conflicting (Marcoux et al. 1989; Klonoff-Cohen et al. 1993; Zhang et al. 1999). Investigators have proposed three mechanisms through which smoking could reduce the risk of preeclampsia (Maynard et al. 2003; Fisher 2004):

  1. exposure to thiocyanate, which has a hypotensive effect (Andrews 1973);
  2. inhibition of thromboxane A2 production, a potent vasoconstrictor and platelet aggregation stimulator, or increase in levels of prostacyclin, a vasodilator and platelet aggregation inhibitor (Ylikorkala et al. 1985; Davis et al. 1987; Marcoux et al. 1989), both of which would improve the ratio of thromboxane A2 to prostacyclin (Lindqvist and Maršál 1999); and
  3. stimulation of proangiogenic factors, such as vascular endothelial growth factor (VEGF), and/or reduction in antiangiogenic factors, such as soluble VEGF receptor Flt-1 (sFlt-1) (Maynard et al. 2003; Fisher 2004; Jeyabalan et al. 2008).

Placenta Previa

Placenta previa is the complete or partial obstruction of the cervical os by the placenta that affects approximately 0.4 percent of all births (Comeau et al. 1983; Iyasu et al. 1993; Faiz and Ananth 2003). Placenta previa has been associated with maternal and infant complications, such as preterm delivery, a hemorrhage that requires a blood transfusion, maternal death, and fetal or neonatal death (Salihu et al. 2003; Creasy et al. 2004). Neonatal mortality in pregnancies complicated by placenta previa may be up to three times higher than that in the general obstetric population (Salihu et al. 2003). The cause of placenta previa is unknown. However, risk factors with plausible etiologic mechanisms include advanced maternal age, multiparity, multifetal gestation, and a history of a cesarean section or a previous abortion (Ananth et al. 2003; Faiz and Ananth 2003; Creasy et al. 2004).

Epidemiologic studies have consistently reported an increased risk of placenta previa among smokers, and many studies show a dose-response relationship (Meyer et al. 1976; Zhang and Fried 1992; Monica and Lilja 1995). The estimated relative risks (RRs) from smoking are 1.3 to 3.0 (Castles et al. 1999; Andres and Day 2000; Cnattingius 2004). The 2004 Surgeon General’s report found the evidence sufficient to infer a causal relationship between smoking and placenta previa (USDHHS 2004). A mechanism commonly proposed to explain this association is the chronic hypoxemia and ischemia that result from smoking, with compensatory placental enlargement. However, not all studies have shown a clinically significant increase in placental size in smokers (Zhang et al. 1999; Larsen et al. 2002).

Placental Abruption

Placental abruption, the premature separation of the placenta from the uterine wall, affects 0.5 to 2 percent of pregnancies (Rasmussen et al. 1996a; Ananth et al. 2001, 2005; Kyrklund-Blomberg et al. 2001). However, reported perinatal mortality in affected women is 8 to 12 percent (Raymond and Mills 1993; Ananth and Wilcox 2001; Kyrklund-Blomberg et al. 2001). Abruption may account for up to 14 percent of perinatal deaths (Rasmussen et al. 1996b; Ananth and Wilcox 2001). Ananth and Wilcox (2001) estimated that the perinatal mortality rate associated with abruption was 119 per 1,000 births compared with 8.2 per 1,000 among all births. Abruption can also result in neonatal asphyxia (Heinonen and Saarikoski 2001), preterm delivery, and maternal disseminated intra-vascular coagulation if thromboplastic material is released into the mother’s circulatory system (Hladky et al. 2002).

It is likely that the etiology of placental abruption is multifactorial (Misra and Ananth 1999). Potential risk factors include advanced maternal age (35 years or older), high parity, previous abruption, a history of infertility, preterm premature rupture of membranes (PPROM), small for gestational age (SGA), infant congenital malformations, multifetal pregnancy, hypertensive disorders, polyhydramnios, thrombophilia, diabetes, trauma, sudden uterine decompression, previous cesarean section, and uterine infections (Abdella et al. 1984; Williams et al. 1991; Raymond and Mills 1993; Ananth et al. 1996a,b; Kramer et al. 1997; Rasmussen et al. 1999; Cunningham et al. 2001; Kyrklund-Blomberg et al. 2001). Underlying causes of abruption could include vessel fragility, vascular malformations, uterine scarring from previous cesarean section, and placentation abnormalities (Dommisse and Tiltman 1992; Rasmussen et al. 1999; Hladky et al. 2002). In addition, failure of the maternal spiral arteries to transform into low-resistance dilated vessels could predispose the mother to ischemia and vessel rupture (Eskes 1997). In one study, a high percentage of placentas from women with severe abruption showed an absence of trophoblastic transformation, and not all cases were attributable to pre-eclampsia (Dommisse and Tiltman 1992).

Studies have consistently associated smoking with an increased risk of placental abruption. Relative risks range from 1.4 to 1.9 (Raymond and Mills 1993; Ananth et al. 1999; Castles et al. 1999; Andres and Day 2000). The 2004 Surgeon General’s report found the evidence sufficient to infer a causal relationship (USDHHS 2004). In addition, study findings support a dose-response relationship (Ananth et al. 1999). Raymond and Mills (1993) found a 20-percent increase in the risk of abruption for every 10 cigarettes the mother smoked per day. Etiologic mechanisms proposed by researchers to explain this relationship include smoking-related degenerative and/or inflammatory changes in the placenta (Cnattingius 2004); decreased vitamin C (ascorbic acid) levels in smokers (Faruque et al. 1995), leading to impaired collagen synthesis (Cnattingius 2004); microinfarcts; and atheromatous changes in placental vessels (Naeye 1979; Andres and Day 2000) (see “Placenta” and “Maternal and Fetal Cardiovascular System” later in this chapter). Analyses of consecutive pregnancies indicate that abruption risk is decreased when women stop smoking between pregnancies, suggesting that effects of smoking are transient and not cumulative across pregnancies (Ananth and Cnattingius 2007).

Preterm Delivery

Delivery at less than 37 completed weeks of gestation (preterm delivery) is a leading cause of neonatal mortality and morbidity in developed countries and is often divided into categories of moderate preterm (32 to 36 weeks) and very preterm (<32 weeks) delivery. Preterm delivery complicated 12.3 percent of pregnancies in the United States in 2003 (Hamilton et al. 2004). Rates of preterm delivery in the United States and other industrialized countries have been increasing in the past decade and are partially attributable to an increase in the frequency of multiple births (Hamilton et al. 2004).

The underlying causes of preterm delivery are complex and multifactorial. Contributing factors include multigestational pregnancy, preeclampsia, placental abruption, placenta previa, intrauterine infections, uterine overdistension, and abnormal uterine anatomy, in addition to disorders of the cervix, endocrine system, and placenta. Other risk factors include race (e.g., African Americans have higher risk), low socioeconomic status (SES), underlying maternal medical conditions, genitourinary infections, poor maternal weight gain or nutrition, young or advanced maternal age, short maternal stature, and fetal abnormalities (Haram et al. 2003; Iams 2003). Approximately 25 percent of preterm deliveries are medically indicated and are attributable to conditions affecting the mother and/or the fetus, and the remaining 75 percent are spontaneous (Meis et al. 1995; Iams 2003). A substantial body of evidence indicates that intrauterine bacterial infections are associated with preterm labor and delivery, especially at earlier gestational ages (Cassell et al. 1993; Kimberlin and Andrews 1998; Andrews et al. 2000; Goldenberg and Culhane 2003). Most intrauterine infections are believed to result from ascending infection, resulting from changes in vaginal/cervical flora, including bacterial vaginosis, or from the introduction of pathologic organisms. If these organisms ascend to the intrauterine cavity, they can cause an inflammatory reaction. The infection may progress to involve the chorion and/or amnion, fetal vessels, or the amniotic cavity, and even the fetus (review by Gonçalves et al. 2002; Romero et al. 2002). Systemic maternal infection or maternal infections remote from the genitourinary tract have also been associated with preterm labor and delivery, but the risk of preterm labor and delivery attributable to these conditions is thought to be low (Romero et al. 2002). One mechanism proposed to explain the onset of preterm labor attributable to intrauterine infection is that bacterial invasion of the choriodecidual space results in the release of endotoxins and exotoxins, which, in turn, stimulate the production of cytokines such as TNFα, interleukin-6 (IL-6), IL-8, IL-1α, IL-1β, and granulocyte colony-stimulating factor. One hypothesis is that cytokines, endoxins, and exotoxins stimulate the release of prostaglandins and initiate neutrophil activation, which results in the release of metalloproteases. This process results in stimulation of uterine contractions by prostaglandins, rupture of chorioamniotic membranes, and softening of the cervix by metalloproteinases (review by Goldenberg et al. 2000).

Researchers have consistently associated smoking with preterm delivery, and smoking likely increases the risk of both very preterm and moderate preterm births (Kyrklund-Blomberg and Cnattingius 1998; Ancel et al. 1999; Cnattingius et al. 1999; Gardosi and Francis 2000). The 2004 Surgeon General’s report found that the evidence was sufficient to infer a causal relationship between smoking and preterm delivery (USDHHS 2004). Smoking appears to increase the risk of both medically indicated and spontaneous preterm delivery (Kyrklund-Blomberg and Cnattingius 1998). However, estimates of the magnitude of the association vary among studies. In a meta-analysis of pooled data from 20 prospective studies, the estimate for any maternal smoking versus none was 1.27 (95 percent CI, 1.21–1.33), and the ORs were 1.25, 1.38, and 1.31 for light, moderate, and heavy maternal smoking, respectively (Shah and Bracken 2000), suggesting a truncated dose-response relationship.

Exposure to secondhand smoke is also associated with preterm delivery in several studies. The 2006 Surgeon General’s report concluded that the evidence was suggestive but not sufficient to infer a causal relationship (USDHHS 2006). A study by Kharrazi and colleagues (2004) included measurement of cotinine and found that nonsmokers with higher levels had earlier delivery than did those with no measurable exposure to secondhand smoke. The risk increased about 30 percent with each log increase in cotinine (adjusted OR [AOR] = 1.29 [95 percent CI, 0.97–1.72]).

Parity may modify the association between preterm delivery and smoking. As previously stated, the incidence of preeclampsia is highest among nulliparous women (see “Preeclampsia” earlier in this chapter). Because smoking protects against preeclampsia and preeclampsia can result in preterm delivery, the adverse effects of smoking on risk of preterm delivery may be masked in nulliparous women (Burguet et al. 2004).

Mechanisms through which smoking may contribute to preterm delivery are unknown. Researchers have proposed that smoking could increase risk of intrauterine infections (review by Cnattingius 2004). Smokers have a twofold-to-threefold increase in risk for bacterial vaginosis, which is a risk factor for preterm delivery (Morris et al. 2001). Researchers have hypothesized that smoking increases this risk through its effects on vaginal flora or through depletion of Langerhans cells, resulting in local immunosuppression (Smart et al. 2004). Alterations in the cervical cytokine profile have been associated with increased risk of preterm delivery; women with a high anti-inflammatory and low proinflammatory profile are at highest risk (Simhan and Krohn 2009). Cigarette smoking has been associated with increased cervical anti-inflammatory cytokines in early pregnancy, which could make women who smoke more vulnerable to reproductive tract infections and subsequent preterm delivery (Simhan et al. 2005). Smoking can also reduce zinc levels, which could increase susceptibility to vaginal infections (Edman et al. 1986; Sikorski et al. 1990; Shubert et al. 1992). Immunosuppressive effects of smoking could also increase the risk of upper genital infections, known to be associated with preterm labor and PPROM. Neonates born to smokers have been noted to have a decrease in all leukocytes, indicating possible fetal immune dysregulation (Pachlopnik Schmid et al. 2007). Pathways other than those involving infections have also been proposed. For example, investigators have suggested that smoking during pregnancy increases contractile sensitivity and activity of the myometrium, with exposure to oxytocin by upregulating expression of messenger RNA (mRNA) for oxytocin receptor (Egawa et al. 2003). Compared with unexposed pregnant rats, those with exposure to cigarette smoke were found to have higher contractile sensitivity and activity in response to oxytocin (Egawa et al. 2003).

Finally, findings have also suggested that smoking may disrupt the integrity of type III collagen, leading to weakening and rupture of the membranes and an increased risk of medical indications for preterm delivery, such as placental abruption and intrauterine growth restriction (IUGR) (Cnattingius 2004).

Preterm Premature Rupture of Membranes

PPROM is defined as the rupture of amniotic membranes before the onset of labor and before 37 completed weeks of gestation. PPROM occurs in up to 4.5 percent of deliveries and in approximately 40 percent of preterm births (Mercer et al. 2000). Pregnancies complicated by PPROM have higher rates of neonatal morbidity than do pregnancies complicated by idiopathic preterm labor (Arias and Tomich 1982).

Factors that researchers have associated with PPROM include (1) nutritional deficiencies in vitamin C (Hadley et al. 1990; Casanueva et al. 1993), copper (Artal et al. 1979; Kiilholma et al. 1984), and zinc (Sikorski et al. 1990; Scholl et al. 1993); (2) vaginal bleeding (Harger et al. 1990; Ekwo et al. 1992); (3) multifetal pregnancies (Mercer et al. 1993); (4) a history of preterm delivery or PPROM in a previous pregnancy (Naeye 1982; Harger et al. 1990; Ekwo et al. 1992; Mercer et al. 2000); (5) obstetric complications involving uterine overdistension (French and McGregor 1996); and (6) bacterial vaginosis (Kurki et al. 1992; Mercer et al. 2000) and intra-amniotic infections (Naeye and Peters 1980; Ekwo et al. 1993; Heffner et al. 1993). However, it can be difficult to determine whether an intra-amniotic infection precedes or follows the rupture of membranes. A review by Lee and Silver (2001) discusses in detail the risk factors for PPROM.

Researchers suggest that structural deficiencies in the architecture of the amniotic membrane could increase the risk of PPROM (Shubert et al. 1992; Lee and Silver 2001). Studies of spontaneously ruptured membranes demonstrate that membranes are thinner and collagen content is lower near the site of rupture. Moreover, these alterations appear to be focal rather than generalized (Skinner et al. 1981; Kanayama et al. 1985; French and McGregor 1996). The tensile strength of tissue depends on the collagens, especially types I and III. The amniotic membranes of women with PPROM have decreased amounts of type III, type V, and total collagen (Skinner et al. 1981; Kanayama et al. 1985; al-Zaid et al. 1988). In addition, Athayde and colleagues (1998) found that women with PPROM had higher amniotic fluid levels of metalloproteinases that degrade collagen types IV and V than did women with term labor. These researchers also suggested that infection could be an additional trigger if the host responds to an infection by activating matrix-degrading enzymes (Athayde et al. 1998).

Many studies have associated smoking with an increased risk of PPROM (Lee and Silver 2001). The 2004 Surgeon General’s report found sufficient evidence to infer a causal relationship between smoking and PPROM (USDHHS 2004). Researchers have hypothesized that smoking increases the risk of PPROM through several pathways. The effects of smoking on the immune system could increase the risk of genital tract infection or disrupt the cytokine system (French and McGregor 1996). Smoking could increase the inflammatory response and reduce the availability of nutrients such as vitamin C or decrease the uptake of nutrients by the placenta (French and McGregor 1996; Lykkesfeldt et al. 1996,2000) (see “Other Molecular Mechanisms” later in this chapter).

Developmental Endpoints

This section on developmental effects summarizes the epidemiologic evidence for prenatal effects of maternal smoking on the infant and child, including endpoints such as birth weight, perinatal or infant mortality, birth defects, and neurobehavioral. The discussion also briefly notes the evidence for effects from exposure to secondhand smoke on these outcomes. Studies have examined the effects of smoking on child growth, but this topic is not addressed in this report. Studying childhood health in relation to prenatal smoking is complicated by the possibility of exposure to secondhand smoke subsequent to birth, as well as other intervening factors between birth and some later outcomes that are difficult to assess.

Fetal Size and Growth

The first and the most widely studied effect of maternal smoking is the influence on fetal growth. Fetal growth cannot be directly assessed, so birth weight is used as a surrogate. However, birth weight reflects not only growth but also gestational age, as well as genetic potential, which is not commonly assessed. To account for gestational age, studies may examine IUGR, which is usually assessed from the distribution of birth weight by gestational week, in a standard population. The common definition of SGA is less than the 10th percentile of weight for the age. Another parameter that is examined includes low birth weight (LBW) (<2,500 grams [g]), sometimes among term births only (≥37 weeks).

The first Surgeon General’s report on smoking and health in 1964 noted an association of maternal smoking with LBW (U.S. Department of Health, Education, and Welfare 1964). The 2001 Surgeon General’s report on women and smoking concluded that “infants born to women who smoke during pregnancy have a lower average birth weight and are more likely to be SGA than are infants born to women who do not smoke” (USDHHS 2004, p. 15). Furthermore, the 2004 Surgeon General’s report concluded that “the evidence is sufficient to infer a causal relationship between maternal active smoking and fetal growth restriction and low birth weight” (USDHHS 2004, p. 28). These conclusions are based on a multitude of studies with consistent evidence of a dose-response relationship, confirmed by more recent studies using a biomarker of exposure to tobacco smoke.

Infants of smokers typically weigh 150 to 200 g less than infants of nonsmokers and are twice as likely (ORs = 1.5 to 2.5) to be LBW or SGA. Maternal smoking appears to have the strongest effect on birth weight through growth retardation and, to a lesser extent, through a shortened gestation (Ananth and Platt 2004; USDHHS 2004). On the basis of a maternal smoking rate of about 12 percent during pregnancy, the etiologic fraction (EF) for LBW from smoking was calculated as 6.4 percent for all births and 10.9 percent for single births (Magee et al. 2004). The EF for LBW from smoking among births at full term was slightly higher at 13.4 percent or 16.7 percent for single births, which comprise most births. The authors also reported that 60 percent of the effect of smoking on LBW in the overall population was among light smokers.

Because of the established effects of maternal active smoking, many studies have also examined fetal growth in relation to exposure of the mother to secondhand smoke. Several reviews concluded that exposure to secondhand smoke is associated with adverse effects on infant growth or an increased risk of LBW and SGA (NCI 1999; WHO 1999a; USDHHS 2001; British Medical Association 2004). Moreover, the 2006 Surgeon General’s report concludes that “the evidence is sufficient to infer a causal relationship between exposure to secondhand smoke and a small reduction in birth weight” (USDHHS 2006, p. 13). The highest quality studies indicate birth weight decrements of 15 to 100 g and an OR for LBW or SGA of 1.1 to 1.7 from exposure to secondhand smoke (NCI 1999). A meta-analysis of pooled data conducted through 1995 calculated a mean weight decrement of 28 g (95 percent CI, 16–40) among infants of mothers who did not smoke but were exposed to secondhand smoke and ORs of 1.2 for IUGR and 1.4 for LBW (Windham et al. 1999a). One study based on a sensitive assay for cotinine showed a birth weight decrement of 27.2 g (95 percent CI, 0.6–53.7) per unit change in log cotinine, which represented a decrement of about 100 g between the highest and lowest cotinine quintiles (Kharrazi et al. 2004).

Several studies have shown that the effects of exposure to tobacco smoke, primarily active but also involuntary exposure, appear to be stronger among older mothers (Wen et al. 1990; Wisborg et al. 1996; Haug et al. 2000; Windham et al. 2000; Salihu et al. 2005). Risk may also vary by racial and ethnic groups, and some studies (Mainous and Hueston 1994; USDHHS 1998; Windham et al. 2000) noted stronger effects among non-Whites or Blacks. Some of these variations may be a result of differences in nicotine metabolism among racial groups or differences in smoking and exposure patterns. Smoking may cause reduced birth weight or fetal growth due to fetal hypoxia resulting from exposure to CO, other effects on fetal nutrition, or the action of PAHs (see “Tobacco Smoke Toxicants and the Reproductive System” and “Other Molecular Mechanisms” later in this chapter).

Perinatal and Infant Mortality

The definition of perinatal mortality may vary slightly across studies, but it commonly includes stillbirth at more than 28 weeks of gestation and early neonatal deaths (first 7 days of life). Infant mortality includes death of a live-born child in the first year of life and can be divided into the neonatal (first month) and postneonatal (1 month to 1 year) periods. Neonatal mortality is more related to prenatal conditions. Previous reports of the Surgeon General have reviewed the data for an effect of smoking on mortality. The 2001 report concluded, “the risk for perinatal mortality—both stillbirth and neonatal deaths—and the risk for sudden infant death syndrome (SIDS) are increased among the offspring of women who smoke during pregnancy” (USDHHS 2001, p. 15). The 2004 Surgeon General’s report also concluded, “the evidence is sufficient to infer a causal relationship between sudden infant death syndrome and maternal smoking during and after pregnancy” (USDHHS 2004, p. 7). However, the report noted the difficulty of separating prenatal from postnatal effects of maternal smoking.

Many studies have found a slightly increased risk of approximately 20 to 30 percent for stillbirth or neonatal mortality associated with smoking (USDHHS 2004). A meta-analysis of pooled data from 23 cohort studies of perinatal mortality calculated a RR of 1.26 (95 percent CI, 1.19–1.34) (DiFranza and Lew 1995). In one study, the risk was higher for postneonatal death (AOR = 1.6; 95 percent CI, 1.41–1.85) than for neonatal death (AOR = 1.2; 95 percent CI, 1.05–1.30), which was primarily attributable to two causes: respiratory disease and SIDS (Malloy et al. 1988). A study in India (Gupta and Subramoney 2006) reports an adjusted risk for stillbirth three times higher for mothers who use smokeless tobacco than for those who do not use smokeless tobacco. Some evidence for a dose-response relationship was shown for frequency of use. Two previous studies from India had also reported an increased risk of stillbirth or perinatal death with use of smokeless tobacco (primarily chewing tobacco) (Krishna 1978; Shah et al. 2000). These investigations lend further support to the literature on the adverse effects of tobacco use, which may be related to heavy metals or nicotine, because CO from tobacco smoke would not be present (see “Tobacco Smoke Toxicants and the Reproductive System” later in this chapter).

Studies of SIDS and maternal smoking that controlled for other factors showed ORs of 1.8 to 3.1. Several of those studies also report a dose-response relationship (NCI 1999; USDHHS 2004). A meta-analysis comparing women who did or did not smoke during pregnancy, regardless of smoking status after delivery, calculated a pooled OR of 2.98 (95 percent CI, 2.51–3.54) (DiFranza and Lew 1995). Some studies have attempted to separate the effects of prenatal exposure from those of postnatal exposure. In one study, the risk of SIDS was increased in infants with only postpartum exposure to tobacco smoke but was even greater with both prenatal and postnatal exposures (Schoendorf and Kiely 1992). A large study in which participants were asked detailed questions on exposure to tobacco smoke found similar risks for maternal or paternal smoking, but the risks increased with more smokers in the household (Klonoff-Cohen et al. 1995). In addition, some studies that attempted to examine the independent effects of paternal smoking observed elevated risks of SIDS (Mitchell et al. 1993; Blair et al. 1996). Rates of SIDS have decreased over time with strong public education campaigns to place infants in the supine position while they sleep. Subsequent studies found that the risk attributable to maternal smoking has concomitantly increased and smoking may now be the greatest preventable cause of SIDS (Chong et al. 2004; Anderson et al. 2005).

Birth weight is one of the strongest predictors of infant survival. However, the effects of reduced growth versus shortened gestation are important to consider in determining etiology. Both reduced growth and shortened gestation appear to be related to infant mortality and SIDS (McCormick 1985; Oyen et al. 1995; Paneth 1995; Ananth and Platt 2004). The longer the gestation for a given birth weight, the lower is the mortality (McCormick 1985; Wilcox and Skjærven 1992). The increased risk of mortality associated with LBW appears to continue beyond infancy into childhood (Samuelson et al. 1998; Xu et al. 1998). Furthermore, studies suggest an association of maternal smoking with a higher mortality rate that continues beyond infancy. This effect was greater after adjustment for birth weight (Hofvendahl 1995). Infants who experience symmetrical growth retardation (in weight, length, and head circumference) associated with maternal smoking may be less likely to exhibit later “catch-up” growth and appear to be more likely to have cognitive deficits and difficulties in school (McCormick 1985). Thus, other effects associated with maternal smoking, such as perinatal mortality, may be mediated through reduced fetal growth and, to some extent, through a shortened gestation period (Ananth and Platt 2004). Some studies have found higher risks of infant mortality associated with smoking among mothers who are 35 years of age or older or of certain racial groups (Cnattingius et al. 1988; Li and Daling 1991). Studies have also found an increased risk of SIDS with placental abnormalities (Li and Wi 1999), thus suggesting another mechanism by which smoking may lead to SIDS.

Birth Defects

The 2004 Surgeon General’s report summarized epidemiologic studies published between 1974 and 1998 on the relationship between maternal smoking during pregnancy and the risk for congenital malformations (USDHHS 2004). The report concluded that “the evidence is inadequate to infer the presence or absence of a causal relationship between maternal smoking and congenital malformations in general” (USDHHS 2004, p. 28). For oral clefts, however, several studies reported increased risks, and the evidence was considered to be suggestive, but not sufficient, to infer a causal relationship with smoking.

Since the 2004 Surgeon General’s report, additional studies have examined possible associations of maternal smoking with major birth malformations. The evidence in support of an association between smoking and an increased risk for oral clefts has become stronger (Table 8.3). A meta-analysis of data from studies published between 1974 and 2001 focused on 9 studies that examined total orofacial clefts and 15 that examined cleft lip with or without cleft palate and cleft palate alone. The study found an association between maternal smoking and a 34-percent increase in the risk of cleft lip with or without cleft palate and a 22-percent increase in the risk of cleft palate alone (Little et al. 2004a). More recently, similar findings were also observed by Honein and colleagues (2007). Other studies provide evidence of a dose-response relationship for maternal smoking and the risk for cleft lip with or without cleft palate (Wyszynski and Wu 2002; Little et al. 2004b; Honein et al. 2007) and for cleft palate alone (Little et al. 2004b). A recent study assessing maternal tobacco exposure by cotinine levels in mid-pregnancy serum samples found an OR of 2 for cleft lip with or without cleft palate (Shaw et al. 2009).

Table 8.3. Association between maternal smoking and orofacial clefts (OFCs), 1999–2009.

Table 8.3

Association between maternal smoking and orofacial clefts (OFCs), 1999–2009.

Studies on interactions between genes and smoking and between vitamin use and smoking contribute to an understanding of the etiology of oral clefts (van Rooij et al. 2002; Jugessur et al. 2003; Shi et al. 2007) (see “Fetal Tissue and Organogenesis” and “Smoking and Maternal and Neonatal Genetic Polymorphisms” later in this chapter). One study reported an increase in the risk for cleft lip with or without cleft palate that was strongest among offspring whose mothers had smoked but had not consumed multivitamins during the periconceptive period (Shaw et al. 2002). Results did not suggest an interaction for isolated cleft palate. Study findings also supported an increased risk of clefting with paternal smoking or involuntary exposure to tobacco smoke (Savitz et al. 1991; Zhang et al. 1992; Shaw et al. 1996). Whether paternal smoking acts through exposure of the mother to secondhand smoke or directly on male gametes is not clear.

A number of studies have also investigated maternal smoking in relation to cardiovascular malformations. A review of data from 13 studies published between 1971 and 1999 found mixed results. Twelve of the studies provided results for cardiovascular malformations combined and seven studies for specific subgroups of cardiovascular defects examined separately (Källén 2002a). Combining all cardiovascular malformations represents a heterogeneous group but examining subgroups resulted in low power for several studies. The conflicting results probably reflect differences in research methods, including case ascertainment, classification, control of confounding, and sample size of the case group. Other studies have reported associations of maternal smoking with cardiovascular malformations (Table 8.4), including conotruncal defects, atrial septal defects, and atrioventricular septal defects (Torfs and Christianson 1999); l-transposition of the great arteries (Steinberger et al. 2002; Kuehl and Loffredo 2003); and conotruncal defects among offspring whose mothers did not use vitamins (Shaw et al. 2002). Steinberger and colleagues (2002) found an association between paternal smoking and single-ventricle defects. These more recent exploratory studies present methodologic issues similar to those noted in the meta-analysis by Källén (2002a). In addition, Malik and colleagues (2008) found an association between periconceptual smoking and septal heart defects. There is a need for further research with large, population-based studies that incorporate standardized methods for case ascertainment and classification to determine whether a relationship exists between maternal smoking and the risk of cardiovascular malformations.

Table 8.4. Association between maternal smoking and cardiovascular malformations, by phenotype, 1999–2008.

Table 8.4

Association between maternal smoking and cardiovascular malformations, by phenotype, 1999–2008.

Studies of other birth defects have found an association between maternal smoking and an increased risk for clubfoot (Honein et al. 2000; Skelly et al. 2002), craniosynostosis (Källén 1999; Carmichael et al. 2008), and gastroschisis (Werler et al. 2003), but not for spina bifida (Table 8.5) (Shaw et al. 2002; van Rooij et al. 2002). Studies report mixed results for maternal smoking and limb deficiency defects (Hwang et al. 1998; Shaw et al. 2002; Carmichael et al. 2004), Down syndrome (Chen et al. 1999; Yang et al. 1999), and for cryptorchidism and hypospadias (Akre et al. 1999; Källén 2002b; Pierik et al. 2004).

Table 8.5. Association between maternal smoking and noncardiovascular congenital malformations, by type of malformation, 1998–2008.

Table 8.5

Association between maternal smoking and noncardiovascular congenital malformations, by type of malformation, 1998–2008.

Maternal smoking may interfere with normal organ development in offspring in several ways, including through fetal hypoxia, alterations in essential nutrients, teratogenic effects, and DNA damage. Those effects may be related to exposure to tobacco smoke components such as CO, nicotine, cadmium, and PAHs (Chernoff 1973; Mochizuki et al. 1984; Lammer et al. 2004; Munger et al. 2004; Ziaei et al. 2005). In addition, certain populations with genetic polymorphisms may be more susceptible to damage attributable to exposure to tobacco smoke because of alterations in metabolic pathways (see “Fetal Tissue and Organogenesis” and “Smoking and Maternal and Neonatal Genetic Polymorphisms” later in this chapter).

Neurodevelopment

Maternal smoking and exposure to secondhand tobacco smoke during pregnancy affect infant health status at birth as described earlier and are hypothesized to affect physical and mental development in infancy and early childhood as well. Studies have reported evidence of lower weights and shorter heights into the preschool period (Fox et al. 1990), in addition to correlations of maternal smoking with microcephaly and hydrocephaly, particularly among female infants (Honein et al. 2001). Reviews have also examined the links between maternal smoking and mental development in offspring (Hardy and Mellits 1972; Lassen and Oei 1998). Earlier Surgeon General’s reports examined this topic and reported possible effects. However, at the time of the 2004 Surgeon General’s report, the evidence was considered “inadequate to infer the presence or absence of a causal relationship between maternal smoking and physical growth and neurocognitive development of children” (USDHHS 2004, p. 601), and this conclusion was echoed in the examination of secondhand smoke (USDHHS 2006). Some key studies, as well as others published since those included in the prior reports of the Surgeon General (e.g., 2004 and later), are summarized below.

Researchers have suggested that prenatal exposure to smoking poses a unique risk for neurologic development and intellectual abilities attributable to impairments of the central nervous system (Olds et al. 1994). Drews and colleagues (1996) studied a sample of 221 children aged 10 years and reported that those with mental retardation were more likely than control participants with no mental retardation to have mothers who had smoked during pregnancy. Moreover, the rates of retardation increased with the number of cigarettes mothers smoked. McCartney and colleagues (1994) speculated that intrauterine exposure to nicotine specifically affects the physiology of outer hair cells in the ear that underlies language ability and leads to poorer performance scores among offspring on assessments that rely heavily on verbal abilities.

Investigators have found it difficult to document a consistent impact of maternal smoking on cognitive development in infants and young children, because many factors affect cognitive development. For example, in a study of two-and four-year-old children of mothers who smoked compared with children in the same age groups whose mothers did not smoke, Baghurst and colleagues (1992) reported small but significant group differences on the Bayley Scales of Infant Development (BSID) and the McCarthy Scales of Children’s Abilities (MSCA). However, group differences were not significant after controlling for SES, maternal intelligence quotient, and quality of the home learning environment. Sexton and colleagues (1990) also reported better scores among three-year-olds whose mothers had stopped smoking during pregnancy compared with children whose mothers had smoked more than 10 cigarettes a day during pregnancy. Group differences in performance on the Minnesota Child Development Inventory and the MSCA were small, but differences remained significant after adjustment for birth weight, SES, and certain maternal and child characteristics. Trasti and colleagues (1999) reported lower scores on the Wechsler Preschool and Primary Scale of Intelligence-Revised for a sample of 369 children aged five years whose mothers had smoked during pregnancy compared with children of mothers who did not smoke. However, significant group differences were not found after adjustment for maternal education level. These researchers also reported no differences on the BSID in a sample of 376 children from the same population at 13 months of age by mothers’ smoking status.

Batstra and colleagues (2003) reported poorer performance on mathematics and spelling achievement tests among a group of 1,186 children aged 5 through 11 years whose mothers smoked, and differences remained after adjustment for SES and for prenatal and perinatal complications. A Danish study found effects of prenatal smoking during the third trimester on adult intelligence even after adjustment for sociodemographic variables (Mortensen et al. 2005). In contrast to other studies, Eskenazi and Trupin (1995) reported slightly higher but nonsignificant scores on the Peabody Picture Vocabulary Test and the Raven Progressive Matrices Test for five-year-old children whose mothers had smoked during pregnancy compared with those for children of mothers who had not smoked, even after adjustment for parental education, SES, age, race, and preschool attendance. Some significant decrements in performance on these same measures and significant differences in the maternal-rated activity levels were attributable to exposure to secondhand tobacco smoke during childhood. Other studies show cognitive deficits with prenatal exposure to secondhand smoke that are exacerbated by conditions of material hardship (Rauh et al. 2004). After adjustment, decrements in cognitive and academic abilities were reported with increasing cotinine levels within the range indicating exposure to secondhand smoke during childhood (Yolton et al. 2005).

Despite these inconsistent findings on general assessments of children’s cognition and intelligence, findings more consistently show an association between maternal smoking and children’s lower performance on assessments of verbal skills in general, as well as on specific language and auditory tests. For example, a sample of 110 children aged 6 to 11 years whose mothers had smoked during pregnancy performed more poorly on tasks tapping phonologic processing skills that are known to be related to both language and reading abilities (McCartney et al. 1994). Follow-up studies of the same cohort reported that maternal smoking and maternal involuntary exposure to tobacco smoke negatively affected the performance of children aged 9 and 12 years on standardized assessments of language and reading, as well as on assessments of general intelligence skills (Fried et al. 1997). Butler and Goldstein (1973) studied a sample of more than 9,000 children aged 7 and 11 years whose mothers had smoked during pregnancy. These children were three to five months behind children of nonsmoking mothers in reading, mathematics, and general cognitive abilities. In more than 5,000 youth aged 6 through 16 years from the Third National Health and Nutrition Examination Survey, deficits in reading and mathematics scores were associated with higher current exposure to secondhand smoke (Yolton et al. 2005).

Researchers have used various types of tests that measure both cognitive and behavioral aspects of development to study the relationship between possible language impairments and maternal smoking. Data from studies using evoked brain responses indicate that infants born to mothers who smoked approximately one pack of cigarettes per day showed atypical patterns of brain organization, which reflected poorer speech discrimination than that of infants born to mothers who did not smoke. Compared with infants of smokers, the unexposed infants exhibited more common forms of brain lateralization for speech and showed evidence of better discrimination of consonant and vowel syllables (Molfese et al. 2004). This finding parallels findings in studies that reported long-term impacts on language and cognitive domains in children whose mothers smoked (Makin et al. 1991; McCartney et al. 1994). These results indicate that prenatal exposure to smoking in otherwise healthy infants can be linked to significant changes in brain physiology associated with basic perceptual skills. These effects may be long term, with impacts noted in later school performance. A study of gravid mice exposed to tobacco smoke supports these findings. The study revealed that the offspring had a developmental delay in neonatal reflexes and notable behavioral deficits in adulthood, including impaired learning and memory abilities (Li and Wang 2004). CO in tobacco smoke induces fetal hypoxia and may contribute to these effects (see “Carbon Monoxide” later in this chapter).

Pathophysiological and Cellular and Molecular Mechanisms of Smoking

This section explores various mechanisms by which smoking may affect reproductive and developmental outcomes at the pathophysiological and cellular levels.

Endocrine System

One mechanism by which smoking may contribute to various reproductive outcomes is alterations in hormone function. Researchers have suggested that smoking has antiestrogenic effects (Baron et al. 1990). However, there is also evidence of effects on hormones other than estrogen, which may vary by gender and the stage of life.

Premenopausal Women

Hormone function has been difficult to study in non-clinic-based populations, because of the cyclic nature of hormone excretion and day-to-day variations in premenopausal women. During regular menstrual cycles, the hormone dynamics are predictable in a pattern that reflects the integrity of the hypothalamic-pituitary-gonadal (HPG) axis. Excretion of the follicle-stimulating hormone (FSH) from the pituitary gland is critical for ovarian follicle recruitment, development, and maturation (van Santbrink et al. 1995). The synthesis and excretion of estrogen by the follicles reflect ovarian activity that then modulates the release of gonadotropins from the pituitary through a negative-feedback loop. After ovulation has occurred, the follicle undergoes luteinization, and the corpus luteum excretes progesterone and some estrogen to prepare the uterine lining for implantation. In the absence of conception, estrogen and progesterone levels decline, followed by menstruation. Should fertilization occur, the steroid levels continue to rise along with levels of other hormones, such as human chorionic gonadotropin (hCG), to maintain the pregnancy. The placenta takes over hormone production during pregnancy.

Smoking has been considered potentially antiestrogenic (Baron et al. 1990), primarily because of the nature of its association with hormonally related diseases such as reproductive cancers. However, the 2001 Surgeon General’s report on women and smoking concluded that circulting levels of the major endogenous estrogens are not altered among smokers (USDHHS 2001). Some studies were hampered by a lack of biosampling points, small numbers of participants, or the inclusion of postmenopausal or potentially perimenopausal women. Details on 15 studies of premenopausal women are provided in Table 8.6. Most of these studies excluded women who were taking hormones or who were known to have menstrual problems. Nevertheless, the studies represent a variety of ages and did not always adjust for factors such as age and obesity. Two studies (MacMahon et al. 1982b; Westhoff et al. 1996) reported levels of urinary excretion of estrone, estradiol, and/or estriol in the luteal phase among smokers that were lower than those among nonsmokers, suggesting reduced estrogen production. However, several other studies did not observe significant differences in serum levels of estradiol by smoking status among premenopausal women (Longcope and Johnston 1988; Key et al. 1991; Berta et al. 1992). The study by Michnovicz and colleagues (1986) is often cited for the discovery that smoking induced the 2-hydroxylation of estrone to relatively inactive metabolites and decreased estriol excretion. A later, much larger study, however, did not find differences in the circulating levels of the 2α- or 16α-hydroxy metabolites in nulliparous smokers versus nonsmokers after adjustment for age, ethnicity, and length of menstrual cycle (Jernström et al. 2003). Zumoff and colleagues (1990) measured serum at multiple points during the cycle and found that estradiol was actually increased among heavy smokers in the follicular phase, particularly early, at baseline. A study with only a single serum sample obtained in the early follicular phase (Lucero et al. 2001) found that current smokers had higher baseline estradiol levels than did former olifetime nonsmokers, but this finding was not significant after adjustment. Examination of dose by pack-years1 did not indicate a dose-response pattern, but this analysis may have been diluted by including former smokers with smokers if the effects do not persist after smoking cessation.

Table 8.6. Association between smoking and reproductive hormones in women.

Table 8.6

Association between smoking and reproductive hormones in women.

Among women who had IVF, smokers had higher baseline levels of 17-β-estradiol than did nonsmokers (Weigert et al. 1999). A later study examined hormonal dynamics by daily measurement of urinary levels of estrone and progesterone metabolites throughout the cycle, in relation to smoking level that was verified by cotinine bioassay (Windham et al. 2005). This analysis showed that heavy smokers had elevated baseline (e.g., early follicular phase) levels of the steroid metabolites, a finding consistent with results in other studies (Longcope and Johnston 1988; Zumoff et al. 1990; Key et al. 1996; Lucero et al. 2001). A study of Chinese nonsmokers examined the effects of secondhand smoke on urinary levels of hormone metabolites and found an association with lower mean levels of estrone conjugates only for nonconceptive cycles (Chen et al. 2005).

Some of the disease patterns observed with smoking may reflect changes in androgen or progesterone levels, rather than estrogen levels, or changes in the ratio of androgens to estrogens. Some studies have reported that smoking increases adrenal activity and have found elevations in adrenal androgens among postmenopausal smokers (Friedman et al. 1987; Khaw et al. 1988; Longcope and Johnston 1988; Key et al. 1991). Researchers have found elevated serum testosterone levels in female smokers that were positively correlated with estradiol levels in menstrual cycling women who had IVF (pre-hCG treatment) (Barbieri et al. 2005). Elevated testosterone levels in female smokers were also positively correlated with obesity (Longcope and Johnston 1988; Sowers et al. 2001). Zumoff and colleagues (1990) reported elevated serum levels of progesterone among heavy smokers during the early follicular phase, a time when most progesterone is from the adrenal cortex. This finding is again consistent with the urine metabolite results reported by Windham and colleagues (2005) (Table 8.6). However, Zumoff and colleagues (1990) observed little difference in progesterone levels in the luteal phase. Windham and colleagues (2005) observed dampened progesterone metabolites in the luteal phase with heavy smoking. Berta and colleagues (1992) found that regular smokers had lower plasma levels of progesterone in a single sample per day during the mid-luteal phase. However, the small study by Westhoff and colleagues (1996) did not find these differences in examining data on all smokers without considering the amount smoked. In addition, the study on exposure to secondhand smoke did not report reductions in progesterone metabolite levels with exposure (Chen et al. 2005).

In vitro experiments support the effects on progesterone by showing that granulosa and tumor cells treated with alkaloids found in cigarette smoke or with an aqueous extract of cigarette smoke showed a dose-dependent inhibition of progesterone production (Bódis et al. 1997; Gocze et al. 1999; Gocze and Freeman 2000; Miceli et al. 2005). In contrast, estradiol production was little affected or was slightly stimulated. Cell growth and DNA content also decreased with treatment, leading the authors to suggest that smoking directly inhibits cellular progesterone synthesis through less specific cytotoxic effects on progesterone-producing cells (Gocze and Freeman 2000). Other proposed mechanisms include modulations in the prostaglandin system (Miceli et al. 2005) or inhibition of aromatase enzymes.

Some studies examined gonadotropin FSH levels by smoking status (Table 8.6). Three studies that measured a single serum FSH level in the first few days of the cycle found higher levels associated with smoking (Cramer et al. 1994; Cooper et al. 1995; Lucero et al. 2001). Another study with a similar finding of higher FSH in smokers did not include the time during the menstrual cycle when the single serum sample was obtained (Backer et al. 1999). In addition to the limitation of single serum samples, these studies tended to include some perimenopausal or postmenopausal older women even though FSH levels naturally rise during and after menopause. Another study measured daily urinary levels of FSH metabolites in women of reproductive age. These findings also showed mean FSH levels among moderate-to-heavy smokers (≥10 cigarettes per day) that were higher than those among nonsmokers during the luteal-follicular phase transition between cycles (Windham et al. 2005).

Serum levels of FSH increase with age, and researchers think this increase reflects the diminishing supply of oocyte- and gonadotropin-responsive follicles that leads to the release of the HPG axis from ovarian control (Marcus et al. 1993; Cramer et al. 1994; Westhoff et al. 1996). The FSH level is thus considered a marker of ovarian reserve or competence, and as such, it may also be useful for identifying agents with toxic effects on the ovaries (Scott et al. 1989; Scott and Hofmann 1995). As progesterone modulates FSH in the endocrine feedback loop, the lower levels of luteal phase progesterone metabolites observed in some studies are consistent with the decreased entrainment of FSH, which would lead to the observed elevations. The increase in FSH may accelerate the recruitment and development of follicles, moving ovulation earlier, and perhaps leading to inadequate follicle development followed by inadequate function of the corpus luteum. Progesterone controls the endometrial response and is critical for early maintenance of pregnancy. Studies have implicated a luteal phase deficiency as a cause of infertility and fetal loss (Pittaway et al. 1983; Tulppala et al. 1991). Earlier ovulation would also be consistent with the shortening of the menstrual cycle or of the follicular phase observed in smokers (see “Menstrual Function, Menopause, and Menarche” earlier in this chapter). The pattern of higher FSH levels, shorter cycles, and thus more frequent ovulation in smokers is also consistent with the observation that smokers tend to experience earlier menopause (see “Menstrual Function, Menopause, and Menarche” earlier in this chapter).

