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Office of the Surgeon General (US); Office on Smoking and Health (US). The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2004.

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The Health Consequences of Smoking: A Report of the Surgeon General.

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5Reproductive Effects

Introduction

Smoking harms many aspects of reproduction. An estimated 6 million women become pregnant each year in the United States, and more than 11,000 give birth each day (Ventura et al. 2000; Martin et al. 2002). Studies have shown that women who smoke are at an increased risk for a delay in becoming pregnant and for both primary and secondary infertility. Research has also shown that women who smoke during pregnancy risk complications, premature birth, low birth weight (LBW) infants, stillbirth, and infant mortality. LBW is a leading cause of infant deaths (Martin et al. 2002). Despite increased knowledge of the adverse health effects of smoking during pregnancy, only 18 to 25 percent of women quit smoking once they become pregnant. Data also suggest that a substantial number of pregnant women and girls continue to smoke (estimates range from 12 to 22 percent) (U.S. Department of Health and Human Services [USDHHS] 2001). This chapter reviews the evidence for a relationship between smoking and adverse reproductive effects. In particular, it examines the associations between smoking and fertility, smoking and pregnancy complications, and the health of children born to smokers.

Conclusions of Previous Surgeon General’s Reports

Numerous previous reports of the Surgeon General on smoking and health have examined the effects of active smoking on the reproductive capabilities and outcomes for both men and women (Table 5.1). The 1964 Surgeon General’s report (U.S. Department of Health, Education, and Welfare [USDHEW] 1964) identified an association between smoking during pregnancy and LBW (infants weighing <2,500 grams [g] at birth) that has been further explored in subsequent reports. The 1969 Surgeon General’s report (USDHEW 1969) presented evidence on smoking during pregnancy and preterm delivery (<37 weeks completed gestation), spontaneous abortion, stillbirths, and neonatal mortality. The 1978 Surgeon General’s report (USDHEW 1978) introduced new findings concerning smoking and pregnancy complications including placental abruption, placenta previa, and the premature rupture of membranes. The 1980 report on the health consequences of smoking for women (USDHHS 1980) extended previous findings on birth weight, retarded fetal growth, benefits of smoking cessation early in pregnancy, pregnancy complications, effects of smoking on the placenta, and mortality including sudden infant death syndrome (SIDS). This report also introduced new information on smoking risks and fertility, congenital malformations, and longer-term morbidity. The 1989 report (USDHHS 1989) evaluated new data and continued to find (1) a relationship between maternal smoking during pregnancy and lower birth weights, (2) higher rates of fetal and perinatal mortality associated with maternal smoking during pregnancy, (3) mixed findings on the relationship of maternal smoking to congenital malformations, (4) a higher risk of infertility among women and possibly men related to smoking, and (5) conflicting findings with regard to maternal smoking and longer-term physical development in the infant and child. The 1990 report on the health benefits of cessation (USDHHS 1990) noted that LBW could be reduced by 26 to 42 percent if smoking during pregnancy were eliminated. The 2001 report described findings on birth weight, infertility, ectopic pregnancy, spontaneous abortion, pregnancy complications, and SIDS (USDHHS 2001). That report also addressed smoking and breastfeeding, a topic not considered in this report. In prior reports, causal conclusions have been reached for a number of adverse reproductive outcomes (Table 5.1).

Table 5.1. Conclusions from previous Surgeon General’s reports concerning smoking as a cause of reproductive effects.

Table 5.1

Conclusions from previous Surgeon General’s reports concerning smoking as a cause of reproductive effects.

Biologic Basis

The biologic basis of smoking and reproductive effects is complicated by how exposure is defined for reproductive effects, and is perhaps best discussed using a methodologic framework. When researchers examine the effects of smoking on reproductive outcomes, measuring exposure to smoking and adjusting for possible confounding are two important methodologic concerns. The critical exposure periods during gestation are brief for some adverse reproductive outcomes that have possible causal associations with active smoking. For example, when examining the relationship between smoking and congenital malformations, relevant data include exposure to tobacco smoke during the early part of pregnancy or during organogenesis. Similarly, for studying fetal growth restrictions, knowledge of smoking habits during the third trimester—the time when most of the growth in the fetus occurs—is of critical importance. However, in many studies the average amount smoked during pregnancy has been used as the exposure measure without collecting or reporting information sorted by the month of pregnancy or by the trimester.

For pregnancy outcomes, several potential confounding factors should be considered along with tobacco use, such as social class and racial and ethnic group. Among women of a lower social standing, not only are rates of smoking higher but rates of adverse pregnancy outcomes are also higher. Whereas lower social standing is thus a potential confounding variable, it may also be part of a common causal pathway serving as one of the determinants of exposure to smoking. Most recent studies do take potential confounders into account, and within the body of relevant literature, confounding has been adequately considered in the aggregate. However, for studies of some outcomes, such as those that examine associations of active smoking during pregnancy with child outcomes (i.e., physical, neurologic, and cognitive development), fully accounting for all potential confounders in the postpartum period is not feasible. The appropriateness of accounting for confounders will be discussed in each of the three sections that follow.

Another challenging issue that should be addressed is the mechanistic role of smoking in the causal pathway of adverse reproductive outcomes. For the role of smoking in preterm deliveries, for example, prenatal cigarette exposure might (1) increase the risk for pregnancy complications leading to a preterm delivery (e.g., the premature rupture of membranes), (2) decrease immune system functioning leading to an increased susceptibility to infections, or (3) act more directly through mechanisms not yet understood. Many studies do not capture data in a way that facilitates an adequate dissection of the underlying pathway. For example, few studies stratify analyses by the presence of pregnancy complications, and most such studies do not account for infections, as this purported risk factor for a preterm delivery has emerged only recently.

This methodologic challenge is further illustrated by SIDS, smoking during pregnancy, and the role of birth weight in the causal pathway. Because prenatal smoking results in lower birth weights and LBW is also a risk factor for SIDS, most studies account for birth weight, and some studies even limit the analyses to infants born weighing at least 2,500 g. It is unclear, however, that this analytic strategy is the most appropriate if the total contribution of smoking to the risk of SIDS is of interest. Only a few studies have examined the association between smoking and SIDS by stratifying the sample by birth weight.

Studies reviewed for this chapter were selected from a MEDLINE literature search from the mid-1960s to 2000, with some earlier studies identified through bibliographies. Title and abstract search terms included “smoking,” and outcomes of interest such as “pregnancy,” “fertility,” “pregnancy complications,” “birth weight,” “preterm delivery,” “cognitive development,” “congenital malformations,” “infant mortality,” and “SIDS.” For some searches (e.g., pregnancy complications), specific disorders were used as a search term (e.g., placenta previa). “Smoking” was also used as a Medical Subject Headings term, and review articles were consulted as additional sources for references.

As some of the topics presented in this chapter have been extensively investigated and the evidence found to support causality (e.g., smoking and birth weight), this chapter focuses on more recent studies and emerging areas such as male erectile dysfunction. When possible, recent studies were reviewed as the patterns of smoking among women of childbearing age and pregnant women have changed over the past few decades. In addition, the topic of smoking and cervical cancer is discussed in Chapter 2.

Fertility

Epidemiologic Evidence

Smoking and Sperm Quality

Cigarette smoking among men can affect spermatogenesis and sperm quality through hormonal and toxic influences. In a review of the literature on male reproduction and smoking, Vine (1996) noted that the cytotoxic effects of exposures to tobacco smoke may reduce the numbers and function of sperm, or may affect male reproductive hormone levels and lead to impairment of spermatogenesis. Although the results of studies supporting the latter mechanism are mixed, several studies have found that levels of testosterone, estradiol, estrone, androstenedione, and follicle-stimulating hormone are increased among smokers compared with nonsmokers (Barrett-Connor and Khaw 1987; Simon et al. 1992; Field et al. 1994; Vine 1996), while other studies have found decreases among smokers compared with nonsmokers or no differences between the two groups (Andersen et al. 1984; Barrett-Connor and Khaw 1987; Klaiber and Broverman 1988; Simon et al. 1992). Small sample sizes may partially explain the conflicting findings (Vine 1996) as larger studies tend to find increased levels of male reproductive hormones in smokers compared with nonsmokers (Simon et al. 1992; Field et al. 1994). Toxins found in tobacco smoke, such as cadmium, nicotine, lead, and radioactive alpha-particle emitting elements (internal emitters in particular), may be directly toxic as they circulate in the blood and reach the testes (Mattison 1982; Ravenholt 1982; Mattison et al. 1989; Oldereid et al. 1989).

In the following discussion, the studies examined associations between sperm production and male smoking and had larger sample sizes as well as some consideration of potential confounders. However, many of the studies on sperm quality included men seeking treatments for infertility, and the findings may have restricted generalizability. Also most do not adequately consider potential confounders such as abstinence, occupational exposures (e.g., teratogens and toxins in the workplace), or health behaviors (e.g., caffeine, alcohol, or drug use). Studies on smoking and sperm quality have examined measures such as ejaculate volume and sperm output, density, viability, motility, and morphology (Vogel et al. 1979; Evans et al. 1981; Godfrey 1981; Andersen et al. 1984; Handelsman et al. 1984; Kulikauskas et al. 1985; Dikshit et al. 1987; Saaranen et al. 1987; Marshburn et al. 1989; Oldereid et al. 1989; Close et al. 1990; Holzki et al. 1991; Lewin et al. 1991; Chia et al. 1994) (Table 5.2). Handelsman and colleagues (1984) studied 119 healthy volunteer sperm donors and examined a variety of physical, demographic, and health behavioral factors and sperm quality. Although it is not clear how the category of smokers was defined, when compared with nonsmokers this group had a significantly reduced total sperm output (316 million versus 181 million sperm), motility (72 million versus 67 million sperm), motile sperm (235 million versus 127 million sperm), and total oval sperm (251 million versus 120 million sperm). These values were unadjusted for other factors. Marshburn and colleagues (1989) studied 445 men and reported a significantly reduced sperm volume for smokers compared with nonsmokers but no differences in sperm density, sperm motility, or the presence of abnormalities or dead sperm. The authors, however, warned against the confounding effect of coffee drinking in this and other studies. Chia and colleagues (1994) studied 618 men receiving treatment for infertility and reported means for volume, density, motility, and morphology adjusted for age, medical history, occupational exposure to cigarette smoke, and testicular size. Current smokers had a lower sperm density, a lower proportion with normal morphology, and a higher proportion with head defects than nonsmokers (lifetime nonsmokers and former smokers). Most studies have not found dose-response relationships with the amount smoked, and a number of studies found no difference in sperm quality between smokers and non-smokers (Saaranen et al. 1987; Oldereid et al. 1989; Close et al. 1990; Holzki et al. 1991; Lewin et al. 1991). One large study found no differences between those exposed to tobacco smoke and chewing and those not exposed to tobacco smoke and chewing (Dikshit et al. 1987).

Table 5.2. Studies on the association between smoking and sperm quality.

Table 5.2

Studies on the association between smoking and sperm quality.

A meta-analysis of 20 different study populations conducted by Vine and colleagues (1994) found that sample size was a major contributor to apparent inconsistencies among the study findings. Overall, the weighted estimate of reduction in sperm density among smokers compared with nonsmokers was 13 percent (95 percent confidence interval [CI], 8.0–21.0) adjusted for population source, minimum number of cigarettes smoked by smokers, number of specimens analyzed, and whether laboratory staff were blinded to the status of the participants (Vine et al. 1994). This estimate is somewhat lower than that of an earlier review of 10 studies, which found a reduction in smokers compared with nonsmokers to be 22 percent.

In summary, studies on the association between smoking and sperm quality have produced conflicting findings. Many studies have small sample sizes comprised of men who may have problems with infertility unrelated to smoking. And despite comments about similarities between smokers and nonsmokers, few included adjustments for potential confounders such as sexual abstinence, occupational exposures, and health practices of participants (e.g., consumption of alcohol, caffeine, or drugs). Nonetheless, the evidence suggests that smokers may have decreased semen volume and sperm number and increased abnormal forms, although any clinical relevance of these findings is not clear.

Smoking and Fertility in Women

Numerous studies have shown that smoking results in reduced fertility and fecundity for couples with one or both partners who smoke (Table 5.3). Fertility might be reduced by active smoking through numerous mechanisms. Animal studies suggest that prenatal exposure to polycyclic aromatic hydrocarbons has a destructive effect on oocytes and may affect the release of gonadotropins, corpora lutea formation, gamete interaction, and implantation. Studies in rats and humans also have shown that postfertilization cleavage is delayed in smokers (Mattison et al. 1989; Hughes et al. 1992; Rowlands et al. 1992). In the rat, nicotine delays implantation of the fertilized ovum, but whether this delay affects fertility remains to be determined. Smoking also has been shown to affect menstrual function by shortening cycles and increasing anovulation, which may also contribute to subfecundity and infertility (Windham et al. 1999).

Table 5.3. Studies on the association between smoking and fertility in women.

Table 5.3

Studies on the association between smoking and fertility in women.

The literature uses a number of different indicators to measure fertility and fecundity. Infertility in the United States is defined as the inability to conceive for 12 months; the World Health Organization uses failure to conceive for 24 months or more. Primary infertility refers to women who have not had prior pregnancies while secondary infertility concerns women who have been pregnant before. Unfortunately, the literature on smoking and fertility among women does not consistently employ these standard measures.

Laurent and colleagues (1992) studied primary infertility in 2,714 cases and controls. Primary infertility was associated with smoking more than one pack per day compared with nonsmokers (odds ratio [OR] = 1.36 [95 percent CI, 1.14–1.61]) and starting to smoke before 18 years of age compared with nonsmokers (OR = 1.30 [95 percent CI, 1.0–1.68]). These estimates were adjusted for education, age, race, and history of ovarian disease. Joffe and Li (1994) examined the time to first pregnancy among 3,132 women. After adjusting for age, education, and smoking status of the father in a Cox survival model, women who smoked before conception were less likely to become pregnant than nonsmokers; the risk ratio for time to pregnancy for women who smoked was 0.89 (95 percent CI, 0.83–0.97). Alderete and colleagues (1995) studied 1,341 primiparas and reported that women who smoked, regardless of whether they drank coffee, had about one-half the fertility (OR = 0.5 to 0.6 for conception times of 6 and 12 months) of nonsmokers who did not drink coffee.

As early as the 1960s, an association between smoking and decreased fertility was observed. In a sample of 2,016 women in Tennessee, women who smoked had a 46 percent higher rate of infertility than women who did not smoke (Tokuhata 1968). In a large prospective family planning study of more than 17,000 women, which included 6,199 episodes of contraceptive stoppage for the purpose of becoming pregnant, Howe and colleagues (1985) demonstrated a dose-response relationship between the amount of current smoking and reduced fertility that was based on pregnancy rates five years after terminating contraception. Women who smoked more than 20 cigarettes per day had their fertility reduced by 22 percent compared with lifetime nonsmokers and former smokers. Lighter smokers (<15 cigarettes per day) did not show demonstrable reductions in fertility. Although this study did not adjust for potential confounders, reduced fertility in smokers did not vary significantly by social class. Suonio and colleagues (1990) demonstrated a dose-response relationship between any current smoking and a delay to conception for short (6-month) and long (18-month) periods of time. In this sample of 2,198 mothers interviewed at 20 weeks of gestation, with adjustments for several confounders (age, prior pregnancies, prior terminations and spontaneous abortions, alcohol consumption, occupation of the mother, employment, smoking status and alcohol consumption of the father), the OR of conception delay for smokers (>four cigarettes per day) compared with nonsmokers at six months was 1.6. Conception delays continued for smokers (any smoking) compared with nonsmokers at 12 and 18 months after discontinuing contraception. Women who smoked more than four cigarettes per day had a 2.1 OR for conception delay at 18 months compared with nonsmokers. Dose-response relationships were demonstrated for lighter and heavier smokers for most outcomes (Suonio et al. 1990).