Pregnant Women

The 2001 Surgeon General’s report noted that smoking more clearly affects estrogen levels during pregnancy than when a woman is not pregnant (USDHHS 2001). Several studies show that smokers have lower circulating levels of estriol and estradiol than do nonsmokers (USDHHS 2001), confirmed for estriol measured multiple times throughout pregnancy (Kaijser et al. 2000). Furthermore, the study found a positive correlation of estriol and birth weight. This study’s results support the hypothesis of Michnovicz and colleagues (1986) that smokers and nonsmokers may metabolize estrogens differently, with acceleration of the 2-hydroxylation versus the 16α-hydroxylation pathway in smokers. In addition, some studies show an increase in 2-hydroxylation and 4-hydroxylation activity in placental tissues of smokers (Chao et al. 1981; Juchau et al. 1982). In a later study using placental microsomes, smokers had increased placental formation of 4-hydroxyestradiol, 7α-hydroxyestradiol, and most markedly, 15α-hydroxyestradiol, but little or no difference in the overall rate of placental estradiol metabolism or in the formation of the estrone, 2α-hydroxyestradiol, and other metabolites (Zhu et al. 2002). A study of progesterone in placental tissue samples revealed that levels among smokers were lower than those among nonsmokers (Piasek et al. 2001), a finding consistent with the data for nonpregnant women.

Using stored serum samples, Kandel and Udry (1999) found that the cotinine levels were positively correlated with the testosterone levels, especially in samples obtained during the second trimester of pregnancy. In turn, maternal testosterone levels were correlated with those in adult daughters. An animal study also showed that nicotine infusion resulted in increased plasma testosterone in ovine fetuses. This study also associated maternal exposure to nicotine with increased testosterone levels in 30-day-old (adolescent) female offspring of rats but not in male offspring (Smith et al. 2003). Changes in hormone patterns during pregnancy may therefore affect both pregnancy outcome and the endocrine profile of the offspring, thus relating to possible effects on neurobehavioral endpoints, puberty, or later reproductive status, including semen quality.

Men

Numerous studies have also examined hormone levels in men in relation to smoking (Table 8.7). Some studies examined the acute effects of smoking cigarettes in a standardized protocol, and others studied baseline hormone levels in smokers compared with those in nonsmokers. The results from studies spanning many years are inconsistent. These studies also vary in considering obesity, which may be important because increased weight is associated with the peripheral conversion of androgens to estrogens. Also, studies generally report total circulating levels of hormones but vary in reports of free or bioavailable levels.

Table 8.7. Association between smoking and reproductive hormones in healthy men.

Table 8.7

Association between smoking and reproductive hormones in healthy men.

The most consistent finding is an increase of androstenedione in smokers in three studies (Barrett-Connor and Khaw 1987; Dai et al. 1988; Field et al. 1994). Testosterone levels also increased with smoking in many studies, but some studies found decreases or no differences (Table 8.7). The study by Sofikitis and colleagues (1995) is noteworthy for demonstrating differences between apparent endocrine versus paracrine levels of testosterone related to effects from smoking. Animal studies show that prenatal exposure to nicotine is related to decreased testosterone levels in adult male rats (Segarra and Strand 1989) and that cotinine, but not nicotine, inhibits testosterone synthesis in testes of neonatal rats (Sarasin et al. 2003).

Four studies that measured estradiol or estrone had inconsistent results. However, results from one of the studies showing an association with smoking were not adjusted for BMI or weight, although adjustment was made for age. The findings for the gonadotropins, FSH and luteinizing hormone (LH), tend to show no effect of smoking.

In 1990, one study (Barrett-Connor 1990) suggested that the ratio of androgen to estrogen is critical in determining the gender-specific risk of some hormone-related diseases and that smoking may alter this ratio. Nicotine or its metabolites may influence endocrine profiles directly and indirectly. PAHs also act on the cytochrome P-450 systems involved in the metabolism of endogenous hormones and of xenobiotics such as those found in tobacco smoke.

Tubal Function

The mammalian oviduct transports gametes to the fertilization site and provides a suitable environment for fertilization and development before implantation. Factors that impair oviductal physiology can lead to reproductive problems, such as fertilization failure, ectopic pregnancy, and failure of implantation. Numerous epidemiologic studies have correlated maternal smoking with reproductive problems that can originate in the oviduct, including increased infertility and ectopic pregnancy (Stillman et al. 1986; Buck et al. 1997) (see “Review of Epidemiologic Literature on Smoking” earlier in this chapter).

The mammalian oviduct has three anatomic regions: (1) the infundibulum, which picks up the oocyte cumulus complex after it is ovulated from the ovary; (2) the ampulla, where fertilization occurs; and (3) the isthmus, which conducts sperm to the ampulla and provides a site for preimplantation development. Proper functioning of each region is necessary for normal reproduction.

The oviduct is an in vivo target of cigarette smoke and its components. Contraction of both the human oviduct (Neri and Eckerling 1969) and the rabbit oviduct (Ruckebusch 1975) is altered by exposure to tobacco smoke. Inhalation of mainstream or sidestream smoke at doses that produce serum cotinine levels within the range of those found in active smokers and persons involuntarily exposed to tobacco smoke caused blebbing of the oviductal epithelium and decreased the ratio of ciliated to secretory cells in hamsters (Magers et al. 1995). In another study of hamsters, in which the oviduct was directly observed before, during, and after inhalation of tobacco smoke at doses equivalent to those received by humans, both mainstream and sidestream smoke decreased ampullary smooth muscle contractions and slowed embryo transport through the oviduct (DiCarlantonio and Talbot 1999). Nicotine altered the motility of oviducts of rhesus monkeys (Neri and Marcus 1972), decreased oviductal blood flow (Mitchell and Hammer 1985), decreased sodium and potassium levels in oviductal epithelial cells of mice (Jin et al. 1998), and increased lactate dehydrogenase levels in oviductal epithelium of rats (Rice and Yoshinaga 1980).

In vitro studies using oviductal explants have been valuable in characterizing the effects of cigarette smoke on various biologic processes, including ciliary beat frequency, oocyte pickup rate, and smooth muscle contraction (Huang et al. 1997; Riveles et al. 2003). Solutions of particulate matter, whole mainstream smoke, and mainstream and sidestream smoke in the gas phase inhibited ciliary beat frequency, oocyte pickup rate, and smooth muscle contraction in a dose-dependent manner in hamsters (Knoll and Talbot 1998). Although this inhibition was originally reported for unfiltered (2R1) research cigarettes, a similar inhibition was subsequently shown for filter-tipped (1R4F) research cigarettes, unfiltered and filter-tipped commercial cigarettes, and “harm-reduction” cigarettes that are lower in carcinogens than are traditional brands (Riveles 2004). The data on harm-reduction cigarettes are important in demonstrating that these cigarettes still contain toxicants that can adversely affect diverse biologic processes. Exposure to sidestream whole smoke, in contrast to mainstream smoke, stimulated ciliary beat frequency (Knoll and Talbot 1998). The oocyte pickup rate was inhibited even in samples in which beat frequency was stimulated, which shows that pickup depends on factors other than ciliary beating. Adhesion between the extracellular matrix of the oocyte cumulus complex and the tips of the cilia is an additional factor essential for pickup (Talbot et al. 1999; Lam et al. 2000). If adhesion is too strong or too weak, oocyte pickup can fail (Lam et al. 2000). Exposure to both mainstream and sidestream smoke increases adhesion (Gieseke and Talbot 2003), which could account for decreased pickup rates even when cilia beat at normal or accelerated rates. Exposure to tobacco smoke adversely affects other adhesive processes involving cells, asbestos, and bacteria (Cantral et al. 1995; Churg et al. 1998; El Ahmer et al. 1999).

Therefore, in vitro studies demonstrate that exposure to tobacco smoke adversely affects oviductal structure and functioning and that nicotine can impair oviductal physiology. Together with in vitro data, in vivo studies demonstrate that maternal smoking adversely affects the oviduct in ways that could impair fertility and complicate pregnancy.

Placenta

Normal Development

Formation of the placenta in the uterus (placentation) is a complex process that is not fully understood. Fetal stem cells (cytotrophoblasts) form a polarized epithelium attached to a basement membrane that surrounds a stromal core containing the placental vasculature and forming chorionic villi. These villi are surrounded by a multinucleate syncytial covering. Floating villi are attached only to the fetal side of the placenta. In contrast, anchoring villi are formed when cytotrophoblastic cells detach from the basement membrane, penetrate the uterine wall, and invade maternal arteries and veins. Cytotrophoblasts travel deeply into uterine arterioles, replace the maternal endothelial lining, and disrupt the smooth muscle wall. This physiological transformation converts the maternal vasculature from a high-resistance, low-capacitance system to a low-resistance, high-capacitance system that allows for increased blood flow to the fetus. Blood from the spiral arteries then enters the intervillous space where an exchange of substances between the mother and the fetus occurs (Khong 2004). As the placenta develops, the villous system also undergoes remodeling. The terminal villi elongate, and there is a large increase in the peripheral villi capillary volume (Mayhew 2002; Torry et al. 2004). In addition, the thickness of the collective layers of the villi that separate maternal and fetal circulatory systems (villous membrane) decreases, enhancing the exchange of nutrients and metabolic products between the mother and fetus (Mayhew 1998). Interference with the development and remodeling of the placental vasculature likely contributes to adverse pregnancy outcomes.

Effects of Smoking

Studies have examined the effects of maternal smoking on the placenta, but the results are often conflicting. Real or apparent inconsistencies among studies may reflect differences in laboratory techniques and terminology. However, many studies appear to fall into one of three general areas of research: (1) cytotrophoblastic invasion of the uterus and subsequent transformation of uterine blood vessels; (2) development of the fetal capillary and villous system, particularly with respect to whether the placenta can compensate for maternal hypoxia by increasing the supply of oxygen (O2) and nutrients to the fetus; and (3) transportation of nutrients across the placenta (see “Amino Acids” later in this chapter).

As previously stated, cytotrophoblastic cells in normal pregnancy invade the uterine arterioles and transform them into a high-capacitance system that allows for an increase in blood flow to the fetus. Incomplete transformation of the spiral arteries results in a high vascular resistance in the placenta and a decrease in blood flow to the intervillous space. Studies have described a diminished physiological transformation in placentas from women with preeclampsia (Brosens et al. 1972; Naicker et al. 2003), SAB (Khong et al. 1987), IUGR (Khong et al. 1986), PPROM (Kim et al. 2002), preterm labor (Kim et al. 2003), preterm birth (Kim et al. 2003), or placental abruption (Dommisse and Tiltman 1992).

Physiological transformation appears to be disturbed in women who smoke cigarettes during pregnancy. In vitro studies have shown that formation of cytotrophoblastic cell columns, which is necessary for the invasion of the uterine wall, is disrupted, perhaps from the effects of exposure to nicotine (Genbacev et al. 1995). Among women who smoke, there also appears to be a reduction in the number of cytotrophoblastic stem cells in the floating villi and a reduction in the number of anchoring villi that successfully invade the uterine wall, which may reflect a premature depletion of cytotrophoblastic stem cells (Genbacev et al. 1995). The interference by smoking in cytotrophoblastic invasion of the uterine wall could lead to increased risk of adverse pregnancy outcomes.

Paradoxically, maternal smoking is protective against preeclampsia, which is also characterized by an incomplete transformation of the spiral arteries. As previously noted, an imbalance between proangiogenic and antiangiogenic placental factors may contribute to manifestations of preeclampsia, and smoking may exert its protective effects by affecting this imbalance (Genbacev et al. 2003; Maynard et al. 2003) (see “Pregnancy Complications” earlier in this chapter). In a normal pregnancy, the placenta releases proangiogenic factors, VEGF, and the placental growth factor (PlGF). Placental soluble FMS-like sFlt-1, which is elevated in preeclampsia, is an antagonist of both VEGF and PlGF. An elevated sFlt-1 level is associated with lower levels of VEGF and PlGF and leads to endothelial dysfunction. Maternal smoking appears to increase the placental expression of VEGF-A (Zhou et al. 2002), a major regulator of cytotrophoblastic differentiation along the invasive pathway that is decreased in the preeclamptic placenta. In contrast, studies have found decreased levels of sFlt-1 in the plasma of smokers (Belgore et al. 2000), but not in pregnant smokers (Kämäräinen et al. 2009). The 2004 Surgeon General’s report on the health consequences of smoking noted that “the decreased risk of preeclampsia among smokers compared with nonsmokers does not outweigh the adverse outcomes that can result from prenatal smoking” (USDHHS 2004, p. 576). Additional research is needed to confirm or refute the notion that the effects on VEGF-A and/or sFlt-1 explain the reduced risk of preeclampsia in smokers.

Findings on the effects of maternal smoking on the development of the villous capillary system are inconsistent. The fetus of a smoker develops under conditions of reduced partial pressure of O2, because hemoglobin has an affinity for CO from cigarette smoke that greatly exceeds its affinity for O2. Thus, the expectation is to see compensatory responses in the placenta similar to those observed with other hypoxic conditions. Such compensatory responses to hypoxia could include increased volume density, branching, and dilation of the fetal capillary system; increased density and proliferation of the cytotrophoblasts; thinning of the villous membrane (Kingdom and Kaufmann 1997; Mayhew 1998; Bush et al. 2000); and increased maternal and fetal hematocrits. Studies have documented increases in both the maternal and fetal hematocrits among smokers (Bodnar et al. 2004), which should lead to increased delivery of O2 to the fetus.

In addition, several studies have found that the placentas of smokers are heavier or larger than those in nonsmokers (Naeye 1978; van der Veen and Fox 1982; Howe et al. 1995; Williams et al. 1997), which suggests an expansion of the peripheral villous tree. However, other researchers have found no increase or only a small increase in placental size and/or weight in smokers (Spira et al. 1975; Picone et al. 1982; Demir et al. 1994; Sanyal et al. 1994; Williams et al. 1997; Zhang et al. 1999; Larsen et al. 2002). In many of these studies, the ratio of placental to fetal weight was higher in smokers than in nonsmokers even when the placental weight did not increase. This increase in the ratio of placental to fetal weight could result from a compensatory response to hypoxia, but this explanation has not been established. Studies of morphology have described increase (Pfarrer et al. 1999), decrease (Asmussen 1980; Burton et al. 1989; Teasdale and Ghislaine 1989; Bush et al. 2000; Larsen et al. 2002), and no appreciable difference (van der Velde et al. 1983; Mayhew 1996) in dimensions of the villous capillary system of smokers.

In contrast, studies have consistently shown that maternal smoking is associated with a thickening of the villous membrane, which would decrease the ability of nutrients to diffuse through the placenta (Burton et al. 1989; Jauniaux and Burton 1992; Demir et al. 1994; Bush et al. 2000; Larsen et al. 2002). This increased thickness was attributed to the increased thickness of the trophoblastic component (Jauniaux and Burton 1992; Bush et al. 2000) and to a thickening of the basement membrane (Asmussen 1980; Demir et al. 1994). The thickening of the villous membrane is opposite from an expected compensatory thinning in response to a hypoxic environment and could contribute to fetal growth restriction. Researchers have hypothesized that direct toxic effects of maternal smoking on the placenta are responsible for the thickening of the villous membrane, perhaps due to the accumulation of cadmium that is associated with a reduction in fetal capillary volume (Burton et al. 1989; Bush et al. 2000).

Studies have also explored other effects of maternal smoking on the cellular and noncellular composition of the villous system. Researchers have described changes in placental morphology of smokers, including cytotrophoblastic hyperplasia, focal syncytial necrosis, the loss or distortion of syncytial microvilli, decreased vasculosyncytial membranes, decreased syncytial pinocytotic vesicles, the degeneration of cytoplasmic organelles, increased syncytial knots and decreased syncytial buds, and increased collagen levels in the villous stroma (van der Veen and Fox 1982; van der Velde et al. 1983, 1985; Demir et al. 1994). Evidence of increases in syncytial knots and necrotic areas suggests an increase in syncytial damage among smokers (Demir et al. 1994). However, these effects are not consistent in all studies (Teasdale and Ghislaine 1989; Ashfaq et al. 2003). Researchers have found it difficult to clearly connect these findings with adverse pregnancy outcomes, because the observed changes are not pathognomonic for any particular disorder. However, these cellular and molecular abnormalities of the villous system could lead to an impaired exchange of metabolic products, O2, and nutrients between the mother and fetus.

Maternal and Fetal Cardiovascular Systems

Smoking acutely increases the heart rate and blood pressure of smokers, particularly after a period of abstinence from smoking (e.g., first cigarette of the day). This finding has led to the suggestion that changes in blood flow may be a mechanism for the lower birth weight observed in infants of smokers. Numerous studies have investigated the effect of cigarette smoke on the cardiovascular system of pregnant women or their fetuses. The studies can be broadly divided into those that examined differences in basal cardiovascular parameters between nonsmokers and smokers after an interval of abstinence and those that examined the acute cardiovascular effects immediately after the pregnant women had each smoked one or two cigarettes. A body of work investigating the relationships of smoking with maternal blood pressure and preeclampsia is not presented here, as preeclampsia is described above.

Seven studies investigated the basal cardiovascular state of mothers who smoked and their fetuses compared with those in a control group of mothers who did not smoke and their fetuses (Table 8.8). Four studies used a radioisotope to study blood flow through the placenta (Table 8.9). In 28 studies, the acute maternal and fetal cardiovascular effects of maternal smoking were examined, and some of these studies also reported baseline differences (Table 8.10). The participants in these 39 studies had healthy singleton pregnancies unless otherwise noted. Most of the percentage differences in the parameters were calculated for this Surgeon General’s report from data and graphs in the original articles, but the statistically significant data are those of the original investigators.

Table 8.8. Basal maternal and fetal cardiovascular effects of smoking.

Table 8.8

Basal maternal and fetal cardiovascular effects of smoking.

Table 8.9. Maternal and fetal cardiovascular effects: radioisotope studies of placental intervillous blood flow (IBF) conducted before and after smoking.

Table 8.9

Maternal and fetal cardiovascular effects: radioisotope studies of placental intervillous blood flow (IBF) conducted before and after smoking.

Table 8.10. Acute maternal and fetal cardiovascular effects of smoking.

Table 8.10

Acute maternal and fetal cardiovascular effects of smoking.

Basal Function

Maternal Heart Rate and Blood Pressure During Smoking Abstinence

One prospective study of 203 smokers and 292 non-smokers at 18, 24, 28, and 34 weeks of gestation found no differences in maternal heart rate during abstinence from smoking (Table 8.8) (Newnham et al. 1990). Two smaller studies also found no differences in the maternal heart rate in smokers and nonsmokers at baseline (Table 8.10) (Bruner and Forouzan 1991; Kimya et al. 1998). Many other studies that investigated maternal blood pressure or fetal heart rate did not report data on maternal heart rate, possibly indicating that they did not find a difference between smokers and nonsmokers.

The first study that prospectively evaluated maternal blood pressure during abstinence from smoking found a significantly lower diastolic blood pressure among smokers than among nonsmokers (MacGillivray et al. 1969). Three later studies have not replicated these results (Newnham et al. 1990; Kimya et al. 1998; Matkin et al. 1999). The largest study, of more than 5,000 participants, also found that smokers tended to have a lower mean diastolic blood pressure of 1 to 3 millimeters of mercury, but this difference was not statistically significant and is unlikely to be clinically significant (Table 8.8) (Matkin et al. 1999). The study by Newnham and colleagues (1990) was larger than that by MacGillivray and colleagues (1969) and of a similar design, but no significant differences in maternal diastolic or systolic blood pressure were observed. Two investigations found that the systolic blood pressure of smokers was higher than that of nonsmokers (MacGillivray et al. 1969; Matkin et al. 1999). However, MacGillivray and colleagues (1969) did not report significance data, and Matkin and colleagues (1999) found the difference to be nonsignificant.

Sufficient clinical data indicate that there is no clinically significant difference in the mean maternal heart rate or blood pressure in healthy pregnant nonsmokers and smokers during abstinence from smoking. Further study of the blood pressure distribution, especially in the tails of the statistical distribution, may be warranted, because the percentage of women with blood pressure at or near the hypertensive range is most important clinically, and this group is at a higher risk of adverse pregnancy outcomes (Lees et al. 2001).

Fetal Heart Rate

Four studies provide data on fetal heart rate collected from smokers during periods of abstinence and compared with data from nonsmokers (Eldridge et al. 1986; Newnham et al. 1990; Bruner and Forouzan 1991; Coppens et al. 2001). These studies found no differences except for the small study by Eldridge and colleagues (1986). This study compared 19 nonsmokers with 5 smokers and found no difference in fetal heart rate during the second or early third trimester, but it did find a significant 9-percent elevation among smokers late in the pregnancy.

Acute Effects of Smoking

Maternal Heart Rate

Twenty-one studies provide data on the immediate effect of smoking one or two cigarettes on maternal heart rate (Table 8.10). The general design of these studies is similar. Healthy active smokers with singleton births in the latter half of pregnancy abstained from smoking overnight and were then studied before and after smoking one or two cigarettes. The different designs of the studies are noted in Table 8.10. All but two of the studies (Jouppila et al. 1983; Bruner and Forouzan 1991) found a statistically significant transient increase in maternal heart rate immediately after smoking. The largest study, with 67 pregnant smokers, found a significant increase of 6 percent in maternal heart rate (Ates et al. 2004), and one smaller study, with 17 pregnant smokers, found a significant 42-percent increase in maternal heart rate immediately after smoking (Sindberg Eriksen and Gennser 1984). Other increases in maternal heart rate ranged from 10 to 30 percent, which were similar to the nonsignificant effect in the study conducted by Jouppila and colleagues (1983).

Sufficient clinical data establish that smoking a cigarette after a period of abstinence transiently elevates maternal heart rate, although the magnitude of the increase varies. This finding holds true even when studies involving nonsmokers are excluded. Only one study (Oncken et al. 1997), however, addressed the effect of ad lib smoking throughout the day on maternal heart rate. Oncken and colleagues (1997) found a maximal increase of 11 beats per minute in maternal heart rate two hours after baseline—an increase of approximately 13 percent—with ad lib smoking. The clinical significance of a transiently elevated maternal heart rate during pregnancy is unknown.

Maternal Blood Pressure

Of the 16 studies that examined the acute effects of smoking on maternal blood pressure (Table 8.10), all but 2 (Huisman et al. 1997; Ates et al. 2004) reported a transient but significant elevation in the mean or median diastolic or systolic blood pressure or in the mean arterial pressure. The largest increases, ranging from 10 to 23 percent, were observed for diastolic blood pressure, but most studies found an increase of less than 15 percent. The largest study, with 67 participants, found a small but nonsignificant increase in diastolic blood pressure after smoking (Ates et al. 2004). In general, the acute effect of smoking on maternal systolic blood pressure was less than the effect on diastolic blood pressure. Three studies reported no significant increase in systolic blood pressure, and the largest study found a small but nonsignificant (p = 0.2) increase (Table 8.10) (Ates et al. 2004). In the remaining 10 studies, transient increases ranged from 5 to 14 percent. These data indicate that smoking after abstinence transiently increases diastolic blood pressure and, to a lesser extent, systolic blood pressure. Because one large study (Ates et al. 2004) found a nonsignificant effect of smoking on maternal blood pressure, additional large studies may be needed.

The release of catecholamine may mediate the elevations in maternal heart rate and blood pressure reported in these studies. In a study of pregnant women, smoking was associated with an acute rise in plasma levels of nor-epinephrine, epinephrine, and dopamine and an associated acute rise in maternal heart rate and blood pressure (Quigley et al. 1979).

Fetal Heart Rate

Twenty-five studies (Table 8.10) collected data on fetal heart rate before and after mothers smoked one or two cigarettes. Ten studies, including the largest study (Ates et al. 2004) and two studies with a control group of nonsmokers (Bruner and Forouzan 1991; Coppens et al. 2001), found no effect of smoking on fetal heart rate. Five studies reported that smoking after abstinence was associated with a 2- to 8-percent transient increase in fetal heart rate, and eight studies reported an increase of 11 to 17 percent in fetal heart rate. The studies that found mean elevations in the fetal heart rate above 10 percent were conducted between 1979 and 1988. The five studies published after 1996 reported no statistically significant difference.

Variability in Fetal Heart Rate

Healthy fetal heart rate is variable, and there are short- and long-term patterns to this variability. The “differential index” is an alternative term for short-term variability, and the “interval index” is an alternative term for long-term variability. Healthy fetal heart rate also has episodes of accelerations. Researchers use the variability in fetal heart rate and the presence of episodes of accelerations to measure fetal well-being. This variability and acceleration are measured in the noninvasive nonstress test (NST). A reactive NST is a sign of fetal well-being, and a nonreactive NST is a sign of fetal distress. The NST is routinely used in the third trimester of pregnancy and during labor to monitor high-risk pregnancies and to assess low-risk pregnancies if concerns develop. Healthy fetuses have transient periods of decreased variability and accelerations, which would appear as a transiently nonreactive NST.

Data on fetal heart rate reactivity and accelerations and the NST are presented in Tables 8.8 and 8.10. A large cohort of mothers with high-risk pregnancies among smokers and nonsmokers was studied repeatedly over the course of the pregnancies (Table 8.8) (Phelan 1980). Although smokers had a high rate of nonreactive NSTs, many were reactive at a subsequent visit. A nonreactive NST in a pregnant smoker should generally be repeated to rule out a false nonreactive result. There are no reports on the prevalence of nontransient, abnormal NSTs among healthy smokers versus healthy nonsmokers.

Nine studies investigated variability in fetal heart rate before and after maternal smoking (Table 8.10). All but two studies (Oncken et al. 1997; Coppens et al. 2001) found that either maternal smoking transiently decreased short- and long-term variability or the NST became non-reactive. Three of the studies with positive findings were conducted with a control group of nonsmokers by the same team of investigators (Forss et al. 1983; Lehtovirta et al. 1983; Kariniemi et al. 1984). One investigator did not find a loss of reactivity from smoking one cigarette but did find a large increase in nonreactive NSTs with additional smoking (Oncken et al. 2002). The two largest studies (Graca et al. 1991; Ates et al. 2004) found a significant decrease in variability of fetal heart rate and an accelerated increase after smoking.

These data indicate that maternal smoking transiently decreases variability of fetal heart rate. However, the clinical significance of these transient decreases in the heart rate of fetuses of smokers is not clear. Generally, the nontransient changes in these parameters are the clinically important changes.

Blood Flow in Uterus, Placenta, and Fetus

Table 8.9 presents data on blood flow in the uterus and placenta from studies that used a radioisotope, which is considered the “gold standard” because it directly measures flow. The development of fetal sonographic technology has replaced radioisotope studies, because radioisotopes measure only maternal blood flow and expose the mother and fetus to radiation. Sonography is noninvasive and can be used to assess blood flow in both the fetus and the mother. Table 8.10 presents data from ultrasound and Doppler sonography on vessel diameter and blood velocity. These data are then used to calculate blood flow, which is difficult to measure, because the sonographer must visually mark the diameter of a vessel. Flow is proportional to the fourth power of the vessel radius, so even very small changes in the measurement of the diameter have a large effect on the calculation. Furthermore, all of the studies are unblinded. Sonographic technology advanced greatly between 1978 and 2004, which may partly explain the variations in the results from more than 25 years of publications, as is discussed here.

The most commonly used surrogate measures of blood flow are the ratio of systolic to diastolic blood flow velocity (S/D ratio), pulsatile index, and resistance index (RI). The S/D ratio is defined as the ratio of the time- averaged maximal systolic and diastolic blood flow velocities. The pulsatile index is defined as the difference between peak velocity and the lowest diastolic velocity, divided by the mean velocity during the heart cycle. The RI is defined as the difference between the maximal systolic and diastolic flow velocities, divided by the systolic flow velocity.

Independent of studies of smoking, researchers have used the S/D ratio, pulsatile index, and RI measures to monitor high-risk pregnancies and to predict outcomes (Maulik et al. 1990; Alatas et al. 1996; Fong et al. 1999; Özeren et al. 1999; Coleman et al. 2000; Gudmundsson et al. 2003; Axt-Fliedner et al. 2005; Li et al. 2005). In low-risk pregnancies, these measures of blood flow are not sensitive to or specific predictors of adverse outcomes such as preeclampsia or IUGR (Kurmanavichius et al. 1990; Irion et al. 1998; Albaiges et al. 2000; Harrington et al. 2004; Schwarze et al. 2005), except when the measures are markedly abnormal (Becker et al. 2002; Papageorghiou et al. 2005).

Four radioisotope studies of placental intervillous blood flow (IBF) have been performed (Table 8.9). Historically, these four studies have provided the initial data for the hypothesis that decreased maternal blood flow through the placenta caused fetal growth retardation. Three studies by the same group of investigators used xenon133 to determine the acute effect of smoking on IBF among nonsmokers (Lehtovirta and Forss 1978, 1980; Rauramo et al. 1983). The results of the three studies are contradictory. Smoking resulted in either an acute increase or a decrease in IBF, depending on the patient and the study. The fourth radioisotope study used indium113-labeled transferrin to compare smokers immediately after smoking with nonsmokers (Philipp et al. 1984). This study found a significant difference in the distribution of normal and abnormal blood flow between the two groups, and a smaller proportion of scans were normal among the smokers.

Of four studies conducted during abstinence from smoking, two found no difference in blood flow parameters of uterine arteries between nonsmokers and smokers (Table 8.8) (Newnham et al. 1990; Albuquerque et al. 2004); the latter did find a difference in blood flow in umbilical arteries, but the larger Newnham study did not. The very small study by Eldridge and colleagues (1986) found an increase in aortic blood flow. The most important study found an association between the risk of a severe adverse pregnancy outcome and a pulsatile index for the uterine artery that doubled among smokers (Lees et al. 2001).

Sixteen studies used Doppler sonography to examine blood flow parameters in maternal smokers and their fetuses before and after smoking or in smokers after smoking compared with nonsmokers and their fetuses (Table 8.10). Four studies by the same group of investigators found that smoking dramatically increased four parameters (blood flow, velocity, diameter, and pulsatile index) (Sindberg Eriksen et al. 1984; Sindberg Eriksen and Marsal 1984, 1987; Lindblad et al. 1988). One study found an acute 76-percent increase in the pulsatile index of the umbilical artery after maternal smoking (Coppens et al. 2001). Six studies found no effect on blood flow, velocity, diameter, S/D ratio, pulsatile index, and RI in the uteroplacental or fetal blood vessels (Jouppila et al. 1983; Pijpers et al. 1984; Sorensen and Borlum 1987; Bruner and Forouzan 1991; Kimya et al. 1998; Ates et al. 2004). However, Oncken and colleagues (1997) found a negligible change, and four studies found either increases or decreases in the S/D ratio and the pulsatile index (Table 8.10) (Morrow et al. 1988; Castro et al. 1993; Oncken et al. 1996; Huisman et al. 1997).

In summary, differences between blood flow in smokers during abstinence and that in nonsmokers do not appear to be significant. However, the study by Lees and colleagues (2001) raises concerns because it indicates that with an elevated pulsatile index in the uterine artery, maternal cigarette smoking doubles the risk of a severe, adverse pregnancy outcome. The data on the acute effects of smoking on maternal and fetal blood flow are more contradictory, and no generalizations can be made at this time.

Fetal Tissue and Organogenesis

Timing and Critical Periods

The embryonic period includes the first eight weeks after fertilization and constitutes a significant period in human development. During this time, all major internal and external structures start to develop, involving many complex interactions that must occur in an orderly sequence. The embryonic period is a time of rapid differentiation, and the developing organs are particularly susceptible to the effects of exogenous agents. The stage of embryonic development determines the embryo’s susceptibility to unfavorable environmental factors. The embryo is most easily disturbed during the organogenesis period, from day 15 to day 60 after conception. In addition, each system or organ of an embryo has a critical period when its development may be altered. The effects of some environmental toxins on the developing embryo and fetus can be direct and lethal or subtle with delayed but serious consequences. Thus, multiple factors are involved in identifying and evaluating the effects of exposure to tobacco smoke on the developing baby.

Evidence on Effects of Smoking

Some epidemiologic studies report an association between maternal smoking and various congenital malformations. In this area of research, the associations with smoking most frequently examined and published relate to nonsyndromic orofacial clefting, congenital heart disease, malformations of the lower extremities such as club-foot or limb deficiency defects, hypospadias, gastroschisis, and craniosynostosis (see “Birth Defects” earlier in this chapter). Data supporting a causal association between nonsyndromic orofacial clefting and maternal smoking have strengthened, but few studies have addressed possible pathogenetic mechanisms.

Traditionally, investigators have used animal models and postmortem tissues to detect the effects on organogenesis of exposure to tobacco smoke by conducting gross morphologic, soft tissue, and skeletal examinations. Early studies of this type involving exposure to mainstream cigarette smoke provide little data supporting an effect on organogenesis. Of seven studies, four did not find any effects (Wagner et al. 1972; Reznik and Marquard 1980; Peterson et al. 1981; Bassi et al. 1984), and three mentioned limited findings but lacked sufficient details for a full evaluation (Schoeneck 1941; Tachi and Aoyama 1983; Amankwah et al. 1985).

A subsequent set of experiments exposed pregnant Wistar rats to sidestream cigarette smoke, and the pups were then examined for gross morphologic changes (Table 8.11). Researchers observed a dose-dependent reduction in birth weight (p <0.001) but no increase in macroscopically visible gross anomalies (Nelson et al. 1999a). Ossification was delayed throughout the skeleton in all exposed groups regardless of the dose. The second part of the experiment studied the histopathologic changes in tissues such as the lung, liver, stomach, kidney, and intestines (Nelson et al. 1999b). The lung tissues of pups of dams exposed to smoke showed increased apoptosis, mesenchymal changes, and hyperplasia of bronchial muscles. Researchers found abnormal hematopoiesis, proliferation of bile ducts in the liver, and delayed maturation of the glomeruli, gastric epithelia, and intestinal villi. Another study exposed Sprague-Dawley rats to mainstream tobacco smoke by nose-only inhalation (Carmines et al. 2003). Males were exposed four weeks before and during mating, and females were exposed two weeks before and during mating and through gestational day 20. Exposure to tobacco smoke was confirmed by biomarker evaluation. Researchers evaluated external and internal abnormal macroscopic findings, histopathology of the placenta and fetal tissue, and skeletal radiograms. They concluded that exposure to tobacco smoke was not associated with any congenital malformations in the offspring. However, numerous abnormalities were described, including hypoplasia of the internal genital structures in the exposed adult male rats and decreased ossification in the fetuses of the exposed dams.

Table 8.11. Animal and in vitro studies on association between maternal smoking and congenital abnormalities with relevant genetic and/or molecular hypotheses.

Table 8.11

Animal and in vitro studies on association between maternal smoking and congenital abnormalities with relevant genetic and/or molecular hypotheses.

Epidemiologic studies show that offspring of maternal smokers have abnormal lung function and associated higher incidences of lower respiratory disorders. The identification of nicotinic acetylcholine receptors in fetal lung suggests a mechanism that may underlie the observed postnatal pulmonary abnormalities. This hypothesis was tested in monkeys to determine whether maternal exposure to nicotine would produce changes in lung function or morphology in newborn monkeys similar to the changes observed in human infants (Sekhon et al. 2001). Pregnant rhesus monkeys were infused with either nicotine comparable to heavy smoking in humans (1.5 milligrams per kilogram per day [mg/kg/day], n = 7) or saline (n = 7) timed to days 26 through 160 of gestation. The fetuses were delivered by cesarean section and on the next day had pulmonary function testing. They were then sacrificed, and their lungs were weighed and fixed. There was a significant decrease in fetal lung weight (16 percent) and fixed lung volume (14 percent) after in utero exposure to nicotine. All lung function tests (e.g., peak tidal expiratory volume, mean mid-expiratory volume, and forced expiratory volume at peak expiratory flows) were also significantly lower in the newborns exposed to nicotine, demonstrating that prenatal exposure to nicotine compromises lung growth and pulmonary function. Although there was no histopathologic description of the examined lungs, researchers have described changes in lung morphology in humans (DiFranza et al. 2004), as well as in rats (Nelson et al. 1999b). Another experiment exposed female Sprague-Dawley rats aged 12 weeks to tobacco smoke and then mated them to unexposed males. Post-natal measurements of the pups’ lung surfactant levels of protein (SP-A and SP-B) in bronchoalveolar lavage fluids showed a reduced level of SP-A on day 1 and a higher level of SP-A and phospholipid on day 21 among pups exposed to smoke (Subramaniam et al. 1999).

One study examined the induction of cleft palate by Nicotiana glauca (wild-tree tobacco) or anabasine-rich extracts during the first trimester of pregnancy and compared Spanish-type goats with crossbred Western-type sheep (Panter et al. 2000). Bilateral cleft palate was induced in 100 percent of the embryonic and fetal goats by gavage of the pregnant mothers with anabasine-rich extracts. Eleven percent of the newborn goats showed extracranial abnormalities, mainly contractures of the metacarpal joints, in addition to bilateral cleft palate. Most of these contractures resolved spontaneously within four to six weeks after delivery. In contrast, only two lambs from ewes exposed to both substances had cleft palate. However, all lambs exposed to both substances had contractures, which indicated differential susceptibility of the species. The researchers postulated that an alkaloid-induced reduction in fetal movement during the period of normal palate closure caused the cleft palate and the multiple flexion contractures. This postulation is supported by a later study that used the chick embryo model to conduct an in vivo examination of the effects of different preparations of solutions of nicotine and of mainstream whole smoke on embryonic movements during neonatal development (Ejaz et al. 2005). In this experiment, low doses of nicotine induced hyperactivity and high doses induced hypoactivity. Accordingly, there was a significant (p <0.01) decrease in movements after applying 10 mg of nicotine and different preparations of whole mainstream smoke solutions. The decrease in embryonic movements was dose dependent and did not resolve by the end of the experiment. The researchers concluded that nicotine could alter embryonic movements that are important during embryogenesis for the differentiation and maturation of the body systems.

In a clinical study, researchers collected amniocytes from routine amniocenteses of 25 control women and 25 women who smoked (≥10 cigarettes per day for ≥10 years). Amniocytes of the smokers showed increased chromosomal instability; breakpoints involving band 11q23, which is commonly implicated in hematopoietic malignancies, was the chromosomal region most affected (de la Chica et al. 2005). Another study examined autopsy specimens from 42 stillborn infants (Lavezzi et al. 2005). Researchers studied the brainstem tissue by immunohistochemistry to evaluate the expression of the EN2 gene, somatostatin, and the tyrosine hydroxylase enzyme. Brainstem sections from stillborn infants whose mothers had smoked during pregnancy showed hypoplasia of the arcuate nucleus and an abnormal staining pattern with the antibodies applied. Thus, in utero exposure to maternal smoking may strongly interfere with brain biologic parameters of brain development, including a decrease in the noradrenergic activity in the brainstem, resulting in pulmonary hypodevelopment and even an apparently unexplained sudden death of the fetus (Lavezzi et al. 2005).

Researchers have identified an increasing number of polymorphisms of genes encoding drug- and/or toxin-metabolizing enzymes, transporters, and receptors. Some of these genetic factors have a major impact on drug sensitivity, adverse reactions, or variations of responses to environmental toxins. As a result, many investigators have studied polymorphisms of certain candidate genes to elucidate the pathogenesis of the effects of maternal smoking on the developing embryo and fetus (see “Smoking and Maternal and Neonatal Genetic Polymorphisms” later in this chapter).

Investigators have proposed other mechanisms for the adverse effects of smoking on organogenesis, particularly orofacial clefting. CO contributes to fetal hypoxia, which investigators have associated with an increased risk for cleft lip and cleft palate in susceptible strains of mice (Millicovsky and Johnston 1981; Bronsky et al. 1986; Bailey et al. 1995). Impaired uteroplacental circulation may result in a reduced supply of essential nutrients for embryonic tissues (van Rooij et al. 2001). Studies have associated poor intake of vitamin B6 and multivitamins with a risk of oral clefts (Botto et al. 2004; Munger et al. 2004). Other possible mechanisms include (1) reductions in serum folate levels mediated by maternal smoking (McDonald et al. 2002; Mannino et al. 2003; Ortega et al. 2004), (2) exposure to cadmium that is present in increased amounts in the placentas of smokers (Ronco et al. 2005) and is associated with teratogenic effects in certain rats (Ferm 1971; Chernoff 1973), and (3) DNA damage by PAHs (Lammer et al. 2004; Perera et al. 2004). Further work is needed to elucidate the extent to which these or other mechanisms involving the complex mixture of chemicals in cigarette smoke account for the increased risk of oral clefts.

Immune System

Cigarette smoking is associated with an increased risk for many types of infectious diseases including pneumococcal pneumonia, Legionnaires’ disease, meningococcal disease, influenza, the common cold, and infection with Helicobacter pylori (Arcavi and Benowitz 2004). In addition, studies have associated smoking with seropositivity for human immunodeficiency virus (HIV) and an increase in the transmission of HIV from infected mothers to their offspring (Boulos et al. 1990; Royce and Winkelstein 1990; Burns et al. 1991, 1994).

The mechanisms through which smoking increases the risk of infection are not well defined and are likely complex, involving both innate and adaptive immune responses. Compared with nonsmokers, smokers appear to have a leukocytosis (Corre et al. 1971; Friedman et al. 1973; Yeung and Buncio 1984; Hughes et al. 1985; Calori et al. 1996; Jensen et al. 1998a) and elevations in levels of all major blood cell types (Corre et al. 1971). This leukocytosis could be a result of nicotine-induced increases in the release of catecholamine (Friedman et al. 1973). However, the consequences of an increased white blood cell count are unclear. It appears that there are increases in both CD4+ (an HIV-helper white blood cell) and CD8+ (an HIV-suppressor white blood cell) T-cell populations in smokers, although heavy smokers may have reduced CD4+ cell counts, and effects may vary by race (Sopori 2002; Arcavi and Benowitz 2004). A decline in CD4+ cell counts could contribute to a decrease in B-cell proliferation and immunoglobulin (Ig) synthesis, which would increase the risk of infection (Arcavi and Benowitz 2004). However, in a study of pregnant smokers compared with pregnant nonsmokers, a decline in CD4+ count was not described (Luppi et al. 2007).

In general, smoking appears to have immunosuppressive effects. For example, lymphocytes in smokers appear to have a decreased response to T-cell mitogens (Sopori 2002), and polymorphonuclear leukocytes show decreases in chemotaxis and migration (Noble and Penny 1975; Corberand et al. 1979), which do not appear to be attributable to exposure to nicotine (Sasagawa et al. 1985). Study findings suggest that smokers have reduced titers of antibodies to the influenza virus and low serum levels of all Ig classes except IgE (Gerrard et al. 1980; Sopori 2002). In addition, smoking may increase levels of autoantibodies, perhaps contributing to some autoimmune disorders (Mathews et al. 1973; Másdóttir et al. 2000; Sopori 2002). Smoking may also affect the balance of function between helper T-cell subsets 1 and 2 (Th1 and Th2), because researchers have observed increases in Th2- and/or Th1-related cytokines in smokers (Tsunoda et al. 2003; Cozen et al. 2004). In vitro experiments suggest that nicotine impairs the immunostimulatory activity of dendritic cells (antigen-presenting cells) and adversely affects the differentiation of monocytes into dendritic cells (Nouri-Shirazi and Guinet 2003; Guinet et al. 2004). Finally, studies have also associated smoking with low counts and reduced cytotoxic activity of natural killer cells, which are important components of innate immunity (Tollerud et al. 1989; Zeidel et al. 2002). Potential mechanisms through which exposure to tobacco or nicotine might result in an altered immune function include the induction of glucocorticoid hypersecretion and the increased release of catecholamines, which both inhibit the immune response or the activation of the autonomic nervous system (Sopori and Kozak 1998; Borovikova et al. 2000; Sopori 2002). Activation of the parasympathetic arm of the autonomic nervous system attenuates the systemic inflammatory response.

Studies suggest that smoking also induces systemic chronic inflammatory effects, which is possibly a consequence of increased oxidative stress (Cross et al. 1999; Hecht 1999; van der Vaart et al. 2005). As described earlier in this section, smokers have a leukocytosis compared with white blood cell counts in nonsmokers, and studies have associated smoking with elevated levels of C-reactive protein (Tracy et al. 1997; Wong et al. 2001; Bermudez et al. 2002). However, findings in studies of cytokine profiles in blood are not consistent (van der Vaart et al. 2005). Some studies suggest that smoking suppresses the production of proinflammatory cytokines such as IL-1, IL-6, and TNFα, which are important components of the immune response to intracellular pathogens such as viruses and fungi (Sopori and Kozak 1998; Ouyang et al. 2000). However, other studies have shown an enhanced production of IL-6 and TNFα, as well as other cytokines including IL-1β (Zeidel et al. 2002; van der Vaart et al. 2005).