In a large multicountry study, Bolumar and colleagues (1996) examined the association between smoking and time to pregnancy that exceeded nine and one-half months in two large samples: (1) a population-based sample of women aged 25 through 44 years and (2) a sample of pregnant women recruited from prenatal clinics. Each sample had more than 4,000 couples. The OR was 1.7 (95 percent CI, 1.3–2.1) for a longer time to pregnancy for women smoking 11 or more cigarettes per day compared with nonsmokers in the population sample. For current pregnancy in the pregnant sample, the OR was also 1.7 (95 percent CI, 1.3–2.3), demonstrating a dose-response relationship for this outcome. Women who smoked 1–10 cigarettes per day had an OR of 1.4 in the population sample (95 percent CI, 1.1–1.7) and also in the pregnant sample (95 percent CI, 1.0–1.8). In the population-based sample, associations were also examined for the most recent pregnancies. For the most recent wait time, women who smoked 11 cigarettes or more per day compared with nonsmokers had an OR of 1.6 (95 percent CI, 1.3–2.1). ORs in this study were adjusted for age, coital frequency, education, oral contraceptive use, and coffee consumption (Bolumar et al. 1996). Curtis and colleagues (1997) reported a decreased fecundability (the monthly probability of conception), measured by time to pregnancy after discontinuing contraception, among smokers compared with nonsmokers. The fecundability ratio of smokers was 0.90 (95 percent CI, 0.81–0.95), and a dose-response relationship was observed for heavier smokers. Fecundability ratios for those smoking 11–20 cigarettes and more than 20 cigarettes per day were 0.87 (95 percent CI, 0.77–0.99) and 0.74 (95 percent CI, 0.59–0.92), respectively. Curtis and colleagues (1997) also reported associations with spousal smoking habits. Compared with both partners who were nonsmokers, when both the woman and her spouse smoked the fecundability ratio was 0.77 (0.68–0.86). In their study of 678 pregnant women, Baird and Wilcox (1985) reported that smokers had 3.4 times the risk of taking more than one year to conceive than nonsmokers, and heavy smokers showed an even greater reduced fertility than light smokers. In a review of 13 studies on this topic, Hughes and Brennan (1996) reported that all but one study found a reduced fecundity among smokers compared with nonsmokers.

Not all studies have reported positive associations between smoking and reduced fertility. A prospective study of fertility conducted by de Mouzon and colleagues (1988) with 1,887 couples found that reduced fertility associated with smoking was no longer statistically significant once possible confounders (method of birth control, attempting to conceive, oral contraceptive use as the most recent method, social class, prior deliveries, and year) were included in the analyses. Specifically comparing smokers with nonsmokers, cigarette smoking by the woman produced a 0.86 rate of relative fertility (95 percent CI, 0.63–1.19) and by the man a rate of 0.99 (95 percent CI, 0.85–1.14) after accounting for oral contraceptive methods, previous deliveries, social class, and prior attempts to conceive.

An increasing number of studies have used couples seeking treatment for infertility. These studies have consistently shown that treatment success is affected by smoking. Several studies documented that the success of in vitro fertilization (IVF) is significantly reduced among smokers compared with nonsmokers (Elenbogen et al. 1991; Pattinson et al. 1991; Hughes et al. 1992; Rosevear et al. 1992; Rowlands et al. 1992; Van Voorhis et al. 1996; El-Nemr et al. 1998), but other studies have not shown this reduction (Trapp et al. 1986; Sharara et al. 1994; Sterzik et al. 1996). Joesbury and colleagues (1998) examined the association of smoking by both partners with the likelihood of pregnancy within 498 consecutive IVF treatment cycles. Although female smoking had no association, male smoking was associated with a reduction in the probability of achieving a 12-week pregnancy. This study observed that age did modify the effect of smoking. For every one-year increase in age, there was a 2.4 percent reduction in the probability that the man’s partner would achieve a 12-week pregnancy (Joesbury et al. 1998). The authors suggest that pre-zygotic genetic damage is the mechanism causing these reductions in a successful pregnancy.

Evidence Synthesis

Although mechanisms for an effect of smoking on sperm quality have been proposed, study findings are inconsistent for an association between active smoking and sperm quality. Some studies have shown positive associations, with a few demonstrating dose-response relationships with the amount smoked; others find no association. Many of the studies have potential flaws related to participant selection and confounding.

The evidence for a positive association between active smoking and subfertility and subfecundity in women consistently shows that active cigarette smoking reduces fecundity and increases the risk of primary infertility. The number of studies is substantial and various study designs and outcome measures have been used. Several studies demonstrated a dose-response relationship with the number of cigarettes smoked. Although the evidence is less consistent in studies examining the impact of smoking on the success of IVF, these studies may be limited by inadequate adjustment for fertility-related confounders. Moreover, animal and human studies are beginning to provide an understanding of the mechanisms by which cigarette smoke or its components affect fertilization in females, pointing to the plausibility of this association. The evidence reviewed shows consistency, dose-response relationships, and appropriate temporality, and partially characterizes the mechanistic basis. Based on the evidence through 2000, the 2001 Surgeon General’s report concluded that “women who smoke have increased risks for conception delay and for primary and secondary infertility” (USDHHS 2001, p. 307).

Conclusions

  1. The evidence is inadequate to infer the presence or absence of a causal relationship between active smoking and sperm quality.
  2. The evidence is sufficient to infer a causal relationship between smoking and reduced fertility in women.

Implications

Regarding smoking and sperm quality, future studies should also include more samples of men not seeking treatment for infertility, larger study populations, and the information to adjust for potential confounding factors such as occupational exposures (e.g., teratogens and toxins in the workplace) and health behaviors (e.g., caffeine, alcohol, or drug use). Women intending to become pregnant should be warned that their smoking reduces fertility; health care workers should be aware of the causal association of smoking by women with reduced fertility.

Pregnancy and Pregnancy Outcomes

Epidemiologic Evidence

Smoking Patterns Among Women During Childbearing Years

National data for the United States indicate that somewhere between 13 percent (National Center for Health Statistics, reported in Guyer et al. 1999) and 17 percent (Substance Abuse and Mental Health Services Administration 2001) of pregnant women smoke. For 1998, the 2001 Surgeon General’s report gives a figure of 12.9 percent based on birth certificate data (USDHHS 2001). The prevalence of pregnant women who smoked in 2001 was 12 percent, and the prevalence of teenage mothers aged 15 through 19 years who smoked during pregnancy was 17.5 percent in 2001 (Martin et al. 2002). The proportion of women who smoke during pregnancy has declined over the last 10 years; in 1990, 18 percent of women reported prenatal smoking (Guyer et al. 2000). At the same time, smoking among teenage mothers was increasing. In 1994, 16.7 percent of teenage mothers smoked during pregnancy, rising to 17.5 percent in 2001 (Martin et al. 2002). Since somewhere between 18 and 25 percent of women quit smoking once they become pregnant, the proportion of women who smoke around the time of pregnancy is greater than these numbers suggest (Lumley 1987; O’Campo et al. 1995).

Most information on smoking during pregnancy, including that obtained for studies on reproductive effects, comes from self-reports by the pregnant woman. In the United States, smoking during pregnancy is now widely viewed as unacceptable— that is, women are considered responsible for exposing the fetus to tobacco metabolites, and a number of researchers have noted that underreporting of smoking during pregnancy is common. High rates of underreporting have been reported in intervention trials. In a randomized trial from public health maternity clinics, Windsor and colleagues (1993) found a deception rate of 28 percent for self-reports provided at the end of pregnancy using salivary cotinine as a comparison. Underreporting can be a result of the social stigma associated with smoking or the typical change in patterns of smoking during pregnancy. Most women who smoke before pregnancy either quit or reduce their levels of smoking during pregnancy (O’Campo et al. 1995). Thus, if women reduce smoking levels as the pregnancy progresses, they may report the lowest smoking level rather than the greatest, or an average level over the course of their pregnancy. This underreporting, however, is likely to move any positive associations toward a null relationship as this type of misclassification will result in classifying heavy smokers as light smokers and classifying some true smokers as nonsmokers. Researchers have tried to address this problem by incorporating biochemical measures of tobacco exposure into their studies. Three studies showed that cotinine levels in blood collected along with self-reports during the prenatal period were more highly correlated with birth weight than were self-reported smoking levels (Haddow et al. 1987; English et al. 1994; Peacock et al. 1998).

Smoking and Ectopic Pregnancy

Ectopic pregnancy, a rare yet serious complication, occurs when implantation of the fertilized ovum takes place outside of the uterus, often in the fallopian tubes. The etiology of ectopic pregnancy is not fully known but involves the motility and patency of the fallopian tubes. Exposure to nicotine in rhesus monkeys has been shown to decrease tubal motility. Reduced motility may result in the fertilized ovum remaining in the tubes for a longer time which, in turn, may increase the chance of tubal implantation and ectopic pregnancy (Mattison et al. 1989). Cigarette smoking also has been associated with pelvic inflammatory disease, a strong risk factor for tubal pregnancy (Marchbanks et al. 1990). It is unclear whether this association is due to confounding factors such as more sex partners among smokers compared with nonsmokers, or to a direct biologic effect through suppressed immune function in smokers (Holt 1987).

Several studies report an increased risk of ectopic pregnancy among active smokers (Matsunaga and Shiota 1980; Handler et al. 1989; Coste et al. 1991; Kalandidi et al. 1991; Stergachis et al. 1991; Tuomivaara and Ronnberg 1991) (Table 5.4). ORs for active smokers compared with nonsmokers in these studies ranged from 1.3 to 2.5. Dose-response relationships have been reported in some studies (Handler et al. 1989; Coste et al. 1991) but not others (Phillips et al. 1992). Confounding is a potential source of bias when examining maternal smoking and ectopic pregnancy, although most studies adjusted for some potential confounders (e.g., prior problems relating to fertility involving the fallopian tubes or prior infections). The association with smoking does not appear to represent confounding alone.

Table 5.4. Studies on the association between maternal smoking and ectopic pregnancy.

Table 5.4

Studies on the association between maternal smoking and ectopic pregnancy.

Smoking and Spontaneous Abortion

Fetal loss or spontaneous abortion is defined as the involuntary termination of an intrauterine pregnancy before 20 weeks of gestation; some studies define spontaneous abortion as occurring before 28 weeks. Spontaneous abortions are extremely difficult to study, as most early fetal losses are underreported and unrecognized. As many as 50 percent of all pregnancies end in miscarriage, and 20 to 40 percent of all pregnancy losses may occur too early to be recognized or confirmed (Wilcox et al. 1988; Eskenazi et al. 1995a). Furthermore, the etiology of spontaneous abortions is multifactorial and not fully understood. Some early miscarriages result from chromosomal abnormalities in the developing embryo; others are related to factors associated with maternal age, the pregnancy, or exposures (e.g., occupational, alcohol consumption, or fever). There is evidence that smoking has a role in promoting spontaneous abortions, and various mechanisms have been proposed. Exposure to nicotine in sea urchins prevents the cortical granule reaction, which eliminates the entry of additional sperm into the egg. If this same process operates in humans, it may be a mechanism by which abnormalities in the developing embryo result in spontaneous abortions (Longo and Anderson 1970; Mattison et al. 1989). Several tobacco components and metabolites are potentially toxic to the developing fetus, including lead, nicotine, cotinine, cyanide, cadmium, carbon monoxide, and polycyclic aromatic hydrocarbons (Lambers and Clark 1996; Werler 1997).

Several studies have reported an increased risk of spontaneous abortion among smokers compared with nonsmokers; the reported ORs range from 1.2 to 3.4 (Kline et al. 1977; Stein et al. 1981; Armstrong et al. 1992; Dominguez-Rojas et al. 1994) (Table 5.5). Various potential confounding factors have been considered in these studies (USDHHS 2001). Dose-response relationships also have been reported (Stein et al. 1981; Armstrong et al. 1992). Armstrong and colleagues (1992) examined three strata of cigarette smoking and compared rates of early fetal loss among smokers and nonsmokers. ORs and CIs for spontaneous abortions for women smoking 1 to 9, 10 to 19, and 20 or more cigarettes compared with nonsmokers were 1.07 (95 percent CI, 0.97–1.18), 1.22 (95 percent CI, 1.13–1.32), and 1.68 (95 percent CI, 1.57–1.79), respectively. Most studies of smoking have not provided an opportunity to explore the basis for a spontaneous abortion. In a study of 2,305 karyotyped cases of miscarriage that separated chromosomally normal from abnormal fetuses, Kline and colleagues (1995) found a higher risk of aborting a chromosomally normal fetus among heavier smokers (>14 cigarettes per day) compared with nonsmokers (OR = 1.3 [95 percent CI, 1.1–1.7]). Data from a study of women undergoing IVF indicate that smokers have a higher rate of spontaneous abortions compared with nonsmokers, 42 percent versus 19 percent, respectively (Pattinson et al. 1991).

Table 5.5. Studies on the association between maternal smoking and spontaneous abortion.

Table 5.5

Studies on the association between maternal smoking and spontaneous abortion.

Some studies have found no association between smoking and spontaneous abortions (Sandahl 1989). In a review of 13 U.S. and European studies, DiFranza and Lew (1995) reported fairly consistent findings across studies despite differences in design, sample selection, and adjustments for confounding. Pooled relative risks (RRs) and ORs were 1.2 (95 percent CI, 1.19–1.3) for cohort studies and 1.32 (95 percent CI, 1.18–1.48) for case-control studies for smokers compared with nonsmokers.

Smoking and Pregnancy Complications

Placenta Previa

Placenta previa occurs when the maturing placenta is close to the cervical os or completely obstructs the os. The etiology of placenta previa is still largely unknown. Some researchers claim that placental enlargement among smokers increases the chance that the placenta implants near or at the cervical os. However, others have found that placentas in smokers and nonsmokers are similar in size, so differences in placental size may be due to factors other than smoking (Zhang and Fried 1992). Zhang and Fried (1992) also note that a detection bias may lead to the greater ascertainment of placenta previa among smokers and will consequently inflate this association in many studies.

Placenta previa consistently has been found to be more frequent in smokers compared with nonsmokers; ORs range from 1.3 to 4.4 with most estimates around 2.3 (Kramer et al. 1991; Williams et al. 1991b; Zhang and Fried 1992; Handler et al. 1994; Chelmow et al. 1996) (Table 5.6). A few studies have examined dose-response associations based on the number of cigarettes smoked per day; one reported a significant dose-dependent relationship (Monica and Lilja 1995) while others were only suggestive (Handler et al. 1994; Chelmow et al. 1996). Most recent studies adjusted for potential confounders including age, parity, prior caesarean sections, and prior pregnancy terminations.

Table 5.6. Studies on the association between maternal smoking and placenta previa.

Table 5.6

Studies on the association between maternal smoking and placenta previa.

Placental Abruption

A placental abruption occurs when the normally implanted placenta prematurely separates from the wall of the uterus, and it is associated with high rates of preterm deliveries, stillbirths, and early infant deaths. The etiology of this rare pregnancy complication is not fully known, but risk factors are trauma, multiple births, uterine tumors, advanced maternal age, hypertensive disorders, history of uterine scarring, and prior history of placental abruption (Ananth et al. 1996). Active smoking during pregnancy results in decreased intervillous placental blood flow (Lambers and Clark 1996). Smoking has been proposed as a link to placental abruptions through vasoconstriction and underperfusion around the site of placental implantation, leading to necrosis and hemorrhage (Lehtovirta and Forss 1978).

Most studies have found an increased risk of placental abruption associated with active smoking during pregnancy (Voigt et al. 1990; Williams et al. 1991a; Raymond and Mills 1993; Spinillo et al. 1994a) (Table 5.7). Studies have reported adjusted ORs ranging from 1.4 to 2.4; some report a dose-response relationship, with risks increasing for heavy smokers compared with light smokers (Ananth et al. 1996).

Table 5.7. Studies on the association between maternal smoking and placental abruption.

Table 5.7

Studies on the association between maternal smoking and placental abruption.

Preeclampsia and Eclampsia

Preeclampsia is a hypertensive disorder developed during pregnancy with proteinuria and edema. The more severe form, eclampsia, includes one or more seizures and/or coma. Preeclampsia is a severe disorder in pregnancy that is associated with maternal mortality, intrauterine growth retardation (IUGR), and preterm birth. Smoking has been negatively associated with hypertensive disorders during pregnancy, although the underlying mechanism is uncertain (Salafia and Sheverick 1999).

Studies on smoking during pregnancy consistently find reduced rates of preeclampsia among smokers compared with nonsmokers (Marcoux et al. 1989; Eskenazi et al. 1991; Klonoff-Cohen et al. 1993; Spinillo et al. 1994b; Sibai et al. 1995; Cnattingius et al. 1997) (Table 5.8). ORs for smokers range from 0.45 to 0.71. Some studies have reported a dose-response relationship, with the lowest rates of preeclampsia among heavier smokers compared with light smokers and nonsmokers (Marcoux et al. 1989).