Smoking could contribute to an increased risk of adverse pregnancy outcomes by its effects on the immune system through an increased risk of maternal infection, an alteration of the inflammatory response, or both. For example, studies have consistently associated smoking with a twofold-to-threefold increase in risk for bacterial vaginosis (Morris et al. 2001), which is a risk factor for preterm delivery. Researchers have hypothesized that smoking increases this risk through its effects on vaginal flora or through the depletion of Langerhans cells, resulting in local immunosuppression (Smart et al. 2004). Smoking can also reduce zinc levels, which could increase susceptibility to vaginal infections (Edman et al. 1986; Sikorski et al. 1990; Shubert et al. 1992). Cigarette smoking has been associated with increased cervical anti-inflammatory cytokines in early pregnancy, which could make women who smoke more vulnerable to reproductive tract infections and subsequent preterm delivery (Simhan et al. 2005, 2009). Finally, the immunosuppressive effects of smoking could contribute to protective effects against preeclampsia, because preeclampsia appears to involve an exaggerated or inappropriate immune response. More research is needed to fully define these potential relationships and pathways.

Tobacco Smoke Toxicants and the Reproductive System

Carbon Monoxide

Toxicity

CO is formed as a by-product of combustion and is thus present in tobacco smoke. It is a potent and even lethal toxin whose primary target organ is the brain. The fetus is more susceptible to the toxic effects of CO than is the mother. Symptomatic exposures to CO that the mother will fully recover from may end in permanent neurologic damage to the fetus or even fetal death (e.g., stillbirth) (Norman and Halton 1990; Koren et al. 1991). The fetal effects of CO are well studied (Koren et al. 1991; Penney 1996).

CO is the toxin found in the highest concentration in cigarette smoke. The dose per cigarette is 10 to 20 times the dose of nicotine (Hoffman et al. 1997). Furthermore, CO is not found in unsmoked tobacco products. The toxic effects of CO result predominantly from its binding to hemoglobin (Longo 1976, 1977). Each molecule of hemoglobin can carry four molecules of O2 (Hsia 1998). The binding and unbinding of O2 to hemoglobin depends on the local level of O2. High levels of O2 facilitate binding to hemoglobin, and low levels (hypoxia) facilitate the release of O2 from hemoglobin. The O2 binds to hemoglobin as blood passes through the O2-rich lungs and is delivered to tissues as blood traverses the capillary beds. When one molecule of O2 is released from hemoglobin, a conformational change in hemoglobin facilitates the release of further O2 molecules.

Hypoxia, Fetal Growth, and Other Abnormalities

CO binds to hemoglobin with an affinity more than 200 times that of O2 (Sauter 1994). Once CO binds to one of the four binding sites of hemoglobin, the hemoglobin is altered so greater tissue hypoxia is required before O2 will be released from the other binding sites (Hsia 1998). In addition, CO prevents the conformational change in hemoglobin that occurs with O2 unbinding. The release of one O2 molecule does not facilitate the release of subsequent O2 molecules when hemoglobin also binds CO.

The binding of CO to hemoglobin is tenacious, with a half-life of five to six hours. Fetal hemoglobin binds CO more tightly than does adult hemoglobin, and the fetus has higher levels of carboxyhemoglobin than those of the mother; the average ratio of fetal to maternal carboxyhemoglobin is 1.8 (Cole et al. 1972; Longo 1977; Bureau et al. 1982). It takes approximately seven hours for CO to equilibrate between the mother and the fetus (Bureau et al. 1982). The net effect of the CO and hemoglobin interaction is chronic hypoxia in fetal tissue (Longo 1977) or, more accurately, chronic cellular hypoxia that persists during periods of maternal abstinence from smoking, such as during sleep. Simply put, CO from cigarette smoke deprives the fetus of O2, which is essential for the aerobic metabolism that produces adenosine triphosphate (ATP). ATP stores chemical energy that is ubiquitously used to drive all manner of chemical reactions in the body. This chronic yet mild O2 deprivation in the fetus is likely a major underlying mechanism of smoking-associated fetal growth retardation (Longo 1976, 1977).

Data from both clinical and animal studies indicate that CO is probably the foremost toxin responsible for the LBW associated with maternal smoking (Garvey and Longo 1978; Lynch and Bruce 1989; Penney 1996; England et al. 2003). A well-designed study found a decrease in birth weight that was almost five times greater for infants of smokers than for infants of snuff users, even after adjustment for variables (England et al. 2003). The mean adjusted decrease in birth weight was 39 g for infants of snuff users and 190 g for infants of smokers compared with infants of nonsmokers. Because CO is the main toxin in cigarette smoke but not in snuff, this difference in birth weight implicates CO as the likely hazard. Even mild, long-term exposure to CO in animals resulted in fetal growth retardation; maternal carboxyhemoglobin levels were 4 to 9 percent (Garvey and Longo 1978; Penney 1996). The carboxyhemoglobin levels associated with smoking are 5 to 10 percent.

Studies have found central nervous system abnormalities in fetuses and pups of pregnant rats with long-term exposure to CO (Storm and Fechter 1985a,b; Storm et al. 1986; Fechter 1987; Carratù et al. 1993a,b; Packianathan et al. 1993). Behavioral studies of prenatally exposed animals have revealed persistent postnatal effects associated with CO exposure that produced maternal carboxyhemoglobin levels of 6 to 16 percent. These levels were not associated with small litter size or altered duration of gestation but with LBW (Fechter and Annau 1976, 1980, 1997; Abbatiello and Mohrmann 1979; Mactutus and Fechter 1984, 1985; Singh 1986; Fechter 1987). CO-induced hypoxia appears related to other congenital anomalies including cleft lip and cleft palate in susceptible strains of mice (Millicovsky and Johnston 1981; Bronsky et al. 1986; Bailey et al. 1995). Subsequent epidemiologic studies of birth defects in relation to CO levels from air pollution early in gestation found associations between higher CO levels and various cardiac defects, but the findings were not consistent (Ritz et al. 2002; Gilboa et al. 2005).

Blood Hyperviscosity

Carboxyhemoglobin results in functional anemia in both the mother and fetus that stimulates production of red blood cells and elevates maternal and fetal hematocrits (Meberg et al. 1979; Bureau et al. 1983; Bili et al. 1996). As the hematocrit increases, the viscosity of the blood increases. At birth, the healthy newborn hematocrit is normally 44 to 64 percent, which is well above adult values. Because of the increased viscosity, healthy newborns are at risk for stroke if the hematocrit is above 65 percent. The hematocrit can be lowered with partial-exchange transfusions. Compared with newborns of nonsmokers, newborns of smokers have higher hematocrits that therefore increase the risk of stroke and a need for exchange transfusion (D’Souza et al. 1978; Buchan 1983). Elevated maternal hematocrits and a consequently higher blood viscosity in the mother may also be risk factors for suboptimal placental perfusion (Bureau et al. 1983; Knottnerus et al 1990).

Preeclampsia

Data indicate that CO functions as a gaseous localized messenger (Ryter et al. 2004). CO appears to activate guanylate cyclase and modulate the mitogen-activated protein kinase signaling pathway (Ryter et al. 2004). Heme oxygenases (HO-1, HO-2, and HO-3) degrade heme into ferrous ion, CO, and biliverdin, which all have important physiological functions at low concentrations but are toxic in high concentrations (Ryter et al. 2004). CO appears to have localized functions similar to those of nitric oxide (NO), a gas that affects vascular tone and platelet aggregation (Ryter et al. 2004). CO also appears to have cytoprotective effects against oxidative stress by reducing inflammation and suppressing apoptosis (Ryter et al. 2004; Tsuchihashi et al. 2004).

Researchers think it is likely that the CO from cigarette smoke is responsible for the reduced risk of preeclampsia associated with smoking. The basis for this rationale is that users of snuff, which does not contain CO, have an increased risk of preeclampsia (England et al. 2003). The pathophysiology of preeclampsia remains to be elucidated, but the transformation of the spiral arterioles, which supply blood to the placenta, into low-resistance high-flow vessels appears to be incomplete (see “Preeclampsia” and “Placenta” earlier in this chapter). Spiral arteries may still be responsive to vasoconstrictive stimuli. Episodic constriction resulting in reduced blood flow to the placenta can cause hypoxia-reperfusion injury, which elicits endothelial damage and an inflammatory response. A hypoxic uterine environment appears to be a normal stimulus for the transformation of spiral arterioles during pregnancy (Lyall 2003). CO via carboxyhemoglo-bin can augment this tissue hypoxia and may stimulate the normal transformation of spiral arterioles. Additionally, CO functions similarly to NO as a vasorelaxant and may counteract the effects of circulating vasoconstrictive agents on preeclamptic spiral arterioles. Both hypoxic environment and vasorelaxation may help to prevent hypoxia-reperfusion injury and the consequential inflammation and endothelial damage, thereby reducing the risk of preeclampsia (Bainbridge et al. 2005).

Independent of preventing hypoxia-reperfusion injury, CO may function similarly to NO in maintaining normal endothelial function and preventing platelet aggregation. Also, research in the area of tissue transplantation has found that exogenous CO significantly reduces the inflammatory environment in allograft rejections (Tsuchihashi et al. 2004). Researchers postulate that CO may have a similar role in the heightened inflammatory environment of the preeclamptic placenta. Although some evidence supports this model of CO and preeclampsia, the data are not extensive (Barber et al. 2001; McLaughlin et al. 2001). Investigators do not know how important CO is as a local messenger during pregnancy or how exogenous CO supplements endogenous CO.

Summary

CO is the toxin in cigarette smoke that is found in the highest concentrations. The major effect of CO is to deprive the fetus of O2 by binding to hemoglobin. The binding of CO to hemoglobin also results in functional anemia that eventually produces a rise in the hematocrit. Elevated hematocrit in the mother may adversely affect blood flow in the placenta, leading to placental problems and potentially to fetal growth retardation. CO appears to prevent preeclampsia by augmenting uterine hypoxia and, thus, development of arterioles or other local effects similar to those of NO. However, this possibly beneficial role for CO is far outweighed by its hypoxic effects involving hemoglobin.

Nicotine

Nicotine, the principal alkaloid in tobacco, is a major contributor to the addictive properties of smoking. The diverse pharmacologic and toxicologic properties of nicotine are discussed in Chapter 4, “Nicotine Addiction: Past and Present,” and are only briefly touched on here. Nicotine has both short- and long-term effects and is likely causally related to several of the endpoints discussed in this chapter. The Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency (Cal/EPA) lists nicotine as a developmental toxicant. Nicotine is known to cross the placenta and concentrate in the fetus at levels slightly higher than those in the mother. Nicotine may decrease placental perfusion, leading to hypoxia of the fetus and acidosis.

As noted earlier in this chapter, nicotine may be involved in the development of various congenital anomalies or neurobehavioral problems. Experimental studies of rhesus monkeys exposed to nicotine in utero showed decreases in fetal lung weight, volume, and function (Sekhon et al. 2001) similar to those observed in offspring of maternal smokers (see “Fetal Tissue and Organogenesis” earlier in this chapter). Thus, nicotine may be the key constituent of tobacco smoke to impair fetal lung development and lead to altered lung function and perhaps increased respiratory illness. In an experiment with chick embryos, low doses of nicotine induced hyperactivity and higher doses induced hypoactivity (Ejaz et al. 2005). The researchers concluded that nicotine could alter embryonic movements that are important during embryogenesis for the differentiation and maturation of the embryo’s organ systems. McCartney and colleagues (1994) speculated that intrauterine exposure to nicotine specifically affects the outer hair cells in the ear, which influence language ability, leading to poorer performance scores on assessments that rely heavily on verbal abilities.

Nicotine may also interfere with pregnancy by affecting oviduct function, which may lead to ectopic pregnancy or problems with fertilization and implantation, or by affecting transport of essential nutrients, which could affect fetal growth (see earlier sections). For example, nicotine altered oviduct motility in rhesus monkeys (Neri and Marcus 1972), decreased oviductal blood flow in rats (Mitchell and Hammer 1985), and decreased sodium and potassium concentrations in oviductal epithelial cells of mice (Jin et al. 1998). In vitro studies report that nicotine, CO, and cyanide impair amino acid uptake in placental microvilli (Rowell and Sastry 1978; Horst and Sastry 1988; Sastry 1991). In addition, nicotine may impair amino acid transport (Fisher et al. 1984). Studies show reduced levels of several amino acids in fetal plasma, umbilical plasma, and placental villi in maternal smokers compared with those in nonsmokers (Jauniaux et al. 1999, 2001), and nicotine inhibits in vitro transport of arginine in human placentas (Pastrakuljic et al. 2000) (see “Amino Acids” later in this chapter). The reports of associations of smokeless tobacco use with several adverse pregnancy outcomes, such as LBW, preterm delivery, stillbirth, and placental morphologic changes (Agrawal et al. 1983; Gupta and Sreevidya 2004; Gupta and Subramoney 2006), suggest that a component of tobacco smoke in addition to CO, perhaps nicotine, contributes to these toxic effects.

Nicotine appears to be one of the components of tobacco smoke that has endocrine-disrupting effects, which, in turn, may affect several other reproductive and developmental endpoints. In vitro experiments show that treatment of cells with alkaloids found in tobacco smoke (namely, nicotine, cotinine, anabasine, or a combination of these substances) or with an aqueous extract of cigarette smoke resulted in a dose-dependent inhibition of progesterone production (Bódis et al. 1997; Gocze et al. 1999; Gocze and Freeman 2000; Miceli et al. 2005), whereas estradiol production showed little effect or was slightly stimulated. These findings support the effects of smoking on progesterone observed in epidemiologic studies. Cell growth and DNA content also decreased with treatment, leading the authors to suggest that smoking directly inhibits cellular progesterone synthesis through less specific cytotoxic effects on progesterone-producing cells (Gocze and Freeman 2000). Other scientists concluded that nicotine and M-nicotine, the methylated metabolite, can induce a type of luteal insufficiency by inhibiting progesterone release, probably through modulations in the prostaglandin system (Miceli et al. 2005) or inhibition of aromatase enzymes.

In animal models, nicotine acts on the HPG axis to increase secretion of adrenocorticotropic hormone from the pituitary gland, which then stimulates production of adrenocortical hormone (Matta et al. 1998). This finding is consistent with hormone profiles observed in clinical studies (see “Endocrine System” earlier in this chapter). Studies have also reported that nicotine acts directly on steroidogenesis by inhibiting various hydroxylases involved in their metabolism and on aromatases involved in converting androgens to estrogens (Barbieri et al. 1986a,b, 1987). Animal studies show that prenatal exposure to nicotine is related to decreased testosterone levels in adult male rats (Segarra and Strand 1989). They also report that cotinine, but not nicotine, inhibits testosterone synthesis in testes of neonatal rats (Sarasin et al. 2003). A small study of administration of nicotine to men and women by a transdermal patch found that the patch significantly lengthened the interpulse interval of pulsatile LH secretion in male nonsmokers but not in female nonsmokers or in smokers (Funabashi et al. 2005).

Metals

Presence in Tobacco Smoke

The particulate component of tobacco smoke contains metals. Their presence depends on the origin of the tobacco, the formulation of the cigarette product, and the method of smoking; detection depends on the method and sensitivity of the analysis. Analyses have quantified cadmium (<1.2 to 90.3 nanograms [ng] per cigarette), lead (0 to 41.4 ng/microgram [μg]), and mercury (<0.25 to 4.3 ng/μg) in mainstream smoke (Houlgate 2003). Nickel and chromium were not detectable (limit of detection = 1.8 and 1.7 ng per cigarette, respectively), although other studies have identified these metals in tobacco smoke (Smith et al. 1997; Torjussen et al. 2003). Arsenic was detectable but not quantifiable (limit of quantitation = 2.7 ng per cigarette). Studies have also detected additional metals such as zinc (U.S. Environmental Protection Agency [USEPA] 1992) and beryllium (Smith et al. 1997) in cigarette smoke. In sidestream smoke, there are estimated amounts only for cadmium, nickel, and zinc (National Research Council 1986). Very few animal toxicology studies of metals, which are reviewed here, used inhalation exposure. Clinical data are available on the bio-availability of cadmium and nickel from cigarette smoke, but researchers have studied only cadmium in connection with smoking-induced toxic effects on reproduction and development.

Exposure of reproductive organs to metals from cigarette smoke depends on (1) the uptake from the lung to the circulation, (2) the presence of transporters at blood-tissue barriers, and (3) the regulation of uptake and egress at the cellular level. In the fetus and the testes, there are physical barriers to blood flow (the placenta and the blood-testes barrier) and highly selective metal transport mechanisms (Hidiroglou and Knipfel 1984; Sylvester and Griswold 1994; Ballatori 2002; Asano et al. 2004; Gruper et al. 2005).

General Mechanisms

Metals reaching the cells and reproductive organs of the fetus can act through several common mechanisms. Transition metals, which can assume more than one valence state, can influence electron-exchange reactions and oxidative stress within cells. Metals can also substitute for the appropriate trace element at sites where nutritionally essential trace elements are important, such as active sites of enzymes, sites for regulatory elements of transcription factors, and metal-binding sites in receptor complexes or ion channels. Metals can also displace essential trace elements at storage sites, such as the bone matrix or heme molecules. Most mechanisms are posited for metals in the ionic form. Various compounds that incorporate metals may take metals from cigarette smoke before reaching the circulatory system and reproductive organs. However, the relevance of the various biologic actions of metals in smoking-related reproductive disease awaits further research. Current assessments must rely on parallels between smoking-related and metal-induced adverse reproductive effects.

Reproductive Effects of Specific Metals

The toxic effects of the heavy metals lead, mercury, and cadmium on reproduction and development are well known and widely reviewed in both clinical and animal studies (Clarkson et al. 1985; Andrews et al. 1994; Goyer and Clarkson 2001). The toxicity of mercury and lead is highly dependent on whether the metal is organic or inorganic. The most sensitive endpoint for lead and methyl mercury is the neurobehavior of children (Mendola et al. 2002). In addition, male and female reproductive effects from metal toxicity are well documented, including effects on fertility, menstrual cycle function, and adverse pregnancy outcomes (Ward et al. 1987; Golub 2005b; Hoyer 2005; Sokol 2005). At low levels of exposure that are potentially relevant to cigarette smoke, studies have not demonstrated effects on fertility in women but have associated infertility with paternal occupational exposure to lead (Sallmén et al. 2000). Literature reviews have indicated associations between prenatal exposure to lead and SAB, preterm delivery, and reduced birth weight (Andrews et al. 1994; Antilla and Sallmén 1995; Borja-Aburto et al. 1999). One study associated exposure to lead with delayed puberty (Selevan et al. 2003), but exposure to mercury had little effect on the timing of puberty (Denham et al. 2005).

An extensive number of studies on exposure to lead in male animals all report abnormalities in spermatogenesis and production of reproductive hormones. Studies of men report an inverse relationship between levels of lead in blood and levels in sperm, in addition to adverse pregnancy outcomes in their partners (Anttila and Sallmén 1995; Lin et al. 1998; Sokol 2005). The use of mercury in dental amalgams has led to studies of dentists and dental assistants, but evidence for reproductive effects in either males or females is limited. One study found decreased fertility in female dental assistants with greater exposure to lead (Rowland et al. 1994). Sperm production is affected in animal models with exposure to some mercury doses. Finally, experimental studies of exposure to mercury in birds and fish demonstrate hormonal effects relevant to endocrine disruption (Golub 2005b).

Researchers have investigated cadmium as the agent in cigarette smoke responsible for LBW in newborns of smokers. Studies document that cadmium accumulation in the blood and placentas of pregnant smokers correlated with LBW (Kuhnert et al. 1982, 1987a). Other studies associated placental cadmium, but not blood cadmium, with LBW of newborns of smokers (Ward et al. 1987; Sikorski et al. 1988). Studies have reported inconsistent associations between exposure to cadmium and birth weight in newborns of women exposed to cigarette smoke in the workplace or by environmental contamination (Huel et al. 1981, 1984; Bonithon-Kopp et al. 1986; Berlin et al. 1992; Loiacono et al. 1992; Fréry et al. 1993; Nishijo et al. 2002). LBW was a significant finding in some studies that administered cadmium, usually as cadmium chloride, to rats and mice by injection, inhalation, or orally in food and drinking water (Cal/EPA 1996). Many of these studies found delayed ossification, another indicator of developmental delay. At higher doses, fetal viability was affected.

One proposed mechanism of the effect of cadmium on birth weight is interference with the placental transfer of the essential trace elements zinc and copper (Sowa et al. 1982; Steibert et al. 1984; Sasser et al. 1985; Sowa and Steibert 1985; Kuhnert et al. 1987a; Chmielnicka and Sowa 1996). Researchers hypothesize that cadmium also interferes with progesterone production in the placenta (Jolibois et al. 1999a,b; Piasek et al. 2001; Kawai et al. 2002; Henson and Chedrese 2004). Studies have found that cadmium acts as an estrogenic agent. Initially, in vitro studies demonstrated that cadmium binds to a specific site on the estrogen receptor and mimics estradiol-induced gene transcription (Garcia-Morales et al. 1994; Choe et al. 2003; Johnson et al. 2003b). Other studies found that the effects of in vivo administration of cadmium on the uterus and mammary glands could be blocked by antiestrogenic agents (Johnson et al. 2003b). Animal studies show that cadmium accumulates in ovaries, that there is a loss of ovarian follicles, and that steroid production declines (Hoyer 2005). Elevated levels of cadmium in the follicular fluid of smokers (Zenzes et al. 1995) were not associated with impaired fertility (Drbohlav et al. 1998; Younglai et al. 2002). Studies have also associated smoking with elevated cadmium levels in seminal fluid. At least one study noted a negative correlation with cadmium levels and semen quality, but another found no correlation (Saaranen et al. 1989; Chia et al. 1994). Animal studies have shown some negative effects on spermatogenesis.

Chromium, nickel, and zinc are essential human dietary nutrients (Institute of Medicine 2000). They are present in tobacco and have been studied for their toxic effects on reproduction and development (Keen 1996; Golub 2005a). Almost all information on toxicity comes from laboratory animal studies, and very little is known about exposure through inhalation. Exposure to chromium (as Cr+6) produced embryo and fetal loss, growth restrictions, and malformations when administered in drinking water to mice at a minimum dose of 60 mg/kg per day (Trivedi et al. 1989; Junaid et al. 1995, 1996). Studies show that chromium is a testicular and ovarian toxicant that also affects fertility when administered in drinking water to rodents (Saxena et al. 1990; Zahid et al. 1990; Murthy et al. 1991, 1996; Bataineh et al. 1997). Nickel is teratogenic in mice and rats when it is injected (Lu et al. 1979; Mas et al. 1985). When nickel was administered over a long period in drinking water, perinatal mortality was a common finding (Smith et al. 1993). Studies have also demonstrated the testicular toxicity of nickel that was injected intraperitoneally or administered orally to rodents, but ovarian toxicity and male fertility were not studied (Kakela et al. 1999; Doreswamy et al. 2004). Long-term studies that administered zinc to male and female rodents found no effects on fertility (Ogden et al. 2002; Johnson et al. 2003a).

Growing evidence suggests adverse effects on human pregnancy outcomes (e.g., stillbirth, SAB, and LBW) from exposure to arsenic in drinking water (Hopenhayn-Rich et al. 2000; Ahmad et al. 2001; Hopenhayn et al. 2003; Yang et al. 2003). Animal studies demonstrate toxic effects on ovaries and testicles from arsenic in drinking water (Chattopadhyay et al. 1999, 2001; Pant et al. 2001), and earlier literature discusses arsenic teratogenesis (Golub et al. 1998). These studies support further efforts to assess the bioavailability of arsenic from cigarette smoke.

Most of these metals, such as lead, cadmium, mercury and mercury compounds, nickel carbonyl, and inorganic oxides of arsenic, are listed as “known by the state to cause reproductive toxicity” under California’s Proposition 65 program, affecting a variety of endpoints. (Information supporting the listings can be found at the agency’s web site [http://www.oehha.ca.gov].) Thus, some or all of these compounds may contribute to the adverse effects of smoking on reproduction, but direct links in smokers have not been established.

Polycyclic Aromatic Hydrocarbons

Formation and Toxicity

PAHs are ubiquitous products of the partial combustion of carbon-containing materials, and they appear as important components of environmental pollution. Although some sources are natural, the predominant sources of PAHs found in the air are usually anthropogenic. Examples include vehicle exhausts, products from industrial processes, and emissions from fossil fuel power plants (International Agency for Research on Cancer [IARC] 1983), as well as tobacco smoke (IARC 1986, 2004; USEPA 1992). The usual definition of a PAH specifies hydrocarbons with no heteroatom substitutents or ring members that include at least two or, according to some authors, three concatenated aromatic (usually benzene-like) rings. The two-ring members of the class, primarily naphthalenes, are included within the definition used in EPA’s identification of “polycyclic organic material” as a hazardous air pollutant. These two-ring members are abundant in tobacco smoke and show some chemical and toxicologic differences from other PAHs. This discussion primarily addresses the effects of PAHs with three or more rings, while also noting some specific effects of naphthalenes. The five-ring compound benzo[a]pyrene (B[a]P) is one of the most extensively studied PAHs. In addition to carcinogenesis, studies have reported direct fetotoxic and teratogenic effects associated with PAHs, as well as adverse effects on reproduction. Other notable effects include immunotoxicity, endocrine effects, and toxic effects on the lungs. Key studies are summarized in Table 8.12, and the results are discussed in detail here.

Table 8.12. Reproductive and developmental effects of polycyclic aromatic hydrocarbons (PAHs), by endpoint.

Table 8.12

Reproductive and developmental effects of polycyclic aromatic hydrocarbons (PAHs), by endpoint.

The toxic effects and dose-response relationships described for specific PAHs are primarily based on experiments on toxic effects in animals, which are the focus of this summary. Several corresponding effects in humans result from exposure to pollutant mixtures containing PAHs, such as diesel exhaust. Human exposure to PAHs generally involves mixtures that are ill defined and poorly quantified, so it is difficult to separate the effects of PAHs from those of other components of the mixtures.

Most of the toxic endpoints described for PAHs appear to result from the generation of reactive intermediate agents by metabolism, followed by reactions of these intermediates (e.g., as B[a]P 7,8,9,10-dihydrodiol) with the cellular components, particularly DNA, in both adult and fetal tissues (Kleihues et al. 1980; Bolognesi et al. 1985; Shugart and Matsunami 1985). Unless repaired, the adducts that are produced give rise to mutations that are then followed by cytotoxicity and/or cancer and possibly teratogenicity (Wells and Winn 1996). Both phase I (activation) enzymes and phase II (detoxification and conjugation) enzymes are important in the metabolism and toxicity of PAHs, and both are inducible by PAHs. The structural genes determining the stability and activity of the enzymes and the regulatory genes controlling the expression of the enzymes, show polymorphisms in both humans and animals. One of these enzymes is aryl hydrocarbon hydroxylase (AHH), which is influenced by induction of cytochrome P-450 activity. Animals are described as genetically “responsive” when AHH activity is induced by exposure to PAHs and to other activators of the AH receptor. There are also important changes in the levels and types of enzymes expressed at different developmental stages, particularly during the latter part of fetal development and the immediate postnatal period (Cresteil et al. 1986). Researchers have used the resulting variations in metabolic capabilities of the fetus and young animal to investigate the mechanisms of and differential susceptibility to PAH toxicity.

Toxic Effects on Reproduction

Investigators have known for some time that exposure of the adult female rodent to PAHs damages the resting ovarian follicle complexes, leading to oocyte destruction (Krarup 1969; Mattison and Thorgeirsson 1979; Mattison and Nightingale 1982) (Table 8.12). Studies have revealed similar effects in women, primarily as premature reproductive senescence (menopause), after exposure to mixed pollutants. As noted previously, premature senescence is associated with smoking (Jick et al. 1977; USDHHS 1980) (see “Menstrual Function, Menarche, and Menopause” earlier in this chapter).

Mattison and Nightingale (1982) reported a 30-percent destruction of primordial oocytes in adult mice exposed to a single dose of B[a]P. After comparing susceptibility to this effect in different strains of mice that were responsive or unresponsive to inducers of cytochrome P-450 enzymes, these researchers suggested that the determining factor for oocyte destruction involves the ratio of phase II (detoxifying) to phase I (activating) enzyme activities. Later investigations have shown the involvement of mechanisms that control apoptosis in oocyte destruction (e.g., Matikainen et al. 2001). The researchers described three sets of studies using treatment with 7,12-dimethylbenz[a]anthracene in young mice, isolated oocytes, or xenografts of human ovary tissue. They found that both a functional AH receptor and a functional BAX promoter gene were necessary for oocyte destruction in mice. Moreover, this apoptosis control system was induced in oocytes by the activation of the aryl-hydrocarbon-responsive AH receptor. This finding provides an alternative direct route for triggering the cytotoxic response to PAHs, which is in contrast to the earlier proposal involving reactive PAH metabolites.

Toxic Effects on Development

Teratogenicity. Many fetotoxins, including PAHs, produce a spectrum of effects: anatomic and functional teratogenesis; prenatal, perinatal, and postnatal mortality; growth retardation; and developmental delay. To observe the combination of these outcomes in a particular experiment may depend on dose level and timing, the test species used, and other experimental conditions. The most commonly observed effects of PAHs in animal studies are growth retardation and fetal mortality, but a few experiments have demonstrated anatomic teratogenic effects. The number of surviving offspring is reduced in these experiments, so it appears that the dose range over which surviving, but malformed, offspring are produced is narrow.

Intraperitoneal B[a]P given to mice at day 7 or 10 of gestation causes toxic effects in utero (e.g., a reduction in the number of surviving offspring) and teratogenicity (Table 8.12) (Shum et al. 1979). The severity of the effect was correlated with the ability of the fetus and the maternal systems to metabolize B[a]P. A greater impact on prenatal and postnatal mortality was noted in C57BL/6 mice, which are responsive to induction of AHH, than in unresponsive AKR inbred mice. This finding suggests a role for reactive intermediate agents of PAHs. Malformations observed only in the responsive mice included clubfoot, hemangioendothelioma, cleft palate, and other anomalies of the skeleton and soft tissues.

Nicol and colleagues (1995) also observed malformations and an increased rate of fetal death after in utero exposure to B[a]P. The embryotoxicity and teratogenicity were twofold-to-fourfold higher in mice deficient in the P53 tumor-suppressor gene than in the controls with the normal P53 gene. The P53 gene, which is important in the regulation of DNA repair and apoptosis, thus has a significant embryoprotective effect in the fetus exposed to B[a]P, which is also characteristic in relation to other DNA-damaging teratogens such as phenytoin (Nicol et al. 1995; Wells and Winn 1996).

Prenatal impacts on adult reproductive function. Animal studies have demonstrated similar but more drastic reproductive effects in both males and females exposed to PAHs in utero rather than as adults. As adults, offspring exposed to B[a]P in utero showed a loss of fertility in controlled breeding studies with untreated partners (Table 8.12). High doses of B[a]P resulted in complete infertility and histologic abnormalities of the gonads (Mackenzie and Angevine 1981). Although most observations of reduced fertility in adults focused on females, this experiment also showed a clear reduction in fertility among the treated F1 males. Examination of the testes showed severely atrophied and essentially aspermic seminiferous tubules. The ovaries of females were hypoplastic and had very few follicles or corpora lutea. Most of the animals exposed to the high doses had no identifiable ovaries or only remnants of ovarian tissue.

Kristensen and colleagues (1995) also reported reductions in fertility among female NMRI mice after exposure in utero to 10 mg of B[a]P/kg per day given orally. Watanabe (2005) reported decreases in the number of spermatozoa and Sertoli cells in the testes of adult rats exposed in utero to diesel exhaust.

Investigations of the mechanism of oocyte depletion have emphasized the importance of the AH receptor and BAX activation in the induction of apoptotic destruction of oocytes and in the natural process that reduces the initial fetal complement of primordial oocytes early in their development to the lower levels that characterize the adult female. These findings do not necessarily exclude a separate role for cytotoxic effects from DNA damage by reactive PAH metabolites in the destruction of germ cells. The mechanisms involved in the induction of impaired sperm quality and male infertility after adult or fetal exposure to PAHs are less extensively studied. Therefore, it is unclear whether other factors and/or mechanisms apply.

Effects on birth weight and developmental delay. Clinical studies of exposure to PAH-containing mixtures of pollutants in utero have reported reductions in birth weight, apparently attributable to both premature birth and IUGR, as well as variations in other size measures, such as length and head circumference at birth. More recent studies have used correlations with PAH- derived DNA adducts and the differential impact of pollution sources with high versus low PAH levels to more clearly establish the role of PAHs on LBW.

Perera and colleagues (1998) studied developmental effects of fetal exposure to PAHs through ambient pollution from burning coal in Poland (Table 8.12). Plasma cotinine and PAH-DNA adducts in leukocytes were measured in umbilical cord blood as dosimeters of cigarette smoke and transplacental PAH, respectively. Newborns whose levels of PAH-DNA adducts were above the median (3.85 per 108 nucleotides) had a significantly decreased birth weight, length, and head circumference. Cotinine was also significantly and inversely associated with birth weight and length. Similarly, Dejmek and colleagues (2000) studied birth outcomes in relation to air pollution in two towns in the Czech Republic, one industrialized (Teplice) and one rural (Prachatice) (Table 8.12). The authors defined IUGR as a birth weight below the 10th percentile by gender and gestational week. In Teplice, IUGR was observed in 9.6 percent of pregnancies, while at Prachatice, 8.2 percent were affected. There was a significant association of IUGR with exposure to air pollution, particularly to PAHs rather than to particulate matter (Table 8.12). The association between PAH exposure and IUGR was only significant during the first month of gestation. The AOR was 1.63 (95 percent CI, 0.87–3.06) for a medium exposure and 2.39 (95 percent CI, 1.01–5.65) for a high exposure. Researchers interpreted these findings as indications that the induction of IUGR by a PAH exposure resulted from an early developmental effect.

Despite the exposures to mixed pollutants, these studies provide specific correlations of impacts on birth weight and development with PAH exposure either through a determination of specific DNA adducts or on the basis of differential exposures to PAHs and other pollutants. Extensive evidence from other studies shows an impact of air pollution on birth weight and other pregnancy outcomes (Šrám et al. 2005), supporting the plausibility of a causal relationship between LBW and exposure to PAHs, in spite of the difficulties in assigning causality to specific compounds within mixtures.

Animal studies also show developmental delay and LBW after in utero exposure to pure PAHs, thus strengthening the epidemiologic data. MacKenzie and Angevine (1981) reported statistically significant reductions in weights of exposed pups compared with those of controls for all in utero doses of B[a]P, as well as evidence of a progressive dose response. Similarly, Bui and colleagues (1986) observed reductions in fetal weight in a mechanistic study that compared the effects of B[a]P with those of methadone, another known fetotoxicant. These authors also observed reductions in uterine weight among the pregnant dams, which suggest that B[a]P treatment affects both the fetus and the maternal system.

Developmental Immunotoxicity

PAH exposures have a variety of effects on the immune system. Extensive literature describes the effects of exposure to pollutant mixtures containing PAHs in adult humans. Researchers have demonstrated interest in performing studies on the initiation and exacerbation of asthma and other allergic respiratory conditions from exposure to diesel exhaust, often in combination with other allergens (Riedl and Diaz-Sanchez 2005). Findings suggest that these exposures can potentiate allergic reactions to antigens such as pollen. Exposure early in life may result in a shift in T-cell activity patterns toward a more atopic profile. Studies have also linked these effects to exposures to other pollutant mixtures that contain PAHs, including tobacco smoke (NCI 1999). Literature reviews also describe mechanistic studies of similar processes in animals. As noted earlier, the presence of PAHs in these pollutant mixtures raises the likelihood that these substances are among the causative agents. However, it is not generally possible to separate the PAH effects from those of other components in the mixture. Synergistic interactions among these components may also be a significant factor.

In contrast to the stimulatory or adjuvant effects at comparatively low exposure levels, higher doses of PAHs in humans have immunosuppressive effects (Karakaya et al. 2004). Similar findings and investigations of the mechanisms involved have been extensively described in adult animals (Table 8.12). The primary effects noted after fetal and neonatal exposures involved immunosuppression, which is often profound and persistent (Urso and Gengozian 1982; Urso and Johnson 1988; Urso et al. 1992), and includes both selective and overall reductions in various cellular components of the immune system, particularly T cells (Holladay and Smith 1994; Lummus and Henningsen 1995). Holladay and Luster (1996) have reviewed the effects of B[a]P on T-cell development and the long-term consequences on the development of the immune system. Although development of the immune system begins in utero, important structural and functional changes occur after birth. In view of this continuing development, enhanced sensitivity to exposures to immunotoxicants both during gestation and infancy is to be expected.

Toxic Effects of Naphthalene

Studies have not widely reported or characterized naphthalene as a cause of toxic effects on reproduction and fetotoxic or teratogenic effects. However, Plasterer and colleagues (1985) did report a slight reduction in the number of pups per litter, as well as toxic effects in the mother after high oral doses of naphthalene, that is, the lethal dose for 50 percent of the population (LD50). However, the reports of preferential toxic effects in the neonate or infant described here are examples of toxic effects on postnatal development.

Researchers have reported hemolysis in infants exposed to very high doses of naphthalene (Siegel and Wason 1986). This effect appears to be caused by the metabolites (1- and 2-naphthol and 1- and 2-naphthoquinones) that produce methemoglobinemia. Also, naphthalene damaged both ciliated and Clara cells of the bronchiolar epithelium in mice (Plopper 1992a,b; Van Winkle et al. 1995). Neonatal mice were more sensitive to this damage than were adult mice (Fanucchi et al. 1997). Although the experiment involved intraperitoneal dosing, the effects appear to depend on the metabolism of naphthalene in the target tissues and are therefore probably independent of the route of administration.

Endocrine Disruption

Many investigators have reported that PAHs disrupt reproductive and developmental events and other physiological processes under endocrine control. Some of these effects appear to reflect direct action on hormones and their receptors as opposed to the cytotoxic action of reactive metabolites noted earlier. The nuclear AH receptor is responsible for regulating several cytochrome P-450 iso-enzymes and triggering their induction in the presence of various xenobiotics, including PAHs, chlorinated dioxins, and coplanar polychlorinated biphenyls. This receptor also appears to have a range of other functions, including the modulation and proliferation of cell growth. The role of this receptor in the regulation of apoptosis, which includes the BAX gene product, has already been noted in the context of oocyte loss and may be involved in other processes in which apoptosis occurs.

The AH receptor also appears to interact with and in some cases control the expression of other nuclear receptors. B[a]P reduces the expression of receptors for the epidermal growth factor and the in vitro secretion of chorionic gonadotropin by human placental cells (Zhang et al. 1995). PAHs reportedly have antiestrogenic effects. Chaloupka and colleagues (1992) used MCF-7 human breast cancer cells to investigate in vitro the inhibition by 3-methylcholanthrene (a synthetic PAH) of estradiol-stimulated cell growth. Subsequently, Navas and Segner (2000) described antiestrogenic effects of various PAHs on synthesis of vitellogenin in cultured hepatocytes of rainbow trout by 17-β-estradiol. In both systems, the binding of the PAH to the AH receptor appears to be the event that triggers a range of cellular responses, including a reduced expression of the estrogen receptor.

Other Compounds

Tobacco smoke contains thousands of compounds, some of which have also been identified as known or suspected reproductive toxicants, in addition to the compounds already described here in detail. Examples include toluene, carbon disulfide, dichlorodiphenyltrichloroethane, styrene, benzene, and vinyl chloride.

Other compounds that are less well studied may also influence reproductive outcomes. As noted earlier in this chapter (see “Tubal Function”), cigarette smoke impairs oviductal functioning (Knoll and Talbot 1998) and inhibits the growth of the chick chorioallantoic membrane (CAM) (Melkonian et al. 2000, 2002). To identify which chemicals in tobacco smoke are responsible for these toxic effects, solutions of mainstream smoke were fractionated and the eluates were screened for inhibitory activity in the CAM and oviductal assays. The CAM assay measures CAM and embryonic growth, and the oviductal assays measure ciliary beat frequency, oocyte pickup rate, and rate of smooth muscle contraction. The chemicals in each eluate that retained 80 percent or more of the inhibitory activity were identified by gas chromatography and mass spectrometry. This approach identified pyridine, pyrazine, phenol, indole, and quinoline derivatives as the major groups of inhibitory compounds (Ji et al. 2002; Melkonian et al. 2003; Riveles et al. 2003, 2004, 2005). Members of each group were highly effective in both the CAM and oviductal assays that measure diverse biologic processes. In every group, some chemicals were inhibitory at nanodoses and picomolar doses, and indole was inhibitory in the oviductal assays at femtomolar doses. In general, methyl and ethyl substitutions increased the toxicity of these compounds. Some of the inhibitory chemicals (e.g., 3-ethylpyridine and pyrazine) are on the Flavor and Extract Manufacturer’s Association’s Generally Recognized as Safe list and the “Everything” Added to Food in the United States list from the U.S. Food and Drug Administration (FDA); some are added to cigarettes to enhance flavor.

Other Molecular Mechanisms

In addition to the molecular mechanisms of specific toxins outlined here, researchers have conducted general investigations of smoking in relation to pathways for molecular mechanisms.

Genetic Damage to Sperm

Concern exists that exposures to toxins such as those in cigarette smoke may cause damage to sperm DNA that could be transmitted to offspring (Chapin et al. 2004). This important question of male-mediated toxic effects on development can now be addressed directly through use of tools of molecular genetics that detect and measure chromosomal changes and DNA damage in ejaculated sperm cells (Perreault et al. 2003). Studies have reported significant increases in sperm DNA and chromatin damage, including oxidative DNA damage, in smokers compared with nonsmokers from both infertility clinic and nonclinic populations (Fraga et al. 1996; Shen et al. 1997); strand breaks (Sun et al. 1997; Potts et al. 1999); native DNA stainability (Sofikitis et al. 1995; Spanò et al. 1998); denaturation of labile sites (Potts et al. 1999); DNA adducts (Zenzes et al. 1999a,b; Horak et al. 2003); and apoptosis (Belcheva et al. 2004). Only a few studies did not find statistically significant differences related to exposure to cigarette smoke. One of these studies focused on DNA strand breaks (Sergerie et al. 2000) and another on oxidative DNA damage (Loft et al. 2003). Both studies were conducted in nonclinical populations.

Researchers have determined a statistically significant trend across published studies (p <0.001) for sperm aneuploidy associated with smoking (Robbins et al. 2005). Sperm carrying aberrant chromosomes are capable of fertilizing eggs that result in aneuploid offspring. For example, the father contributes the extra Y chromosome in 100 percent of XYY offspring, the extra chromosome in approximately 30 to 50 percent of XXY offspring with Klinefelter syndrome, and in up to an estimated 80 percent of the offspring with missing X in Turner’s syndrome (Hassold 1998; Martínez-Pasarell et al. 1999). In addition to congenital anomalies, damage to genetic material could affect sperm quality and could be manifested as infertility or very early pregnancy loss if the damage is incompatible with survival.

Nutrient Deficiencies

Micronutrients

Deficiencies of micronutrients may contribute to adverse pregnancy outcomes, and smoking could act through this relationship. As previously mentioned, a decrease in the amount of collagen III likely leads to a weakening of the tensile strength of amniotic membranes, which could increase the risk of PPROM. Vitamin C is required for collagen formation in amnion epithelial cells, and studies have noted reduced vitamin C in women with PPROM (Wideman et al. 1964; Casanueva et al. 1993). Studies consistently show that plasma vitamin C levels are lower in smokers than in nonsmokers, a finding that appears to be attributable to a lower intake as well as increased utilization in the body (Preston 1991; Lykkes-feldt et al. 2000; Cogswell et al. 2003). Vitamin C levels in the amniotic fluid of smokers are also lower than those in nonsmokers (Barrett et al. 1991). Vitamin C is important for normal immune functioning. Deficiencies of vitamin C are associated with impaired immunocompetence, reduced counts of polymorphonuclear leukocytes, phagocytosis, and depressed cell-mediated immunity (Long and Santos 1999). A vitamin C deficiency in smokers could contribute to adverse pregnancy outcomes by impairing maternal immune responses to genital tract infections. Data on other antioxidant levels in smokers are conflicting (Cogswell et al. 2003).

Zinc deficiency may also play a causal role in PPROM and other adverse outcomes. Zinc is necessary for DNA synthesis, transcription, and translation, as well as cell division and cell growth (Fisher 1975; Vallee and Falchuk 1993; Prasad 1996). Low zinc levels result in impaired immune function (Fraker and King 2004), increased susceptibility to infectious diseases (Fischer Walker and Black 2004), and cell death (Fraker 2005). Researchers have found reduced serum and amniotic fluid levels of zinc in pregnant women with PPROM (Anderson 1979; Kiilholma et al. 1984). A prospective study of pregnant women associated a low zinc intake with a threefold increase in PPROM (Scholl et al. 1993). Some data suggest that smokers are more likely to experience a zinc deficiency than are nonsmokers (Cogswell et al. 2003). Levels of maternal dietary zinc, plasma zinc, and zinc in red blood cells are similar in smokers and nonsmokers close to the time of delivery. However, shortly after delivery, zinc levels in cord blood and polymorphonuclear cells, which may be a more sensitive indicator of zinc depletion, were lower in smokers than in nonsmokers (Simmer and Thompson 1985; Kuhnert et al. 1987b). Cadmium, which accumulates in the placenta and binds to zinc, may contribute to a local zinc deficiency in smokers (Kuhnert et al. 1987a,b, 1988a,b; Preston 1991).