Table 5.8. Studies on the association between maternal smoking and preeclampsia.

Table 5.8

Studies on the association between maternal smoking and preeclampsia.

Preterm Premature Rupture of Membranes

The rupture of the amniotic sac before the onset of labor is called a premature rupture of membranes (PROM). When PROM occurs before 37 weeks of gestation, it is referred to as preterm PROM. PROM is multifaceted in its etiology, possibly involving multiple steps before the membranes rupture (French and McGregor 1996). Potential determinants of PROM include infections, inflammation, physical stress, disturbance of collagen metabolism, and health behaviors such as nutrition and smoking. Cigarette smoke components may increase the risk of PROM through several mechanisms, including disruption of the cytokine system, impairment of immune function in the reproductive tract, and promotion of inflammatory mechanisms (French and McGregor 1996). It also is possible that impaired nutrition, specifically the reduction of available nutrients and cellular amino acid uptake, is involved in PROM (French and McGregor 1996). However, confirmation of any one of these pathways from smoking to PROM awaits future studies. It is likely that preterm PROM and non-preterm PROM have somewhat different etiologies (French and McGregor 1996).

Preterm PROM has been studied in relation to smoking during pregnancy (Harger et al. 1990; Williams et al. 1992; Spinillo et al. 1994d), with most studies finding an elevated risk (Table 5.9). Adjusted ORs for smokers range from 1.6 to 2.1, and dose-response relationships of risk with daily smoking levels have been investigated but with mixed results (Williams et al. 1992; Spinillo et al. 1994d). Studies that have shown no increased risk for smokers generally had small sample sizes and inadequate consideration of potential confounding (Harger et al. 1990).

Table 5.9. Studies on the association between maternal smoking and premature rupture of membranes.

Table 5.9

Studies on the association between maternal smoking and premature rupture of membranes.

Shortened Gestation

A shortened gestational period can be measured in two ways: by the number of days or weeks of pregnancy and by a preterm delivery, defined as less than 37 weeks of completed gestation. One major mechanism whereby active smoking leads to a shortened gestation is through pregnancy complications. Smoking during pregnancy increases the risk for and exacerbates several pregnancy complications such as PROM, infections, placenta previa, and placental abruption, which in turn are associated with shortened gestations. When a shortened gestation is measured in continuous days, differences between smokers and nonsmokers are on the order of two to three days.

A shortened gestation attributable to smoking, measured by a preterm delivery, has been reported in numerous studies. In a meta-analysis of 20 prospective studies, Shah and Bracken (2000) reported an overall adjusted OR for a preterm delivery of 1.27 (95 percent CI, 1.21–1.33) for smokers compared with non-smokers. Not all of the 20 studies reported a significantly elevated risk for smokers compared with nonsmokers, and very few accounted for complications such as PROM, infections, placenta previa, or others. Shiono and colleagues (1986b) studied preterm delivery risks for light and heavy smokers, stratifying their sample by the presence of pregnancy complications (PROM, placenta previa, or placental abruption) and no complications. These authors reported that the risk of a preterm delivery was elevated both among the subsamples with complications and within the sample with no pregnancy complications, suggesting that prenatal smoking may act to increase rates of preterm deliveries by causing complications and also by a more direct pathway.

Birth Weight and Intrauterine Growth Retardation

Key outcomes in relation to maternal smoking during pregnancy include birth weight, LBW, and IUGR. Infants with LBW, defined as weighing less than 2,500 g at birth, have a higher risk of subsequent infant morbidity, mortality, and longer-term childhood and adult adverse consequences. IUGR, as the name implies, is reduced fetal physical growth during gestation. One indicator of IUGR, small for gestational age, is often defined as the lowest 10 percent of birth weights (or sometimes the lowest 5 percent) for any gestational age. A number of possible mechanisms leading to reductions in birth weight and fetal growth as a result of smoking have been suggested.

On the basis of animal studies, it appears that nicotine acts on the respiratory and central nervous systems of the fetus and concentrates in maternal and fetal blood, amniotic fluid, and breast milk (Lambers and Clark 1996). The physiologic effects of tobacco on fetal growth may result from the vasoconstrictive effects of nicotine on the uterine and umbilical arteries and an increase in carboxyhemoglobin, leading to reduced oxygenation of the fetus (Lambers and Clark 1996; Werler 1997). Nicotine may have a direct toxic effect on the fetal cardiovascular system resulting in reduced blood flow (Bruner and Forouzan 1991). Abstaining from smoking for 48 hours during the third trimester increased the available oxygen to the fetus by 8 percent (Davies et al. 1979). Cadmium from cigarette smoke accumulates in the placenta and leads to morphologic and functional impairment (Sikorski et al. 1988). The fetus is likely exposed to the cadmium because this element has been detected in cord blood (Chatterjee et al. 1988).

Some researchers have argued against a nutritional effect of smoking on reduced fetal weight and size; smoking mothers have been found to eat more than nonsmoking mothers, and an increased energy intake does not prevent IUGR (Muscati et al. 1996). Furthermore, tricep and subscapular skinfold measurements of infants of smokers were found to be normal and/or similar to those of infants of nonsmoking mothers (Harrison et al. 1983). In fact, infants of smokers lose lean body mass and not adipose tissue, which is consistent with the hypothesis that maternal nutrition is not a mediator of this effect. Hypoxia has been suggested as mediating part of this process (Harrison et al. 1983).

The primary mechanism by which birth weights are reduced among infants of smokers compared with those of nonsmokers is through fetal growth restriction. Birth weight and LBW, however, were often examined for research purposes, as both are available and reliably reported for nearly all infants. Accurate determination of IUGR, however, requires an estimate of the gestational age of the infant, which is subject to greater uncertainty and misreporting.

Reported birth weight differences between infants of smokers and infants of nonsmokers are surprisingly consistent across studies and populations (Simpson 1957; Butler et al. 1972; D’Souza et al. 1981; Sexton and Hebel 1984; Backe 1993; Bardy et al. 1993; Wilcox 1993; Ellard et al. 1996) (Table 5.10). On average, women who smoke throughout their pregnancies have infants who weigh about 200 g less than infants of women who do not smoke during pregnancy. Women who quit smoking early in their pregnancy have infants with similar weights to infants of non-smokers (USDHHS 1990). Thus, the evidence on birth weights after smoking cessation by the mother supports the hypothesis that smoking contributes to lighter infants. Numerous studies also document the association between active smoking during pregnancy and LBW (Hopkins et al. 1990; McDonald et al. 1992; Mainous and Hueston 1994). Only a few studies have not found an association between lower birth weights among smoking compared with nonsmoking mothers, and numerous studies have demonstrated a dose-response relationship with the number of cigarettes smoked and the degree of reduction in birth weights. Studies with biochemically measured smoking exposures (e.g., cotinine levels) also have confirmed, in an even stronger dose-response pattern than that seen from self-reported data, the relationship between pre-natal smoking and birth weight (Haddow et al. 1987; Bardy et al. 1993; Li et al. 1993; Eskenazi et al. 1995b; Peacock et al. 1998).

Table 5.10. Studies on the association between maternal smoking, birth weight, and intrauterine growth retardation.

Table 5.10

Studies on the association between maternal smoking, birth weight, and intrauterine growth retardation.

The greatest risk of subsequent mortality and morbidity is among infants born with very low birth weight (VLBW), or weight at birth of less than 1,500 g. VLBW occurs in approximately 3 percent or fewer births; thus, very few studies have a large enough sample size to be able to break out VLBW infants to examine the association with smoking. Hopkins and colleagues (1990) examined the association between smoking and VLBW for births in Ohio for 1989 and reported elevated risks (adjusted OR = 1.4 and population attributable risk = 8.4 percent) among smokers compared with nonsmokers. More recent reviews, however, suggest that the effect of smoking during pregnancy on birth weight is primarily on infants who weigh around 2,500 g and that smoking does not substantially increase the risk of VLBW (Shiono and Behrman 1995; Strobino 1999). Further studies are needed to determine whether and how smoking during pregnancy is related to VLBW births.