Amino Acids

In addition to a supply of nutrients delivered to the fetus through the uteroplacental circulation, fetal growth depends on nutrient transport across the syncytiotrophoblast. Because the placenta is impermeable to most proteins, almost all of the fetal proteins are synthesized by the fetus from amino acids supplied by the mother. Amino acids from the mother’s blood are taken up by the active transport of placental trophoblasts and then diffused into the umbilical venous blood. There is accumulating evidence that abnormalities in amino acid transport across the placenta can contribute to impaired fetal growth (Pastrakuljic et al. 1999). In addition, many studies suggest that maternal smoking adversely affects this transport, and this effect may be one mechanism by which smoking restricts fetal growth. Levels of several amino acids in fetal plasma, umbilical plasma, and placental villi are lower in smokers than in nonsmokers (Jauniaux et al. 1999, 2001) (see “Carbon Monoxide” and “Nicotine” earlier in this chapter). Additional research is needed to determine more precisely how the results of the in vivo and in vitro studies may be related to adverse pregnancy outcomes among maternal smokers.

Nitric Oxide Activity

Researchers have also studied the effects of smoking on NO activity. Endothelial NO is a potent vasodilator synthesized by NO synthase in vascular endothelial cells (ENOS) (Moncada and Higgs 1993). NO regulates blood pressure by its effects on vascular resistance. Evidence suggests that a decrease in the release of basal NO may predispose a person to hypertension, vasospasm, and thrombosis, whereas elevated levels may be associated with shock (Moncada and Higgs 1993; Änggård 1994; Cooke and Dzau 1997; Oemar et al. 1998). In pregnancy, NO is also present in placental villi and is believed to play an important role in the vasodilatory response of the maternal, uteroplacental, and fetoplacental circulatory systems (Myatt et al. 1991, 1992; Poston et al. 1995). Reductions of NO activity in placental villi from pregnancies with preeclampsia and IUGR suggest a role for NO in pregnancy complications (Sooranna et al. 1995). In vitro research indicates that the mRNA and the protein expression of ENOS are decreased in endothelial cells from preeclamptic pregnancies (Wang et al. 2004).

Studies have associated maternal smoking with a dose-dependent decrease in endothelial-dependent vessel dilation (Lekakis et al. 1998; Poredoš et al. 1999) and with an inhibition of ENOS activity, depending on the ENOS genotype (Wang et al. 2000b). Researchers have reported that endothelial cells from the umbilical cords of infants born to smokers had a 40-percent reduction in ENOS activity and a 32-percent reduction in ENOS levels compared with those in cells from infants born to nonsmokers. Furthermore, the ENOS activity level was associated with the number of cigarettes smoked per day (Andersen et al. 2004). The effects of maternal smoking on ENOS activity could lead to lower NO levels, resulting in a loss of dilatory capacity and contributing to IUGR.

Smoking and Maternal and Neonatal Genetic Polymorphisms

Investigators have reported differences in the human metabolism of toxic constituents in tobacco smoke (Benowitz et al. 1999; Lee et al. 2000; Yang et al. 2001). These metabolic differences may reflect a differential induction of toxins and drug-metabolizing enzymes, such as phase I cytochrome P-450; phase II glutathione-S-transferase (GST); NAT1 and 2; placental alkaline phospholipase; lysyl oxidase; the platelet-activating factor acetylhydrolase; TGFα; TGFβ3; and microsomal epoxide hydrolase. Genetic polymorphisms that alter the expression of these enzymes are in the pathway of development of disease such as lung cancer. These polymorphisms also appear to modify the relationship between prenatal exposure to tobacco smoke and birth outcomes. Studies of prenatal exposure to fetotoxins present in tobacco smoke (e.g., PAHs, AH, and benzene) have linked these toxins to adverse pregnancy outcomes through the inducibility of phase I enzymes such as CYP1A1 (Huel et al. 1993; Lagueux et al. 1999; Dejmek et al. 2000; Wang et al. 2000a), which can vary by host genotype.

Birth Defects

Initial investigations of the mechanisms of maternal or neonatal metabolism of tobacco smoke toxins and adverse birth outcomes were conducted in studies of birth defects. Several studies examined the potential interaction of maternal exposure to tobacco smoke and maternal and/or neonatal genotypes in association with orofacial cleft in newborns (Table 8.13). The genetic polymorphisms that code for the expression of tissue damage, inflammatory response, and immune mediator enzymes and that were examined in those studies include TGFα and TGFβ3, MSX1, and EPHX1, as well as gene variants of both phase I activation and phase II detoxification enzymes CYP1A1, GSTM1, GSTT1, NAT1, and NAT2. Prenatal exposure to tobacco smoke was measured by self-reports of maternal active smoking, maternal exposure to secondhand smoke, and paternal active smoking. Most of these studies examined the TGFα genotype in neonates. In one study, genotyping was performed in both neonates and parents.

Table 8.13. Studies of interactions between genotype and exposure to tobacco related to oral clefting.

Table 8.13

Studies of interactions between genotype and exposure to tobacco related to oral clefting.

A case-control study of infants with a TGFα *TAQ1 genotype that contained a rare allele and whose mothers had smoked during pregnancy found a significantly elevated risk for cleft palate in offspring (Table 8.13) (Hwang et al. 1995). In a large, population-based, case-control study conducted by the California Birth Defects Monitoring Program registry, the risks of cleft palate and cleft lip with or without cleft palate were significantly elevated among White infants with TGFα *rare genotypes (*A2) whose mothers were heavy smokers (Shaw et al. 1996). However, three subsequent case-control studies (Christensen et al. 1999; Romitti et al. 1999; Beaty et al. 2001) that failed to replicate these findings had fewer cases and one study had used a lower cutpoint for smoking than that used by Shaw and colleagues (1996). None of the five studies cited above presented regression models with terms for estimating maternal smoking levels and the TGFα genotype interactions. Zeiger and colleagues (2005) conducted a meta-analysis of data from these five studies and found a marginally significant interaction between maternal smoking and infant TGFα *allele genotypes (*A2) in relation to cleft palate (OR = 1.95 [95 percent CI, 1.22–3.10]). There was no evidence of an interaction in relation to cleft lip and cleft palate (OR = 0.86 [95 percent CI, 0.53–1.40]).

Romitti and colleagues (1999) also examined the TGFβ3 genotype and maternal smoking in relation to the risk of cleft palate or cleft lip and cleft palate (Table 8.13). These researchers found a significantly elevated risk for the conditions among infants who were homozygous for the common *1 allele at the X5.1 or 5′UTR.1 site and whose mothers had smoked 10 or more cigarettes per day. There was no evidence of an interaction for infant genotypes that included the rare *2 allele.

Hartsfield and colleagues (2001) did not observe any significant interaction between maternal smoking and EPHX1 (codon 113) or null GSTM1 genotypes in a case-control study of isolated cleft lip and cleft palate (Table 8.13). van Rooij and colleagues (2001) examined the association of maternal prenatal smoking and the maternal GSTT1 genotype. The researchers found that mothers who smoked and carried the GSTT1 null genotype had a marginally higher risk for delivering an infant with oral clefting than that of nonsmokers who carried the wild-type genotype. Although the RR was not statistically significant, it was almost five times greater when both mothers and their infants carried the GSTT1 null genotype. There was no evidence of an interaction between maternal smoking and the CYP1A1 genotype with a recessive allele in relation to oral clefting. In a case-control study, the CYP1A1, GSTT1, and GSTM1 polymorphisms were also examined as risk factors for hypospadias, a congenital anomaly of the male reproductive organs (Kurahashi et al. 2005). The study did not observe any increased risk of hypospadias among children born to mothers who smoked and had various genotypes, including CYP1A1 *MSPI variant allele genotype or the GSTT1 null genotype or GSTM1 null genotype. In a case-only, haplotypic analysis of an intronic CA repeat of the MSX1 gene in 206 infants with oral clefting, there was evidence for an interaction with maternal prenatal smoking (Fallin et al. 2003). In the Iowa study (Romitti et al. 1999), infants whose MSX1 X1.3 or MSX1 X2.4 genotype contained the *2 allele and whose mothers smoked 10 or more cigarettes per day also had a significantly elevated risk of cleft palate (Table 8.13). In a study of limb deficiency defects, Carmichael and colleagues (2004) did not observe any significantly elevated risk for infants with MSX1 intronic CA repeat genotype whose mothers smoked during pregnancy. In another case-control study from the California Birth Defects Monitoring Program, the NAT1 1088 genotype *A/*A and the NAT1 1095 genotype *A/*A, but not NAT2 polymorphisms, were strongly associated with isolated oral clefting in infants whose mothers had smoked during pregnancy (Table 8.13) (Lammer et al. 2004).

Other Reproductive Endpoints

Several studies have also examined the potential interaction among phase I and II toxins, genes for drug metabolism, and prenatal exposure to tobacco smoke in relation to other outcomes, such as LBW, preterm birth, IUGR, and neonatal oxidative damage (Table 8.14).

Table 8.14. Decreased birth weight, preterm delivery, intrauterine growth retardation, and neonatal oxidative damage: interactions between host genotype and exposure to tobacco smoke.

Table 8.14

Decreased birth weight, preterm delivery, intrauterine growth retardation, and neonatal oxidative damage: interactions between host genotype and exposure to tobacco smoke.

A large case-control study described an interaction between self-reported smoking during pregnancy and maternal genetic polymorphisms for CYP1A1 MSPI and GSTT1, which were associated with reduced birth weight, preterm delivery, reduced gestation, and IUGR (Table 8.14) (Wang et al. 2002). Mothers who had smoked continuously during pregnancy and who were heterozygous variant type (*A/*a) or homozygous variant type (*a/*a) for CYP1A1 MSPI, were at a threefold higher risk of having a LBW (<2,500 g) infant compared with lifetime non-smokers who were homozygous wild type (*A/*A). In these genotype-exposure groups, gestation was reduced on average by 1.5 weeks among smokers who were CYP1A1 MSPI *A/*a or *a/*a. Smokers with the GSTT1 null genotype gave birth to infants with significant decrements in birth weight compared with birth weight of infants of non-smokers who carried at least one GSTT1 allele. The risk of growth retardation, defined as less than 85 percent of the ratio of observed birth weight to mean birth weight for gestational age, was associated with smoking in mothers who carried the CYP1A1 MSPI *A/*a or *a/*a. This study was unique because it presented regression models that evaluated interaction terms along with analyses stratified by gene variant and smoking status, but it lacked an objective measure of smoking.

In a study conducted in Korea, Hong and colleagues (2003) examined the potential interaction of the GST family gene variants and exposure to secondhand smoke in association with mean birth weight (Table 8.14). Women classified as exposed to secondhand smoke, as determined by assays of urinary levels of cotinine, who carried the GSTM1 null genotype delivered infants with a mean birth weight decrement of −158 g, after adjustment for gestational age. A similar pattern was observed among mothers with the GSTT1 null genotype (decrement of −203 g). In a subsample of 81 women in the same study population, Hong and colleagues (2001) examined the effect of exposure to secondhand smoke and maternal GST family genotypes in relation to measurements of neonatal oxidative damage as urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OH-dG). Infants born to women classified as exposed to secondhand smoke who carried the GSTM1 null genotype had significantly higher levels of log urinary 8-OH-dG (geometric mean level = 4.03 [95 percent CI, 2.13–7.61]) than did women classified as unexposed who carried the GSTM1 wild type. Significant differences in 8-OH-dG remained after adjusting for confounders.

One study evaluated phase I and II metabolic enzyme gene variants (Table 8.14) (Nukui et al. 2004). The authors reported that the most significantly elevated risk of premature birth occurred when both mother and infant carried the GSTT1 null genotype. The results were the same for smokers and nonsmokers, so no interaction was observed. Phase I genetic polymorphisms (e.g., CYP1A1) were not associated with an elevated risk of a premature birth. A study that examined PLAP polymorphisms found an elevated risk of LBW when the PLAP *1/*1 genotype was absent in mothers who smoked (Magrini et al. 2003).

Implications

The evidence of a causal relationship between smoking during pregnancy and increased risk for adverse pregnancy outcomes is sufficient to warrant promoting smoking cessation among women early in pregnancy or before they become pregnant, because the critical period may be quite early. For example, the impact of smoking on oral clefts could be lessened by 5 to 22 percent if women stopped smoking before pregnancy. Thus, there is a need for widespread implementation of interventions for effective smoking cessation that target all women of childbearing age.

Smoking may have several ramifications of alterations in fertility, menstrual cycle function, or sperm quality, including a burden on the health care system and loss of work productivity. These changes may affect a woman’s ability to conceive and maintain a pregnancy at a desired time in a couple’s life. The reproductive life span may be shortened, and early menopause is associated with other hormone-related health problems such as osteoporosis and cardiovascular disease (Harlow and Ephross 1995; Sowers and La Pietra 1995; Cooper and Sandler 1998). Women with short menstrual cycles may also be at a higher risk of breast cancer (Kelsey et al. 1993). Such effects warrant smoking cessation early in the reproductive age span, or ideally, prevention of smoking initiation among youth.

Smoking Prevention and Cessation

Smoking cessation is one of the most important actions a woman can take to improve the outcome of her pregnancy, and most women who stop smoking during pregnancy do so on their own. Because women know about the adverse effects of smoking on their health and that of a fetus, pregnancy may be a time when smoking cessation efforts and interventions are potentially more effective (Mullen 1999; Fiore et al. 1996, 2008). Nevertheless, most smokers do not stop smoking during pregnancy. Tobacco addiction is progressive and chronic and, in consequence, smoking cessation interventions focusing on the prenatal period have failed to achieve long-term abstinence among most pregnant smokers. Two-thirds of women who smoke during the first pregnancy also smoke during the second, exposing the first infant to tobacco smoke both in utero and postnatally (Dietz et al. 1997).

Population-based, cross-sectional surveys have been widely used to monitor prenatal smoking rates (Connor and McIntyre 1999; Owen and Penn 1999; Ebrahim et al. 2000). However, such data do not provide information on changes in smoking behaviors during pregnancy, in contrast to data collected during prenatal care, in which smoking behaviors are recorded on more than one occasion, as described by Kirkland and colleagues (2000). Such longitudinal data can usefully supplement survey data to monitor progress in control of prenatal exposure to tobacco smoke. Because of the social desirability of non-smoking status, which is greater during pregnancy, the actual prevalence of smoking may be even higher than is self-reported. In the United Kingdom, 16 percent of respondents to a survey reported that they did not admit to their physicians that they smoked (Bulletin of the World Health Organization 1999). A study in the United States found nondisclosure rates of 28 percent at enrollment into prenatal care and 35 percent at follow-up (Kendrick et al. 1995). Therefore, biochemical verification of smoking status of each woman during each contact with a clinician is needed to evaluate cessation interventions.

Clinicians who provide health care to women have an important role in reducing the burden of smoking among women. Clinically proven programs for smoking cessation that can be delivered in primary care settings are now available. However, there is a dearth of information specifically addressing the most effective smoking prevention and cessation interventions for women of childbearing age, especially those of low socioeconomic status. For this reason NC1 has implemented the TReND: Low SES Women and Girls Project. This project was created to strategically address and examine the effects of multiple tobacco control policies on diverse populations of low SES women and girls. In addition, the USDHHS Office of Women’s Health has developed an interagency work group to address this issue. The FDA Office of Women’s Health has also developed a guide for providers to educate women about medications available to assist them if they are ready to quit smoking.

Experts attending the 1998 Consensus Workshop on Smoking Cessation During Pregnancy reviewed the evidence related to counseling on smoking cessation during pregnancy, including the U.S. Public Health Service Clinical Practice Guideline, Treating Tobacco Use and Dependence (Fiore et al. 1996; Mullen 1999). This group concluded that brief cessation counseling (5 to 15 minutes), delivered by a trained provider with pregnancy-specific self-help materials, significantly increases rates of cessation among pregnant smokers. The 5A strategy of smoking intervention—Ask, Advise, Assess, Assist, and Arrange—and recommended procedures are outlined in the one-page form, Brief Smoking Cessation Counseling for Pregnant Patients. More intense efforts may be needed for groups of women who are less likely to stop smoking and more likely to relapse (Connor and McIntyre 1999). Smoking cessation interventions should be continued after delivery to prevent relapse, and partners who smoke should be included in such interventions. More than 50 percent of women do not recognize that they are pregnant until after the fourth week of gestation. Therefore, efforts to prevent exposure to tobacco smoke should begin before conception to avoid pregnancy complications or to avoid exposing the fetus to tobacco smoke. Furthermore, to prevent subfertility, cessation efforts should begin even earlier in the reproductive period.

Despite evidence that provider-administered cessation counseling significantly increases rates of cessation among pregnant smokers, evidence suggests that such interventions may do little to decrease overall prenatal smoking prevalence. It has been estimated that universal implementation of a provider-administered psychosocial cessation intervention on a national level would result in only a modest decline (0.8 percentage points) in the overall prevalence of smoking among pregnant women (Kim et al. 2009). Larger reductions in prenatal smoking prevalence will likely require implementation of comprehensive tobacco control policies that effectively decrease smoking prevalence among women of reproductive age.

Unfortunately, pregnant women who smoke most heavily do not appear to respond to the type of behavioral intervention indicated here. The U.S. Public Health Service has suggested, as have others, the need to explore the use of pharmacologic approaches to achieve cessation in women who are unable to stop smoking (Fiore et al. 1996, 2000, 2008). These approaches include nicotine replacement therapy (e.g., gum, patch, inhaler, or spray); nonnicotine products, such as varenicline and bupropion hydrochloride; and second-line pharmacotherapies, such as clonidine and nortriptyline. However, the efficacy and safety of these approaches during pregnancy are not well documented. Pharmacologic interventions should be considered on an individual basis as an adjunct to behavioral interventions. These interventions should be considered for pregnant women only if the increased likelihood of smoking cessation outweighs the harmful effects on the fetus of nicotine replacement therapy and possible continued smoking.

To minimize the effects of smoking among all women and to foster effective perinatal tobacco control, focus and efforts should expand beyond prenatal care to include both the whole family and the entire reproductive life span of women. The complexities associated with smoking cessation among established smokers are underscored by reports of persistent high smoking rates among pregnant women in Canada, the United Kingdom, and the United States (Connor and McIntyre 1999; Owen and Penn 1999; Ebrahim et al. 2000). Long-term reduction in tobacco exposure during pregnancy can be achieved only by encouraging adolescent girls and young women not to start smoking.

Regulation and Policy

Ranking of infant mortality rates in established market economies placed the United States twenty-eighth in 2005 compared with twelfth in 1960. Rates of smoking remain high among women in three categories related to pregnancy—pregnant, planning a pregnancy, and at risk of pregnancy. Substantial efforts would be needed to reduce known risks to pregnancy and infant health, to reverse the stagnant trends in infant mortality rates in the near future. Because only about 20 percent of women successfully control tobacco dependence during pregnancy, smoking cessation is recommended before pregnancy (U.S. Preventive Services Task Force [USPSTF] 2003). National recommendations to support preconception care as an opportunity to reduce maternal risks during pregnancy have been introduced (USPSTF 2003). Therefore, high rates of smoking in the preconception period, almost the same as that among all women of childbearing age, pose both a challenge and an opportunity to the implementation of the preconception care initiative. After childbirth, smoking does not usually decline below the level achieved during pregnancy (USPSTF 2003). Therefore, further challenges to preventing smoking-related harm to infant health include continued postnatal exposure to secondhand tobacco smoke from maternal smoking.

Intervention tools to aid smoking cessation among pregnant women are now available. One report estimated that the costs of implementing such interventions range from $24 to $34 per pregnant smoker counseled (Ayadi et al. 2006). Potential neonatal cost savings that could be accrued for women who stop smoking during pregnancy were estimated at $881 per maternal smoker (Ayadi et al. 2006). A woman’s contact with the health care system during and after pregnancy provides enough opportunities to engage women for smoking cessation and provide follow-up and support services to prevent relapse during the interconception period. Furthermore, women of childbearing age in the United States have on average 6.4 health care visits per year (Adams and Marano 1995), and such opportunities can be used to improve access to the 5A strategy of smoking intervention.

Smoking behaviors of partners of women who smoke are important considerations for achieving cessation and prevention of relapse. Extension of services or facilitation of use of services by the partners would be needed to maintain the benefit from smoking cessation services provided to the women. Because men have fewer contacts with the health care system than do women (Everett et al. 2005), smoking cessation efforts among women provide an opportunity for access to health care for their male partners also for cessation efforts.

Efforts to reduce smoking in the United States have shifted from a primary focus on smoking cessation for individuals to more population-based interventions that emphasize prevention of smoking initiation, reduction of exposure to secondhand tobacco smoke, and policy changes in health care systems to promote cessation. Parallel to these efforts, concerted efforts are needed to reduce the disparity in smoking rates among socially disadvantaged women and White women; targeted efforts aimed at women in the preconception period and those at risk for pregnancy; and efforts to promote smoking cessation among women who are pregnant. One report indicated that bundling of services to address common preventable risks, such as tobacco and alcohol use and risks for sexually transmitted diseases, through a preconceptional approach, would benefit about one-half of all women of childbearing age in the United States (CDC 2006). Tobacco use in women coexists with other risk behaviors or morbidities, including mental health disorders and substance use. Some factors, such as illicit drug use or alcohol use, may synergistically elevate the risk from other factors such as tobacco use or acquisition of sexually transmitted infections, requiring intervention approaches through case management that address more than one risk factor. Use of tobacco and alcohol are comorbidities that can benefit from many efforts to provide several interventions to a woman simultaneously. Such case-management approaches may help to increase adherence to treatment and reduce relapse to smoking after delivery.

Earlier data have indicated that the observed declines during the past four decades in the United States in smoking rates among pregnant women reflect declines that occurred in general among women and were not specific to pregnancy. Therefore, efforts to close the gaps in the diffusion of smoking cessation intervention to individual smokers are still needed and should be a priority. However, large reductions in smoking rates among pregnant women over time are more likely to come from efforts to reduce smoking initiation by young women.

Evidence Summary

Health professionals have long considered exposure to tobacco smoke harmful to reproduction, affecting aspects from fertility to fetal and child development and pregnancy outcome. Tobacco smoke contains thousands of compounds, some of which are known toxicants to reproductive health, such as CO, nicotine, and metals. About 10 percent of couples who want to conceive a child experience infertility or reduced fertility, approximately 10 to 20 percent of women who do conceive have miscarriage or stillbirth before delivery, and others have pregnancy complications and adverse outcomes that affect infant health and survival (CDC 2005).

In 2007, 17.4 percent of women and approximately 19 percent of women of reproductive age (18 through 44 years) smoked cigarettes (CDC 2008). From 2002 to 2005, 17.3 percent of pregnant women reported smoking cigarettes in the past month (NSDUH Report 2007). Because smoking rates have declined, persons involuntarily exposed to tobacco smoke probably now outnumber active smokers and they are exposed to some of the same toxins to which smokers are exposed.

Previous Surgeon General’s reports and subsequent studies have found that smoking is related to several reproductive health endpoints. The 2001 report on women and smoking and the 2004 report on the health consequences of smoking noted a causal link between smoking and reduced fertility in women. Smoking may contribute to reduced fertility and other related reproductive endpoints, including earlier menopause or altered menstrual cycle parameters, through similar mechanisms such as by producing alterations in hormone function. Study findings suggest effects of smoking on estrogen and other hormones, which may vary by gender and the stage of life. Researchers have suggested that smoking has antiestrogenic effects, but more recent data are less consistent, at least for nonpregnant, premenopausal women. Studies implicate smoking and its effects on other hormones, such as progesterone, gonadotropins (FSH), and androgens (including in men). In animal studies, cells treated with alkaloids found in tobacco smoke, including nicotine, showed a dose-dependent inhibition of progesterone production, whereas estradiol production showed little effect or was slightly stimulated (Bódis et al. 1997; Gocze et al. 1999; Gocze and Freeman 2000; Miceli et al. 2005). Other scientists concluded that nicotine affects the menstrual cycle by inhibiting progesterone release just after ovulation. In animal models, nicotine acts on the HPG axis, which is involved in normal sexual development and control of reproductive function (Matta et al. 1998). Studies show that prenatal exposure to nicotine is related to decreased testosterone levels in adult male rats and that cotinine, but not nicotine, inhibits testosterone synthesis in testes of neonatal rats (Sarasin et al. 2003).

Spermatogenesis is also affected by the hormonal milieu. Recent studies have provided more evidence that tobacco smoke exposure is associated with reduced sperm quality, which, in turn, may be a mechanism leading to reduced fertility in couples. Smoking-associated DNA damage in sperm could also be related to birth defects in offspring or producing nonviable gametes, resulting in apparent infertility or early fetal loss.

Many epidemiologic studies have related maternal smoking to reproductive problems that can originate in the oviduct (e.g., fallopian tube) (Stillman et al. 1986; Buck et al. 1997), including infertility and ectopic pregnancy. Studies have shown that exposure to tobacco smoke diminishes oviductal functioning. Exposure to cigarette smoke and its components has been shown to alter contraction in human and rabbit oviducts (Neri and Eckerling 1969; Ruckebusch 1975) and to form blebs on the oviductal epithelium in hamsters (Magers et al. 1995). In other studies of hamster oviducts, effects included decreased smooth muscle contractions and changed the ratio of ciliated to secretory cells, both of which would affect transit time of the egg through the oviduct (Huang et al. 1997; Knoll and Talbot 1998; DiCarlantonio and Talbot 1999; Riveles et al. 2003). Adhesion between the extracellular matrix of the oocyte cumulus complex and the tips of the cilia is essential for pickup of the oocyte and transport through the oviduct (Talbot et al. 1999; Lam et al. 2000). Exposure to both mainstream and sidestream smoke increases adhesion, which could account for decreased pickup rates even when cilia beat at normal or accelerated rates.

Ectopic pregnancy occurs when a fertilized egg is implanted outside the uterus, usually in the fallopian tube; it is estimated to occur in 1 to 2 percent of pregnancies. This condition accounts for approximately 6 percent of pregnancy-related deaths in the United States (Chow et al. 1987; Goldner et al. 1993; Berg et al. 2003; Chang et al. 2003; Van Den Eeden et al. 2005). Affected women are at increased risk of subsequent infertility and recurrent ectopic pregnancy, as would be expected among women with tubal damage (Chow et al. 1987; Coste et al. 1991; Washington and Katz 1993; Skjeldestad et al. 1998). The 2004 Surgeon General’s report found the evidence suggestive but not sufficient to infer a causal relationship between smoking and ectopic pregnancy (USDHHS 2004) on the basis of a number of studies with significant associations between smoking and increased risk of ectopic pregnancy, yielding a pooled OR of 1.8 or an 80-percent increase with smoking (Castles et al. 1999). Two subsequent methodologically strong studies also indicate an increased risk with dose-response effects, further strengthening the evidence.

Studies have found evidence of a dose-response relationship even after adjustment for important potential confounders such as a history of sexually transmitted diseases and infertility (Bouyer et al. 2003; Karaer et al. 2006). In addition, plausible mechanisms for a relationship between smoking and ectopic pregnancy exist. As noted, the oviduct plays a critical role in the pickup and transport of the oocyte, and failure of this function can result in ectopic pregnancy (Talbot and Riveles 2005).

Spontaneous abortion, the involuntary termination of an intrauterine pregnancy before 20 weeks of gestation, has been reported in approximately 12 percent of recognized pregnancies; the majority occur before 12 weeks of gestation. Including very early pregnancy loss that may be unreported suggests an estimated 30 to 45 percent of conceptions actually end in pregnancy loss, some before implantation (Wilcox et al. 1988; Eskenazi et al. 1995). In addition to fetal abnormalities, other factors that likely contribute to SAB include maternal anatomic abnormalities of the uterus, immunologic disturbances, thrombotic disorders, and endocrine abnormalities (Christianson 1979; Cramer and Wise 2000; Regan and Rai 2000), some of which are affected by tobacco smoke. The 2004 Surgeon General’s report (USDHHS 2004) found the evidence suggestive but not sufficient to infer a causal relationship between tobacco and SAB. Additional studies have shown positive associations, including two with measurement of cotinine (Ness et al. 1999; George et al. 2006) and two showing associations with secondhand smoke (Venners et al. 2004; George et al. 2006). Proposed mechanisms for an effect from tobacco smoke include vasoconstrictive and antimetabolic effects resulting in placental insufficiency and the subsequent demise of the embryo or fetus, fetal hypoxia from CO exposure, and direct toxic effects of cigarette smoke constituents.

Preeclampsia, marked by proteinuria, hypertension, and dysfunction of the cells lining the uterus, is a leading cause of pregnancy-related mortality in the United States (Berg et al. 2003). The 2004 Surgeon General’s report found the evidence sufficient to infer a causal relationship between smoking and a reduced risk of preeclampsia (USDHHS 2004). Smoking has been proposed to reduce the risk of preeclampsia by effects of exposure to thiocyanate, which has a hypotensive effect (Andrews 1973), by changing the thromboxane A2 to prostacyclin ratio, which would alter the way blood vessels constrict and dilate (Ylikorkala et al. 1985; Davis et al. 1987; Marcoux et al. 1989; Lindqvist and Maršál 1999), or by stimulating the growth of new blood vessels in the placenta (Maynard et al. 2003; Fisher 2004; Jeyabalan et al. 2008).

Numerous studies have demonstrated the immediate effect of smoking one or two cigarettes on maternal heart rate and blood pressure (Lindblad et al. 1988; Morrow et al. 1988; Castro et al. 1993; Kimya et al. 1998; Ates et al. 2004). The clinical significance of a transiently elevated maternal heart rate on pregnancy is unknown. Studies that examined the acute effects of smoking after abstinence reported a transient increase in diastolic blood pressure and, to a lesser extent, systolic blood pressure. The release of catecholamine may trigger the elevations in maternal heart rate and blood pressure reported in these studies. However, smoking was also associated with an acute rise in plasma levels of norepinephrine, epinephrine, and dopamine, which could mediate the rise in maternal heart rate and blood pressure (Quigley et al. 1979). The literature indicates a transient increase in fetal heart rate with acute maternal smoking that was not statistically significant, although fetal heart rate variability, used to assess fetal well-being, was significantly transiently decreased (Graca et al. 1991; Ates et al. 2004). The clinical significance of these transient changes is not known. Studies on uterine and placental blood flow did not indicate basal differences between smokers and non-smokers and results were inconsistent with respect to acute changes from smoking, so this mechanism is not supported as a possible cause of the well-documented fetal growth retardation among smokers.

Maintenance of pregnancy and fetal growth and development are dependent on normal formation of the placenta for exchange of nutrients and metabolic products between the mother and fetus. Studies have consistently shown that maternal smoking is associated with a thickening of the villous membrane of the placenta, which would decrease the ability of nutrients to pass through the placenta by diffusion (Burton et al. 1989; Jauniaux and Burton 1992; Demir et al. 1994; Bush et al. 2000; Larsen et al. 2002). The thickening of the villous membrane could contribute to fetal growth restriction. Researchers have hypothesized that toxic effects of maternal smoking on the placenta are responsible for the thickening of the villous membrane, perhaps caused by the accumulation of cadmium that is associated with a reduction in fetal capillary volume (Burton et al. 1989; Bush et al. 2000). Smoking appears to interfere with transformation of uterine spiral arteries, which is critical for the formation of the high-capacitance system that allows increased blood flow from the mother to the fetus. Such interference could lead to increased risk of adverse pregnancy outcomes such as miscarriage.

Epidemiologic studies have consistently found an increased risk of partial obstruction of the cervix by the placenta (placenta previa) among maternal smokers, which may lead to preterm delivery or maternal or fetal or neonatal death (Meyer et al. 1976; Zhang and Fried 1992; Monica and Lilja 1995). One mechanism commonly proposed to explain this association is the lower blood levels of O2 and reduced blood flow that result from smoking, with compensatory placental enlargement.

Premature separation of the placenta from the uterus (placental abruption) increases the risk of perinatal mortality, and although several factors are involved (Misra and Ananth 1999), studies have consistently associated smoking with an increased risk (Raymond and Mills 1993; Ananth et al. 1999; Castles et al. 1999; Andres and Day 2000). The 2004 Surgeon General’s report found the evidence sufficient to infer a causal relationship (USDHHS 2004), and researchers have observed a dose-response relationship (Raymond and Mills 1993; Ananth et al. 1999). One researcher has hypothesized that smoking-related degenerative and/or inflammatory changes in the placenta are factors related to abruption (Cnattingius 2004). Other hypotheses include low levels of vitamin C in maternal smokers (Faruque et al. 1995), leading to impaired collagen synthesis (Cnattingius 2004), microinfarcts, and accumulation of fatty deposits in placental vessels (Naeye 1979; Andres and Day 2000).

The 2004 Surgeon General’s report found that the evidence was sufficient to infer a causal relationship between smoking and preterm delivery, a leading cause of neonatal morbidity and mortality in developed countries (USDHHS 2004). Smoking appears to increase the risk of both medically indicated and spontaneous preterm delivery (Kyrklund-Blomberg and Cnattingius 1998). Mechanisms through which smoking may contribute to preterm delivery include placental abruption or effects on the integrity of collagen, leading to a weakening and rupture of the membranes and increased risk of infections.

The same Surgeon General’s report found sufficient evidence to infer a causal relationship between smoking and preterm premature rupture of membranes (PPROM) (USDHHS 2004). Researchers have hypothesized that smoking increases the risk of PPROM through several pathways. The effects of smoking on the immune system could increase the risk of genital tract infection or disrupt the cytokine system (French and McGregor 1996). Smoking could also increase the inflammatory response and reduce the availability of nutrients such as vitamin C or decrease the uptake of nutrients by the placenta (French and McGregor 1996; Lykkesfeldt et al. 1996, 2000), which would affect collagen content and membrane structure.

Maternal smoking has also been investigated for an association with birth defects, and although the 2004 Surgeon General’s report (USDHHS 2004) found inadequate evidence for birth defects in general, maternal smoking was considered suggestive for oral clefts. Evidence accumulated since the studies in that report is even stronger in supporting an association with smoking and cleft lip and/or palate (Little et al. 2004a), with some dose-response effects noted (Little et al. 2004b). Animal studies support these findings with evidence that nicotine can alter embryonic movements that are important during embryogenesis for the differentiation and maturation of organ systems, including palate closure (Panter et al. 2000; Ejaz et al. 2005). Other possible mechanisms include smoking-induced reductions in supply of essential nutrients for embryonic tissues, such as multivitamins and folate, fetal hypoxia from CO, or DNA damage from PAHs.

Deficiencies of micronutrients may contribute to adverse pregnancy outcomes, and smoking may contribute to this relationship. Vitamin C is required for collagen formation in amnion epithelial cells, and studies have noted reduced vitamin C levels in women with PPROM (Wideman et al. 1964; Casanueva et al. 1993). A decrease in the amount of collagen III likely leads to a weakening of the tensile strength of amniotic membranes, which could increase the risk of PPROM. Studies consistently show that smokers consume less and metabolize more vitamin C than do nonsmokers and thus have lower levels of vitamin C in plasma (Preston 1991; Lykkesfeldt et al. 2000; Cogswell et al. 2003) and in amniotic fluid (Barrett et al. 1991). Vitamin C is important for normal immune functioning, and a vitamin C deficiency in maternal smokers could contribute to adverse pregnancy outcomes by impairing maternal immune responses to genital tract infections. Because the placenta is impermeable to most proteins, proteins are usually synthesized by the fetus from amino acids supplied by the mother. Abnormalities in amino acid transport across the placenta can contribute to impaired fetal growth. Compared with nonsmokers, smokers have reduced levels of several amino acids in fetal plasma, umbilical plasma, and placental villi (Jauniaux et al. 1999, 2001).

CO forms as a by-product of combustion and is the toxin found in the highest concentration in cigarette smoke—10 to 20 times the dose of nicotine (Hoffman et al. 1997). The toxic effects of CO result predominantly from its binding to hemoglobin (Longo 1976, 1977), which is more than 200 times that of O2 to hemoglobin (Hsia 1998). Fetal hemoglobin binds CO more tightly than does adult hemoglobin, so the fetus of a smoking mother has much higher levels of carboxyhemoglobin than those of the mother. The fetus experiences chronic hypoxia of fetal tissue, which persists for five or six hours of maternal smoking abstinence, such as during sleeping (Cole et al. 1972; Longo 1977; Bureau et al. 1982). CO from cigarette smoke deprives the fetus of O2, which is essential for the aerobic metabolism that produces ATP, a coenzyme that stores the energy to fuel cellular activity throughout the body. Chronic mild O2 deprivation in the fetus is likely a major underlying mechanism of smoking-associated fetal growth retardation, one of the most consistent and earliest identified adverse effects in infants of maternal smokers (Longo 1976, 1977; USDHHS 1980, 2004). Furthermore, infants of maternal smokers showed a decrease in birth weight nearly five times lower than that in infants of snuff users, even after adjustment for variables, implicating CO as the likely hazard (Longo 1976, 1977; England et al. 2003). Reduced fetal growth is associated with adverse effects on other endpoints, including perinatal mortality, birth defects, and neurodevelopment, which may also be directly affected by CO exposure.

Other components of tobacco smoke, including nicotine (see Chapter 3, “Chemistry and Toxicology of Cigarette Smoke and Biomarkers of Exposure and Harm”); heavy metals such as cadmium, lead, and mercury; and PAHs have been found to be causally associated with several adverse reproductive outcomes described here. Furthermore, levels of these components are found to be higher in smokers than in nonsmokers. It is more difficult to determine whether the levels generated from tobacco smoke are sufficient to cause these outcomes, but the evidence is suggestive for several of the components. The metabolism of these toxic constituents likely varies by genetic polymorphisms that reflect differential induction of drug-or toxin-metabolizing enzymes, such as cytochrome P-450s and GSTs, which, in turn, may modify the relationship between maternal smoking and birth outcomes, such as LBW or congenital anomalies. Genetic polymorphisms coding for the expression of tissue damage, inflammatory response, and immune mediator enzymes have been examined for interaction with maternal smoking in several studies of oral facial clefts, with TGFα and TGFβ3 alleles most often implicated.

Conclusions

  1. There is consistent evidence that links smoking in men to chromosome changes or DNA damage in sperm (germ cells), affecting male fertility, pregnancy viability, and anomalies in offspring.
  2. There is consistent evidence for association of peri-conceptional smoking to cleft lip with or without cleft palate.
  3. There is consistent evidence that increases in follicle-stimulating hormone levels and decreases in estrogen and progesterone are associated with cigarette smoking in women, at least in part due to effects of nicotine on the endocrine system.
  4. There is consistent evidence that maternal smoking leads to transient increases in maternal heart rate and blood pressure (primarily diastolic), probably mediated by the release of norepinephrine and epinephrine into the circulatory system.
  5. There is consistent evidence that links maternal smoking to interference in the physiological transformation of spiral arteries and thickening of the villous membrane in forming the placenta; placental problems could lead to fetal loss, preterm delivery, or low birth weight.
  6. There is consistent evidence of the presence of histo-pathologic changes in the fetus from maternal smoking, particularly in the lung and brain.
  7. There is consistent evidence that suggests smoking leads to immunosuppressive effects, including dys-regulation of the inflammatory response, that may lead to miscarriage and preterm delivery.
  8. There is consistent evidence that suggests a role for polycyclic aromatic hydrocarbons from tobacco smoke in the adverse effects of maternal smoking on a variety of reproductive and developmental endpoints.
  9. There is consistent evidence that tobacco smoke exposure leads to diminished oviductal functioning, which could impair fertilization.
  10. There is consistent evidence that links prenatal smoke exposure and genetic variations in metabolizing enzymes such as GSTT1 with increased risk of adverse pregnancy outcomes such as lowered birth weight and reduced gestation.
  11. There is consistent evidence that genetic polymorphisms, such as variants in transforming growth factor-alpha, modify the risks of oral clefting in offspring related to maternal smoking.
  12. There is consistent evidence that carbon monoxide leads to birth weight deficits and may play a role in neurologic deficits (cognitive and neurobehavioral endpoints) in the offspring of smokers.

References

  1. Abbatiello ER, Mohrmann K. Effects on the offspring of chronic low exposure carbon monoxide during mice pregnancy. Clinical Toxicology. 1979;14(4):401–6. [PubMed: 466982]
  2. Abdella TN, Sibai BM, Hays JM Jr, Anderson GD. Relationship of hypertensive disease to abruptio placentae. Obstetrics and Gynecology. 1984;63(3):365–70. [PubMed: 6700860]
  3. Adams PF, Marano MA. Current estimates from the National Health Interview Survey, 1994. Vital Health Statistics. 1995;10(193 Pt 1):1–260. [PubMed: 15789506]
  4. Agrawal P, Chansoriya M, Kaul KK. Effect of tobacco chewing by mothers on placental morphology. Indian Pediatrics. 1983;20(8):561–5. [PubMed: 6662580]
  5. Ahmad SA, Sayed MHSU, Barua S, Khan MH, Faruquee MH, Jalil A, Hadi SA, Talukder HK. Arsenic in drinking water and pregnancy outcomes. Environmental Health Perspectives. 2001;109(6):629–31. [PMC free article: PMC1240346] [PubMed: 11445518]
  6. Akre O, Lipworth L, Cnattingius S, Sparen P, Ekbom A. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology. 1999;10(4):364–9. [PubMed: 10401869]
  7. Alatas C, Aksoy E, Akarsu C, Yakin K, Bahceci M. Prediction of perinatal outcome by middle cerebral artery Doppler velocimetry. Archives of Gynecology and Obstetrics. 1996;258(3):141–6. [PubMed: 8781702]
  8. Albaiges G, Missfelder-Lobos H, Lees C, Parra M, Nico-laides KH. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation. Obstetrics and Gynecology. 2000;96(4):559–64. [PubMed: 11004359]
  9. Albuquerque CA, Smith KR, Johnson C, Chao R, Harding R. Influence of maternal tobacco smoking during pregnancy on uterine, umbilical and fetal cerebral artery blood flows. Early Human Development. 2004;80(1):31–42. [PubMed: 15363837]
  10. al-Zaid NS, Gumaa KA, Bou-Resli MN, Ibrahim MEA. Premature rupture of fetal membranes changes in collagen type. Acta Obstetricia et Gynecologica Scandinavica. 1988;67(4):291–5. [PubMed: 3176950]
  11. Amankwah KS, Kaufmann RC, Weberg AD. Ultrastructural changes in neonatal sciatic nerve tissue: effects of passive maternal smoking. Gynecologic and Obstetric Investigation. 1985;20(4):186–93. [PubMed: 4085921]
  12. American Journal of Obstetrics and Gynecology. Geographic variation in the incidence of hypertension in pregnancy. American Journal of Obstetrics and Gynecology. 1988;158(1):80–3. [PubMed: 2962500]
  13. Ananth CV, Cnattingius S. Influence of maternal smoking on placental abruption in successive pregnancies: a population-based prospective cohort study in Sweden. American Journal of Epidemiology. 2007;166(3):289–95. [PubMed: 17548787]
  14. Ananth CV, Demissie K, Smulian JC, Vintzileos AM. Placenta previa in singleton and twin births in the United States, 1989 through 1998: a comparison of risk factor profiles and associated conditions. American Journal of Obstetrics and Gynecology. 2003;188(1):275–81. [PubMed: 12548229]
  15. Ananth CV, Oyelese Y, Yeo L, Pradhan A, Vintzileos AM. Placental abruption in the United States, 1979 through 2001: temporal trends and potential determinants. American Journal of Obstetrics and Gynecology. 2005;192(1):191–8. [PubMed: 15672024]
  16. Ananth CV, Platt RW. Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality. BMC Pregnancy and Childbirth. 2004;4(1):22. [PMC free article: PMC535930] [PubMed: 15574192]
  17. Ananth CV, Savitz DA, Williams MA. Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodologic review and meta-analysis. Obstetrics and Gynecology. 1996a;88(2):309–18. [PubMed: 8692522]
  18. Ananth CV, Smulian JC, Demissie K, Vintzileos AM, Knuppel RA. Placental abruption among singleton and twin births in the United States: risk factor profiles. American Journal of Epidemiology. 2001;153(8):771–8. [PubMed: 11296149]
  19. Ananth CV, Smulian JC, Vintzileos AM. Incidence of placental abruption in relation to cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies. Obstetrics and Gynecology. 1999;93(4):622–8. [PubMed: 10214847]
  20. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. American Journal of Epidemiology. 2001;153(4):332–7. [PubMed: 11207150]
  21. Ananth CV, Wilcox AJ, Savitz DA, Bowes WA Jr, Luther ER. Effect of maternal age and parity on the risk of uteroplacental bleeding disorders in pregnancy. Obstetrics and Gynecology. 1996b;88(4 Pt 1):511–6. [PubMed: 8841208]
  22. Ancel P-Y, Saurel-Cubizolles M-J, Di Renzo GC, Papiernik E, Bréart G. Very and moderate preterm births: are the risk factors different? British Journal of Obstetrics and Gynaecology. 1999;106(11):1162–70. [PubMed: 10549961]
  23. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. American Journal of Obstetrics and Gynecology. 1982;144(6):655–60. [PubMed: 7137249]
  24. Andersen MR, Walker LR, Stender S. Reduced endothelial nitric oxide synthase activity and concentration in fetal umbilical veins from maternal cigarette smokers. American Journal of Obstetrics and Gynecology. 2004;191(1):346–51. [PubMed: 15295390]
  25. Anderson R. Effects of ascorbate on leucocytes. Part II: effects of ascorbic acid and calcium and sodium ascorbate on neutrophil phagocytosis and post-phagocytic metabolic activity. South African Medical Journal. 1979;56(10):401–4. [PubMed: 95138]
  26. Anderson ME, Johnson DC, Batal HA. Sudden infant death syndrome and prenatal maternal smoking: rising attributed risk in the Back to Sleep era. BMC Medicine. 2005;3(1):4. [PMC free article: PMC545061] [PubMed: 15644131]
  27. Andres RL, Day M-C. Perinatal complications associated with maternal tobacco use. Seminars in Neonatology. 2000;5(3):231–41. [PubMed: 10956448]
  28. Andrews J. Thiocyanate and smoking in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth. 1973;80(9):810–4. [PubMed: 4743070]
  29. Andrews KW, Savitz DA, Hertz-Picciotto I. Prenatal lead exposure in relation to gestational age and birth weight: a review of epidemiologic studies. American Journal of Industrial Medicine. 1994;26(1):13–32. [PubMed: 8074121]
  30. Andrews WW, Hauth JC, Goldenberg RL. Infection and preterm birth. American Journal of Perinatology. 2000;17(7):357–65. [PubMed: 12141522]
  31. Änggård E. Nitric oxide: mediator, murderer, and medicine. Lancet. 1994;343(8907):1199–206. [PubMed: 7909873]
  32. Anttila A, Sallmén M. Effects of parental occupational exposure to lead and other metals on spontaneous abortion. Journal of Occupational and Environmental Medicine. 1995;37(8):915–21. [PubMed: 8520953]
  33. Arcavi L, Benowitz NL. Cigarette smoking and infection. Archives of Internal Medicine. 2004;164(20):2206–16. [PubMed: 15534156]
  34. Arias F, Tomich P. Etiology and outcome of low birth weight and preterm infants. Obstetrics and Gynecology. 1982;60(3):277–81. [PubMed: 7121906]
  35. Artal R, Burgeson R, Fernandez FJ, Hobel CJ. Fetal and maternal copper levels in patients at term with and without premature rupture of membranes. Obstetrics and Gynecology. 1979;53(5):608–10. [PubMed: 440673]
  36. Asano N, Kondoh M, Ebihara C, Fujii M, Nakanishi T, Soares MJ, Nakashima E, Tanaka K, Sato M, Watanabe Y. Expression profiles of zinc transporters in rodent placental models. Toxicology Letters. 2004;154(1–2):45–53. [PubMed: 15475177]
  37. Ashfaq M, Janjua MZ, Nawaz M. Effects of maternal smoking on placental morphology. Journal of Ayub Medical College, Abbottabad. 2003;15(3):12–5. [PubMed: 14727331]
  38. Asmussen I. Ultrastructure of the villi and fetal capillaries in placentas from smoking and nonsmoking mothers. British Journal of Obstetrics and Gynaecology. 1980;87(3):239–45. [PubMed: 7387929]
  39. Ates U, Ata B, Armagan F, Has R, Sidal B. Acute effects of maternal smoking on fetal hemodynamics. International Journal of Gynaecology and Obstetrics. 2004;87(1):14–8. [PubMed: 15464770]
  40. Athayde N, Edwin SS, Romero R, Gomez R, Maymon E, Pacora P, Menon R. A role for matrix metalloprotein-ase-9 in spontaneous rupture of the fetal membranes. American Journal of Obstetrics and Gynecology. 1998;179(5):1248–53. [PubMed: 9822510]
  41. Augood C, Duckitt K, Templeton AA. Smoking and female infertility: a systematic review and meta-analysis. Human Reproduction. 1998;13(6):1532–9. [PubMed: 9688387]
  42. Axt-Fliedner R, Schwarze A, Nelles I, Altgassen C, Fried-rich M, Schmidt W, Diedrich K. The value of uterine artery Doppler ultrasound in the prediction of severe complications in a risk population. Archives of Gynecology and Obstetrics. 2005;271(1):53–8. [PubMed: 15175886]
  43. Ayadi MF, Adams EK, Melvin CL, Rivera CC, Gaffney CA, Pike J, Rabius V, Ferguson JN. Costs of a smoking cessation counseling intervention for pregnant women: comparison of three settings. Public Health Reports. 2006;121(2):120–6. [PMC free article: PMC1525265] [PubMed: 16528943]
  44. Backer LC, Rubin CS, Marcus M, Kieszak SM, Schober SE. Serum follicle-stimulating hormone and luteinizing hormone levels in women aged 35–60 in the U.S. population: The Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994). Menopause. 1999;6(1):29–35. [PubMed: 10100177]
  45. Baghurst PA, Tong SL, Woodward A, McMichael AJ. Effects of maternal smoking upon neuropsychological development in early childhood: importance of taking account of social and environmental factors. Paediatric and Perinatal Epidemiology. 1992;6(4):403–15. [PubMed: 1282258]
  46. Bailey LJ, Johnston MC, Billet J. Effects of carbon monoxide and hypoxia on cleft lip in A/J mice. Cleft Palate-Craniofacial Journal. 1995;32(1):14–9. [PubMed: 7727482]
  47. Bainbridge SA, Sidle EH, Smith GN. Direct placental effects of cigarette smoke protect women from pre-eclampsia: the specific roles of carbon monoxide and antioxidant systems in the placenta. Medical Hypotheses. 2005;64(1):17–27. [PubMed: 15533604]
  48. Ballatori N. Transport of toxic metals by molecular mimicry. Environmental Health Perspectives. 2002;110(Suppl 5):689–94. [PMC free article: PMC1241226] [PubMed: 12426113]
  49. Barber A, Robson SC, Myatt L, Bulmer JN, Lyall F. Heme oxygenase expression in human placenta and placental bed: reduced expression of placenta endothelial HO-2 in preeclampsia and fetal growth restriction. FASEB Journal. 2001;15(7):1158–68. [PubMed: 11344084]
  50. Barbieri RL, Gochberg J, Ryan KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. Journal of Clinical Investigation. 1986a;77(6):1727–33. [PMC free article: PMC370526] [PubMed: 3711333]
  51. Barbieri RL, McShane PM, Ryan KJ. Constituents of cigarette smoke inhibit human granulosa cell aromatase. Fertility and Sterility. 1986b;46(2):232–6. [PubMed: 3732529]
  52. Barbieri RL, Sluss PM, Powers RD, McShane PM, Bitonis A, Ginsburg E, Cramer DC. Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertility and Sterility. 2005;83(2):302–8. [PubMed: 15705366]
  53. Barbieri RL, York CM, Cherry ML, Ryan KJ. The effects of nicotine, cotinine and anabasine on rat adrenal 11 beta-hydroxylase and 21-hydroxylase. Journal of Steroid Biochemistry. 1987;28(1):25–8. [PubMed: 3497305]
  54. Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in women. American Journal of Obstetrics and Gynecology. 1990;162(2):502–14. [PubMed: 2178432]
  55. Barrett B, Gunter E, Jenkins J, Wang M. Ascorbic acid concentration in amniotic fluid in late pregnancy. Biology of the Neonate. 1991;60(5):333–5. [PubMed: 1790258]
  56. Barrett JM, Vanhooydonk JE, Boehm FH. Acute effect of cigarette smoking on the fetal heart nonstress test. Obstetrics and Gynecology. 1981;57(4):422–5. [PubMed: 7243086]
  57. Barrett-Connor E. Smoking and endogenous sex hormones in men and women. Smoking and Hormone-Related Disorders. Wald N, Baron JA, editors. New York: Oxford University Press; 1990. pp. 183–96.
  58. Barrett-Connor E, Khaw K-T. Cigarette smoking and increased endogenous estrogen levels in men. American Journal of Epidemiology. 1987;126(2):187–92. [PubMed: 3605047]
  59. Bassi JA, Rosso P, Moessinger AC, Blanc WA, James LS. Fetal growth retardation due to maternal tobacco smoke exposure in the rat. Pediatric Research. 1984;18(2):127–30. [PubMed: 6199726]
  60. Bataineh H, al-Hamood MH, Elbetieha A, Bani Hani I. Effect of long-term ingestion of chromium compounds on aggression, sex behavior and fertility in adult male rat. Drug and Chemical Toxicology. 1997;20(3):133–49. [PubMed: 9292274]
  61. Batstra L, Hadders-Algra M, Neeleman J. Effect of antenatal exposure to maternal smoking on behavioural problems and academic achievement in childhood: prospective evidence from a Dutch birth cohort. Early Human Development. 2003;75(1–2):21–33. [PubMed: 14652157]
  62. Beaty TH, Wang H, Hetmanski JB, Fan YT, Zeiger JS, Liang KY, Chiu YF, Vanderkolk CA, Seifert KC, Wulfs-berg EA, et al. A case-control study of nonsyndromic oral clefts in Maryland. Annals of Epidemiology. 2001;11(6):434–42. [PubMed: 11454503]
  63. Becker R, Vonk R, Vollert W, Entezami M. Doppler sonography of uterine arteries at 20–23 weeks: risk assessment of adverse pregnancy outcome by quantification of impedance and notch. Journal of Perinatal Medicine. 2002;30(5):388–94. [PubMed: 12442602]
  64. Belcheva A, Ivanova-Kicheva M, Tzvetkova P, Marinov M. Effects of cigarette smoking on sperm plasma membrane integrity and DNA fragmentation. International Journal of Andrology. 2004;27(5):296–300. [PubMed: 15379970]
  65. Belgore FM, Lip GYH, Blann AD. Vascular endothelial growth factor and its receptor, Flt-1, in smokers and non-smokers. British Journal of Biomedical Science. 2000;57(3):207–13. [PubMed: 11050771]
  66. Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B, Jacob P III. Ethnic differences in N-glucuronidation of nicotine and cotinine. Journal of Pharmacology and Experimental Therapeutics. 1999;291(3):1196–203. [PubMed: 10565842]
  67. Berg CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancy-related mortality in the United States, 1991–1997. Obstetrics and Gynecology. 2003;101(2):289–96. [PubMed: 12576252]
  68. Berlin M, Blanks R, Catton M, Kazantzis G, Mottet NK, Samiullah Y. Birth weight of children and cadmium accumulation in placentas of female nickel-cadmium (long-life) battery workers. IARC Scientific Publications. 1992;(118):257–62. [PubMed: 1303949]
  69. Bermudez EA, Rifai N, Buring JE, Manson JE, Ridker PM. Relation between markers of systemic vascular inflammation and smoking in women. American Journal of Cardiology. 2002;89(9):1117–9. [PubMed: 11988205]
  70. Berta L, Frairia R, Fortunati N, Fazzari A, Gaidano G. Smoking effects on the hormonal balance of fertile women. Hormone Research. 1992;37(1–2):45–8. [PubMed: 1398476]
  71. Bili H, Mamopoulos M, Tsantali C, Tzevelekis P, Malaka K, Mantalenakis S, Farmakides G. Elevated umbilical erythropoietin levels during labor in newborns of smoking mothers. American Journal of Perinatology. 1996;13(2):85–7. [PubMed: 8672191]
  72. Blair PS, Fleming PJ, Bensley D, Smith I, Bacon C, Taylor E, Berry J, Golding J, Tripp J. Smoking and the sudden infant death syndrome: results from 1993–5 case-control study for confidential inquiry into stillbirths and deaths in infancy. BMJ (British Medical Journal). 1996;313(7051):195–8. [PMC free article: PMC2351602] [PubMed: 8696194]
  73. Bódis J, Hanf V, Török A, Tinneberg HR, Borsay P, Szabó I. Influence of nicotine on progesterone and estradiol production of cultured human granulose cells. Early Pregnancy. 1997;3(1):34–7. [PubMed: 9265557]
  74. Bodnar LM, Siega-Riz AM, Arab L, Chantala K, McDonald T. Predictors of pregnancy and postpartum haemoglobin concentrations in low-income women. Public Health Nutrition. 2004;7(6):701–11. [PubMed: 15369607]
  75. Bolognesi C, Rossi L, Barbieri O, Santi L. Benzo[a]pyrene-induced DNA damage in mouse fetal tissues. Carcinogenesis. 1985;6(8):1091–5. [PubMed: 4017182]
  76. Bonde JPE, Ernst E, Jensen RK, Hjollund NHI, Kolstad H, Henriksen TB, Scheike T, Giwercman A, Olsen J, Skak-kebaek NE. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet. 1998;352(9135):1172–7. [PubMed: 9777833]
  77. Bonithon-Kopp C, Huel G, Grasmick C, Sarmini H, Moreau T. Effects of pregnancy on the inter-individual variations in blood levels of lead, cadmium and mercury. Biological Research in Pregnancy and Perinatology. 1986;7(1):37–42. [PubMed: 3955127]
  78. Borja-Aburto VH, Hertz-Picciotto I, Rojas Lopez M, Farias P, Rios C, Blanco J. Blood lead levels measured prospectively and risk of spontaneous abortion. American Journal of Epidemiology. 1999;150(6):590–7. [PubMed: 10489998]
  79. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458–62. [PubMed: 10839541]
  80. Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. American Journal of Medical Genetics Part C, Seminars in Medical Genetics. 2004;125C(1):12–21. [PubMed: 14755429]
  81. Boulos R, Halsey NA, Holt E, Ruff A, Brutus J-R, Quinn TC, Adrien M, Boulos C. HIV-1 in Haitian women 1982–1988. The Cite Coleil/JHU AIDS Project Team. Journal of Acquired Immune Deficiency Syndromes. 1990;3(7):721–8. [PubMed: 2352124]
  82. Bouyer J, Coste J, Shojaei T, Pouly J-L, Fernandez H, Gerbaud L, Job-Spira N. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France. American Journal of Epidemiology. 2003;157(3):185–94. [PubMed: 12543617]
  83. Brett KM, Cooper GS. Associations with menopause and menopausal transition in a nationally representative US sample. Maturitas. 2003;45(2):89–97. [PubMed: 12787967]
  84. Briggs MH. Cigarette smoking and infertility in men [letter] Medical Journal of Australia. 1973;1(12):616–7. [PubMed: 4700549]
  85. British Medical Association. Smoking and Reproductive Life: The Impact of Smoking on Sexual, Reproductive and Child Health. London: British Medical Association, Board of Science and Education and Tobacco Control Resource Centre; 2004. [accessed: February 2, 2006]. < http://www​.bma.org.uk>.
  86. Bromberger JT, Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prospective study of the determinants of age at menopause. American Journal of Epidemiology. 1997;145(2):124–33. [PubMed: 9006309]
  87. Bronsky PT, Johnston MC, Sulik KK. Morphogenesis of hypoxia-induced cleft lip in CL/Fr mice. Journal of Craniofacial Genetics and Developmental Biology Supplement. 1986;2:113–28. [PubMed: 3491106]
  88. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstetrics and Gynecology Annual. 1972;1:177–91. [PubMed: 4669123]
  89. Brown S, Vessey M, Stratton I. The influence of method of contraception and cigarette smoking on menstrual patterns. British Journal of Obstetrics and Gynaecology. 1988;95(9):905–10. [PubMed: 3191064]
  90. Bruner JP, Forouzan I. Smoking and buccally administered nicotine: acute effect on uterine and umbilical artery Doppler flow velocity waveforms. Journal of Reproductive Medicine. 1991;36(6):435–40. [PubMed: 1865399]
  91. Buchan PC. Cigarette smoking in pregnancy and fetal hyperviscosity. BMJ (British Medical Journal). 1983;286(6374):1315. [PMC free article: PMC1547618] [PubMed: 6404445]
  92. Buck GM, Sever LE, Batt RE, Mendola P. Life-style factors and female infertility. Epidemiology. 1997;8(4):435–41. [PubMed: 9209860]
  93. Bui QQ, Tran MB, West WL. A comparative study of the reproductive effects of methadone and benzo[a]pyrene in the pregnant and pseudopregnant rat. Toxicology. 1986;42(2–3):195–204. [PubMed: 3798468]
  94. Bulletin of the World Health Organization. Antismoking campaigns fail in industrialized countries. Bulletin of the World Health Organization. 1999;77(5):449. [PMC free article: PMC2557662] [PubMed: 10361774]
  95. Bureau MA, Monette J, Shapcott D, Pare C, Mathieu JL, Lippe J, Blovin D, Berthiaume Y, Begin R. Carboxy-hemoglobin concentration in fetal cord blood and in blood of mothers who smoked during labor. Pediatrics. 1982;69(3):371–3. [PubMed: 7063295]
  96. Bureau MA, Shapcott D, Berthiaume Y, Monette J, Blouin D, Blanchard P, Begin R. Maternal cigarette smoking and fetal oxygen transport: a study of P50, 2,3-diphos-phoglycerate, total hemoglobin, hematocrit, and type F hemoglobin in fetal blood. Pediatrics. 1983;72(1):22–6. [PubMed: 6191270]
  97. Burguet A, Kaminski M, Abraham-Lerat L, Schaal J-P, Cambonie G, Fresson J, Grandjean H, Truffert P, Marpeau L, Voyer M, et al. The complex relationship between smoking in pregnancy and very preterm delivery: results of the Epipage study. BJOG. 2004;111(3):258–65. [PubMed: 14961888]
  98. Burns DN, Kramer A, Yellin F, Fuchs D, Wachter H, DiGioia RA, Sanchez WC, Grossman RJ, Gordin FM, Biggar RJ, et al. Cigarette smoking: a modifier of human immuno-deficiency virus type 1 infection? Journal of Acquired Immune Deficiency Syndromes. 1991;4(1):76–83. [PubMed: 1670588]
  99. Burns DN, Landesman S, Muenz LR, Nugent RP, Goedert JJ, Minkoff H, Walsh JH, Mendez H, Rubinstein A, Willoughby A. Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4+ levels. Journal of Acquired Immune Deficiency Syndromes. 1994;7(7):718–26. [PubMed: 7911527]
  100. Burton GJ, Palmer ME, Dalton KJ. Morphometric differences between the placental vasculature of non-smokers, smokers and ex-smokers. British Journal of Obstetrics and Gynaecology. 1989;96(8):907–15. [PubMed: 2775688]
  101. Bush PG, Mayhew TM, Abramovich DR, Aggett PJ, Burke MD, Page KR. A quantitative study on the effects of maternal smoking on placental morphology and cadmium concentration. Placenta. 2000;21(2–3):247–56. [PubMed: 10736249]
  102. Butler NR, Goldstein H. Smoking in pregnancy and subsequent child development. BMJ (British Medical Journal). 1973;4(5892):537–75. [PMC free article: PMC1587764] [PubMed: 4758516]
  103. California Environmental Protection Agency. Evidence on Developmental and Reproductive Toxicity of Cadmium. Sacramento (CA): California Environmental Protection Agency, Office of Environmental Health Hazard Assessment, Reproductive and Cancer Hazard Assessment Section; 1996.
  104. Calori G, D’Angelo A, Della Valle P, Ruotolo G, Ferini-Strambi L, Giusti C, Errera A, Gallus G. The effect of cigarette-smoking on cardiovascular risk factors: a study of monozygotic twins discordant for smoking. Thrombosis and Haemostasis. 1996;75(1):14–8. [PubMed: 8713773]
  105. Campana A, Sakkas D, Stalberg A, Bianchi PG, Comte I, Pache T, Walker D. Intrauterine insemination: evaluation of the results according to the woman’s age, sperm quality, total sperm count per insemination and life table analysis. Human Reproduction. 1996;11(4):732–6. [PubMed: 8671318]
  106. Cantral DE, Sisson JH, Veys T, Rennard SI, Spurzem JR. Effects of cigarette smoke extract on bovine bronchial epithelial cell attachment and migration. American Journal of Physiology. 1995;268(5 Pt 1):L723–L728. [PubMed: 7762674]
  107. Carmichael SL, Ma C, Rasmussen SA, Honein MA, Lammer EJ, Shaw GM. National Birth Defects Prevention Study: craniosynostosis and maternal smoking. Birth Defects Research Part A, Clinical and Molecular Teratology. 2008;82(2):78–85. [PubMed: 18050313]
  108. Carmichael SL, Shaw GM, Yang W, Lammer EJ, Zhu H, Finnell RH. Limb deficiency defects, MSX1, and exposure to tobacco smoke. American Journal of Medical Genetics Part A. 2004;125A(3):285–9. [PubMed: 14994238]
  109. Carmines EL, Gaworski CL, Faqi AS, Rajendran N. In utero exposure to 1R4F reference cigarette smoke: evaluation of developmental toxicity. Toxicological Sciences. 2003;75(1):134–47. [PubMed: 12805648]
  110. Carratù MR, Cagiano R, De Salvia MA, Cuomo V. Wallerian degeneration in rat sciatic nerve: comparative evaluation between prenatal and postnatal exposure to carbon monoxide [abstract] Society for Neuroscience Abstracts. 1993a;19(Part 1):834.
  111. Carratù MR, Renna G, Giustino A, De Salvia MA, Cuomo V. Changes in peripheral nervous system activity produced in rats by prenatal exposure to carbon monoxide. Archives of Toxicology. 1993b;67(5):297–301. [PubMed: 8368938]
  112. Casanueva E, Polo E, Tejero E, Meza C. Premature rupture of amniotic membranes as functional assessment of vitamin C status during pregnancy. Annals of the New York Academy of Sciences. 1993;678:369–70. [PubMed: 8494290]
  113. Cassell G, Hauth J, Andrews W, Cutter G, Goldenberg R. Chorioamnion colonization: correlation with gestational age in women following spontaneous versus indicated delivery [abstract] American Journal of Obstetrics and Gynecology. 1993;168:425.
  114. Castles A, Adams EK, Melvin CL, Kelsch C, Boulton ML. Effects of smoking during pregnancy: five meta-analyses. American Journal of Preventive Medicine. 1999;16(3):208–15. [PubMed: 10198660]
  115. Castro LC, Allen R, Ogunyemi D, Roll K, Platt LD. Cigarette smoking during pregnancy: acute effects on uterine flow velocity waveforms. Obstetrics and Gynecology. 1993;81(4):551–5. [PubMed: 8459965]
  116. Centers for Disease Control and Prevention. Smoking during pregnancy—United States, 1990–2002. Morbidity and Mortality Weekly Report. 2004;53(39):911–5. [PubMed: 15470322]
  117. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2003. Morbidity and Mortality Weekly Report. 2005;54(20):509–13. [PubMed: 15917735]
  118. Centers for Disease Control and Prevention. Recommendations to improve preconception health and health care—United States: a report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. Morbidity and Mortality Weekly Report. 2006;55(RR-6):1–23. [PubMed: 16617292]
  119. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2007. Morbidity and Mortality Weekly Report. 2008;57(45):1221–6. [PubMed: 19008790]
  120. Chaloupka K, Krishnan V, Safe S. Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor. Carcinogenesis. 1992;13(12):2233–9. [PubMed: 1335374]
  121. Chang J, Elam-Evans LD, Berg CJ, Herndon J, Flowers L, Seed KA, Syverson CJ. Pregnancy-related mortality surveillance—United States, 1991–1999. Morbidity and Mortality Weekly Report. 2003;52(SS-2):1–8. [PubMed: 12825542]
  122. Chao ST, Omiecinski CJ, Namkung MJ, Nelson SD, Dvorchik BH, Juchau MR. Catechol estrogen formation in placental and fetal tissues of humans, macaques, rats and rabbits. Developmental Pharmacology and Therapeutics. 1981;2(1):1–16. [PubMed: 6265171]
  123. Chapin RE, Robbins WA, Schieve LA, Sweeney AM, Tabacova SA, Tomashek KM. Off to a good start: the influence of pre- and periconceptional exposures, parental fertility, and nutrition on children’s health. Environmental Health Perspectives. 2004;112(1):69–78. [PMC free article: PMC1241800] [PubMed: 14698934]
  124. Chatenoud L, Parazzini F, di Cintio E, Zanconato G, Benzi G, Bortolus R, La Vecchia C. Paternal and maternal smoking habits before conception and during the first trimester: relation to spontaneous abortion. Annals of Epidemiology. 1998;8(8):520–6. [PubMed: 9802597]
  125. Chattopadhyay S, Ghosh S, Chaki S, Debnath J, Ghosh D. Effect of sodium arsenite on plasma levels of gonado-trophins and ovarian steroidogenesis in mature albino rats: duration-dependent response. Journal of Toxicological Sciences. 1999;24(5):425–31. [PubMed: 10656165]
  126. Chattopadhyay S, Ghosh S, Debnath J, Ghosh D. Protection of sodium arsenite-induced ovarian toxicity by coadministration of l-ascorbate (vitamin C) in mature wistar strain rat. Archives of Environmental Contamination and Toxicology. 2001;41(1):83–9. [PubMed: 11385593]
  127. Chen C, Cho SI, Damokosh AI, Chen D, Li G, Wang X, Xu X. Prospective study of exposure to environmental tobacco smoke and dysmenorrhea. Environmental Health Perspectives. 2000;108(11):1019–22. [PMC free article: PMC1240156] [PubMed: 11102290]
  128. Chen C, Wang X, Wang L, Yang F, Tang G, Xing H, Ryan L, Lasley B, Overstreet JW, Stanford JB, et al. Effect of environmental tobacco smoke on levels of urinary hormone markers. Environmental Health Perspectives. 2005;113(4):412–7. [PMC free article: PMC1278480] [PubMed: 15811831]
  129. Chen CL, Gilbert TJ, Daling JR. Maternal smoking and Down syndrome: the confounding effect of maternal age. American Journal of Epidemiology. 1999;149(5):442–6. [PubMed: 10067903]
  130. Chen Z, Godfrey-Bailey L, Schiff I, Hauser R. Impact of seasonal variation, age and smoking status on human semen parameters: the Massachusetts General Hospital experience. Journal of Experimental and Clinical Assisted Reproduction. 2004;1(1):2. [PMC free article: PMC524369] [PubMed: 15507127]
  131. Chernoff N. Teratogenic effects of cadmium in rats. Teratology. 1973;8(1):29–32. [PubMed: 4737490]
  132. Chia S-E, Lim S-TA, Tay S-K, Lim S-T. Factors associated with male infertility: a case-control study of 218 infertile and 240 fertile men. BJOG. 2000;107(1):55–61. [PubMed: 10645862]
  133. Chia S-E, Xu B, Ong CN, Tsakok FMH, Lee ST. Effect of cadmium and cigarette smoking on human semen quality. International Journal of Fertility and Menopausal Studies. 1994;39(5):292–8. [PubMed: 7820163]
  134. Chmielnicka J, Sowa B. Cadmium interaction with essential metals (Zn, Cu, Fe), metabolism metallothionein, and ceruloplasmin in pregnant rats and fetuses. Ecotoxicology and Environmental Safety. 1996;35(3):277–81. [PubMed: 9007005]
  135. Choe S-Y, Kim S-J, Kim H-G, Lee JH, Choi Y, Lee H, Kim Y. Evaluation of estrogenicity of major heavy metals. Science of the Total Environment. 2003;312(1–3):15–21. [PubMed: 12873394]
  136. Chong DS, Yip PS, Karlberg J. Maternal smoking: an increasing unique risk factor for sudden infant death syndrome in Sweden. Acta Paediatrica. 2004;93(4):471–8. [PubMed: 15188973]
  137. Chow W-H, Daling JR, Cates W Jr, Greenberg RS. Epidemiology of ectopic pregnancy. Epidemiologic Reviews. 1987;9:70–94. [PubMed: 3315720]
  138. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, Murray JC. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case- control study in Denmark, 1991–1994. American Journal of Epidemiology. 1999;149(3):248–55. [PubMed: 9927220]
  139. Christianson RE. Gross differences observed in the placentas of smokers and nonsmokers. American Journal of Epidemiology. 1979;110(2):178–87. [PubMed: 463872]
  140. Churg A, Sun J-P, Zay K. Cigarette smoke increases amosite asbestos fiber binding to the surface of tracheal epithelial cells. American Journal of Physiology. 1998;275(3):L502–L508. [PubMed: 9728044]
  141. Clarkson TW, Nordberg GF, Sager PR. Reproductive and developmental toxicity of metals. Scandinavian Journal of Work, Environment & Health. 1985;11(3 Spec):145–54. [PubMed: 4035317]
  142. Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine & Tobacco Research. 2004;6(Suppl 2):S125–S140. [PubMed: 15203816]
  143. Cnattingius S, Granath F, Petersson G, Harlow BL. The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries. New England Journal of Medicine. 1999;341(13):943–8. [PubMed: 10498489]
  144. Cnattingius V, Haglund B, Meirik O. Cigarette smoking as risk factor for late fetal and early neonatal death. BMJ (British Medical Journal). 1988;297(6643):258–61. [PMC free article: PMC1833960] [PubMed: 3416144]
  145. Cogswell ME, Weisberg P, Spong C. Cigarette smoking, alcohol use and adverse pregnancy outcomes: implications for micronutrient supplementation. Journal of Nutrition. 2003;133(5 Suppl 2):1722S–1731S. [PubMed: 12730490]
  146. Cole PV, Hawkins LH, Roberts D. Smoking during pregnancy and its effects on the fetus. Journal of Obstetrics and Gynaecology of the British Commonwealth. 1972;79(9):782–7. [PubMed: 4651286]
  147. Coleman MAG, McCowan LME, North RA. Mid-trimester uterine artery Doppler screening as a predictor of adverse pregnancy outcome in high-risk women. Ultrasound in Obstetrics & Gynecology. 2000;15(1):7–12. [PubMed: 10776006]
  148. Comeau J, Shaw L, Marcell CC, Lavery JP. Early placenta previa and delivery outcome. Obstetrics and Gynecology. 1983;61(5):577–80. [PubMed: 6601250]
  149. Conde-Agudelo A, Althabe F, Belizán JM, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of pre-eclampsia: a systematic review. American Journal of Obstetrics and Gynecology. 1999;181(4):1026–35. [PubMed: 10521771]
  150. Connor SK, McIntyre L. The sociodemographic predictors of smoking cessation among pregnant women in Canada. Canadian Journal of Public Health. 1999;90(5):352–5. [PMC free article: PMC6979916] [PubMed: 10570583]
  151. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annual Review of Medicine. 1997;48:489–509. [PubMed: 9046979]
  152. Cooper GS, Baird DD, Hulka BS, Weinberg CR, Savitz DA, Hughes CL Jr. Follicle-stimulating hormone concentrations in relation to active and passive smoking. Obstetrics and Gynecology. 1995;85(3):407–11. [PubMed: 7862381]
  153. Cooper GS, Sandler DP. Age at natural menopause and mortality. Annals of Epidemiology. 1998;8(4):229–35. [PubMed: 9590601]
  154. Cooper GS, Sandler DP, Bohlig M. Active and passive smoking and the occurrence of natural menopause. Epidemiology. 1999;10(6):771–3. [PubMed: 10535795]
  155. Coppens M, Vindla S, James DK, Sahota DS. Computerized analysis of acute and chronic changes in fetal heart rate variation and fetal activity in association with maternal smoking. American Journal of Obstetrics and Gynecology. 2001;185(2):421–6. [PubMed: 11518903]
  156. Corberand J, Nguyen F, Do AH, Dutau G, Laharrague P, Fontanilles AM, Gleizes B. Effect of tobacco smoking on the functions of polymorphonuclear leukocytes. Infection and Immunity. 1979;23(3):577–81. [PMC free article: PMC414204] [PubMed: 222675]
  157. Corre F, Lellouch J, Schwartz D. Smoking and leucocyte-counts: results of an epidemiological survey. Lancet. 1971;2(7725):632–4. [PubMed: 4105947]
  158. Coste J, Job-Spira N, Fernandez H, Papiernik E, Spira A. Risk factors for ectopic pregnancy: a case-control study in France, with special focus on infectious factors. American Journal of Epidemiology. 1991;133(9):839–49. [PubMed: 2028974]
  159. Cozen W, Diaz-Sanchez D, Gauderman WJ, Zadnick J, Cockburn MG, Gill PS, Masood R, Hamilton AS, Jyrala M, Mack TM. Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption. Journal of Clinical Immunology. 2004;24(6):617–22. [PubMed: 15622446]
  160. Cramer DW, Barbieri RL, Xu H, Reichardt JKV. Determinants of basal follicle-stimulating hormone levels in premenopausal women. Journal of Clinical Endocrinology and Metabolism. 1994;79(4):1105–9. [PubMed: 7962282]
  161. Cramer DW, Wise LA. The epidemiology of recurrent pregnancy loss. Seminars in Reproductive Medicine. 2000;18(4):331–9. [PubMed: 11355791]
  162. Creasy RK, Resnik R, Iams JD, editors. Placenta previa and abruptio placentae, Maternal-Fetal Medicine. 5th ed. Philadelphia: W.B. Saunders Company; 2004. p. 709.
  163. Cresteil T, Beaune P, Celier C, Leroux JP, Guengerich FP. Cytochrome P-450 isoenzyme content and monooxy-genase activities in rat liver: effect of ontogenesis and pretreatment by phenobarbital and 3-methylcholan-threne. Journal of Pharmacology and Experimental Therapeutics. 1986;236(1):269–76. [PubMed: 3941398]
  164. Cross CE, Traber M, Eiserich J, van der Vliet A. Micronutrient antioxidants and smoking. British Medical Bulletin. 1999;55(3):691–704. [PubMed: 10746357]
  165. Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Hauth JC, Wenstrom KD, editors. Abortion, Williams Obstetrics. 21st ed. New York: McGraw-Hill; 2001. p. 868.
  166. Dai WS, Gutai JP, Kuller LH, Cauley JA. Cigarette smoking and serum sex hormones in men. American Journal of Epidemiology. 1988;128(4):796–805. [PubMed: 3421245]
  167. Davis RB, Leuschen MP, Boyd D, Goodlin RC. Evaluation of platelet function in pregnancy: comparative studies in non-smokers and smokers. Thrombosis Research. 1987;46(2):175–86. [PubMed: 2955542]
  168. de la Chica RA, Ribas I, Giraldo J, Egozcue J, Fuster C. Chromosomal instability in amniocytes from fetuses of mothers who smoke. JAMA: the Journal of the American Medical Association. 2005;293(10):1212–22. [PubMed: 15755944]
  169. Dejmek J, Solanský I, Beneš I, Leníček J, Šrám RJ. The impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome. Environmental Health Perspectives. 2000;108(12):1159–64. [PMC free article: PMC1240197] [PubMed: 11133396]
  170. Dekker G, Robillard P-Y. The birth interval hypothesis—does it really indicate the end of the primipaternity hypothesis. Journal of Reproductive Immunology. 2003;59(2):245–51. [PubMed: 12896826]
  171. Demir R, Demir AY, Yinanc M. Structural changes in placental barrier of smoking mother: a quantitative and ultrastructural study. Pathology, Research and Practice. 1994;190(7):656–67. [PubMed: 7808964]
  172. Denham M, Schell LM, Deane G, Gallo MV, Raven-scroft J, DeCaprio AP. Akwesasne Task Force on the Environment. Relationship of lead, mercury, mirex, dichlorodiphenyldichloroethylene, hexachloroben-zene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls. Pediatrics. 2005;115(2):e127–e134. [PubMed: 15653789]
  173. Deslypere JP, Vermeulen A. Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity. Journal of Clinical Endocrinology and Metabolism. 1984;59(5):955–62. [PubMed: 6480814]
  174. DiCarlantonio G, Talbot P. Inhalation of mainstream and sidestream cigarette smoke retards embryo transport and slows muscle contraction in oviducts of hamsters (Mesocricetus auratus). Biology of Reproduction. 1999;61(3):651–6. [PubMed: 10456841]
  175. Dietz PM, Adams MM, Rochat RW, Mathis MP. Prenatal smoking in two consecutive pregnancies: Georgia, 1989–1992. Maternal and Child Health Journal. 1997;1(1):43–51. [PubMed: 10728225]
  176. DiFranza JR, Aligne CA, Weitzman M. Prenatal and post-natal environmental tobacco smoke exposure and children’s health. Pediatrics. 2004;113(4 Suppl):1007–15. [PubMed: 15060193]
  177. DiFranza JR, Lew RA. Effect of maternal cigarette smoking on pregnancy complications and sudden infant death syndrome. Journal of Family Practice. 1995;40(4):385–94. [PubMed: 7699353]
  178. Dommisse J, Tiltman AJ. Placental bed biopsies in placental abruption. British Journal of Obstetrics and Gynaecology. 1992;99(8):651–4. [PubMed: 1390469]
  179. Doreswamy K, Shrilatha B, Rajeshkumar T, Muralidhara Nickel-induced oxidative stress in testis of mice: evidence of DNA damage and genotoxic effects. Journal of Andrology. 2004;25(6):996–1003. [PubMed: 15477375]
  180. Dotson LE, Robertson LS, Tuchfeld B. Plasma alcohol, smoking, hormone concentrations and self-reported aggression: a study in a social-drinking situation. Journal of Studies on Alcohol. 1975;36(5):578–86. [PubMed: 239280]
  181. Drbohlav P, Bencko V, Masata J, Bendl J, Rezacova J, Zouhar T, Cerny V, Halkova E. Detection of cadmium and zinc in the blood and follicular fluid in women in the IVF and ET program [Czech] Ceska Gynekologie. 1998;63(4):292–300. [PubMed: 9750404]
  182. Drews CD, Murphy CC, Yeargin-Allsopp M, Decoufle P. The relationship between idiopathic mental retardation and maternal smoking during pregnancy. Pediatrics. 1996;97(4):547–53. [PubMed: 8632944]
  183. D’Souza SW, Black PM, Williams N, Jennison RF. Effect of smoking during pregnancy upon the haematological values of cord blood. British Journal of Obstetrics and Gynaecology. 1978;85(7):495–9. [PubMed: 678483]
  184. Duley L. Pre-eclampsia and hypertension. Clinical Evidence. 2003;(9):1584–600. [PubMed: 15366201]
  185. Ebrahim SH, Floyd RL, Merritt RK II, Decoufle P, Holtzman D. Trends in pregnancy-related smoking rates in the United States, 1987–1996. JAMA: the Journal of the American Medical Association. 2000;283(3):361–6. [PubMed: 10647799]
  186. Edman J, Sobel JD, Taylor ML. Zinc status in women with recurrent vulvovaginal candidiasis. American Journal of Obstetrics and Gynecology. 1986;155(5):1082–5. [PubMed: 3777053]
  187. Egawa M, Yasuda K, Nakajima T, Okada H, Yoshimura T, Yuri T, Yasuhara M, Nakamoto T, Nagata F, Kanzaki H. Smoking enhances oxytocin-induced rhythmic myo-metrial contraction. Biology of Reproduction. 2003;68(6):2274–80. [PubMed: 12606462]
  188. Eggert-Kruse W, Schwarz H, Rohr G, Demirakca T, Til-gen W, Runnebaum B. Sperm morphology assessment using strict criteria and male fertility under in-vivo conditions of conception. Human Reproduction. 1996;11(1):139–46. [PubMed: 8671176]
  189. Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Sperm exposure and development of preeclampsia. American Journal of Obstetrics and Gynecology. 2003;188(5):1241–3. [PubMed: 12748491]
  190. Ejaz S, Seok KB, Woong LC. Toxicological effects of mainstream whole smoke solutions on embryonic movements of the developing embryo. Drug and Chemical Toxicology. 2005;28(1):1–14. [PubMed: 15720032]
  191. Ekwo EE, Gosselink CA, Moawad A. Unfavorable outcome in penultimate pregnancy and premature rupture of membranes in successive pregnancy. Obstetrics and Gynecology. 1992;80(2):166–72. [PubMed: 1635725]
  192. Ekwo EE, Gosselink CA, Woolson R, Moawad A. Risks for premature rupture of amniotic membranes. International Journal of Epidemiology. 1993;22(3):495–503. [PubMed: 8359967]
  193. El Ahmer OR, Essery SD, Saadi AT, Raza MW, Ogilvie MM, Weir DM, Blackwell CC. The effect of cigarette smoke on adherence of respiratory pathogens to buccal epithelial cells. FEMS Immunology and Medical Microbiology. 1999;23(1):27–36. [PubMed: 10030544]
  194. Eldridge MW, Berman W Jr, Greene ER. Chronic maternal cigarette smoking and fetal abdominal aortic blood flow in humans. Journal of Ultrasound in Medicine. 1986;5(3):131–6. [PubMed: 3517359]
  195. England LJ, Levine RJ, Mills JL, Klebanoff MA, Yu KF, Cnattingius S. Adverse pregnancy outcomes in snuff users. American Journal of Obstetrics and Gynecology. 2003;189(4):939–43. [PubMed: 14586330]
  196. English KM, Pugh PJ, Parry H, Scutt NE, Channer KS, Jones TH. Effect of cigarette smoking on levels of bio-available testosterone in healthy men. Clinical Science (London). 2001;100(6):661–5. [PubMed: 11352783]
  197. Eskenazi B, Gold EB, Lasley BL, Samuels SJ, Hammond SK, Wight S, Rasnor MO, Hines CJ, Schenker MB. Prospective monitoring of early fetal loss and clinical spontaneous abortion among female semiconductor workers. American Journal of Industrial Medicine. 1995;28(6):833–46. [PubMed: 8588567]