The association between smoking and IUGR also has been demonstrated in a number of studies (Cnattingius 1989; Ferraz et al. 1990; Wen et al. 1990; McDonald et al. 1992; Backe 1993; Bakketeig et al. 1993; Lieberman et al. 1994; Spinillo et al. 1994c) (Table 5.10). The RRs range from 1.5 to 2.5 for smokers compared with nonsmokers. Several studies demonstrated dose-response relationships of risk with the amount smoked, with the highest smoking categories showing RRs of 5.0 to 9.9 (Wen et al. 1990; Bakketeig et al. 1993; Lieberman et al. 1994; Spinillo et al. 1994c). Most studies adjusted for numerous potential confounding factors and still reported strong associations and dose-response relationships with daily smoking levels. These associations with active smoking by the mother may be underestimated as a substantial proportion of women in the nonsmoking control groups are exposed to secondhand cigarette smoke. Exposure to secondhand smoke also reduces birth weight, and removing the group of passively exposed women from the control group increases RRs (Martin and Bracken 1986). One study examining the contributions of smoking, energy intake, weight gain, and fetal growth reported that the effect of smoking was independent of energy intake (which was higher in smokers) and weight gain (which was lower in smokers) (Muscati et al. 1996). Thus, this finding supports a direct effect of smoking on the growth of the fetus rather than an indirect effect through nutritional intake among smokers.

Evidence Synthesis

The evidence addresses smoking during pregnancy and diverse outcomes. For some of the outcomes, causal conclusions have been previously reached. Most studies on the relationship between smoking and ectopic pregnancy have demonstrated a positive association, with several demonstrating a dose-response relationship between risk and amount smoked. However, the number of studies is still limited, and uncontrolled confounding remains as an alternative explanation to a causal association. Biologic mechanisms include a possible indirect causal pathway through an increased risk for a pelvic infection in smokers, a delayed fertilization process, and reduced tubal motility in association with exposures to nicotine.

Despite methodologic challenges in studying spontaneous abortions, most studies on the association between active smoking and spontaneous pregnancy loss have reported increased risks for smokers compared with nonsmokers, and some studies demonstrate dose-response relationships. Animal models have indicated plausible mechanisms that may underlie the association.

Most studies demonstrate an increased risk for maternal smoking and preterm PROM, placenta pre-via, and placental abruption. These findings have been consistently observed across time and across many study populations in multiple countries. Also, biologic evidence supports the contribution of active smoking to these particular pregnancy conditions.

Many studies show an increased risk of preterm delivery among smokers compared with nonsmokers even though the overall risk of preterm delivery may be small, with ORs on the order of 1.2 or 1.3. One major mechanism by which smoking is related to preterm delivery is through an increase in the risks of pregnancy and/or fetal complications that result in a spontaneous abortion or a medically indicated early delivery.

Many studies have consistently demonstrated a positive association between maternal smoking during pregnancy and reduced birth weight, and several have demonstrated dose-response relationships with the amount smoked. For smoking throughout pregnancy the effect is large, and successful cessation of smoking before the third trimester eliminates much of the reduction caused by maternal smoking. Some mechanisms by which smoking reduces birth weight have been established. They act in large part through reduced fetal growth, but the association between smoking and birth weight also results from early delivery, often from pregnancy complications. The biologic evidence supporting this causal effect is strong and includes fetal hypoxia from increased carboxyhemoglobin; reduced blood flow to the uterus, placenta, and fetus; and direct effects of nicotine and other compounds in tobacco smoke on the placenta and fetus.

Conclusions

  1. The evidence is suggestive but not sufficient to infer a causal relationship between maternal active smoking and ectopic pregnancy.
  2. The evidence is suggestive but not sufficient to infer a causal relationship between maternal active smoking and spontaneous abortion.
  3. The evidence is sufficient to infer a causal relationship between maternal active smoking and premature rupture of the membranes, placenta previa, and placental abruption.
  4. The evidence is sufficient to infer a causal relationship between maternal active smoking and a reduced risk for preeclampsia.
  5. The evidence is sufficient to infer a causal relationship between maternal active smoking and preterm delivery and shortened gestation.
  6. The evidence is sufficient to infer a causal relationship between maternal active smoking and fetal growth restriction and low birth weight.

Implications

The evidence reviewed in this chapter suggests that smoking is associated with ectopic pregnancy and spontaneous abortion. As both ectopic pregnancy and infertility are on the rise, reducing smoking among women intending to become pregnant is warranted. More studies are needed that are designed to prospectively assess very early losses and to examine the association of smoking around the time of conception with types of spontaneous abortions.

The evidence of an association of smoking during pregnancy and adverse pregnancy complications, such as preterm PROM, placenta previa, and placental abruption, is sufficient to warrant promoting smoking cessation among women before they become pregnant and during pregnancy. Werler (1997) noted that as much as 10 percent of abnormal placentation could be avoided if smoking during pregnancy were eliminated. The decreased risk of preeclampsia among smokers compared with nonsmokers does not outweigh the adverse outcomes that can result from prenatal smoking.

The occurrence of LBW could be reduced by an estimated 20 percent, and fetal growth restriction by 30 percent, if all women were nonsmokers during pregnancy (Alameda County Low Birth Weight Study Group 1990; Cnattingius et al. 1993; Li et al. 1993; Muscati et al. 1996). The impact of smoking on these outcomes can be lessened if women quit before their third trimester; thus, there is a need for widespread implementation of effective smoking cessation interventions targeting all women of childbearing age as well as those already pregnant.

Congenital Malformations, Infant Mortality, and Child Physical and Cognitive Development

Epidemiologic Evidence

Congenital Malformations

Because of the direct fetal effects observed from exposure to tobacco smoke, and the chemically complex nature of cigarette smoke, researchers have assessed the association between prenatal exposure and congenital malformations. Researchers have examined these associations with malformations as an overall group and with single malformations separately. The etiologies of the multiple congenital malformations vary widely, making the discussion of the contribution of prenatal smoking to an increased risk of birth defects difficult overall.

Most studies investigating associations between maternal smoking during pregnancy and all congenital malformations together have not found an association (Hemminki et al. 1983; Shiono et al. 1986b; Malloy et al. 1989; Seidman et al. 1990; Van den Eeden et al. 1990) (Table 5.11). One study reported an increased risk only among heavy smokers (Kelsey et al. 1978), with an adjusted RR of 1.6 (p = 0.03) for women smoking 21 or more cigarettes per day during pregnancy compared with nonsmokers.

Table 5.11. Studies on the association between maternal smoking and congenital malformations.

Table 5.11

Studies on the association between maternal smoking and congenital malformations.

Down syndrome has been consistently shown not to be associated with maternal smoking in pregnancy (Hook and Cross 1985; Cuckle et al. 1990a; Van den Eeden et al. 1990; Källén 1997a). Neural tube defects are not elevated among smokers compared with non-smokers (Malloy et al. 1989; Wasserman et al. 1996; Källén 1998). However, Källén (1998) demonstrated a significant protective effect for neural tube defects among smokers compared with nonsmokers in the 1.2 million births studied (OR = 0.75 [95 percent CI, 0.61–0.91]).

Li and colleagues (1996) reported an association between maternal smoking and urinary tract anomalies among light smokers (<1,000 cigarettes smoked during pregnancy) compared with nonsmokers; the anomalies occurred mainly in female infants. The OR for light smokers versus nonsmokers was 3.7 (95 percent CI, 1.7–8.6); among mothers of female infants, comparing light smokers with nonsmokers yielded an OR of 6.1 (95 percent CI, 2.0–18.4). This study reported a lower risk for heavy smokers compared with non-smokers (OR = 1.4 [95 percent CI, 0.6–3.3]). As an explanation for this dose-dependent response, Li and colleagues (1996) suggest that heavier smokers may be more likely than light smokers to abort malformed fetuses. Malloy and colleagues (1989) and McDonald and colleagues (1992) found little association between smoking and genitourinary defects at birth.

Gastroschisis is a defect of the abdominal wall closely related to the defect omphalocele thought to result from vascular interruption (Hoyme et al. 1983). Findings on the association between gastroschisis and smoking have been conflicting. Smaller studies show a positive association (Haddow et al. 1993), whereas most larger studies and those controlling for confounders show no association (Werler et al. 1992; Torfs et al. 1994).

The association of fetal limb defects and smoking also has been studied. One study looked at the risk of limb defects from maternal and paternal smoking and found contradictory results (Wasserman et al. 1996). Risk was elevated only with heavy paternal smoking (OR = 2.0 [95 percent CI, 1.3–3.6]) compared with neither parent smoking. Maternal smoking, even heavy maternal smoking, did not elevate the risk of limb defects; nor did having both parents smoke or having passive exposures at home or at work. Because there is no evident biologic explanation for this particular pattern of association, paternal smoking in the absence of maternal smoking may be a proxy for other factors contributing to this risk. This study also reported that the risk of conotruncal heart defects was elevated when both parents smoked (OR = 1.9 [95 percent CI, 1.2–3.1]) (Wasserman et al. 1996).

The most convincing evidence supports an association between smoking and oral clefts (Saxen 1974; Khoury et al. 1987; Hwang et al. 1995; Shaw et al. 1996; Källén 1997b; Wyszynski et al. 1997), yet not all studies report an association (Shiono et al. 1986a; Malloy et al. 1989; Werler et al. 1990). Studies have examined the association with smoking for all oral cleft defects and for the categories of a cleft lip with or without a cleft palate, and cleft palate alone. Even when subgroups are examined, studies produce contradictory findings. One meta-analysis of 11 studies of oral clefts that compared mothers who smoked during the first trimester with mothers who did not smoke reported an overall OR of 1.29 (95 percent CI, 1.18–1.42) for a cleft lip with or without a cleft palate, and 1.32 (1.10– 1.62) for a cleft palate (Wyszynski et al. 1997). Recent studies have examined genetic and environmental interactions in relation to oral clefts. Two studies (Hwang et al. 1995; Shaw et al. 1996) reported that infants who were heterozygous or homozygous for transforming growth factor alpha allele and were exposed to smoking during pregnancy had significantly increased risks for a cleft palate of 7.0 (95 percent CI, 1.18–28) (Hwang et al. 1995) and 4.0 (95 percent CI, 1.7–9.2) (Shaw et al. 1996). Risks for a cleft lip with or without a cleft palate were lower, about twofold, and were only significant in one study where smoking alone significantly elevated the risks of both outcomes (OR = 1.6) (Shaw et al. 1996). In the other study, smoking alone was not associated with either category of oral clefts (Hwang et al. 1995).

Infant Mortality and Stillbirths

Stillbirths (fetal death after 28 weeks) and infant deaths (death within the first year of life) have been examined in relation to smoking in numerous studies. These outcomes have declined significantly in the United States in recent years, as infant mortality has declined from 13 deaths per 1,000 births in 1980 to 7 deaths per 1,000 in 1998 (Guyer et al. 1999). Much of this improvement before and after 1980 has been from advances in medical interventions for the very smallest and sickest infants. Numerous studies have demonstrated associations between active maternal smoking and stillbirths (Meyer and Tonascia 1977; Kiely et al. 1986; Cnattingius 1992; Little and Weinberg 1993; Raymond et al. 1994) and neonatal and perinatal mortality (Comstock and Lundin 1967; Rush and Kass 1972; Cnattingius et al. 1988; Malloy et al. 1988; Schramm 1997). Even in the face of modern neonatal intensive care, numerous studies have demonstrated increased risks for neonatal mortality (death of a live-born infant within 28 days) (Cnattingius et al. 1988; Malloy et al. 1988; Schramm 1997), with reported ORs for infants of smokers around 1.2 compared with infants of non-smokers.

SIDS—or sudden, unexplained, unexpected death before one year of age—has been investigated in relation to fetal exposures to maternal smoking and the exposure of the infant to smoking by the mother and others during the postpartum period. Although social and behavioral risk factors for SIDS have been identified, the biologic mechanism is still unknown. Concerning smoking and SIDS, one proposed mechanism is chronic hypoxia—via elevated levels of carbon monoxide or reduced placental perfusion—affecting factors such as the normal development of the central nervous system (Bulterys et al. 1990). In animal studies designed to investigate neurotoxic effects, nicotine was found to target neurotransmitter receptors in the fetal brain, leading to reduced cell proliferation and, consequently, altered synaptic activity. The cholinergic and catecholaminergic systems and neurotransmitter pathways are affected acutely and, possibly, over the long term. Alterations in the peripheral autonomic pathways may lead to increased susceptibility to hypoxia-induced brain damage and SIDS (Slotkin 1998). In a study of newborns, the auditory arousal threshold for babies whose mothers smoked during pregnancy was greater than for those whose mothers did not smoke (Franco et al. 1999). Stick and colleagues (1996) observed the respiratory function of newborns in the hospital and reported lower function in infants of smokers compared with non-smokers. This observation suggests a fetal effect of smoking that continues beyond the postpartum period.

The death rate attributable to SIDS has declined by more than half over the last two decades; the SIDS rate in 1979 was 151.1 per 100,000 live births, and in 1998 the rate was 64 per 100,000 live births (Guyer et al. 1999). SIDS has decreased dramatically because of interventions such as the “Back to Sleep” campaign implemented in the 1990s. The diagnosis of SIDS, preferably by conducting an autopsy to exclude other causes, makes it a difficult outcome to study. Moreover, studies that examine maternal smoking during pregnancy may not be able to account for levels of postpartum smoking. In such studies (Malloy et al. 1992), the risk estimates for maternal smoking may be underestimated, since many women who quit or reduce the amount they smoke during pregnancy resume or increase their prepregnancy smoking levels after giving birth (Floyd et al. 1993; O’Campo et al. 1995).

Most studies have demonstrated that an increased risk of SIDS is associated with maternal smoking during pregnancy (Bergman and Wiesner 1976; Malloy et al. 1988; Kraus et al. 1989; McGlashan 1989; Bulterys et al. 1990; Haglund and Cnattinguis 1990; Mitchell et al. 1991; Schoendorf and Kiely 1992; MacDorman et al. 1997); adjusted ORs for mothers who smoked compared with nonsmokers ranged from 1.4 to 3.0 (Table 5.12). Some studies reported a dose-response relationship, comparing mothers who smoked 1 to 9 cigarettes with those who smoked 10 or more cigarettes per day (Haglund and Cnattinguis 1990; MacDorman et al. 1997). However, because very few smokers smoke only during pregnancy and not after delivery, it is nearly impossible to identify the risks associated only with prenatal exposure. Recent studies have begun to examine differences in the risk for SIDS between infants of women who smoke only after giving birth and infants of women who smoke both during pregnancy and after delivery (Mitchell et al. 1991; Schoendorf and Kiely 1992; Klonoff-Cohen 1997). These studies suggest that both prenatal and postpartum exposures to tobacco smoke increase the risk of SIDS. For infants exposed to tobacco only during the postpartum period, ORs were 2.4 (95 percent CI, 1.49–3.83) for blacks and 2.2 (95 percent CI, 1.29–3.78) for whites. For infants exposed during pregnancy and after delivery, ORs were 2.9 (95 percent CI, 2.12–4.07) for blacks and 4.07 (95 percent CI, 3.03–5.48) for whites (Schoendorf and Kiely 1992).

Table 5.12. Studies on the association between maternal smoking and infant mortality.

Table 5.12

Studies on the association between maternal smoking and infant mortality.

In a study containing more information about passive exposure to tobacco smoke, Klonoff-Cohen (1997) reported a dose-response relationship for post-partum smoking exposures even after adjusting for prenatal smoking levels of the mother. With one person smoking in the infant’s room, the OR for SIDS was 3.67 (95 percent CI, 1.66–8.13); two to four persons smoking in the infant’s room yielded an OR of 20.91 (95 percent CI, 4.02–108.7). These ORs should be interpreted cautiously given the wide CIs. A dose-response relationship was also demonstrated in this study for the number of cigarettes per day that the infant was exposed to during the postpartum period.

Child Physical and Cognitive Development

Strong associations between maternal smoking during pregnancy and adverse outcomes such as lowered birth weight and IUGR have prompted researchers to investigate the longer-term consequences of smoking during pregnancy on the physical growth and cognitive development of infants, children, and young adults. These studies are difficult to conduct, in part because of the need to consider multiple potential confounding factors that can intervene between pregnancy and the outcome of interest (e.g., family or environmental circumstances). Of particular concern is the effect of a continued exposure to passive smoking in the household on the developing infant or child. Although rates of reducing and quitting smoking during pregnancy are substantial, many women (approximately 70 percent) resume smoking once their infant is delivered (USDHHS 2001). Overpeck and Moss (1991) studied maternal smoking during pregnancy and the exposure to secondhand smoke of children aged five years and younger by mothers and other household members, and found that only 1.2 percent of children were exposed to tobacco smoke prenatally but not postpartum. Thus, a comparison group of infants who had been exposed to smoking during pregnancy but not after delivery is rarely available, making it difficult to attribute any observed effects to prenatal smoking alone.