  198. Eskenazi B, Trupin L. Passive and active maternal smoking during pregnancy, as measured by serum cotinine, and postnatal exposure. II: effects on neurodevelopment at age 5 years. American Journal of Epidemiology. 1995;142(9 Suppl):S19–S29. [PubMed: 7572983]
  199. Eskes TKAB. Abruptio placentae: a “classic” dedicated to Elizabeth Ramsey. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1997;75(1):63–70. [PubMed: 9447349]
  200. Everett KD, Gage J, Bullock L, Longo DR, Geden E, Madsen RW. A pilot study of smoking and associated behaviors of low-income expectant fathers. Nicotine & Tobacco Research. 2005;7(2):269–76. [PubMed: 16036284]
  201. Everson RB, Sandler DP, Wilcox AJ, Schreinemachers D, Shore DL, Weinberg C. Effect of passive exposure to smoking on age at natural menopause. BMJ (British Medical Journal). 1986;293(6550):792. [PMC free article: PMC1341577] [PubMed: 3094660]
  202. Faiz AS, Ananth CV. Etiology and risk factors for placenta previa: an overview and meta-analysis of observational studies. Journal of Maternal-Fetal & Neonatal Medicine. 2003;13(3):175–90. [PubMed: 12820840]
  203. Fallin MD, Hetmanski JB, Park J, Scott AF, Ingersoll R, Fuernkranz HA, McIntosh I, Beaty TH. Family-based analysis of MSX1 haplotypes for association with oral clefts. Genetic Epidemiology. 2003;25(2):168–75. [PubMed: 12916025]
  204. Fanucchi MV, Buckpitt AR, Murphy ME, Plopper CG. Naphthalene cytotoxicity of differentiating Clara cells in neonatal mice. Toxicology and Applied Pharmacology. 1997;144(1):96–104. [PubMed: 9169074]
  205. Faruque MO, Khan MR, Rahman M, Ahmed F. Relationship between smoking and antioxidant nutrient status. British Journal of Nutrition. 1995;73(4):625–32. [PubMed: 7794877]
  206. Fechter LD. Neurotoxicity of prenatal carbon monoxide exposure. Research Report (Health Effects Institute). 1987;(12):3–22. [PubMed: 3269253]
  207. Fechter LD, Annau Z. Effects of prenatal carbon monoxide exposure on neonatal rats. Adverse Effects of Environmental Chemicals and Psychotropic Drugs. Horvath M, editor. Vol. 2. New York: Elsevier; 1976. p. 219.
  208. Fechter LD, Annau Z. Prenatal carbon monoxide exposure alters behavioral development. Neurobehavioral Toxicology. 1980;2(1):7–11. [PubMed: 7442921]
  209. Fechter LD, Annau Z. Toxicity of mild prenatal carbon monoxide exposure. Science. 1997;197(4304):680–2. [PubMed: 877585]
  210. Ferm VH. Developmental malformations induced by cadmium: a study of timed injections during embryogenesis. Biology of the Neonate. 1971;19(1):101–7. [PubMed: 5003301]
  211. Field AE, Colditz GA, Willett WC, Longcope C, McKinlay JB. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men. Journal of Clinical Endocrinology and Metabolism. 1994;79(5):1310–6. [PubMed: 7962322]
  212. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER, Heyman RB, Holbrook J, Jaén CR, Kottke TE, et al. Smoking Cessation, Clinical Practice Guideline No 18. Rockville (MD): U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1996. AHCPR Publication No 96-0692.
  213. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER, Heyman RB, Jaén CR, Kottke TE, Lando HA, et al. Treating Tobacco Use and Dependence, Clinical Practice Guideline. Rockville (MD): U.S. Department of Health and Human Services, Public Health Service; 2000.
  214. Fiore MC, Jaén CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, Dorfma SF, Froelicher ES, Goldstein MG, Healton CG, et al. Treating Tobacco Use and Dependence: 2008 Update, Clinical Practice Guideline. Rockville (MD): U.S. Department of Health and Human Services; 2008.
  215. Fischer Walker CF, Black RE. Zinc and the risk for infectious disease. Annual Review of Nutrition. 2004;24:255–75. [PubMed: 15189121]
  216. Fisher GL. Function and homeostasis of copper and zinc in mammals. Science of the Total Environment. 1975;4(4):373–412. [PubMed: 1105784]
  217. Fisher SJ. The placental problem: linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia. Reproductive Biology and Endocrinology. 2004;2:53. [PMC free article: PMC493282] [PubMed: 15236649]
  218. Fisher SE, Atkinson M, Van Thiel DH. Selective fetal malnutrition: the effect of nicotine, ethanol, and acetaldehyde upon in vitro uptake of alpha-aminoisobutyric acid by human term placental villous slices. Developmental Pharmacology and Therapeutics. 1984;7(4):229–38. [PubMed: 6468224]
  219. Fong KW, Ohlsson A, Hannah ME, Grisaru S, Kingdom J, Cohen H, Ryan M, Windrim R, Foster G, Amankwah K. Prediction of perinatal outcome in fetuses suspected to have intrauterine growth restriction: Doppler US study of fetal cerebral, renal, and umbilical arteries. Radiology. 1999;213(3):681–9. [PubMed: 10580939]
  220. Forss M, Lehtovirta P, Rauramo I, Kariniemi V. Midtrimester fetal heart rate variability and maternal hemody-namics in association with smoking. American Journal of Obstetrics and Gynecology. 1983;146(6):693–5. [PubMed: 6869440]
  221. Fox NL, Sexton M, Hebel JR. Prenatal exposure to tobacco. I: effects on physical growth at age three. International Journal of Epidemiology. 1990;19(1):66–71. [PubMed: 2351526]
  222. Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutation Research. 1996;351(2):199–203. [PubMed: 8622715]
  223. Fraker PJ. Roles for cell death in zinc deficiency. Journal of Nutrition. 2005;135(3):359–62. [PubMed: 15735063]
  224. Fraker PJ, King LE. Reprogramming of the immune system during zinc deficiency. Annual Review of Nutrition. 2004;24:277–98. [PubMed: 15189122]
  225. French JI, McGregor JA. The pathobiology of premature rupture of membranes. Seminars in Perinatology. 1996;20(5):344–68. [PubMed: 8912989]
  226. Fréry N, Nessmann C, Girard F, Lafond J, Moreau T, Blot P, Lellouch J, Huel G. Environmental exposure to cadmium and human birthweight. Toxicology. 1993;79(2):109–18. [PubMed: 8497864]
  227. Fried PA, James DS, Watkinson B. Growth and pubertal milestones during adolescence in offspring prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology. 2001;23(5):431–6. [PubMed: 11711245]
  228. Fried PA, Watkinson B, Siegel LS. Reading and language in 9- to 12-year olds prenatally exposed to cigarettes and marijuana. Neurotoxicology and Teratology. 1997;19(3):171–83. [PubMed: 9200137]
  229. Friedman AJ, Ravnikar VA, Barbieri RL. Serum steroid hormone profiles in postmenopausal smokers and non-smokers. Fertility and Sterility. 1987;47(3):398–401. [PubMed: 2951278]
  230. Friedman GD, Siegelaub AB, Seltzer CC, Feldman R, Collen MF. Smoking habits and the leukocyte count. Archives of Environmental Health. 1973;26(3):137–43. [PubMed: 4688852]
  231. Funabashi T, Sano A, Mitsushima D, Kimura F. Nicotine inhibits pulsatile luteinizing hormone secretion in human males but not in human females, and tolerance to this nicotine effect is lost within one week of quitting smoking. Journal of Clinical Endocrinology and Metabolism. 2005;90(7):3908–13. [PubMed: 15870124]
  232. Garcia-Morales P, Saceda M, Kenney N, Kim N, Salomon DS, Gottardis MM, Solomon HB, Sholler PF, Jordan VC, Martin MB. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. Journal of Biological Chemistry. 1994;269(24):16896–901. [PubMed: 8207012]
  233. Gardosi J, Francis A. Early pregnancy predictors of pre-term birth: the role of a prolonged menstruation– conception interval. BJOG. 2000;107(2):228–37. [PubMed: 10688507]
  234. Garvey DJ, Longo LD. Chronic low level maternal carbon monoxide exposure and fetal growth and development. Biology of Reproduction. 1978;19(1):8–14. [PubMed: 687711]
  235. Gaspari L, Chang S-S, Santella RM, Garte S, Pedotti P, Taioli E. Polycyclic aromatic hydrocarbon-DNA adducts in human sperm as a marker of DNA damage and infertility. Mutation Research. 2003;535(2):155–60. [PubMed: 12581533]
  236. Ge X, Conger RD, Elder GH Jr. Coming of age too early: pubertal influences on girls’ vulnerability to psychological distress. Child Development. 1996;67(6):3386–400. [PubMed: 9071784]
  237. Genbacev O, Bass KE, Joslin RJ, Fisher SJ. Maternal smoking inhibits early human cytotrophoblast differentiation. Reproductive Toxicology. 1995;9(3):245–55. [PubMed: 7579909]
  238. Genbacev O, McMaster MT, Zdravkovic T, Fisher SJ. Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy. Reproductive Toxicology. 2003;17(5):509–18. [PubMed: 14555188]
  239. Gennser G, Marsal K, Brantmark B. Maternal smoking and fetal breathing movements. American Journal of Obstetrics and Gynecology. 1975;123(8):861–7. [PubMed: 1106202]
  240. George L, Granath F, Johansson AL, Anneren G, Cnattingius S. Environmental tobacco smoke and risk of spontaneous abortion. Epidemiology. 2006;17(5):500–5. [PubMed: 16837826]
  241. Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers A, Dosman JA. Immunoglobulin levels in smokers and non-smokers. Annals of Allergy. 1980;44(5):261–2. [PubMed: 7377637]
  242. Gieseke C, Talbot P. Cigarette smoke affects hamster oocyte cumulus complex pickup rate, adhesion and ciliary beat frequency [abstract] Molecular Biology of the Cell. 2003;14(Suppl):388a–389a.
  243. Gilboa SM, Mendola P, Olshan AF, Langlois PH, Savitz DA, Loomis D, Herring AH, Fixler DE. Relation between ambient air quality and selected birth defects, Seven County Study, Texas, 1997–2000. American Journal of Epidemiology. 2005;162(3):238–52. [PubMed: 15987727]
  244. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Human Reproduction. 2005;20(5):1144–7. [PubMed: 15802321]
  245. Gocze PM, Freeman DA. Cytotoxic effects of cigarette smoke alkaloids inhibit the progesterone production and cell growth of cultured MA-10 Leydig tumor cells. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2000;93(1):77–83. [PubMed: 11000509]
  246. Gocze PM, Szabo I, Freeman DA. Influence of nicotine, cotinine, anabasine and cigarette smoke extract on human granulosa cell progesterone and estradiol synthesis. Gynecological Endocrinology. 1999;13(4):266–72. [PubMed: 10533162]
  247. Goldenberg RL, Culhane JF. Infection as a cause of preterm birth. Clinics in Perinatology. 2003;30(4):677–700. [PubMed: 14714919]
  248. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. New England Journal of Medicine. 2000;342(20):1500–7. [PubMed: 10816189]
  249. Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970–1989. Morbidity and Mortality Weekly Report. 1993;42(SS-6):73–85. [PubMed: 8139528]
  250. Golub MS. Intrauterine and reproductive toxicity of nutritionally essential metals. Metals, Fertility, and Reproductive Toxicity. Golub MS, editor. Boca Raton (FL): CRC Press; 2005a. pp. 93–115.
  251. Golub MS. Reproductive toxicity of mercury, cadmium, and arsenic. Metals, Fertility, and Reproductive Toxicity. Golub MS, editor. Boca Raton (FL): CRC Press; 2005b. pp. 6–22.
  252. Golub MS, Macintosh MS, Baumrind N. Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns. Journal of Toxicology and Environmental Health Part B, Critical Reviews. 1998;1(3):199–241. [PubMed: 9644328]
  253. Gonçalves L, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Mental Retardation and Developmental Disabilities Research Reviews. 2002;8(1):3–13. [PubMed: 11921380]
  254. Goodman JD, Visser FG, Dawes GS. Effects of maternal cigarette smoking on fetal trunk movements, fetal breathing movements and the fetal heart rate. British Journal of Obstetrics and Gynaecology. 1984;91(7):657–61. [PubMed: 6743607]
  255. Gossain VV, Sherma NK, Srivastava L, Michelakis AM, Rovner DR. Hormonal effects of smoking—II: effects on plasma cortisol, growth hormone, and prolactin. American Journal of the Medical Sciences. 1986;291(5):325–7. [PubMed: 3010721]
  256. Goyer RA, Clarkson TW. Toxic effects of metals. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. Klaassen CD, editor. New York: McGraw-Hill; 2001. pp. 811–67.
  257. Graca LM, Cardoso CG, Clode N, Calhaz-Jorge C. Acute effects of maternal cigarette smoking on fetal heart rate and fetal body movements felt by the mother. Journal of Perinatal Medicine. 1991;19(5):385–90. [PubMed: 1804949]
  258. Gruper Y, Bar J, Bacharach E, Ehrlich R. Transferrin receptor co-localizes and interacts with the hemochromatosis factor (HFE) and the divalent metal transporter-1 (DMT1) in trophoblast cells. Journal of Cellular Physiology. 2005;204(3):901–12. [PubMed: 15880641]
  259. Gudmundsson S, Korszun P, Olofsson P, Dubiel M. New score indicating placental vascular resistance. Acta Obstetricia et Gynecologica Scandinavica. 2003;82(9):807–12. [PubMed: 12911441]
  260. Guinet E, Yoshida K, Nouri-Shirazi M. Nicotinic environment affects the differentiation and functional maturation of monocytes derived dendritic cells (DCs). Immunology Letters. 2004;95(1):45–55. [PubMed: 15325797]
  261. Gupta PC, Sreevidya S. Smokeless tobacco use, birth weight, and gestational age: population based, prospective cohort study of 1217 women in Mumbai, India. BMJ (British Medical Journal). 2004;328(7455):1538–42. [PMC free article: PMC437147] [PubMed: 15198947]
  262. Gupta PC, Subramoney S. Smokeless tobacco use and risk of stillbirth: a cohort study in Mumbai, India. Epidemiology. 2006;17(1):47–51. [PubMed: 16357594]
  263. Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, Carson SA, Cisneros P, Steinkampf MP, Hill JA, et al. Sperm morphology, motility, and concentration in fertile and infertile men. New England Journal of Medicine. 2001;345(19):1388–93. [PubMed: 11794171]
  264. Hadley CB, Main DM, Gabbe SG. Risk factors for preterm premature rupture of the fetal membranes. American Journal of Perinatology. 1990;7(4):374–9. [PubMed: 2222633]
  265. Hamilton BE, Martin JA, Sutton PD. Births: preliminary data for 2003. National Vital Statistics Reports. 2004;53(9):1–17. [PubMed: 15622995]
  266. Haram K, Mortensen JHS, Wollen A-L. Preterm delivery: an overview. Acta Obstetricia et Gynecologica Scandinavica. 2003;82(8):687–704. [PubMed: 12848639]
  267. Hardy BJ, Welcher DW, Stanley J, Dallas JR. Long-range outcome of adolescent pregnancy. Clinical Obstetrics and Gynecology. 1978;21(4):1215–32. [PubMed: 737929]
  268. Hardy JB, Mellits ED. Does maternal smoking during pregnancy have a long-term effect on the child? Lancet. 1972;2(7791):1332–6. [PubMed: 4118205]
  269. Harger JH, Hsing AW, Tuomala RE, Gibbs RS, Mead PB, Eschenbach DA, Knox GE, Polk BF. Risk factors for preterm premature rupture of fetal membranes: a multicenter case-control study. American Journal of Obstetrics and Gynecology. 1990;163(1 Pt 1):130–7. [PubMed: 2197863]
  270. Harlow BL, Signorello LB. Factors associated with early menopause. Maturitas. 2000;35(1):3–9. [PubMed: 10802394]
  271. Harlow SD, Ephross SA. Epidemiology of menstruation and its relevance to women’s health. Epidemiologic Reviews. 1995;17(2):265–86. [PubMed: 8654511]
  272. Harlow SD, Park M. A longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women. British Journal of Obstetrics and Gynaecology. 1996;103(11):1134–42. [PubMed: 8917003]
  273. Harrington K, Fayyad A, Thakur V, Aquilina J. The value of uterine artery Doppler in the prediction of utero-placental complications in multiparous women. Ultrasound in Obstetrics & Gynecology. 2004;23(1):50–5. [PubMed: 14971000]
  274. Hartsfield JK Jr, Hickman TA, Everett ET, Shaw GM, Lammer EJ, Finnell RA. Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking. American Journal of Medical Genetics. 2001;102(1):21–4. [PubMed: 11471167]
  275. Hassold TJ. Nondisjunction in the human male. Current Topics in Developmental Biology. 1998;37:383–406. [PubMed: 9352193]
  276. Haug K, Irgens LM, Skjaerven R, Markestad T, Baste V, Schreuder P. Maternal smoking and birthweight: effect modification of period, maternal age and paternal smoking. Acta Obstetricia et Gynecologica Scandinavica. 2000;79(6):485–9. [PubMed: 10857873]
  277. He Q, Karlberg J. BMI in childhood and its association with height gain, timing of puberty, and final height. Pediatric Research. 2001;49(2):244–51. [PubMed: 11158521]
  278. Hecht SS. Tobacco smoke carcinogens and lung cancer. Journal of the National Cancer Institute. 1999;91(14):1194–210. [PubMed: 10413421]
  279. Heffner LJ, Sherman CB, Speizer FE, Weiss ST. Clinical and environmental predictors of preterm labor. Obstetrics and Gynecology. 1993;81(5 Pt 1):750–7. [PubMed: 8469467]
  280. Heinonen S, Saarikoski S. Reproductive risk factors of fetal asphyxia at delivery: a population based analysis. Journal of Clinical Epidemiology. 2001;54(4):407–10. [PubMed: 11297890]
  281. Henson MC, Chedrese PJ. Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction. Experimental Biology and Medicine (Maywood, N.J.). 2004;229(5):383–92. [PubMed: 15096650]
  282. Hidiroglou M, Knipfel JE. Zinc in mammalian sperm: a review. Journal of Dairy Science. 1984;67(6):1147–56. [PubMed: 6378991]
  283. Hladky K, Yankowitz J, Hansen WF. Placental abruption. Obstetrical & Gynecological Survey. 2002;57(5):299–305. [PubMed: 11997676]
  284. Hoffmann D, Djordjevic MV, Hoffmann I. The changing cigarette. Preventive Medicine. 1997;26(4):427–34. [PubMed: 9245661]
  285. Hofvendahl EA. Smoking in pregnancy as a risk factor for long-term mortality in the offspring. Paediatric and Perinatal Epidemiology. 1995;9(4):381–90. [PubMed: 8570464]
  286. Hogge WA, Byrnes AL, Lanasa MC, Surti U. The clinical use of karyotyping spontaneous abortions. American Journal of Obstetrics and Gynecology. 2003;189(2):397–402. [PubMed: 14520206]
  287. Holladay SD, Luster MI. Alterations in fetal thymic and liver hematopoietic cells as indicators of exposure to developmental immunotoxicants. Environmental Health Perspectives. 1996;104(Suppl 4):809–13. [PMC free article: PMC1469667] [PubMed: 8880003]
  288. Holladay SD, Smith BJ. Fetal hematopoietic alterations after maternal exposure to benzo[a]pyrene: a cytometric evaluation. Journal of Toxicology and Environmental Health. 1994;42(3):259–73. [PubMed: 8021962]
  289. Honein MA, Paulozzi LJ, Moore CA. Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction. American Journal of Epidemiology. 2000;152(7):658–65. [PubMed: 11032161]
  290. Honein MA, Paulozzi LJ, Watkins ML. Maternal smoking and birth defects: validity of birth certificate data for effect estimation. Public Health Reports. 2001;116(4):327–35. [PMC free article: PMC1497341] [PubMed: 12037261]
  291. Honein MA, Rasmussen SA, Reefhuis J, Romitti PA, Lammer EJ, Sun L, Correa A. Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts. Epidemiology. 2007;18(2):226–33. [PubMed: 17202867]
  292. Hong Y-C, Kim H, Im M-W, Lee K-H, Woo B-H, Christiani DC. Maternal genetic effects on neonatal susceptibility to oxidative damage from environmental tobacco smoke. Journal of the National Cancer Institute. 2001;93(8):645–7. [PubMed: 11309442]
  293. Hong Y-C, Lee K-H, Son B-K, Ha E-H, Moon H-S, Ha M. Effects of the GSTM1 and GSTT1 polymorphisms on the relationship between maternal exposure to environmental tobacco smoke and neonatal birth weight. Journal of Occupational and Environmental Medicine. 2003;45(5):492–8. [PubMed: 12762073]
  294. Hopenhayn C, Ferreccio C, Browning SR, Huang B, Peralta C, Gibb H, Hertz-Picciotto I. Arsenic exposure from drinking water and birth weight. Epidemiology. 2003;14(5):593–602. [PubMed: 14501275]
  295. Hopenhayn-Rich C, Browning SR, Hertz-Picciotto I, Ferreccio C, Peralta C, Gibb H. Chronic arsenic exposure and risk of infant mortality in two areas of Chile. Environmental Health Perspectives. 2000;108(7):667–73. [PMC free article: PMC1638185] [PubMed: 10903622]
  296. Horak S, Polanska J, Widlak P. Bulky DNA adducts in human sperm: relationship with fertility, semen quality, smoking, and environmental factors. Mutation Research. 2003;537(1):53–65. [PubMed: 12742507]
  297. Hornsby PP, Wilcox AJ, Weinberg CR. Cigarette smoking and disturbance of menstrual function. Epidemiology. 1998;9(2):193–8. [PubMed: 9504290]
  298. Horst MA, Sastry BV. Maternal tobacco smoking and alterations in amino acid transport in human placenta: induction of transport systems. Progress in Clinical and Biological Research. 1988;258:249–62. [PubMed: 3380822]
  299. Houlgate P. UK Smoke Constituents Study. Part 11: Determination of Metals Yields in Cigarette Smoke by ICP-MS & CVAAS. Kingston upon Thames (UK): Arista Laboratories Europe; 2003.
  300. Howe DT, Wheeler T, Osmond C. The influence of maternal haemoglobin and ferritin on mid-pregnancy placental volume. British Journal of Obstetrics and Gynaecology. 1995;102(3):213–9. [PubMed: 7794845]
  301. Hoyer PB. Impact of metals on ovarian function. Metals, Fertility, and Reproductive Toxicity. Golub MJ, editor. Boca Raton (FL): CRC Press; 2005. pp. 155–73.
  302. Hsia CC. Respiratory function of hemoglobin. New England Journal of Medicine. 1998;338(4):239–47. [PubMed: 9435331]
  303. Huang S, Driessen N, Knoll M, Talbot P. In vitro analysis of oocyte cumulus complex pickup rate in the hamster Mesocricetus auratus. Molecular Reproduction and Development. 1997;47(3):312–22. [PubMed: 9170111]
  304. Huel G, Boudene C, Ibrahim MA. Cadmium and lead content of maternal and newborn hair: relationship to parity, birth weight, and hypertension. Archives of Environmental Health. 1981;36(5):221–7. [PubMed: 7294886]
  305. Huel G, Everson RB, Menger I. Increased hair cadmium in newborns of women occupationally exposed to heavy metals. Environmental Research. 1984;35(1):115–21. [PubMed: 6489283]
  306. Huel G, Godin J, Fréry N, Girard F, Moreau T, Nessman C, Blot P. Aryl hydrocarbon hydroxylase activity in human placenta and threatened preterm delivery. Journal of Exposure Analysis and Environmental Epidemiology. 1993;3(Suppl 1):187–99. [PubMed: 9857304]
  307. Hughes DA, Haslam PL, Townsend PJ, Turner-Warwick M. Numerical and functional alterations in circulatory lymphocytes in cigarette smokers. Clinical and Experimental Immunology. 1985;61(2):459–66. [PMC free article: PMC1577295] [PubMed: 2931227]
  308. Hughes EG, Brennan BG. Does cigarette smoking impair natural or assisted fecundity? Fertility and Sterility. 1996;66(5):679–89. [PubMed: 8893667]
  309. Huisman M, Risseeuw B, van Eyck J, Arabin B. Nicotine and caffeine: influence on prenatal hemodynamics and behavior in early twin pregnancy. Journal of Reproductive Medicine. 1997;42(11):731–4. [PubMed: 9408873]
  310. Hwang S-J, Beaty TH, McIntosh I, Hefferon T, Panny SR. Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency. American Journal of Medical Genetics. 1998;75(4):419–23. [PubMed: 9482651]
  311. Hwang S-J, Beaty TH, Panny SR, Street NA, Joseph JM, Gordon S, McIntosh I, Francomano CA. Association study of transforming growth factor alpha (TGF α) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects. American Journal of Epidemiology. 1995;141(7):629–36. [PubMed: 7702037]
  312. Iams JD. The epidemiology of preterm birth. Clinical Perinatology. 2003;30(4):651–64. [PubMed: 14714917]
  313. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silica, Vanadium, and Zinc. Washington: National Academy Press; 2000. [PubMed: 11269606]
  314. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Humans: Polynuclear Aromatic Compounds, Part 1: Chemical, Environmental and Experimental Data. Vol. 32. Lyon (France): International Agency for Research on Cancer; 1983. [PubMed: 6586639]
  315. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Tobacco Smoking. Vol. 38. Lyon (France): International Agency for Research on Cancer; 1986.
  316. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Tobacco Smoke and Involuntary Smoking. Vol. 83. Lyon (France): International Agency for Research on Cancer; 2004. [PMC free article: PMC4781536] [PubMed: 15285078]
  317. Irion O, Masse J, Forest JC, Moutquin JM. Prediction of pre-eclampsia, low birthweight for gestation and prematurity by uterine artery blood flow velocity waveforms analysis in low risk nulliparous women. British Journal of Obstetrics and Gynaecology. 1998;105(4):422–9. [PubMed: 9609270]
  318. Iyasu S, Saftlas AK, Rowley DL, Koonin LM, Lawson HW, Atrash HK. The epidemiology of placenta previa in the United States, 1979 through 1987. American Journal of Obstetrics and Gynecology. 1993;168(5):1424–9. [PubMed: 8498422]
  319. Jauniaux E, Biernaux V, Gerlo E, Gulbis B. Chronic maternal smoking and cord blood amino acid and enzyme levels at term. Obstetrics and Gynecology. 2001;97(1):57–61. [PubMed: 11152908]
  320. Jauniaux E, Burton GJ. The effect of smoking in pregnancy on early placental morphology. Obstetrics and Gynecology. 1992;79(5 Pt 1):645–8. [PubMed: 1565343]
  321. Jauniaux E, Gulbis B, Acharya G, Gerlo E. Fetal amino acid and enzyme levels with maternal smoking. Obstetrics and Gynecology. 1999;93(5 Pt 1):680–3. [PubMed: 10912966]
  322. Jensen EJ, Pedersen B, Frederiksen R, Dahl R. Prospective study on the effect of smoking and nicotine substitution on leucocyte blood counts and relation between blood leucocytes and lung function. Thorax. 1998a;53(9):784–9. [PMC free article: PMC1745328] [PubMed: 10319062]
  323. Jensen TK, Henriksen TB, Hjollund NHI, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde JP, Skak-kebæk NE, Olsen J. Adult and prenatal exposures to tobacco smoke as risk indicators of fertility among 430 Danish couples. American Journal of Epidemiology. 1998b;148(10):992–7. [PubMed: 9829871]
  324. Jensen TK, Jørgensen N, Punab M, Haugen TB, Suominen J, Zilaitiene B, Horte A, Andersen A-G, Carlsen E, Magnus Ø, et al. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. American Journal of Epidemiology. 2004;159(1):49–58. [PubMed: 14693659]
  325. Jernström H, Klug TL, Sepkovic DW, Bradlow HL, Narod SA. Predictors of the plasma ratio of 2-hydroxyestrone to 16α-hydroxyestrone among premenopausal, nulliparous women from four ethnic groups. Carcinogenesis. 2003;24(5):991–1005. [PubMed: 12771045]
  326. Jeyabalan A, Powers RW, Durica AR, Harger GF, Roberts JM, Ness RB. Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia. American Journal of Hypertension. 2008;21(8):943–7. [PMC free article: PMC2613772] [PubMed: 18566591]
  327. Ji L, Melkonian G, Riveles K, Talbot P. Identification of pyridine compounds in cigarette smoke solution that inhibit growth of the chick chorioallantoic membrane. Toxicological Sciences. 2002;69(1):217–25. [PubMed: 12215677]
  328. Jick H, Porter J, Morrison AS. Relation between smoking and age of natural menopause: report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet. 1977;309(8026):1354–5. [PubMed: 69066]
  329. Jin Z, Jin M, Nilsson BO, Roomans GM. Effects of nicotine administration on elemental concentrations in mouse granulosa cells, maturing oocytes and oviduct epithelium studied by X-ray microanalysis. Journal of Submicroscopic Cytology and Pathology. 1998;30(4):517–20. [PubMed: 9851060]
  330. Johnson F, Ogden L, Graham T, Thomas T, Gilbreath E, Hammersley M, Wilson L, Knight Q, DeJan B. Developmental effects of zinc chloride in rats. Toxicologist. 2003a;72(1 Suppl):75.
  331. Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, et al. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nature Medicine. 2003b;9(8):1081–4. [PubMed: 12858169]
  332. Jolibois LS Jr, Burow ME, Swan KF, George WJ, Anderson MB, Henson MC. Effects of cadmium on cell viability, trophoblastic development, and expression of low density lipoprotein receptor transcripts in cultured human placental cells. Reproductive Toxicology. 1999a;13(6):473–80. [PubMed: 10613395]
  333. Jolibois LS Jr, Shi W, George WJ, Henson MC, Anderson MB. Cadmium accumulation and effects on progesterone release by cultured human trophoblast cells. Reproductive Toxicology. 1999b;13(3):215–21. [PubMed: 10378470]
  334. Jouppila P, Kirkinen P, Eik-Nes S. Acute effect of maternal smoking on the human fetal blood flow. British Journal of Obstetrics and Gynaecology. 1983;90(1):7–10. [PubMed: 6821673]
  335. Juchau MR, Namkung J, Chao ST. Mono-oxygenase induction in the human placenta: interrelationships among position-specific hydroxylations of 17 beta-estradiol and benzo[a]pyrene. Drug Metabolism and Disposition. 1982;10(3):220–4. [PubMed: 6125353]
  336. Jugessur A, Lie RT, Wilcox AJ, Murray JC, Taylor JA, Saugstad OD, Vindenes HA, Åbyholm FE. Cleft palate, transforming growth factor alpha gene variants, and maternal exposures: assessing gene-environment interactions in case-parent triads. Genetic Epidemiology. 2003;25(4):367–74. [PubMed: 14639706]
  337. Junaid M, Murthy RC, Saxena DK. Chromium fetotoxicity in mice during late pregnancy. Veterinary and Human Toxicology. 1995;37(4):320–3. [PubMed: 8540218]
  338. Junaid M, Murthy RC, Saxena DK. Embryotoxicity of orally administered chromium in mice: exposure during the period of organogenesis. Toxicology Letters. 1996;84(3):143–8. [PubMed: 8600613]
  339. Jurasović J, Cvitković P, Pizent A, Čolak B, Telišman S. Semen quality and reproductive endocrine function with regard to blood cadmium in Croatian male subjects. Biometals. 2004;17(6):735–43. [PubMed: 15689116]
  340. Kaijser M, Granath F, Jacobsen G, Cnattingius S, Ekbom A. Maternal pregnancy estriol levels in relation to anamnestic and fetal anthropometric data. Epidemiology. 2000;11(3):315–9. [PubMed: 10784250]
  341. Kajii T, Ferrier A, Niikawa N, Takahara H, Ohama K, Avirachan S. Anatomic and chromosomal anomalies in 639 spontaneous abortuses. Human Genetics. 1980;55(1):87–98. [PubMed: 7450760]
  342. Kakela R, Kakela A, Hyvarinen H. Effects of nickel chloride on reproduction of the rat and possible antagonistic role of selenium. Comparative Biochemistry and Physiology Part C, Pharmacology, Toxicology & Endocrinology. 1999;123(1):27–37. [PubMed: 10390053]
  343. Källén K. Maternal smoking and craniosynostosis. Teratology. 1999;60(3):146–50. [PubMed: 10471899]
  344. Källén K. Maternal smoking and congenital malformations. Fetal and Maternal Medicine Review. 2002a;13(1):63–86.
  345. Källén K. Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring. Teratology. 2002b;66(4):185–91. [PubMed: 12353215]
  346. Kämäräinen M, Soini T, Wathén K-A, Leinonen E, Stenman U-H, Vuorela P. Smoking and sVEGFR-1: circulating maternal concentrations and placental expression. Molecular and Cellular Endocrinology. 2009;299(2):261–5. [PubMed: 19103251]
  347. Kanayama N, Terao T, Kawashima Y, Horiuchi K, Fujimoto D. Collagen types in normal and prematurely ruptured amniotic membranes. American Journal of Obstetrics and Gynecology. 1985;153(8):899–903. [PubMed: 4073165]
  348. Kandel DB, Udry JR. Prenatal effects of maternal smoking on daughters’ smoking: nicotine or testosterone exposure? American Journal of Public Health. 1999;89(9):1377–83. [PMC free article: PMC1508780] [PubMed: 10474556]
  349. Karaer A, Avsar FA, Batioglu S. Risk factors for ectopic pregnancy: a case-control study. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2006;46(6):521–7. [PubMed: 17116058]
  350. Karakaya A, Ates I, Yucesoy B. Effects of occupational polycyclic aromatic hydrocarbon exposure on T-lymphocyte functions and natural killer cell activity in asphalt and coke oven workers. Human & Experimental Toxicology. 2004;23(7):317–22. [PubMed: 15311848]
  351. Kariniemi V, Forss M, Lehtovirta P, Rauramo I. Significant correlation between maternal hemodynamics and fetal heart rate variability. American Journal of Obstetrics and Gynecology. 1982;144(1):43–6. [PubMed: 7114111]
  352. Kariniemi V, Lehtovirta P, Rauramo I, Forss M. Effects of smoking on fetal heart rate variability during gestational weeks 27 to 32. American Journal of Obstetrics and Gynecology. 1984;149(5):575–6. [PubMed: 6742029]
  353. Kato I, Toniolo P, Koenig KL, Shore RE, Zeleniuch- Jacquotte A, Akhmedkhanov A, Riboli E. Epidemiologic correlates with menstrual cycle length in middle aged women. European Journal of Epidemiology. 1999;15(9):809–14. [PubMed: 10608360]
  354. Kawai M, Swan KF, Green AE, Edwards DE, Anderson MB, Henson MC. Placental endocrine disruption induced by cadmium: effects on P450 cholesterol side-chain cleavage and 3β-hydroxysteroid dehydrogenase enzymes in cultured human trophoblasts. Biology of Reproduction. 2002;67(1):178–83. [PubMed: 12080015]
  355. Keen CL. Teratogenic effects of essential trace metals: deficiencies and excesses. Toxicology of Metals. Chang LW, editor. Boca Raton (FL): CRC Press; 1996. pp. 977–1001.
  356. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiologic Reviews. 1993;15(1):36–47. [PubMed: 8405211]
  357. Kendrick JS, Atrash HK, Strauss LT, Gargiullo OM, Ahn YW. Vaginal douching and the risk of ectopic pregnancy among black women. American Journal of Obstetrics and Gynecology. 1997;176(5):991–7. [PubMed: 9166157]
  358. Kendrick JS, Zahniser SC, Miller N, Salas N, Stine J, Gargiullo PM, Floyd RL, Spierto FW, Sexton M, Merzger RW, et al. Integrating smoking cessation into routine public prenatal care: the Smoking Cessation in Pregnancy project. American Journal of Public Health. 1995;85(2):217–22. [PMC free article: PMC1615299] [PubMed: 7856781]
  359. Key TJ, Pike MC, Baron JA, Moore JW, Wang DY, Thomas BS, Bulbrook RD. Cigarette smoking and steroid hormones in women. Journal of Steroid Biochemistry and Molecular Biology. 1991;39(4A):529–34. [PubMed: 1832941]
  360. Key TJ, Pike MC, Brown JB, Hermon C, Allen DS, Wang DY. Cigarette smoking and urinary oestrogen excretion in premenopausal and post-menopausal women. British Journal of Cancer. 1996;74(8):1313–6. [PMC free article: PMC2075917] [PubMed: 8883424]
  361. Kharrazi M, DeLorenze GN, Kaufman FL, Eskenazi B, Bernert JT Jr, Graham S, Pearl M, Pirkle J. Environmental tobacco smoke and pregnancy outcome. Epidemiology. 2004;15(6):660–70. [PubMed: 15475714]
  362. Khaw KT, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. New England Journal of Medicine. 1988;318(26):1705–9. [PubMed: 2967432]
  363. Khong TY. Placental vascular development and neonatal outcome. Seminars in Neonatology. 2004;9(4):255–63. [PubMed: 15251142]
  364. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. British Journal of Obstetrics and Gynaecology. 1986;93(10):1049–59. [PubMed: 3790464]
  365. Khong TY, Liddell HS, Robertson WB. Defective haemochorial placentation as a cause of miscarriage: a preliminary study. British Journal of Obstetrics and Gynaecology. 1987;94(7):649–55. [PubMed: 3620413]
  366. Kiilholma P, Grönroos M, Erkkola R, Pakarinen P, Näntö V. The role of calcium, copper, iron and zinc in pre-term delivery and premature rupture of fetal membranes. Gynecologic and Obstetric Investigation. 1984;17(4):194–201. [PubMed: 6539271]
  367. Kim SY, England LJ, Kendrick JS, Dietz PM, Callaghan WM. The contribution of clinic-based interventions to reduce prenatal smoking prevalence among US women. American Journal of Public Health. 2009;99(5):893–8. [PMC free article: PMC2667844] [PubMed: 19299672]
  368. Kim YM, Bujold E, Chaiworapongsa T, Gomez R, Yoon BH, Thaler HT, Rotmensch S, Romero R. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. American Journal of Obstetrics and Gynecology. 2003;189(4):1063–9. [PubMed: 14586356]
  369. Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch S, Thaler HT, Romero R. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology. 2002;187(5):1137–42. [PubMed: 12439491]
  370. Kimberlin DF, Andrews WW. Bacterial vaginosis: association with adverse pregnancy outcome. Seminars in Perinatology. 1998;22(4):242–50. [PubMed: 9738988]
  371. Kimya Y, Cengiz C, Ozan H, Kolsal N. Acute effects of maternal smoking on the uterine and umbilical artery blood velocity waveforms. Journal of Maternal-Fetal Investigation. 1998;8(2):79–81. [PubMed: 9685561]
  372. Kingdom JC, Kaufmann P. Oxygen and placental villous development: origins of fetal hypoxia. Placenta. 1997;18(8):613–21. [PubMed: 9364596]
  373. Kirkland SA, Dodds LA, Brosky G. The natural history of smoking during pregnancy among women in Nova Scotia. Canadian Medical Association Journal. 2000;163(3):281–2. [PMC free article: PMC80289] [PubMed: 10951724]
  374. Klaiber EL, Broverman DM, Dalen JE. Serum estradiol levels in male cigarette smokers. American Journal of Medicine. 1984;77(5):858–62. [PubMed: 6496540]
  375. Kleihues P, Doerjer G, Ehret M, Guzman J. Reaction of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene with DNA of various rat tissues in vivo. Archives of Toxicology Supplement. 1980;(Suppl 3):237–46. [PubMed: 6772140]
  376. Kline J, Levin B, Kinney A, Stein Z, Susser M, Warburton D. Cigarette smoking and spontaneous abortion of known karyotype: precise data but uncertain inferences. American Journal of Epidemiology. 1995;141(5):417–27. [PubMed: 7879786]
  377. Kline J, Stein ZA, Susser M, Warburton D. Smoking: a risk factor for spontaneous abortion. New England Journal of Medicine. 1977;297(15):793–6. [PubMed: 895818]
  378. Klonoff-Cohen H, Edelstein S, Savitz D. Cigarette smoking and preeclampsia. Obstetrics and Gynecology. 1993;81(4):541–4. [PubMed: 8459962]
  379. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, Srinivasan IP, Kaegi D, Chang JC, Wiley KJ. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA: the Journal of the American Medical Association. 1995;273(10):795–8. [PubMed: 7861574]
  380. Knoll M, Talbot P. Cigarette smoke inhibits oocyte cumulus complex pick-up by the oviduct in vitro independent of ciliary beat frequency. Reproductive Toxicology. 1998;12(1):57–68. [PubMed: 9431573]
  381. Knottnerus JA, Delgado LR, Knipschild PG, Essed GG, Smits F. Haematologic parameters and pregnancy outcome: a prospective cohort study in the third trimester. Journal of Clinical Epidemiology. 1990;43(5):461–6. [PubMed: 2324786]
  382. Kolasa E. Constitution corporelle et âge à la puberté chez les étudiantes polonaises dans les années 1974–1994 (Body composition and age among Polish students in years 1974–1994) [French] Anthropologie et Préhistoire. 1997;108:35–42.
  383. Kolasa E, Hulanicka B, Waliszko A. Does exposure to cigarette smoke influence girls maturation [Polish] Przeglad Epidemiologiczny. 1998;52(3):339–50. [PubMed: 9919929]
  384. Koren G, Sharav T, Pastuszak A, Garrettson LK, Hill K, Samson I, Rorem M, King A, Dolgin JE. A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reproductive Toxicology. 1991;5(5):397–403. [PubMed: 1806148]
  385. Kramer MS, Usher RH, Pollack R, Boyd M, Usher S. Etiologic determinants of abruptio placentae. Obstetrics and Gynecology. 1997;89(2):221–6. [PubMed: 9015024]
  386. Krarup T. Oocyte destruction and ovarian tumorigenesis after direct application of a chemical carcinogen (9:10-dimethyl-1:2-benzanthrene) to the mouse ovary. International Journal of Cancer. 1969;4(1):61–75. [PubMed: 4310334]
  387. Krishna K. Tobacco chewing in pregnancy. British Journal of Obstetrics and Gynaecology. 1978;85(10):726–8. [PubMed: 708654]
  388. Kristensen P, Eilertsen E, Einarsdóttir E, Haugen A, Skaug V, Øvrebø S. Fertility in mice after prenatal exposure to benzo[a]pyrene and inorganic lead. Environmental Health Perspectives. 1995;103(6):588–90. [PMC free article: PMC1519139] [PubMed: 7556012]
  389. Kritz-Silverstein D, Wingard DL, Garland FC. The association of behavior and lifestyle factors with menstrual symptoms. Journal of Women’s Health & Gender-Based Medicine. 1999;8(9):1185–93. [PubMed: 10595332]
  390. Kuehl KS, Loffredo CA. Population-based study of l-transposition of the great arteries: possible associations with environmental factors. Birth Defects Research Part A, Clinical and Molecular Teratology. 2003;67(3):162–7. [PubMed: 12797457]
  391. Kuhnert BR, Kuhnert PM, Debanne S, Williams TG. The relationship between cadmium, zinc, and birth weight in pregnant women who smoke. American Journal of Obstetrics and Gynecology. 1987a;157(5):1247–51. [PubMed: 3688082]
  392. Kuhnert BR, Kuhnert PM, Lazebnik N, Erhard P. The effect of maternal smoking on the relationship between maternal and fetal zinc status and infant birth weight. Journal of the American College of Nutrition. 1988a;7(4):309–16. [PubMed: 3209781]
  393. Kuhnert BR, Kuhnert PM, Zarlingo TJ. Associations between placental cadmium and zinc and age and parity in pregnant women who smoke. Obstetrics and Gynecology. 1988b;71(1):67–70. [PubMed: 3336544]
  394. Kuhnert PM, Kuhnert BR, Bottoms SF, Erhard P. Cadmium levels in maternal blood, fetal cord blood, and placental tissues of pregnant women who smoke. American Journal of Obstetrics and Gynecology. 1982;142(8):1021–5. [PubMed: 7072770]
  395. Kuhnert PM, Kuhnert BR, Erhard P, Brashear WT, Groh-Wargo SL, Webster S. The effect of smoking on placental and fetal zinc status. American Journal of Obstetrics and Gynecology. 1987b;157(5):1241–6. [PubMed: 3688081]
  396. Künzle R, Mueller MD, Hänggi W, Birkhäuser MH, Drescher H, Bersinger NA. Semen quality of male smokers and nonsmokers in infertile couples. Fertility and Sterility. 2003;79(2):287–91. [PubMed: 12568836]
  397. Kurahashi N, Sata F, Kasai S, Shibata T, Moriya K, Yamada H, Kakizaki H, Minakami H, Nonomura K, Kishi R. Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias. Molecular Human Reproduction. 2005;11(2):93–8. [PubMed: 15579657]
  398. Kurki T, Sivonen A, Renkonen O-V, Savia E, Ylikorkala O. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstetrics and Gynecology. 1992;80(2):173–7. [PubMed: 1635726]
  399. Kurmanavichius J, Baumann H, Huch R, Huch A. Uteroplacental blood flow velocity waveforms as a predictor of adverse fetal outcome and pregnancy-induced hypertension. Journal of Perinatal Medicine. 1990;18(4):255–60. [PubMed: 2262869]
  400. Kyrklund-Blomberg NB, Cnattingius S. Preterm birth and maternal smoking: risks related to gestational age and onset of delivery. American Journal of Obstetrics and Gynecology. 1998;179(4):1051–5. [PubMed: 9790397]
  401. Kyrklund-Blomberg NB, Gennser G, Cnattingius S. Placental abruption and perinatal death. Paediatric and Perinatal Epidemiology. 2001;15(3):290–7. [PubMed: 11489159]