The mechanisms by which maternal smoking during pregnancy may lead to compromised physical and cognitive development are not clear. However, regarding cognitive development, effects of smoking, and nicotine in particular, on central nervous system development have been proposed. Alterations in the peripheral autonomic pathways, mentioned earlier, may lead to an increased susceptibility to hypoxia-induced short-term and long-term brain damage (Slotkin 1998).

Several studies have examined the association between prenatal maternal smoking and subsequent physical growth of the infant or child, with mixed findings (Goldstein 1971; Rantakallio 1983; Barr et al. 1984; Fogelman and Manor 1988; Eskenazi and Bergman 1995) (Table 5.13). Goldstein (1971) observed the growth of approximately 15,000 seven-year-olds and reported that maternal smoking during pregnancy resulted in a 0.6 cm reduction in height after accounting for social class, birth weight, and gender. In a large birth cohort, Rantakallio (1983) observed a 0.4 to 0.6 cm reduction in height at 14 years of age in children of mothers who smoked compared with children whose mothers were nonsmokers. Neither study adjusted for postpartum smoking. Barr and colleagues (1984) examined associations between maternal smoking during pregnancy and infant size at eight months (weight, length, and head circumference) and reported no differences between infants of smokers and infants of nonsmokers. Fox and colleagues (1990) examined the growth of children at three years of age in relation to prenatal smoking; after adjusting for multiple confounders including postpartum smoking, they found no differences in height and weight. In a study of 2,622 children, Eskenazi and Bergman (1995) found that pregnancy serum cotinine levels when divided into low, medium, and high tertiles were associated with a −3 cm, −3 cm, and −8 cm reduction in the heights, respectively, of children of mothers who had smoked during pregnancy compared with children of non-smoking mothers. These authors reported that this effect was largely due to a prenatal exposure rather than to a postpartum secondhand smoke exposure.

Table 5.13. Studies on the association between maternal smoking and cognitive development, behavioral problems, and growth in children.

Table 5.13

Studies on the association between maternal smoking and cognitive development, behavioral problems, and growth in children.

Studies examining associations between maternal smoking during pregnancy and the child’s cognitive development also have reported mixed results. Several studies reported associations with smoking during pregnancy and subsequent cognitive development, behavioral outcomes, and educational achievements of infants and children of varying ages (Rantakallio 1983; Naeye and Peters 1984; Sexton et al. 1990) (Table 5.13). Many studies adjusted for several potentially important confounders, and six reported a dose-response relationship (Fogelman and Manor 1988; Weitzman et al. 1992; McCartney et al. 1994; Fried et al. 1997, 1998; Obel et al. 1998) (Table 5.13). The outcomes examined in these studies were babbling abilities in eight-month-old infants, performances on standardized tests of cognitive abilities in school-age children, auditory processing in school-age children, behavioral problems as reported by parents and teachers, and educational achievements of young adults. A few studies had information on both pre-natal and postpartum smoking by mothers and parents; two of these studies reported that a prenatal but not a postpartum secondhand smoke exposure was associated with adverse outcomes (Weitzman et al. 1992; McCartney et al. 1994). Yet, in both studies, prenatal and postpartum smoking was significantly associated with adverse developmental outcomes. Many studies examined multiple outcomes, and not all were significantly associated with smoking during pregnancy. Overall, observed differences between smokers and nonsmokers were relatively small.

Three studies reported no association between maternal smoking during pregnancy and adverse cognitive or behavioral outcomes (Fergusson and Lloyd 1991; Baghurst et al. 1992; Eskenazi and Trupin 1995). Fergusson and Lloyd (1991) studied children aged 12 years and adjusted for several potential confounders, including postpartum smoke exposure. Once confounders were accounted for, no differences between children of mothers who smoked and children of mothers who did not smoke during their pregnancies were observed. In a study of more than 2,000 five-year-old children, Eskenazi and Trupin (1995) found that active smoking during pregnancy did not result in cognitive deficits in children according to results from the Raven Coloured Progressive Matrices Test and the Peabody Picture Vocabulary Test at five years of age. Thus, studies on cognitive development and behavioral problems report small or no differences among children of pregnant smokers compared with children of pregnant nonsmokers. Confounding by unmeasured factors cannot be ruled out as an explanation for the small differences, which may not be clinically meaningful.

Evidence Synthesis

The evidence on the relationship between maternal smoking during pregnancy and congenital malformations is mixed. Most studies report no association between maternal smoking and congenital malformations as a whole. This finding is not unexpected, as it is unlikely that smoking during pregnancy would be linked to all of the multiple etiologic pathways involved in the various malformations.

For selected malformations, oral clefts in particular, several studies have reported positive associations with smoking. The biologic evidence on the etiology in general for oral clefts is scant, therefore making it difficult to establish a causal role of smoking. Recent studies on interactions between genes and the environment are contributing further to understanding the etiology of oral clefts and the role of smoking, but much work is still needed.

The data on maternal smoking and elevated rates of SIDS are abundant and consistent in the literature. However, evidence is not available to determine whether prenatal smoking alone is causally related to SIDS. Studies have demonstrated that prenatal smoking combined with postpartum passive exposure elevates the risk beyond that for a passive exposure to smoking alone. Some data on biologic plausibility are emerging. One hypothesized mechanism is that exposure to cigarette smoke during pregnancy has effects on the fetal respiratory system and the brain that may, in turn, contribute to SIDS.

Studies examining relationships between maternal smoking during pregnancy and subsequent physical growth of the child report mixed findings. Moreover, the magnitude of reported differences between children of smokers and nonsmokers, especially for physical growth, is extremely small. Information on the mechanisms by which the physical and cognitive development of children are affected by exposures to prenatal smoking is not available and potential confounding is a concern.

Conclusions

  1. The evidence is inadequate to infer the presence or absence of a causal relationship between maternal smoking and congenital malformations in general.
  2. The evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking and oral clefts.
  3. The evidence is sufficient to infer a causal relationship between sudden infant death syndrome and maternal smoking during and after pregnancy.
  4. The evidence is inadequate to infer the presence or absence of a causal relationship between maternal smoking and physical growth and neuro-cognitive development of children.

Implications

Mothers who smoke increase their children’s risk of SIDS substantially; smoking during pregnancy and after the child’s birth should be a target for forceful and effective interventions. Future studies of smoking and congenital malformations should selectively build on the accumulating evidence of the few malformations for which there are elevated risks. Although further studies may elucidate the relationship between prenatal smoking and the risk of SIDS, and subsequent physical and cognitive development, study design issues may be too challenging to overcome. Specifically, the challenges are the identification of a sizable group of infants who are only exposed prenatally and the ability to adjust for the multiple confounders that may intervene between pregnancy and infant or child outcomes.

Conclusions

Fertility

1. The evidence is inadequate to infer the presence or absence of a causal relationship between active smoking and sperm quality.

2. The evidence is sufficient to infer a causal relationship between smoking and reduced fertility in women.

Pregnancy and Pregnancy Outcomes

3. The evidence is suggestive but not sufficient to infer a causal relationship between maternal active smoking and ectopic pregnancy.

4. The evidence is suggestive but not sufficient to infer a causal relationship between maternal active smoking and spontaneous abortion.

5. The evidence is sufficient to infer a causal relationship between maternal active smoking and premature rupture of the membranes, placenta previa, and placental abruption.

6. The evidence is sufficient to infer a causal relationship between maternal active smoking and a reduced risk for preeclampsia.

7. The evidence is sufficient to infer a causal relationship between maternal active smoking and preterm delivery and shortened gestation.

8. The evidence is sufficient to infer a causal relationship between maternal active smoking and fetal growth restriction and low birth weight.

Congenital Malformations, Infant Mortality, and Child Physical and Cognitive Development

9. The evidence is inadequate to infer the presence or absence of a causal relationship between maternal smoking and congenital malformations in general.

10. The evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking and oral clefts.

11. The evidence is sufficient to infer a causal relationship between sudden infant death syndrome and maternal smoking during and after pregnancy.

12. The evidence is inadequate to infer the presence or absence of a causal relationship between maternal smoking and physical growth and neuro-cognitive development of children.

References

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