  402. Lagueux J, Pereg D, Ayotte P, Dewailly E, Poirier GG. Cytochrome P450 CYP1A1 enzyme activity and DNA adducts in placenta of women environmentally exposed to organochlorines. Environmental Research. 1999;80(4):369–82. [PubMed: 10330311]
  403. Lam X, Gieseke C, Knoll M, Talbot P. Assay and importance of adhesive interaction between hamster (Mesocricetus auratus) oocyte-cumulus complexes and the oviductal epithelium. Biology of Reproduction. 2000;62(3):579–88. [PubMed: 10684798]
  404. Lammer EJ, Shaw GM, Iovannisci DM, Van Waes J, Finnell RH. Maternal smoking and the risk of orofacial clefts: susceptibility with NAT1 and NAT2 polymorphisms. Epidemiology. 2004;15(2):150–6. [PubMed: 15127906]
  405. Larsen LG, Clausen HV, Jønsson L. Stereologic examination of placentas from mothers who smoke during pregnancy. American Journal of Obstetrics and Gynecology. 2002;186(3):531–7. [PubMed: 11904619]
  406. Lassen K, Oei TPS. Effects of maternal cigarette smoking during pregnancy on long-term physical and cognitive parameters of child development. Addictive Behaviors. 1998;23(5):635–53. [PubMed: 9768300]
  407. Lavezzi AM, Ottaviani G, Matturri L. Adverse effects of prenatal tobacco smoke exposure on biological parameters of the developing brainstem. Neurobiology of Disease. 2005;20(2):601–7. [PubMed: 15925516]
  408. Lavezzi AM, Ottaviani G, Mauri M, Matturri L. Hypoplasia of the arcuate nucleus and maternal smoking during pregnancy in sudden unexplained perinatal and infant death. Neuropathology. 2004;24(4):284–9. [PubMed: 15641586]
  409. Lee CZ, Royce FH, Denison MS, Pinkerton KE. Effect of in utero and postnatal exposure to environmental tobacco smoke on the developmental expression of pulmonary cytochrome P450 monooxygenases. Journal of Biochemical and Molecular Toxicology. 2000;14(3):121–30. [PubMed: 10711627]
  410. Lee T, Silver H. Etiology and epidemiology of preterm premature rupture of the membranes. Clinics in Perinatology. 2001;28(4):721–34. [PubMed: 11817185]
  411. Lees C, Parra M, Missfelder-Lobos H, Morgans A, Fletcher O, Nicolaides KH. Individualized risk assessment for adverse pregnancy outcome by uterine artery Doppler at 23 weeks. Obstetrics and Gynecology. 2001;98(3):369–73. [PubMed: 11530114]
  412. Lehtovirta P, Forss M. The acute effect of smoking on intervillous blood flow of the placenta. British Journal of Obstetrics and Gynaecology. 1978;85(10):729–31. [PubMed: 708655]
  413. Lehtovirta P, Forss M. The acute effect of smoking on uteroplacental blood flow in normotensive and hypertensive pregnancy. International Journal of Gynaecology and Obstetrics. 1980;18(3):208–11. [PubMed: 6109657]
  414. Lehtovirta P, Forss M, Kariniemi V, Rauramo I. Acute effects of smoking on fetal heart-rate variability. British Journal of Obstetrics and Gynaecology. 1983;90(1):3–6. [PubMed: 6821667]
  415. Lekakis J, Papamichael C, Vemmos C, Stamatelopoulos K, Voutsas A, Stamatelopoulos S. Effects of acute cigarette smoking on endothelium-dependent arterial dilatation in normal subjects. American Journal of Cardiology. 1998;81(10):1225–8. [PubMed: 9604954]
  416. Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, Yu KF, Schisterman EF, Thadhani R, Sacks BP, Epstein FH, et al. Circulating angiogenic factors and the risk of preeclampsia. New England Journal of Medicine. 2004;350(7):672–83. [PubMed: 14764923]
  417. Li DK, Daling JR. Maternal smoking, low birth weight, and ethnicity in relation to sudden infant death syndrome. American Journal of Epidemiology. 1991;134(9):958–64. [PubMed: 1951293]
  418. Li DK, Wi S. Maternal placental abnormality and the risk of sudden infant death syndrome. American Journal of Epidemiology. 1999;149(7):608–11. [PubMed: 10192307]
  419. Li H, Gudnason H, Olofsson P, Dubiel M, Gudmundsson S. Increased uterine artery vascular impedance is related to adverse outcome of pregnancy but is present in only one-third of late third-trimester pre-eclamptic women. Ultrasound in Obstetrics & Gynecology. 2005;25(5):459–63. [PubMed: 15846767]
  420. Li Y, Wang H. In utero exposure to tobacco and alcohol modifies neurobehavioral development in mice offspring: considerations a role of oxidative stress. Pharmacological Research. 2004;49(5):467–73. [PubMed: 14998557]
  421. Liestøl K. Menarcheal age and spontaneous abortion: a causal connection? American Journal of Epidemiology. 1980;111(6):753–8. [PubMed: 7386450]
  422. Lin S, Hwang SA, Marshall EG, Marion D. Does paternal occupational lead exposure increase the risks of low birth weight or prematurity? American Journal of Epidemiology. 1998;148(2):173–81. [PubMed: 9676699]
  423. Lindblad A, Maršál K, Andersson KE. Effect of nicotine on human fetal blood flow. Obstetrics and Gynecology. 1988;72(3 Pt 1):371–82. [PubMed: 3043290]
  424. Lindqvist PG, Maršál K. Moderate smoking during pregnancy is associated with a reduced risk of preeclampsia. Acta Obstetricia et Gynecologica Scandinavica. 1999;78(8):693–7. [PubMed: 10468061]
  425. Little J, Cardy A, Munger RG. Tobacco smoking and oral clefts: a meta-analysis. Bulletin of the World Health Organization. 2004a;82(3):213–8. [PMC free article: PMC2585921] [PubMed: 15112010]
  426. Little J, Vainio H. Mutagenic lifestyles: a review of evidence of associations between germ-cell mutations in humans and smoking, alcohol consumption and use of ‘recreational’ drugs. Mutation Research. 1994;313( 2–3):131–51. [PubMed: 7523899]
  427. Little L, Cardy A, Arslan MT, Mossey PA. Smoking and orofacial clefts: a United Kingdom–based case-control study. Cleft Palate-Craniofacial Journal. 2004b;41(4):381–6. [PubMed: 15222794]
  428. Liu Y, Gold EB, Lasley BL, Johnson WO. Factors affecting menstrual cycle characteristics. American Journal of Epidemiology. 2004a;160(2):131–40. [PubMed: 15234934]
  429. Liu Y, Johnson WO, Gold EB, Lasley BL. Bayesian analysis of risk factors for anovulation. Statistics in Medicine. 2004b;23(12):1901–19. [PubMed: 15195323]
  430. Loft S, Kold-Jensen T, Hjollund NH, Giwercman A, Gyllemborg J, Ernst E, Olsen J, Scheike T, Poulsen HE, Bonde JP. Oxidative DNA damage in human sperm influences time to pregnancy. Human Reproduction. 2003;18(6):1265–72. [PubMed: 12773457]
  431. Loiacono NJ, Graziano JH, Kline JK, Popovac D, Ahmedi X, Gashi E, Mehmeti A, Rajovic B. Placental cadmium and birthweight in women living near a lead smelter. Archives of Environmental Health. 1992;47(4):250–5. [PubMed: 1497377]
  432. Long KZ, Santos JI. Vitamins and the regulation of the immune response. Pediatric Infectious Disease Journal. 1999;18(3):283–90. [PubMed: 10093956]
  433. Longcope C, Johnston CC Jr. Androgen and estrogen dynamics in pre- and postmenopausal women: a comparison between smokers and nonsmokers. Journal of Clinical Endocrinology and Metabolism. 1988;67(2):379–83. [PubMed: 3392163]
  434. Longo LD. Carbon monoxide: effects on oxygenation of the fetus in utero. Science. 1976;194(4264):523–5. [PubMed: 973133]
  435. Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. American Journal of Obstetrics and Gynecology. 1977;129(1):69–103. [PubMed: 561541]
  436. Lu CC, Matsumoto N, Iijima S. Teratogenic effects of nickel chloride on embryonic mice and its transfer to embryonic mice. Teratology. 1979;19(2):137–42. [PubMed: 473066]
  437. Lucero J, Harlow BL, Barbieri RL, Sluss P, Cramer DW. Early follicular phase hormone levels in relation to patterns of alcohol, tobacco, and coffee use. Fertility and Sterility. 2001;76(4):723–9. [PubMed: 11591405]
  438. Lummus ZL, Henningsen G. Modulation of T-cell ontogeny by transplacental benzo(a)pyrene. International Journal of Immunopharmacology. 1995;17(4):339–50. [PubMed: 7672884]
  439. Luppi P, Lain KY, Jeyabalan A, DeLoia JA. The effects of cigarette smoking on circulating maternal leuko-cytes during pregnancy. Clinical Immunology. 2007;122(2):214–9. [PubMed: 17161974]
  440. Lyall F. Development of the utero-placental circulation: the role of carbon monoxide and nitric oxide in trophoblast invasion and spiral artery transformation. Microscopy Research and Technique. 2003;60(4):402–11. [PubMed: 12567397]
  441. Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. American Journal of Clinical Nutrition. 2000;71(2):530–6. [PubMed: 10648268]
  442. Lykkesfeldt J, Prieme H, Loft S, Poulsen HE. Effect of smoking cessation on plasma ascorbic acid concentration. BMJ (British Medical Journal). 1996;313(7049):91. [PMC free article: PMC2351485] [PubMed: 8688760]
  443. Lynch AM, Bruce NW. Placental growth in rats exposed to carbon monoxide at selected stages of pregnancy. Biology of the Neonate. 1989;56(3):151–7. [PubMed: 2804179]
  444. MacGillivray I, Rose GA, Rowe B. Blood pressure survey in pregnancy. Clinical Science. 1969;37(2):395–407. [PubMed: 5358998]
  445. Mackenzie KM, Angevine DM. Infertility in mice exposed in utero to benzo(a)pyrene. Biology of Reproduction. 1981;24(1):183–91. [PubMed: 7470542]
  446. MacMahon B, Trichopoulos D, Brown J, Andersen AP, Cole P, deWaard F, Kauraniemi T, Polychronopoulou A, Ravnihar B, Stormby N, et al. Age at menarche, urine estrogens and breast cancer risk. International Journal of Cancer. 1982a;30(4):427–31. [PubMed: 7141738]
  447. MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens. New England Journal of Medicine. 1982b;307(17):1062–5. [PubMed: 7121516]
  448. Mactutus CF, Fechter LD. Prenatal exposure to carbon monoxide: learning and memory deficits. Science. 1984;223(4634):409–11. [PubMed: 6691152]
  449. Mactutus CF, Fechter LD. Moderate prenatal carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats. Teratology. 1985;31(1):1–12. [PubMed: 4039076]
  450. Magee BD, Hattis D, Kivel NM. Role of smoking in low birth weight. Journal of Reproductive Medicine. 2004;49(1):23–7. [PubMed: 14976791]
  451. Magers T, Talbot P, DiCarlantonio G, Knoll M, Demers D, Tsai I, Hoodbhoy T. Cigarette smoke inhalation affects the reproductive system of female hamsters. Reproductive Toxicology. 1995;9(6):513–25. [PubMed: 8597648]
  452. Magrini A, Bottini N, Gloria-Bottini F, Stefanini L, Bergamaschi A, Cosmi E, Bottini E. Enzyme polymorphisms, smoking, and human reproduction: a study of human placental alkaline phosphatase. American Journal of Human Biology. 2003;15(6):781–5. [PubMed: 14595869]
  453. Mainous AG 3rd, Hueston WJ. Passive smoke and low birth weight: evidence of a threshold effect. Archives of Family Medicine. 1994;3(10):875–8. [PubMed: 8000558]
  454. Makin J, Fried PA, Watkinson B. A comparison of active and passive smoking during pregnancy: long-term effects. Neurotoxicology and Teratology. 1991;13(1):5–12. [PubMed: 2046627]
  455. Malik S, Cleves MA, Honein MA, Romitti PA, Botto LD, Yang S, Hobbs CA. National Birth Defects Prevention Study. Maternal smoking and congenital heart defects. Pediatrics. 2008;121(4):e810–e816. [PubMed: 18381510]
  456. Malloy MH, Kleinman JC, Land GH, Schramm WF. The association of maternal smoking with age and cause of infant death. American Journal of Epidemiology. 1988;128(1):46–55. [PubMed: 3381835]
  457. Mannino DM, Mulinare J, Ford ES, Schwartz J. Tobacco smoke exposure and decreased serum and red blood cell folate levels: data from the Third National Health and Nutrition Examination Survey. Nicotine & Tobacco Research. 2003;5(3):357–62. [PubMed: 12791531]
  458. Marcoux S, Brisson J, Fabia J. The effect of cigarette smoking on the risk of preeclampsia and gestational hypertension. American Journal of Epidemiology. 1989;130(5):950–7. [PubMed: 2816902]
  459. Marcus M, Grunfeld L, Berkowitz G, Kaplan P, Godbold J. Urinary follicle-stimulating hormone as a biological marker of ovarian toxicity. Fertility and Sterility. 1993;59(4):931–3. [PubMed: 8458519]
  460. Marinelli D, Gaspari L, Pedotti P, Taioli E. Mini-review of studies on the effect of smoking and drinking habits on semen parameters. International Journal of Hygiene and Environmental Health. 2004;207(3):185–92. [PubMed: 15330386]
  461. Martin EJ, Brinton LA, Hoover R. Menarcheal age and miscarriage. American Journal of Epidemiology. 1983;117(5):634–6. [PubMed: 6846320]
  462. Martínez-Pasarell O, Nogués C, Bosch M, Egozcue J, Templado C. Analysis of sex chromosome aneuploidy in sperm from fathers of Turner syndrome patients. Human Genetics. 1999;104(4):345–9. [PubMed: 10369165]
  463. Martini AC, Molina RI, Estofán D, Senestrari D, Fiol de Cuneo M, Ruiz RD. Effects of alcohol and cigarette consumption on human seminal quality. Fertility and Sterility. 2004;82(2):374–7. [PubMed: 15302286]
  464. Mas A, Holt D, Webb M. The acute toxicity and teratogenicity of nickel in pregnant rats. Toxicology. 1985;35(1):47–57. [PubMed: 4039856]
  465. Másdóttir B, Jónsson T, Manfreosdóttir V, Víkingsson Á, Brekkan A, Valdimarsson H. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology (Oxford). 2000;39(11):1202–5. [PubMed: 11085797]
  466. Mathews JD, Whittingham S, Hooper BM, Mackay IR, Stenhouse NS. Association of autoantibodies with smoking, cardiovascular morbidity, and death in the Busselton population. Lancet. 1973;2(7832):754–8. [PubMed: 4126476]
  467. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu H-Y, Laine J, Sakai T, Korsmeyer SJ, Casper RF, et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nature Genetics. 2001;28(4):355–60. [PubMed: 11455387]
  468. Matkin CC, Britton J, Samuels S, Eskenazi B. Smoking and blood pressure patterns in normotensive pregnant women. Paediatric and Perinatal Epidemiology. 1999;13(1):22–34. [PubMed: 9987783]
  469. Matovina M, Husnjak K, Milutin N, Ciglar S, Grce M. Possible role of bacterial and viral infections in miscarriages. Fertility and Sterility. 2004;81(3):662–9. [PubMed: 15037417]
  470. Matta SG, Fu Y, Valentine JD, Sharp BM. Response of the hypothalamo-pituitary-adrenal axis to nicotine. Psychoneuroendocrinology. 1998;23(2):103–13. [PubMed: 9621392]
  471. Mattison DR. The effects of smoking on fertility from gametogenesis to implantation. Environmental Research. 1982;28(2):410–33. [PubMed: 6749489]
  472. Mattison DR, Nightingale MS. Oocyte destruction by polycyclic aromatic hydrocarbons is not linked to the inducibility of ovarian aryl hydrocarbon (benzo(a) pyrene) hydroxylase activity in (DBA/2N × C57BL/6N) F1 × DBA/2N backcross mice. Pediatric Pharmacology. 1982;2(1):11–21. [PubMed: 7110752]
  473. Mattison DR, Thorgeirsson SS. Ovarian aryl hydrocarbon hydroxylase activity and primordial oocyte toxicity of polycyclic aromatic hydrocarbons in mice. Cancer Research. 1979;39(9):3471–5. [PubMed: 113091]
  474. Maulik D, Yarlagadda P, Youngblood JP, Ciston P. The diagnostic efficacy of the umbilical arterial systolic/diastolic ratio as a screening tool: a prospective blinded study. American Journal of Obstetrics and Gynecology. 1990;162(6):1518–23. [PubMed: 2193516]
  475. Mayhew TM. Patterns of villous and intervillous space growth in human placentas from normal and abnormal pregnancies. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1996;68(1–2):75–82. [PubMed: 8886685]
  476. Mayhew TM. Thinning of the intervascular tissue layers of the human placenta is an adaptive response to passive diffusion in vivo and may help to predict the origins of fetal hypoxia. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1998;81(1):101–9. [PubMed: 9846723]
  477. Mayhew TM. Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells. Placenta. 2002;23(10):742–50. [PubMed: 12398814]
  478. Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Journal of Clinical Investigation. 2003;111(5):649–58. [PMC free article: PMC151901] [PubMed: 12618519]
  479. McCartney JS, Fried PA, Watkinson B. Central auditory processing in school-age children prenatally exposed to cigarette smoke. Neurotoxicology and Teratology. 1994;16(3):269–76. [PubMed: 7935260]
  480. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. New England Journal of Medicine. 1985;313(2):82–90. [PubMed: 3880598]
  481. McDonald HM, Chambers HM. Intrauterine infection and spontaneous midgestation abortion: is the spectrum of microorganisms similar to that in preterm labor? Infectious Diseases in Obstetrics and Gynecology. 2000;8(5–6):220–7. [PMC free article: PMC1784699] [PubMed: 11220481]
  482. McDonald SD, Perkins SL, Jodouin CA, Walker MC. Folate levels in pregnant women who smoke: an important gene/environment interaction. American Journal of Obstetrics and Gynecology. 2002;187(3):620–5. [PubMed: 12237638]
  483. McLaughlin BE, Lash GE, Graham CH, Smith GN, Vreman HJ, Stevenson DK, Marks GS, Nakatsu K, Brien JF. Endogenous carbon monoxide formation by chorionic villi of term human placenta. Placenta. 2001;22(10):886–8. [PubMed: 11718578]
  484. Meberg A, Haga P, Sande H, Foss OP. Smoking during pregnancy—hematological observations in the newborn. Acta Paediatrica Scandinavica. 1979;68(5):731–4. [PubMed: 575017]
  485. Meikle AW, Bishop DT, Stringham JD, Ford MH, West DW. Relationship between body mass index, cigarette smoking, and plasma sex steroids in normal male twins. Genetic Epidemiology. 1989;6(3):399–412. [PubMed: 2753350]
  486. Meis PJ, Michielutte R, Peters TJ, Wells HB, Sands RE, Coles EC, Johns KA. Factors associated with preterm birth in Cardiff, Wales. I: univariable and multivariable analysis. American Journal of Obstetrics and Gynecology. 1995;173(2):590–6. [PubMed: 7645639]
  487. Melkonian G, Cheung L, Marr R, Tong C, Talbot O. Mainstream and sidestream cigarette smoke inhibit growth and angiogenesis in the day 5 chick chorioallantoic membrane. Toxicological Sciences. 2002;68(1):237–48. [PubMed: 12075126]
  488. Melkonian G, Eckelhofer H, Wu M, Wang Y, Tong C, Riveles K, Talbot P. Growth and angiogenesis are inhibited in vivo in developing tissues by pyrazine and its derivatives. Toxicological Sciences. 2003;75(2):393–401. [PubMed: 12773771]
  489. Melkonian G, Le C, Zheng W, Talbot P, Martins-Green M. Normal patterns of angiogenesis and extracellular matrix deposition in chick chorioallantoic membranes are disrupted by mainstream and sidestream cigarette smoke. Toxicology and Applied Pharmacology. 2000;163(1):26–37. [PubMed: 10662602]
  490. Mendola P, Selevan SG, Gutter S, Rice D. Environmental factors associated with a spectrum of neurodevelopmental deficits. Mental Retardation and Developmental Disabilities Research Reviews. 2002;8(3):188–97. [PubMed: 12216063]
  491. Mercer BM, Crocker LG, Pierce WF, Sibai BM. Clinical characteristics and outcome of twin gestation complicated by preterm premature rupture of the membranes. American Journal of Obstetrics and Gynecology. 1993;168(5):1467–73. [PubMed: 8498429]
  492. Mercer BM, Goldenberg RL, Meis PJ, Moawad AH, Shellhaas C, Das A, Menard MK, Caritis SN, Thurnau GR, Dombrowski MP, et al. The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. American Journal of Obstetrics and Gynecology. 2000;183(3):738–45. [PubMed: 10992202]
  493. Meschia M, Pansini F, Modena AB, de Aloysio D, Gambacciani M, Parazzini F, Campagnoli C, Maiocchi G, Peruzzi E. Determinants of age at menopause in Italy: results from a large cross-sectional study. ICA-RUS Study Group, Italian Climacteric Research Study Group. Maturitas. 2000;34(2):119–25. [PubMed: 10714906]
  494. Meyer MB, Jonas BS, Tonascia JA. Perinatal events associated with maternal smoking during pregnancy. American Journal of Epidemiology. 1976;103(5):464–76. [PubMed: 944999]
  495. Miceli F, Minici F, Tropea A, Catino S, Orlando M, Lamanna G, Sagnells F, Tiberi F, Bompiani A, Mancusco S, Lanzone A, Apa R. Effects of nicotine on human luteal cells in vitro: a possible role on reproductive outcome for smoking women. Biology of Reproduction. 2005;72(3):628–32. [PubMed: 15548733]
  496. Michnovicz JJ, Hershcopf RJ, Haley NJ, Bradlow HL, Fishman J. Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis. Metabolism. 1989;38(6):537–41. [PubMed: 2725292]
  497. Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. New England Journal of Medicine. 1986;315(21):1305–9. [PubMed: 3773953]
  498. Midgette AS, Baron JA. Cigarette smoking and the risk of natural menopause. Epidemiology. 1990;1(6):474–80. [PubMed: 2090286]
  499. Millicovsky G, Johnston MC. Maternal hyperoxia greatly reduces the incidence of phenytoin-induced cleft lip and palate in A/J mice. Science. 1981;212(4495):671–2. [PubMed: 7221553]
  500. Mishra GD, Dobson AJ, Schofield MJ. Cigarette smoking, menstrual symptoms and miscarriage among young women. Australian and New Zealand Journal of Public Health. 2000;24(4):413–20. [PubMed: 11011470]
  501. Misra DP, Ananth CV. Risk factor profiles of placental abruption in first and second pregnancies: heteroge-neousetiologies. Journal of Clinical Epidemiology. 1999;52(5):453–61. [PubMed: 10360341]
  502. Mitchell EA, Ford RPK, Stewart AW, Taylor BJ, Becroft DMO, Thompson JMD, Scragg R, Hassall IB, Barry DMJ, Allen EM, et al. Smoking and the sudden infant death syndrome. Pediatrics. 1993;91(5):893–6. [PubMed: 8474808]
  503. Mitchell JH, Hammer RE. Effects of nicotine on oviducal blood flow and embryo development in the rat. Journal of Reproduction and Fertility. 1985;74(1):71–6. [PubMed: 4020775]
  504. Mochizuki M, Maruo T, Masuko K, Ohtsu T. Effects of smoking on fetoplacental-maternal system during pregnancy. American Journal of Obstetrics and Gynecology. 1984;149(4):413–20. [PubMed: 6203408]
  505. Molfese DL, Molfese VJ, Ferguson M, Key APF, Straub S, Peach K, Pratt N. Birth defects and their association with tobacco smoke. Abstract presented at the International Society for the Prevention of Tobacco Induced Diseases Conference; Oct. 29–Nov. 1, 2004; Louisville (KY).
  506. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. New England Journal of Medicine. 1993;329(27):2002–12. [PubMed: 7504210]
  507. Monica G, Lilja C. Placenta previa, maternal smoking and recurrence risk. Acta Obstetricia et Gynecologica Scandinavica. 1995;74(5):341–5. [PubMed: 7778424]
  508. Morris M, Nicoll A, Simms I, Wilson J, Catchpole M. Bacterial vaginosis: a public health review. BJOG. 2001;108(5):439–50. [PubMed: 11368127]
  509. Morrow RJ, Ritchie JW, Bull SB. Maternal cigarette smoking: the effects on umbilical and uterine blood flow velocity. American Journal of Obstetrics and Gynecology. 1988;159(5):1069–71. [PubMed: 3055994]
  510. Mortensen EL, Michaelsen KF, Sanders SA, Reinisch JM. A dose-response relationship between maternal smoking during late pregnancy and adult intelligence in male offspring. Paediatric and Perinatal Epidemiology. 2005;19(1):4–11. [PubMed: 15670102]
  511. Mullen PD. Maternal smoking during pregnancy and evidence-based intervention to promote cessation. Primary Care. 1999;26(3):577–89. [PubMed: 10436288]
  512. Munger RG, Sauberlich HE, Corcoran C, Nepomuceno B, Daack-Hirsch S, Solon FS. Maternal vitamin B-6 and folate status and risk of oral cleft birth defects in the Philippines. Birth Defects Research Part A, Clinical and Molecular Teratology. 2004;70(7):464–71. [PubMed: 15259036]
  513. Murthy RC, Junaid M, Saxena DK. Ovarian dysfunction in mice following chromium (VI) exposure. Toxicology Letters. 1996;89(2):147–54. [PubMed: 8960157]
  514. Murthy RC, Saxena DK, Gupta SK, Chandra SV. Ultra-structural observations in testicular tissue of chromium-treated rats. Reproductive Toxicology. 1991;5(5):443–7. [PubMed: 1806154]
  515. Myatt L, Brewer A, Brockman DE. The action of nitric oxide in the perfused human fetal-placental circulation. American Journal of Obstetrics and Gynecology. 1991;164(2):687–92. [PubMed: 1899534]
  516. Myatt L, Brewer AS, Langdon G, Brockman DE. Attenuation of the vasoconstrictor effects of thromboxane and endothelin by nitric oxide in the human fetal-placental circulation. American Journal of Obstetrics and Gynecology. 1992;166(1 Pt 1):224–30. [PubMed: 1733199]
  517. Naeye RL. Effects of maternal cigarette smoking on the fetus and placenta. British Journal of Obstetrics and Gynaecology. 1978;85(10):732–7. [PubMed: 708656]
  518. Naeye RL. The duration of maternal cigarette smoking, fetal and placental disorders. Early Human Development. 1979;3(3):229–37. [PubMed: 527525]
  519. Naeye RL. Factors that predispose to premature rupture of the fetal membranes. Obstetrics and Gynecology. 1982;60(1):93–8. [PubMed: 7088456]
  520. Naeye RL, Peters EC. Causes and consequences of premature rupture of fetal membranes. Lancet. 1980;1(8161):192–4. [PubMed: 6101643]
  521. Naicker T, Khedun SM, Moodley J, Pijnenborg R. Quantitative analysis of trophoblast invasion in preeclampsia. Acta Obstetricia et Gynecologica Scandinavica. 2003;82(8):722–9. [PubMed: 12848643]
  522. National Cancer Institute. Health Effects of Exposure to Environmental Tobacco Smoke: The Report of the California Environmental Protection Agency, Smoking and Tobacco Control Monograph No 10. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute; 1999. NIH Publication No 99-4645.
  523. National High Blood Pressure Education Program. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. American Journal of Obstetrics and Gynecology. 2000;183(1):S1–S22. [PubMed: 10920346]
  524. National Research Council. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washington: National Academy Press; 1986.
  525. Navas JM, Segner H. Antiestrogenicity of β-naphthoflavone and PAHs in cultured rainbow trout hepatocytes: evidence for a role of the arylhydrocarbon receptor. Aquatic Toxicology. 2000;51(1):79–92. [PubMed: 10998501]
  526. Neal MS, Hughes EG, Holloway AC, Foster WG. Side-stream smoking is equally as damaging as mainstream smoking on IVF outcomes. Human Reproduction. 2005;20(9):2531–5. [PubMed: 15919779]
  527. Nelson E, Goubet-Wiemers C, Guo Y, Jodscheit K. Maternal passive smoking during pregnancy and fetal developmental toxicity. Part 2: histological changes. Human & Experimental Toxicology. 1999a;18(4):257–64. [PubMed: 10333312]
  528. Nelson E, Jodscheit K, Guo Y. Maternal passive smoking during pregnancy and fetal developmental toxicity. Part 1: gross morphological effects. Human & Experimental Toxicology. 1999b;18(4):252–6. [PubMed: 10333311]
  529. Neri A, Eckerling B. Influence of smoking and adrenaline (epinephrine) on the uterotubal insufflation test (Rubin test). Fertility and Sterility. 1969;20(5):818–27. [PubMed: 5822864]
  530. Neri A, Marcus SL. Effect of nicotine on the motility of the oviducts in the rhesus monkey: a preliminary report. Journal of Reproduction and Fertility. 1972;31(1):91–7. [PubMed: 4627858]
  531. Ness RB, Grisso JA, Hirschinger N, Markovic N, Shaw LM, Day NL, Kline J. Cocaine and tobacco use and the risk of spontaneous abortion. New England Journal of Medicine. 1999;340(5):333–9. [PubMed: 9929522]
  532. Newnham JP, Patterson L, James I, Reid SE. Effects of maternal cigarette smoking on ultrasonic measurements of fetal growth and on Doppler flow velocity waveforms. Early Human Development. 1990;24(1):23–36. [PubMed: 2265596]
  533. Nicol CJ, Harrison ML, Laposa RR, Gimelshtein IL, Wells PG. A teratologic suppressor role for p53 in benzo[a] pyrene-treated transgenic p53-deficient mice. Nature Genetics. 1995;10(2):181–7. [See also erratum in Nature Genetics 1995;11(1):104.] [PubMed: 7663513]
  534. Nielsen A, Hannibal CG, Lindekilde BE, Tolstrup J, Frederiksen K, Munk C, Bergholt T, Buss L, Ottesen B, Gronback M, et al. Maternal smoking predicts the risk of spontaneous abortion. Acta Obstetricia et Gynecologica Scandinavica. 2006;85(9):1057–65. [PubMed: 16929410]
  535. Nishijo M, Nakagawa H, Honda R, Tanebe K, Saito S, Teranishi H, Tawara K. Effects of maternal exposure to cadmium on pregnancy outcome and breast milk. Occupational and Environmental Medicine. 2002;59(6):394–7. [PMC free article: PMC1740300] [PubMed: 12040115]
  536. Noble RC, Penny BB. Comparison of leukocyte count and function in smoking and nonsmoking young men. Infection and Immunity. 1975;12(3):550–5. [PMC free article: PMC415322] [PubMed: 1100522]
  537. Norman CA, Halton DM. Is carbon monoxide a workplace teratogen: a review and evaluation of the literature. Annals of Occupational Hygiene. 1990;34(4):335–47. [PubMed: 2240988]
  538. Nouri-Shirazi M, Guinet E. Evidence for the immunosup-pressive role of nicotine on human dendritic cell functions. Immunology. 2003;109(3):365–73. [PMC free article: PMC1782971] [PubMed: 12807482]
  539. Cigarette use among pregnant women and recent mothers, NSDUH Report. NSDUH Report. Feb 9, 2007.
  540. Nukui T, Day RD, Sims CS, Ness RB, Romkes M. Maternal/newborn GSTT1 null genotype contributes to risk of pre-term, low birthweight infants. Pharmacogenetics. 2004;14(9):569–76. [PubMed: 15475730]
  541. Nylund L, Lunell NO, Persson B, Fredholm BB, Lager-crantz H. Acute metabolic and circulatory effects of cigarette smoking in late pregnancy. Gynecologic and Obstetric Investigation. 1979;10(1):39–45. [PubMed: 226461]
  542. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Lüscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97(25):2494–8. [PubMed: 9657467]
  543. Ogden L, Graham T, Mahboob M, Atkinson A, Hammersley M, Sarkar N. Effects of zinc chloride on reproductive parameters of cd-1 mice. Toxicologist. 2002;66(1–S):33.
  544. Olds DL, Henderson CR Jr, Tatelbaum R. Intellectual impairment in children of women who smoke cigarettes during pregnancy. Pediatrics. 1994;93(2):221–7. [PubMed: 8121734]
  545. Oncken C, Kranzler H, O’Malley P, Gendreau P, Campbell WA. The effect of cigarette smoking on fetal heart rate characteristics. Obstetrics and Gynecology. 2002;99(5):751–5. [PubMed: 11978283]
  546. Oncken CA, Hardardottir H, Hatsukami DK, Lupo VR, Rodis JF, Smeltzer JS. Effects of transdermal nicotine or smoking on nicotine concentrations and maternal-fetal hemodynamics. Obstetrics and Gynecology. 1997;90(4 Pt 1):569–74. [PubMed: 9380317]
  547. Oncken CA, Hatsukami DK, Lupo VR, Lando HA, Gibeau LM, Hansen RJ. Effects of short-term use of nicotine gum in pregnant smokers. Clinical Pharmacology and Therapeutics. 1996;59(6):654–61. [PubMed: 8681490]
  548. Ortega RM, Requejo AM, López-Sobaler AM, Navia B, Mena MC, Basabe B, Andrés P. Smoking and passive smoking as conditioners of folate status in young women. Journal of the American College of Nutrition. 2004;23(4):365–71. [PubMed: 15310741]
  549. Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM. Suppression of human IL-1β, IL-2, IFN-γ, and TNF-α production by cigarette smoke extracts. Journal of Allergy and Clinical Immunology. 2000;106(2):280–7. [PubMed: 10932071]
  550. Owen L, Penn G. Smoking in Pregnancy: A Survey of Knowledge, Attitudes and Behaviours, 1992–1999. London: Health Education Authority; 1999.
  551. Oyen N, Skjaerven R, Little RE, Wilcox AJ. Fetal growth retardation in sudden infant death syndrome (SIDS) babies and their siblings. American Journal of Epidemiology. 1995;142(1):84–90. [PubMed: 7785678]
  552. Özeren M, Dinç H, Ekmen Ü, Senekayli C, Aydemir V. Umbilical and middle cerebral artery Doppler indices in patients with preeclampsia. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1999;82(1):11–6. [PubMed: 10192477]
  553. Ozgur K, Isikoglu M, Seleker M, Donmez L. Semen quality of smoking and non-smoking men in infertile couples in a Turkish population. Archives of Gynecology and Obstetrics. 2005;271(2):109–12. [PubMed: 14685893]
  554. Pachlopnik Schmid JM, Kuehni CE, Strippoli MP, Roiha HL, Pavlovic R, Latzin P, Gallati S, Kraemer R, Dahinden C, Frey U, et al. Maternal tobacco smoking and decreased leukocytes, including dendritic cells, in neonates. Pediatric Research. 2007;61(4):462–6. [PubMed: 17515872]
  555. Packianathan S, Cain CD, Stagg RB, Longo LD. Ornithine decarboxylase activity in fetal and newborn rat brain: responses to hypoxic and carbon monoxide hypoxia. Brain Research Developmental Brain Research. 1993;76(1):131–40. [PubMed: 8306425]
  556. Paneth NS. The problem of low birth weight. The Future of Children: Low Birth Weight. 1995;5(1):19–34. < http://www​.futureofchildren.org>. [PubMed: 7633862]
  557. Pant N, Kumar R, Murthy RC, Srivastava SP. Male reproductive effect of arsenic in mice. Biometals. 2001;14(2):113–7. [PubMed: 11508843]
  558. Panter KE, Weinzweig J, Gardner DR, Stegelmeier BL, James LF. Comparison of cleft palate induction by Nicotiana glauca in goats and sheep. Teratology. 2000;61(3):203–10. [PubMed: 10661910]
  559. Papageorghiou AT, Yu CKH, Erasmus IE, Cuckle HS, Nicolaides KH. Assessment of risk for the development of pre-eclampsia by maternal characteristics and uterine artery Doppler. BJOG. 2005;112(6):703–9. [PubMed: 15924523]
  560. Parazzini F, Tozzi L, Mezzopane R, Luchini L, Marchini M, Fedele L. Cigarette smoking, alcohol consumption and risk of primary dysmenorrhea. Epidemiology. 1994;5(4):469–72. [PubMed: 7918820]
  561. Pastrakuljic A, Derewlany LO, Knie B, Koren G. The effects of cocaine and nicotine on amino acid transport across the human placental cotyledon perfused in vitro. Journal of Pharmacology and Experimental Therapeutics. 2000;294(1):141–6. [PubMed: 10871305]
  562. Pastrakuljic A, Derewlany LO, Koren G. Maternal cocaine use and cigarette smoking in pregnancy in relation to amino acid transport and fetal growth. Placenta. 1999;20(7):499–512. [PubMed: 10452903]
  563. Penney DG. Effects of carbon monoxide exposure on developing animals and humans. Carbon Monoxide. Penney DG, editor. Boca Raton (FL): CRC Press; 1996. pp. 109–44.
  564. Perera FP, Tang D, Tu Y-H, Cruz LA, Borjas M, Bernert T, Whyatt RM. Biomarkers in maternal and newborn blood indicate heightened fetal susceptibility to procarcinogenic DNA damage. Environmental Health Perspectives. 2004;112(10):1133–6. [PMC free article: PMC1247389] [PubMed: 15238289]
  565. Perera FP, Whyatt RM, Jedrychowski W, Rauh V, Manchester D, Santella RM, Ottman R. Recent developments in molecular epidemiology: a study of the effects of environmental polycyclic aromatic hydrocarbons on birth outcomes in Poland. American Journal of Epidemiology. 1998;147(3):309–14. [PubMed: 9482506]
  566. Perreault SD, Aitken RJ, Baker HWG, Evenson DP, Huszar G, Irvine DS, Morris ID, Morris RA, Robbins WA, Sakkas D, et al. Integrating new tests of sperm genetic integrity into semen analysis: breakout group discussion. Advances in Male Mediated Developmental Toxicity. Advances in Experimental Medicine and Biology. Robaire B, Hales BF, editors. Vol. 518. New York: Kluwer Academic; 2003. pp. 253–68. [PubMed: 12817694]
  567. Peterson KL, Heninger RW, Seegmiller RE. Fetotoxicity following chronic prenatal treatment of mice with tobacco smoke and ethanol. Bulletin of Environmental Contamination and Toxicology. 1981;26(6):813–9. [PubMed: 7196271]
  568. Pfarrer C, Macara L, Leiser R, Kingdom J. Adaptive angiogenesis in placentas of heavy smokers. Lancet. 1999;354(9175):303. [PubMed: 10440311]
  569. Phelan JP. Diminished fetal reactivity with smoking. American Journal of Obstetrics and Gynecology. 1980;136(2):230–3. [PubMed: 7352504]
  570. Philipp K, Pateisky N, Endler M. Effects of smoking on uteroplacental blood flow. Gynecologic and Obstetric Investigation. 1984;17(4):179–82. [PubMed: 6724346]
  571. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Human Reproduction. 2003;18(8):1724–32. [PubMed: 12871891]
  572. Piasek M, Blanuša M, Kostial K, Laskey JW. Placental cadmium and progesterone concentrations in cigarette smokers. Reproductive Toxicology. 2001;15(6):673–81. [PubMed: 11738520]
  573. Picone TA, Allen LH, Olsen PN, Ferris ME. Pregnancy outcome in North American women. II: effects of diet, cigarette smoking, stress, and weight gain on placentas, and on neonatal physical and behavioral characteristics. American Journal of Clinical Nutrition. 1982;36(6):1214–24. [PubMed: 7148740]
  574. Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RFA. Maternal and paternal risk factors for cryptor-chidism and hypospadias: a case-control study in newborn boys. Environmental Health Perspectives. 2004;112(15):1570–6. [PMC free article: PMC1247623] [PubMed: 15531444]
  575. Pijpers L, Wladimiroff JW, McGhie JS, Bom N. Acute effect of maternal smoking on the maternal and fetal cardiovascular system. Early Human Development. 1984;10(1–2):95–105. [PubMed: 6499724]
  576. Pisarska MD, Carson SA, Buster JE. Ectopic pregnancy. Lancet. 1998;351(9109):1115–20. [PubMed: 9660597]
  577. Pittaway DE, Maxson W, Daniell J, Herbert C, Wentz AC. Luteal phase defects in infertility patients with endo-metriosis. Fertility and Sterility. 1983;39(5):712–3. [PubMed: 6840312]
  578. Plasterer MR, Bradshaw WS, Booth GM, Carter MW, Schuler RL, Hardin BD. Developmental toxicity of nine selected compounds following prenatal exposure in the mouse: naphthalene, p-nitrophenol, sodium selenite, dimethyl phthalate, ethylenethiourea, and four glycol ether derivatives. Journal of Toxicology and Environmental Health. 1985;15(1):25–38. [PubMed: 3981663]
  579. Plopper CG, Macklin J, Nishio SJ, Hyde DM, Buckpitt AR. Relationship of cytochrome P-450 to Clara cell cytotoxicity. III: morphometric comparison of changes in the epithelial populations of terminal bronchioles and lobar bronchi in mice, hamsters, and rats after parenteral administration of naphthalene. Laboratory Investigation. 1992a;67(5):553–65. [PubMed: 1434534]
  580. Plopper CG, Suverkropp C, Morin D, Nishio S, Buckpitt A. Relationship of cytochrome P-450 to Clara cell cytotoxicity. I: hisopathological comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene. Journal of Pharmacology and Experimental Therapeutics. 1992b;261(1):353–63. [PubMed: 1560379]
  581. Polansky FF, Lamb EJ. Do the results of semen analysis predict future fertility: a survival analysis study. Fertility and Sterility. 1988;49(6):1059–65. [PubMed: 3371484]
  582. Poredoš P, Orehek M, Tratnik E. Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction. Angiology. 1999;50(3):201–8. [PubMed: 10088799]
  583. Poston L, McCarthy AL, Ritter JM. Control of vascular resistance in the maternal and feto-placental arterial beds. Pharmacology & Therapeutics. 1995;65(2):215–39. [PubMed: 7792316]
  584. Potts RJ, Newbury CJ, Smith G, Notarianni LJ, Jefferies TM. Sperm chromatin damage associated with male smoking. Mutation Research. 1999;423(1–2):103–11. [PubMed: 10029686]
  585. Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility. Fertility and Sterility. 2004;81(4):1181–6. [PubMed: 15066502]
  586. Prasad AS. Zinc deficiency in women, infants and children. Journal of the American College of Nutrition. 1996;15(2):113–20. [PubMed: 8778139]
  587. Preston AM. Cigarette smoking-nutritional implications. Progress in Food & Nutrition Science. 1991;15(4):183–217. [PubMed: 1784736]
  588. Quigley ME, Sheehan KL, Wilkes MM, Yen SS. Effects of maternal smoking on circulating catecholamine levels and fetal heart rates. American Journal of Obstetrics and Gynecology. 1979;133(6):685–90. [PubMed: 426024]
  589. Rasch V. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. Acta Obstetricia et Gynecologica Scandinavica. 2003;82(2):182–8. [PubMed: 12648183]
  590. Rasmussen S, Irgens LM, Bergsjø P, Dalaker K. Perinatal mortality and case fatality after placental abruption in Norway 1967–1991. Acta Obstetricia et Gynecologica Scandinavica. 1996a;75(3):229–34. [PubMed: 8607334]
  591. Rasmussen S, Irgens LM, Bergsjø P, Dalaker K. The occurrence of placental abruption in Norway 1967–1991. Acta Obstetricia et Gynecologica Scandinavica. 1996b;75(3):222–8. [PubMed: 8607333]
  592. Rasmussen S, Irgens LM, Dalaker K. A history of placental dysfunction and risk of placental abruption. Paediatric and Perinatal Epidemiology. 1999;13(1):9–21. [PubMed: 9987782]
  593. Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, Diaz D, Camann D, Perera FP. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicology and Teratology. 2004;26(3):373–85. [PMC free article: PMC3376003] [PubMed: 15113599]
  594. Rauramo I, Forss M, Kariniemi V, Lehtovirta P. Antepartum fetal heart rate variability and intervillous placental blood flow in association with smoking. American Journal of Obstetrics and Gynecology. 1983;146(8):967–9. [PubMed: 6881230]
  595. Raymond EG, Mills JL. Placental abruption: maternal risk factors and associated fetal conditions. Acta Obstetricia et Gynecologica Scandinavica. 1993;72(8):633–9. [PubMed: 8259750]
  596. Reefhuis J, de Walle HE, Cornel MC. Maternal smoking and deformities of the foot: results of the EUROCAT Study. European Registries of Congenital Anomalies. American Journal of Public Health. 1998;88(10):1554–5. [PMC free article: PMC1508471] [PubMed: 9772862]
  597. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ (British Medical Journal). 1989;299(6698):541–5. [PMC free article: PMC1837397] [PubMed: 2507063]
  598. Regan L, Owen EJ, Jacobs HS. Hypersecretion of lutei-nising hormone, infertility, and miscarriage. Lancet. 1990;336(8724):141–4. [PubMed: 1978024]
  599. Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Bailliere’s Best Practice & Research Clinical Obstetrics & Gynaecology. 2000;14(5):839–54. [PubMed: 11023804]
  600. Reynolds P, Hurley SE, Hoggatt K, Anton-Culver H, Bernstein L, Deapen D, Peel D, Pinder R, Ross RK, West D, et al. Correlates of active and passive smoking in the California Teachers Study Cohort. Journal of Women’s Health. 2004;13(7):778–90. [PubMed: 15385072]
  601. Reznik G, Marquard G. Effect of cigarette smoke inhalation during pregnancy in Sprague-Dawley rats. Journal of Environmental Pathology and Toxicology. 1980;4(5–6):141–52. [PubMed: 7217842]
  602. Rice C, Yoshinaga K. Effect of nicotine on oviducal lactate dehydrogenase during early pregnancy in the rat. Biology of Reproduction. 1980;23(2):445–51. [PubMed: 7417684]
  603. Riedl M, Diaz-Sanchez D. Biology of diesel exhaust effects on respiratory function. Journal of Allergy and Clinical Immunology. 2005;115(2):221–8. [PubMed: 15696072]
  604. Ritz B, Yu F, Fruin S, Chapa G, Shaw GM, Harris JA. Ambient air pollution and risk of birth defects in southern California. American Journal of Epidemiology. 2002;155(1):17–25. [PubMed: 11772780]
  605. Riveles KA. Identification and quantification of toxicants in mainstream and sidestream smoke that affect hamster oviductal functioning [dissertation]. Riverside (CA): University of California; 2004.
  606. Riveles K, Iv M, Arey J, Talbot P. Pyridines in cigarette smoke inhibit hamster oviductal functioning in picomolar doses. Reproductive Toxicology. 2003;17(2):191–202. [PubMed: 12642152]
  607. Riveles K, Roza R, Arey J, Talbot P. Pyrazine derivatives in cigarette smoke inhibit hamster oviductal functioning. Reproductive Biology and Endocrinology. 2004;2:23. [PMC free article: PMC428586] [PubMed: 15140253]
  608. Riveles K, Roza R, Talbot P. Phenols, quinolines, indoles, benzene, and 2-cyclopenten-1-ones are oviductal toxicants in cigarette smoke. Toxicological Sciences. 2005;86(1):141–51. [PubMed: 15716489]
  609. Robbins WA, Elashoff DA, Xun L, Jia J, Li N, Wu G, Wei F. Effect of lifestyle exposures on sperm aneuploidy. Cytogenetic and Genome Research. 2005;111(3–4):371–7. [PubMed: 16192719]
  610. Roberts JM, Redman CWG. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet. 1993;341(8858):1447–51. [PubMed: 8099148]
  611. Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. American Journal of Hypertension. 1991;4(8):700–8. [PubMed: 1930853]
  612. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. American Journal of Obstetrics and Gynecology. 1989;161(5):1200–4. [PubMed: 2589440]
  613. Romero R, Espinoza J, Chaiworapongsa T, Kalache K. Infection and prematurity and the role of preventive strategies. Seminars in Neonatology. 2002;7(4):259–74. [PubMed: 12401296]
  614. Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC. Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts. Teratology. 1999;59(1):39–50. [PubMed: 9988882]
  615. Ronco AM, Arguello G, Muñoz L, Gras N, Llanos M. Metals content in placentas from moderate cigarette consumers: correlation with newborn birth weight. Biometals. 2005;18(3):233–41. [PubMed: 15984568]
  616. Rowell PP, Sastry BVR. The influence of cholinergic blockade on the uptake of α-aminoisobutyric acid by isolated human placental villi. Toxicology and Applied Pharmacology. 1978;45(1):79–93. [PubMed: 694941]
  617. Rowland AS, Baird DD, Long S, Wegienka G, Harlow SD, Alavanja M, Sandler DP. Influence of medical conditions and lifestyle factors on the menstrual cycle. Epidemiology. 2002;13(6):668–74. [PubMed: 12410008]
  618. Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. The effect of occupational exposure to mercury vapour on the fertility of female dental assistants. Occupational and Environmental Medicine. 1994;51(1):28–34. [PMC free article: PMC1127897] [PubMed: 8124459]
  619. Royce RA, Winkelstein W Jr. HIV infection, cigarette smoking and CD4+ T-lymphocyte counts: preliminary results from the San Francisco Men’s Health Study. AIDS. 1990;4(4):327–33. [PubMed: 1972021]
  620. Ruckebusch Y. Relationship between the electrical activity of the oviduct and the uterus of the rabbit in vivo. Journal of Reproduction and Fertility. 1975;45(1):73–82. [PubMed: 1195258]
  621. Ryter SW, Morse D, Choi AM. Carbon monoxide: to boldly go where NO has gone before. Science’s STKE. 2004;(230):RE6. [PubMed: 15114002]
  622. Saaranen M, Kantola M, Saarikoski S, Vanha-Perttula T. Human seminal plasma cadmium: comparison with fertility and smoking habits. Andrologia. 1989;21(2):140–5. [PubMed: 2712368]
  623. Salihu HM, Li Q, Rouse DJ, Alexander GR. Placenta previa: neonatal death after live births in the United States. American Journal of Obstetrics and Gynecology. 2003;188(5):1305–9. [PubMed: 12748503]
  624. Salihu HM, Shumpert MN, Aliyu MH, Kirby RS, Alexander GR. Smoking-associated fetal morbidity among older gravidas: a population study. Acta Obstetricia et Gynecologica Scandinavica. 2005;84(4):329–34. [PubMed: 15762961]
  625. Sallmén M, Lindbohm ML, Nurminen M. Paternal exposure to lead and infertility. Epidemiology. 2000;11(2):148–52. [PubMed: 11021611]
  626. Samuelson SO, Magnus P, Bakketeig LS. Birth weight and mortality in childhood in Norway. American Journal of Epidemiology. 1998;148(10):983–91. [PubMed: 9829870]
  627. Sandler DP, Wilcox AJ, Horney LF. Age at menarche and subsequent reproductive events. American Journal of Epidemiology. 1984;119(5):765–74. [PubMed: 6720673]
  628. Sanyal MK, Li Y-L, Belanger K. Metabolism of polynuclear aromatic hydrocarbon in human term placenta influenced by cigarette smoke exposure. Reproductive Toxicology. 1994;8(5):411–8. [PubMed: 7841660]
  629. Sarasin A, Schlumpf M, Müller M, Fleischmann I, Lauber ME, Lichtensteiger W. Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat. Reproductive Toxicology. 2003;117(2):153–62. [PubMed: 12642147]
  630. Sasagawa S, Suzuki K, Sakatani T, Fujikura T. Effects of nicotine on the functions of human polymorphonuclear leukocytes in vitro. Journal of Leukocyte Biology. 1985;37(5):493–502. [PubMed: 2984301]
  631. Sasser LB, Kelman BJ, Levin AA, Miller RK. The influence of maternal cadmium exposure or fetal cadmium injection on hepatic metallothionein concentrations in the fetal rat. Toxicology and Applied Pharmacology. 1985;80(2):299–307. [PubMed: 4024119]
  632. Sastry BVR. Placental toxicology: tobacco smoke, abused drugs, multiple chemical interactions, and placental function. Reproduction, Fertility, and Development. 1991;3(4):355–72. [PubMed: 1957023]
  633. Sauter D. Hematologic principles. Goldfrank’s Toxicologic Emergencies. 5th ed. Goldfrank LR, Weisman RS, Flomenbaum NE, Howland MA, Lewin NA, Hoffman RS, editors. Norwalk (CT): Appleton & Lange; 1994. pp. 345–64.
  634. Savitz DA, Schwingl PJ, Keels MA. Influence of paternal age, smoking, and alcohol consumption on congenital anomalies. Teratology. 1991;44(4):429–40. [PubMed: 1962288]
  635. Saxena DK, Murthy RC, Lal B, Srivastava RS, Chandra SV. Effect of hexavalent chromium on testicular maturation in the rat. Reproductive Toxicology. 1990;4(3):223–8. [PubMed: 2136040]
  636. Schoendorf KC, Kiely JL. Relationship of sudden infant death syndrome to maternal smoking during and after pregnancy. Pediatrics. 1992;90(6):905–8. [PubMed: 1437432]
  637. Schoeneck JF. Cigarette smoking in pregnancy. New York State Journal of Medicine. 1941;41:1945–48.
  638. Scholl TO, Hediger ML, Schall JI, Fischer RL, Khoo C-S. Low zinc intake during pregnancy: its association with preterm and very preterm delivery. American Journal of Epidemiology. 1993;137(10):1115–24. [PubMed: 8317441]
  639. Schwarze A, Nelles I, Krapp M, Friedrich M, Schmidt W, Diedrich K, Axt-Fliedner R. Doppler ultrasound of the uterine artery in the prediction of severe complications during low-risk pregnancies. Archives of Gynecology and Obstetrics. 2005;271(1):46–52. [PubMed: 15185101]
  640. Schwingl PJ. Prenatal smoking exposure in relation to female adult fecundability [dissertation]. Ann Arbor (MI): United Microfilms International; 1992.
  641. Scott RT Jr, Hofmann GE. Prognostic assessment of ovarian reserve. Fertility and Sterility. 1995;63(1):1–11. [PubMed: 7805895]
  642. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertility and Sterility. 1989;51(4):651–4. [PubMed: 2494082]
  643. Segarra AC, Strand FL. Perinatal administration of nicotine alters subsequent sexual behavior and testosterone levels of male rats. Brain Research. 1989;480(1–2):151–9. [PubMed: 2713649]
  644. Sekhon HS, Keller JA, Benowitz NL, Spindel ER. Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys. American Journal of Respiratory and Critical Care Medicine. 2001;164(6):989–94. [PubMed: 11587984]
  645. Selevan SG, Rice DC, Hogan KA, Euling SY, Pfahles-Hutchens A, Bethel J. Blood lead concentration and delayed puberty in girls. New England Journal of Medicine. 2003;348(16):1527–36. [PubMed: 12700372]
  646. Sergerie M, Ouhilal S, Bissonnette F, Brodeur J, Bleau G. Lack of association between smoking and DNA fragmentation in the spermatozoa of normal men. Human Reproduction. 2000;15(6):1314–21. [PubMed: 10831562]
  647. Sexton M, Fox NL, Hebel JR. Prenatal exposure to tobacco. II: effects on cognitive functioning at age three. International Journal of Epidemiology. 1990;19(1):72–7. [PubMed: 2351527]
  648. Seyler LE Jr, Pomerleau OF, Fertig JB, Hunt D, Parker K. Pituitary hormone response to cigarette smoking. Pharmacology, Biochemistry, and Behavior. 1986;24(1):159–62. [PubMed: 3945662]
  649. Shaarawy M, Mahmoud KZ. Endocrine profile and semen characteristics in male smokers. Fertility and Sterility. 1982;38(2):255–7. [PubMed: 6809501]
  650. Shah D, Shroff S, Gania K. Factors affecting perinatal mortality in India (perinatal audit). Prenatal and Neonatal Medicine. 2000;5(5):288–302.
  651. Shah NR, Bracken MB. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. American Journal of Obstetrics and Gynecology. 2000;182(2):465–72. [PMC free article: PMC2706697] [PubMed: 10694353]
  652. Shaw GM, Carmichael SL, Vollset SE, Yang W, Finnell RH, Blom H, Midttun Ø, Ueland PM. Mid-pregnancy cotinine and risks of orofacial clefts and neural tube defects. Journal of Pediatrics. 2009;154(1):17–9. [PubMed: 18990410]
  653. Shaw GM, Nelson V, Carmichael SL, Lammer EJ, Finnell RH, Rosenquist TH. Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies? Epidemiology. 2002;13(6):625–30. [PubMed: 12410002]
  654. Shaw GM, Wasserman CR, Lammer EJ, O’Malley CD, Murray JC, Basart AM, Tolarova MM. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. American Journal of Human Genetics. 1996;58(3):551–61. [PMC free article: PMC1914570] [PubMed: 8644715]
  655. Shen H-M, Chia S-E, Ni Z-Y, New A-L, Lee B-L, Ong C-N. Detection of oxidative DNA damage in human sperm and the association with cigarette smoking. Reproductive Toxicology. 1997;11(5):675–80. [PubMed: 9311575]
  656. Shi M, Christensen K, Weinberg CR, Romitti P, Bathum L, Lozada A, Morris RW, Lovett M, Murray JC. Orafacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. American Journal of Human Genetics. 2007;80(1):76–90. [PMC free article: PMC1785306] [PubMed: 17160896]
  657. Shubert PJ, Diss E, Iams JD. Etiology of preterm premature rupture of membranes. Obstetrics and Gynecology Clinics of North America. 1992;19(2):251–63. [PubMed: 1630736]
  658. Shugart L, Matsunami R. Adduct formation in hemoglobin of the newborn mouse exposed in utero to benzo[a] pyrene. Toxicology. 1985;37(3–4):241–5. [PubMed: 3934797]
  659. Shum S, Jensen NM, Nebert DW. The murine Ah locus: in utero toxicity and teratogenesis associated with genetic differences in benzo[a]pyrene metabolism. Teratology. 1979;20(3):365–76. [PubMed: 542892]
  660. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstetrics and Gynecology. 2003;102(1):181–92. [PubMed: 12850627]
  661. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–99. [PubMed: 15733721]
  662. Siegel E, Wason S. Mothball toxicity. Pediatric Clinics of North America. 1986;33(2):369–74. [PubMed: 3515301]
  663. Sikorski R, Juszkiewicz T, Paszkowski T. Zinc status in women with premature rupture of membranes at term. Obstetrics and Gynecology. 1990;76(4):675–7. [PubMed: 2216202]
  664. Sikorski R, Radomanski T, Paszkowski T, Skoda J. Smoking during pregnancy and the perinatal cadmium burden. Journal of Perinatal Medicine. 1988;16(3):225–31. [PubMed: 3210108]
  665. Simhan HN, Caritis SN, Hillier SL, Krohn MA. Cervical anti-inflammatory cytokine concentrations among first-trimester pregnant smokers. American Journal of Obstetrics and Gynecology. 2005;193(6):1999–2003. [PubMed: 16325603]
  666. Simhan HN, Krohn MA. First-trimester cervical inflammatory milieu and subsequent early preterm birth. American Journal of Obstetrics and Gynecology. 2009;200(4):377.e1–377.e4. [PubMed: 19200941]
  667. Simmer K, Thompson RPH. Maternal zinc and intrauterine growth retardation. Clinical Science (London). 1985;68(4):395–9. [PubMed: 3971668]
  668. Sindberg Eriksen P, Gennser G. Acute responses to maternal smoking of the pulsatile movements in fetal aorta. Acta Obstetricia et Gynecologica Scandinavica. 1984;63(7):647–54. [PubMed: 6393688]
  669. Sindberg Eriksen P, Gennser G, Lindvall R, Nilsson K. Acute effects of maternal smoking on fetal heart beat intervals. Acta Obstetricia et Gynecologica Scandinavica. 1984;63(5):385–90. [PubMed: 6496041]
  670. Sindberg Eriksen P, Marsál K. Acute effects of maternal smoking on fetal blood flow. Acta Obstetricia et Gyne-cologica Scandinavica. 1984;63(5):391–7. [PubMed: 6388221]
  671. Sindberg Eriksen P, Marsál K. Circulatory changes in the fetal aorta after maternal smoking. British Journal of Obstetrics and Gynaecology. 1987;94(4):301–5. [PubMed: 3555602]
  672. Singh J. Early behavioral alterations in mice following prenatal carbon monoxide exposure. Neurotoxicology. 1986;7(2):475–81. [PubMed: 3785762]
  673. Skelly AC, Holt VL, Mosca VS, Alderman BW. Talipes equinovarus and maternal smoking: a population-based case-control study in Washington state. Teratology. 2002;66(2):91–100. [PubMed: 12210013]
  674. Skinner SJM, Campos GA, Liggins GC. Collagen content of human amniotic membranes: effect of gestation length and premature rupture. Obstetrics and Gynecology. 1981;57(4):487–9. [PubMed: 7243099]
  675. Skjeldestad FE, Hadgu A, Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study. Obstetrics and Gynecology. 1998;91(1):129–35. [PubMed: 9464736]
  676. Sloss EM, Frerichs RR. Smoking and menstrual disorders. International Journal of Epidemiology. 1983;12(1):107–9. [PubMed: 6840951]
  677. Smart S, Singal A, Mindel A. Social and sexual risk factors for bacterial vaginosis. Sexually Transmitted Infections. 2004;80(1):58–62. [PMC free article: PMC1758378] [PubMed: 14755039]
  678. Smith CJ, Livingston SD, Doolittle DJ. An international literature survey of “IARC Group I carcinogens” reported in mainstream cigarette smoke. Food and Chemical Toxicology. 1997;35(10–11):1107–30. [PubMed: 9463546]
  679. Smith LM, Cloak CC, Poland RE, Torday J, Ross MG. Prenatal nicotine increases testosterone levels in the fetus and female offspring. Nicotine & Tobacco Research. 2003;5(3):369–74. [PubMed: 12791533]
  680. Smith MK, George EL, Stober JA, Feng HLA, Kimmel GL. Perinatal toxicity associated with nickel chloride exposure. Environmental Research. 1993;61(2):200–11. [PubMed: 8495662]
  681. Sofikitis N, Miyagawa I, Dimitriadis D, Zavos P, Sikka S, Hellstrom W. Effects of smoking on testicular function, semen quality and sperm fertilizing capacity. Journal of Urology. 1995;154(3):1030–4. [PubMed: 7637048]
  682. Sokol RZ. Lead exposure and its effects on the reproductive system. Metals, Fertility, and Reproductive Toxicity. Golub MS, editor. Boca Raton (FL): CRC Press; 2005. pp. 118–54.
  683. Sooranna SR, Morris NH, Steer PJ. Placental nitric oxide metabolism. Reproduction, Fertility, and Development. 1995;7(6):1525–31. [PubMed: 8743159]
  684. Sopori M. Effects of cigarette smoke on the immune system. Nature Reviews Immunology. 2002;2(5):372–7. [PubMed: 12033743]
  685. Sopori ML, Kozak W. Immunomodulatory effects of cigarette smoke. Journal of Neuroimmunology. 1998;83( 1–2):148–56. [PubMed: 9610683]
  686. Sorensen KE, Borlum KG. Acute effects of maternal smoking on human fetal heart function. Acta Obstetricia et Gynecologica Scandinavica. 1987;66(3):217–20. [PubMed: 3661129]
  687. Sowa B, Steibert E. Effect of oral cadmium administration to female rats during pregnancy on zinc, copper, and iron content in placenta, foetal liver, kidney, intestine, and brain. Archives in Toxicology. 1985;56(4):256–62. [PubMed: 3994509]
  688. Sowa B, Steibert E, Gralewska K, Piekarski M. Effect of oral cadmium administration to female rats before and/or during pregnancy on the metallothionein level in the fetal liver. Toxicology Letters. 1982;11(3–4):233–6. [PubMed: 7101316]
  689. Sowers MF, Beebe JL, McConnell D, Randolph J, Jannausch M. Testosterone concentrations in women aged 25–50 years: associations with lifestyle, body composition, and ovarian status. American Journal of Epidemiology. 2001;153(3):256–64. [PubMed: 11157413]
  690. Sowers MR, La Pietra MT. Menopause: its epidemiology and potential association with chronic diseases. Epidemiologic Reviews. 1995;17(2):287–302. [PubMed: 8654512]
  691. Spanò M, Kolstad AH, Larsen SB, Cordelli E, Leter G, Giwercman A, Bonde JP, Asclepios The applicability of the flow cytometric sperm chromatin structure assay in epidemiological studies. Human Reproduction. 1998;13(9):2495–505. [PubMed: 9806274]
  692. Spira A, Spira N, Goujard J, Schwartz D. Smoking during pregnancy and placental weight: a multivariate analysis on 3759 cases. Journal of Perinatal Medicine. 1975;3(4):237–41. [PubMed: 1225957]
  693. Šrám RJ, Binková B, Dejmek J, Bobak M. Ambient air pollution and pregnancy outcomes: a review of the literature. Environmental Health Perspectives. 2005;113(4):375–82. [PMC free article: PMC1278474] [PubMed: 15811825]
  694. Steibert E, Król B, Sowa B, Gralewska K, Kamiński M, Kamińska O, Kusz E. Cadmium-induced changes in the histoenzymatic activity in liver, kidney and duodenum of pregnant rats. Toxicology Letters. 1984;20(2):127–32. [PubMed: 6141654]
  695. Steinberger EK, Ferencz C, Loffredo CA. Infants with single ventricle: a population-based epidemiological study. Teratology. 2002;65(3):106–15. [PubMed: 11877773]
  696. Stillman RJ, Rosenberg MJ, Sachs BP. Smoking and reproduction. Fertility and Sterility. 1986;46(4):545–66. [PubMed: 3530822]
  697. Storgaard L, Bonde JP, Ernst E, Spanô M, Andersen CY, Frydenberg M, Olsen J. Does smoking during pregnancy affect sons’ sperm counts? Epidemiology. 2003;14(3):278–86. [PubMed: 12859027]
  698. Storm JE, Fechter LD. Alteration in the postnatal ontogeny of cerebellar norepinephrine content following chronic prenatal carbon monoxide. Journal of Neurochemistry. 1985a;45(3):965–9. [PubMed: 4031872]
  699. Storm JE, Fechter LD. Prenatal carbon monoxide exposure differentially affects postnatal weight and mono-amine concentration of rat brain regions. Toxicology and Applied Pharmacology. 1985b;81(1):139–46. [PubMed: 4049415]
  700. Storm JE, Valdes JJ, Fechter LD. Postnatal alterations in cerebellar GABA content, GABA uptake and morphology following exposure to carbon monoxide early in development. Developmental Neuroscience. 1986;8(4):251–61. [PubMed: 2881771]
  701. Subramaniam S, Srinivasan S, Bummer PM, Gairola CG. Perinatal sidestream cigarette smoke exposure and the developing pulmonary surfactant system in rats. Human & Experimental Toxicology. 1999;18(4):206–11. [PubMed: 10333303]
  702. Sun J-G, Jurisicova A, Casper RF. Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro. Biology of Reproduction. 1997;56(3):602–7. [PubMed: 9047003]
  703. Sylvester SR, Griswold MD. The testicular iron shuttle: a “nurse” function of the Sertoli cells. Journal of Andrology. 1994;15(5):381–5. [PubMed: 7860417]
  704. Tachi N, Aoyama M. Effect of cigarette smoke and carbon monoxide inhalation by gravid rats on the conceptus weight. Bulletin of Environmental Contamination and Toxicology. 1983;31(1):85–92. [PubMed: 6882944]
  705. Tajtakova M, Farkasova E, Klubertova M, Konradova I, Machovcakova L. [The effect of smoking on menopause] [Slovak] Vnitrní Lékarství 1990;36(7):649–53. [PubMed: 2247965]
  706. Talbot P, Geiske C, Knoll M. Oocyte pickup by the mammalian oviduct. Molecular Biology of the Cell. 1999;10(1):5–8. [PMC free article: PMC25149] [PubMed: 9880322]
  707. Talbot P, Riveles K. Smoking and reproduction: the oviduct as a target of cigarette smoke. Reproductive Biology and Endocrinology. 2005;3:52. [PMC free article: PMC1266059] [PubMed: 16191196]
  708. Teasdale F, Ghislaine J-J. Morphological changes in the placentas of smoking mothers: a histomorphometric study. Biology of the Neonate. 1989;55(4–5):251–9. [PubMed: 2719997]
  709. Tollerud DJ, Clark JW, Brown LM, Neuland CY, Mann DL, Pankiw-Trost LK, Blattner WA, Hoover RN. Association of cigarette smoking with decreased numbers of circulating natural killer cells. American Review of Respiratory Disease. 1989;139(1):194–8. [PubMed: 2912340]
  710. Torfs CP, Christianson RE. Maternal risk factors and major associated defects in infants with Down syndrome. Epidemiology. 1999;10(3):264–70. [PubMed: 10230836]
  711. Torjussen W, Zachariasen H, Andersen I. Cigarette smoking and nickel exposure. Journal of Environmental Monitoring. 2003;5(2):198–201. [PubMed: 12729253]
  712. Torry DS, Hinrichs M, Torry RJ. Determinants of placental vascularity. American Journal of Reproductive Immunology. 2004;51(4):257–68. [PubMed: 15212678]
  713. Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, Kuller LH. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17(10):2167–76. [PubMed: 9351386]
  714. Trasti N, Vik T, Jacobsen G, Bakketeig L. Smoking in pregnancy and children’s mental and motor development at age 1 and 5 years. Early Human Development. 1999;55(2):137–47. [PubMed: 10390089]
  715. Trivedi B, Saxena DK, Murthy RC, Chandra SV. Embryo-toxicity and fetotoxicity of orally administered hexavalent chromium in mice. Reproductive Toxicology. 1989;3(4):275–8. [PubMed: 2520531]
  716. Trummer H, Habermann H, Haas J, Pummer K. The impact of cigarette smoking on human semen parameters and hormones. Human Reproduction. 2002;17(6):1554–9. [PubMed: 12042277]
  717. Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW. Heme oxygenase system in ischemia and reperfusion injury. Annals of Transplantation. 2004;9(1):84–7. [PubMed: 15478901]
  718. Tsunoda M, Litonjua AA, Kuniak MP, Weiss ST, Satoh T, Guevarra L, Tollerud DJ. Serum cytokine levels, cigarette smoking and airway responsiveness among pregnant women. International Archives of Allergy and Immunology. 2003;130(2):158–64. [PubMed: 12673070]
  719. Tulppala M, Bjorses UM, Stenman UH, Wahlstrom T, Ylikorkala O. Luteal phase defect in habitual abortion: progesterone in saliva. Fertility and Sterility. 1991;56(1):41–4. [PubMed: 2065803]
  720. US Department of Health and Human Services. The Health Consequences of Smoking for Women A Report of the Surgeon General. Washington: U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health; 1980.
  721. US Department of Health and Human Services. Tobacco Use Among US Racial/Ethnic Minority Groups—African Americans, American Indians and Alaska Natives, Asian Americans and Pacific Islanders, and Hispanics A Report of the Surgeon General. Atlanta: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 1998.
  722. US Department of Health and Human Services. Women and Smoking: A Report of the Surgeon General. Rockville (MD): U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001.
  723. US Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004.
  724. US Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2006.
  725. US Department of Health, Education, and Welfare. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington: U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control; 1964. PHS Publication No 1103.
  726. US Environmental Protection Agency. Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington: US Environmental Protection Agency, Office of Health and Environmental Assessment, Office of Research and Development; 1992. Publication No. EPA/600/6-90/006F.
  727. US Preventive Services Task Force. Counseling to Prevent Tobacco Use and Tobacco-Caused Disease. Rockville (MD): U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force; 2003. [accessed: January 7, 2008]. AHRQ Publication No. 04–0526 < http://www​.ahrq.gov/clinic​/3rduspstf/tobacccoun/tobcounrs​.pdf>;
  728. Urso P, Gengozian N. Alterations in the humoral immune response and tumor frequencies in mice exposed to benzo[a]pyrene and x-rays before or after birth. Journal of Toxicology and Environmental Health. 1982;10(4–5):817–35. [PubMed: 6298435]
  729. Urso P, Johnson RA. Quantitative and functional change in T cells of primiparous mice following injection of benzo(a)pyrene at the second trimester of pregnancy. Immunopharmacology and Immunotoxicology. 1988;10(2):195–217. [PubMed: 2971711]
  730. Urso P, Zhang W, Cobb JR. Immunological consequences from exposure to benzo(a)pyrene during pregnancy. Scandinavian Journal of Immunology. 1992;(Supplement 11):203–6. [PubMed: 1514042]
  731. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiological Reviews. 1993;73(1):79–118. [PubMed: 8419966]
  732. Van Den Eeden SK, Shan J, Bruce C, Glasser M. Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstetrics and Gynecology. 2005;105(5 Part 1):1052–7. [PubMed: 15863544]
  733. van der Vaart H, Postma DS, Timens W, Hylkema MN, Willemse BWM, Boezen HM, Vonk JM, de Reus DM, Kauffman HF, Ten Hacken NHT. Acute effects of cigarette smoking on inflammation in healthy intermittent smokers. Respiratory Research. 2005;6(1):22. [PMC free article: PMC554761] [PubMed: 15740629]
  734. van der Veen F, Fox H. The effects of cigarette smoking on the human placenta: a light and electron microscopic study. Placenta. 1982;3(3):243–56. [PubMed: 7134194]
  735. van der Velde WJ, Copius Peereboom-Stegeman JHJ, Treffers PE, James J. Structural changes in the placenta of smoking mothers: a quantitative study. Placenta. 1983;4(3):231–40. [PubMed: 6622428]
  736. van der Velde WJ, Copius Peereboom-Stegeman JHJ, Treffers PE, James J. Basal lamina thickening in the placentae of smoking mothers. Placenta. 1985;6(4):329–40. [PubMed: 4059184]
  737. van Rooij IALM, Groenen PMW, Van Drongelen M, Te Morsche RHM, Peters WHM, Steegers-Theunissen RPM. Orofacial clefts and spina bifida: N-acetyltransferase phenotype, maternal smoking, and medication use. Teratology. 2002;66(5):260–6. [PubMed: 12397635]
  738. van Rooij IALM, Wegerif MJM, Roelofs HMJ, Peters WHM, Kuijpers-Jagtman A-M, Zielhuis GA, Merkus HMWM, Steegers-Theunissen RPM. Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction. Epidemiology. 2001;12(5):502–7. [PubMed: 11505167]
  739. Van Santbrink EJ, Hop WC, van Dessel TJ, de Jong FH, Fauser BC. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertility and Sterility. 1995;64(1):37–43. [PubMed: 7789578]
  740. Van Winkle LS, Buckpitt AR, Nishio SJ, Isaac JM, Plopper CG. Cellular response in naphthalene-induced Clara cell injury and bronchiolar epithelial repair in mice. American Journal of Physiology. 1995;269(6 Pt 1):L800–L818. [PubMed: 8572242]
  741. Venners SA, Wang X, Chen C, Wang L, Chen D, Guang W, Huang A, Ryan L, O’Connor J, Lasley B, et al. Paternal smoking and pregnancy loss: a prospective study using a biomarker of pregnancy. American Journal of Epidemiology. 2004;159(10):993–1001. [PubMed: 15128612]
  742. Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, Merialdi M. Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia. International Journal of Gynaecology and Obstetrics. 2004;85(Suppl 1):S28–S41. [PubMed: 15147852]
  743. Vine MF. Smoking and male reproduction: a review. International Journal of Andrology. 1996;19(6):323–37. [PubMed: 9051418]
  744. Vine MF, Margolin BH, Morrison HI, Hulka BS. Cigarette smoking and sperm density: a meta-analysis. Fertility and Sterility. 1994;61(1):35–43. [PubMed: 8293842]
  745. von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertension in Pregnancy. 2003;22(2):143–8. [PubMed: 12908998]
  746. Wagner B, Lazar P, Chouroulinkov I. The effects of cigarette smoke inhalation upon mice during pregnancy. Revue Europeenne D’Etudes Cliniques et Biologiques. 1972;17(10):943–8. [PubMed: 4659994]
  747. Wang X, Chen D, Niu T, Wang Z, Wang L, Ryan L, Smith T, Christiani DC, Zuckerman B, Xu X. Genetic susceptibility to benzene and shortened gestation: evidence of gene-environment interaction. American Journal of Epidemiology. 2000a;152(8):693–700. [PubMed: 11052546]
  748. Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, Niu T, Wise PH, Bauchner H, Xu X. Maternal cigarette smoking; metabolic gene polymorphism, and infant birth weight. JAMA: the Journal of the American Medical Association. 2002;287(2):195–202. [PubMed: 11779261]
  749. Wang XL, Sim AS, Wang MX, Murrell GAC, Trudinger B, Wang J. Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity. FEBS Letters. 2000b;471(1):45–50. [PubMed: 10760510]
  750. Wang Y, Gu Y, Zhang Y, Lewis DF. Evidence of endothelial dysfunction in preeclampsia: decreased endothelial nitric oxide synthase expression is associated with increased cell permeability in endothelial cells from preeclampsia. American Journal of Obstetrics and Gynecology. 2004;190(3):817–24. [PubMed: 15042020]
  751. Ward NI, Watson R, Bryce-Smith C. Placental elemental levels in relation to fetal development for obstetrically ‘normal’ births: a study of 37 elements. Evidence for effects of cadmium, lead and zinc on fetal growth, and for smoking as a source of cadmium. International Journal of Biosocial Research. 1987;9(1):63–81.
  752. Washington AE, Katz P. Ectopic pregnancy in the United States: economic consequences and payment source trends. Obstetrics and Gynecology. 1993;81(2):287–92. [PubMed: 8423966]
  753. Watanabe N. Decreased number of sperms and Sertoli cells in mature rats exposed to diesel exhaust as fetuses. Toxicology Letters. 2005;155(1):51–8. [PubMed: 15585359]
  754. Weigert M, Hofstetter G, Kaipl D, Gottlich H, Krischker U, Bichler K, Poehl M, Feichtinger W. The effect of smoking on oocyte quality and hormonal parameters of patients undergoing in vitro fertilization-embryo transfer. Journal of Assisted Reproduction and Genetics. 1999;16(6):287–93. [PMC free article: PMC3455531] [PubMed: 10394523]
  755. Weinberg CR, Wilcox AJ, Baird DD. Reduced fecundability in women with prenatal exposure to cigarette smoking. American Journal of Epidemiology. 1989;129(5):1072–8. [PubMed: 2705427]
  756. Wells PG, Winn LM. Biochemical toxicology of chemical teratogenesis. Critical Reviews in Biochemistry and Molecular Biology. 1996;31(1):1–40. [PubMed: 8744954]
  757. Wen SW, Goldenberg RL, Cutter GR, Hoffman HJ, Cliver SP, Davis RO, DuBard MB. Smoking, maternal age, fetal growth, and gestational age at delivery. American Journal of Obstetrics and Gynecology. 1990;162(1):53–8. [PubMed: 2301517]
  758. Werler MM, Sheehan JE, Mitchell A. Association of vaso-constrictive exposures with risks of gastroschisis and small intestinal atresia. Epidemiology. 2003;14(3):349–54. [PubMed: 12859037]
  759. Westhoff C, Gentile G, Lee J, Zacur H, Helbig D. Predictors of ovarian steroid secretion in reproductive-age women. American Journal of Epidemiology. 1996;144(4):381–8. [PubMed: 8712195]
  760. Whelan EA, Sandler DP, McConnaughey DR, Weinberg CR. Menstrual and reproductive characteristics and age at natural menopause. American Journal of Epidemiology. 1990;131(4):625–32. [PubMed: 2316494]
  761. Wideman GL, Baird GH, Bolding OT. Ascorbic acid deficiency and premature rupture of fetal membranes. American Journal of Obstetrics and Gynecology. 1964;88:592–5. [PubMed: 14128191]
  762. Wilcox AJ, Baird DD, Weinberg CR. Do women with childhood exposure to cigarette smoking have increased fecundability? American Journal of Epidemiology. 1989;129(5):1079–83. [PubMed: 2705428]
  763. Wilcox AJ, Skjaerven R. Birth weight and perinatal mortality: the effect of gestational age. American Journal of Public Health. 1992;82(3):378–82. [PMC free article: PMC1694365] [PubMed: 1536353]
  764. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. Incidence of early loss of pregnancy. New England Journal of Medicine. 1988;319(4):189–94. [PubMed: 3393170]
  765. Wilkins JN, Carlson HE, Van Vunakis H, Hill MA, Gritz E, Jarvik ME. Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Psychopharmacology. 1982;78(4):305–8. [PubMed: 6818588]
  766. Wilks DJ, Hay AW. Smoking and female fecundity: the effect and importance of study design. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2004;112(2):127–35. [PubMed: 14746945]
  767. Williams L, Morrow B, Shulman H, Stephens R, D’Angelo D, Fowler CI. PRAMS 2002 Surveillance Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health; 2006.
  768. Williams LA, Evans SF, Newnham JP. Prospective cohort study of factors influencing the relative weights of the placenta and the newborn infant. BMJ (British Medical Journal). 1997;314(7098):1864–8. [PMC free article: PMC2126977] [PubMed: 9224128]
  769. Williams MA, Lieberman E, Mittendorf R, Monson RR, Schoenbaum SC. Risk factors for abruptio placentae. American Journal of Epidemiology. 1991;134(9):965–72. [PubMed: 1951294]
  770. Wilson DM, Killen JD, Hayward C, Robinson TN, Hammer LD, Kraemer HC, Varady A, Taylor CB. Timing and rate of sexual maturation and the onset of cigarette and alcohol use among teenage girls. Archives of Pediatric & Adolescent Medicine. 1994;148(8):789–95. [PubMed: 8044254]
  771. Windham GC, Bottomley C, Birner C, Fenster L. Age at menarche in relation to maternal use of tobacco, alcohol, coffee, and tea during pregnancy. American Journal of Epidemiology. 2004;159(9):862–71. [PubMed: 15105179]
  772. Windham GC, Eaton A, Hopkins B. Evidence for an association between environmental tobacco smoke exposure and birthweight: a meta-analysis and new data. Paediatric and Perinatal Epidemiology. 1999a;13(1):35–57. [PubMed: 9987784]
  773. Windham GC, Elkin EP, Swan SH, Waller KO, Fenster L. Cigarette smoking and effects on menstrual function. Obstetrics and Gynecology. 1999b;93(1):59–65. [PubMed: 9916957]
  774. Windham GC, Hopkins B, Fenster L, Swan SH. Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight. Epidemiology. 2000;11(4):427–33. [PubMed: 10874550]
  775. Windham GC, Mitchell P, Anderson M, Lasley BL. Cigarette smoking and effects on hormone function in premenopausal women. Environmental Health Perspectives. 2005;113(10):1285–90. [PMC free article: PMC1281267] [PubMed: 16203235]
  776. Windham GC, Von Behren J, Waller K, Fenster L. Exposure to environmental and mainstream tobacco smoke and risk of spontaneous abortion. American Journal of Epidemiology. 1999c;149(3):243–7. [PubMed: 9927219]
  777. Winternitz WW, Quillen D. Acute hormonal response to cigarette smoking. Journal of Clinical Pharmacology. 1977;17(7):389–97. [PubMed: 881471]
  778. Wisborg K, Kesmodel U, Henriksen TB, Hedegaard M, Secher NJ. A prospective study of maternal smoking and spontaneous abortion. Acta Obstetricia et Gynecologica Scandinavica. 2003;82(10):936–41. [PubMed: 12956844]
  779. Wisborg K, Henriksen TB, Hedegaard M, Secher NJ. Smoking during pregnancy and preterm birth. British Journal of Obstetrics and Gynaecology. 1996;103(8):800–5. [PubMed: 8760711]
  780. Wong ND, Pio J, Valencia R, Thakal G. Distribution of C-reactive protein and its relation to risk factors and coronary heart disease risk estimation in the National Health and Nutrition Examination Survey (NHANES) III. Preventive Cardiology. 2001;4(3):109–14. [PubMed: 11828186]
  781. Woods SE, Raju U. Maternal smoking and the risk of congenital birth defects: a cohort study. Journal of the American Board of Family Medicine. 2001;14(5):330–4. [PubMed: 11572537]
  782. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Singapore: Press Concern; 1980.
  783. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 2nd ed. Cambridge: Cambridge University Press; 1987.
  784. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 3rd ed. Cambridge: Cambridge University Press; 1992.
  785. World Health Organization. International Consultation on Environmental Tobacco Smoke (ETS) and Child Health. Geneva: World Health Organization, Division of Communicable Diseases, Tobacco Free Initiative; 1999a. WHO/NCD/TF1//99.10.
  786. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge: Cambridge University Press; 1999b.
  787. Wyszynski DF, Wu T. Use of U.S. birth certificate data to estimate the risk of maternal cigarette smoking for oral clefting. Cleft Palate-Craniofacial Journal. 2002;39(2):188–92. [PubMed: 11879077]
  788. Xu B, Rantakallio P, Jarvelin MR. Mortality and hospitalizations of 24-year old members of the low-birth-weight cohort in Northern Finland. Epidemiology. 1998;9(6):662–5. [PubMed: 9799178]
  789. Yang C-Y, Chang C-C, Tsai S-S, Chuang H-Y, Ho C-K, Wu T-N. Arsenic in drinking water and adverse pregnancy outcome in an arseniasis-endemic area in northeastern Taiwan. Environmental Research. 2003;91(1):29–34. [PubMed: 12550085]
  790. Yang M, Kunugita N, Kitagawa K, Kang S-H, Coles B, Kadlubar FF, Katoh T, Matsuno K, Kawamoto T. Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes. Cancer Epidemiology, Biomarkers & Prevention. 2001;10(6):589–93. [PubMed: 11401907]
  791. Yang Q, Sherman SL, Hassold TJ, Allran K, Taft L, Pettay D, Khoury MJ, Erickson JD, Freeman SB. Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study. Genetics in Medicine. 1999;1(3):80–8. [PubMed: 11336457]
  792. Yeung MC, Buncio AD. Leukocyte count, smoking, and lung function. American Journal of Medicine. 1984;76(1):31–7. [PubMed: 6691359]
  793. Ylikorkala O, Viinikka L, Lehtovirta P. Effect of nicotine on fetal prostacyclin and thromboxane in humans. Obstetrics and Gynecology. 1985;66(1):102–5. [PubMed: 3839296]
  794. Yolton K, Dietrich K, Auinger P, Lanphear BP, Hornung R. Exposure to environmental tobacco smoke and cognitive abilities among U.S. children and adolescents. Environmental Health Perspectives. 2005;113(1):98–103. [PMC free article: PMC1253717] [PubMed: 15626655]
  795. Younglai EV, Foster WG, Hughes EG, Trim K, Jarrell JF. Levels of environmental contaminants in human follicular fluid, serum, and seminal plasma of couples undergoing in vitro fertilization. Archives of Environmental Contamination and Toxicology. 2002;43(1):121–6. [PubMed: 12045882]
  796. Zahid ZR, Al-Hakkak ZS, Kadhim AHH, Elias EA, Al-Jumaily IS. Comparative effects of trivalent and hexavalent chromium on spermatogenesis of the mouse. Toxicology and Environmental Chemistry. 1990;25(2–3):131–6.
  797. Zeidel A, Beilin B, Yardeni I, Mayburd E, Smirnov G, Bessler H. Immune response in asymptomatic smokers. Acta Anaesthesiologica Scandinavica. 2002;46(8):959–64. [PubMed: 12190796]
  798. Zeiger JS, Beaty TH, Liang K-Y. Oral clefts, maternal smoking, and TGFA: a meta-analysis of gene-environment interaction. Cleft Palate-Craniofacial Journal. 2005;42(1):58–63. [PubMed: 15643916]
  799. Zenzes MT, Bielecki R, Reed TE. Detection of benzo(a) pyrene diol epoxide–DNA adducts in sperm of men exposed to cigarette smoke. Fertility and Sterility. 1999a;72(2):330–5. [PubMed: 10439006]
  800. Zenzes MT, Krishnan S, Krishnan B, Zhang H, Casper RF. Cadmium accumulation in follicular fluid of women in in vitro fertilization-embryo transfer is higher in smokers. Fertility and Sterility. 1995;64(3):599–603. [PubMed: 7641916]
  801. Zenzes MT, Puy LA, Bielecki R, Reed TE. Detection of benzo[a]pyrene diol epoxide-DNA adducts in embryos from smoking couples: evidence for transmission by spermatozoa. Molecular Human Reproduction. 1999b;5(2):125–31. [PubMed: 10065867]
  802. Zhang J, Fried DB. Relationship of maternal smoking during pregnancy to placenta previa. American Journal of Preventive Medicine. 1992;8(5):278–82. [PubMed: 1419126]
  803. Zhang J, Klebanoff MA, Levine RJ, Puri M, Moyer P. The puzzling association between smoking and hypertension during pregnancy. American Journal of Obstetrics and Gynecology. 1999;181(6):1407–13. [PubMed: 10601921]
  804. Zhang J, Meikle S, Trumble A. Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertension in Pregnancy. 2003;22(2):203–12. [PubMed: 12909005]
  805. Zhang J, Savitz DA, Schwingl PJ, Cai WW. A case-control study of paternal smoking and birth defects. International Journal of Epidemiology. 1992;21(2):273–8. [PubMed: 1428480]
  806. Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced hypertension. Epidemiologic Reviews. 1997;19(2):218–32. [PubMed: 9494784]
  807. Zhang L, Connor EE, Chegini N, Shiverick KT. Modulation by benzo[a]pyrene of epidermal growth factor receptors, cell proliferation, and secretion of human chorionic gonadotropin in human placental cell lines. Biochemical Pharmacology. 1995;50(8):1171–80. [PubMed: 7488231]
  808. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. American Journal of Pathology. 2002;160(4):1405–23. [PMC free article: PMC3277330] [PubMed: 11943725]
  809. Zhu BT, Cai MX, Spink DC, Hussain MM, Busch CM, Ranzini AC, Lai Y-L, Lambert GH, Thomas PE, Conney AH. Stimulatory effect of cigarette smoking on the 15 α-hydroxylation of estradiol by human term placenta. Clinical Pharmacology and Therapeutics. 2002;71(5):311–24. [PubMed: 12011817]
  810. Ziaei S, Nouri K, Kazemnejad A. Effects of carbon monoxide air pollution in pregnancy on neonatal nucleated red blood cells. Paediatric and Perinatal Epidemiology. 2005;19(1):27–30. [PubMed: 15670105]
  811. Zitzmann M, Rolf C, Nordhoff V, Schräder G, Rickert-Föhring M, Gassner P, Behre HM, Greb RR, Kiesel L, Nieschlag E. Male smokers have a decreased success rate for in vitro fertilization and intracytoplasmic sperm injection. Fertility and Sterility. 2003;79( Suppl 3):1550–4. [PubMed: 12801558]
  812. Zumoff B, Miller L, Levit CD, Miller EH, Heinz U, Kalin M, Denman H, Jandorek R, Rosenfeld RS. The effect of smoking on serum progesterone, estradiol, and luteinizing hormone levels over a menstrual cycle in normal women. Steroids. 1990;55(11):507–11. [PubMed: 2075617]

Footnotes

1

Pack-years = the number of years of smoking multiplied by the number of packs of cigarettes smoked per day.

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