Introduction

Tobacco use before and during pregnancy remains a major cause of reduced fertility as well as maternal, fetal, and infant morbidity and mortality. Smoking prevalence among women grew in the decades before the 1964 Surgeon General's report, Smoking and Health: Report of the Advisory Committee of the Surgeon General of the Public Health Service, and continued to increase across the 1970s as products were aggressively marketed to women (U.S. Department of Health and Human Services [USDHHS] 2001). Despite declines in recent decades, more than 400,000 live-born infants are exposed in utero to tobacco from maternal smoking annually (Hamilton et al. 2012; Tong et al. 2013). The women most likely to smoke are among the most vulnerable—those disadvantaged by low income, low education, and mental health disorders, further exacerbating the adverse health effects from smoking on mothers and their offspring (Adams et al. 2008; Holtrop et al. 2010; Maxson et al. 2012; Page et al. 2012a). Women in these groups are also less likely to quit smoking when they become pregnant and are more likely to relapse after delivery (Adams et al. 2008). Reducing the prevalence of smoking among pregnant women and women of reproductive age remains a critical component of public health efforts to improve maternal and child health.

This chapter includes the following updates to previous Surgeon General's reports:

An overview of surveillance systems of pregnant women that include data related to prenatal smoking status.

• A review of what is currently known about smoking cessation during pregnancy, including clinical- and policy-based interventions.
• A summary of the advances in our understanding of the mechanisms underlying previously established effects of tobacco on reproductive health since the 1964 report. Topics include fetal growth, preeclampsia, stillbirth and perinatal mortality, sudden infant death syndrome (SIDS), and neurocognitive development.
• Evidence reviews for outcomes not addressed or not causally related to smoking in previous Surgeon General's reports, including congenital malformations, male sexual function, neurobehavioral disorders of childhood, ectopic pregnancy, and spontaneous abortion. These topics were last reviewed in the 2004, 2006, and 2010 Surgeon General's reports.

Surveillance

Before 1989, surveillance of the prevalence of smoking during pregnancy in the United States was limited to self-reported data collected through periodic surveys, which sampled new mothers or reproductive age women, regarding their most recent pregnancy within the last 5 years (Table 9.1). The earliest data available are from the 1967 National Natality Survey, which sampled married women with live-born infants (Kleinman and Kopstein 1987). In 1989, smoking status during pregnancy was added to the U.S. Standard Certificate of Live Birth, and New York City, the District of Columbia, and all states, except California, collected this information (Tolson et al. 1991). In 2003, the U.S. Standard Certificate of Live Birth was revised to include the average number of cigarettes smoked per day during the 3 months before pregnancy and during the first, second, or third trimesters of pregnancy (Osterman et al. 2011). Because the 1989 and 2003 birth certificate smoking variables are not comparable and state uptake of the 2003 revised birth certificate has been gradual (in 2011, 38 states had implemented the 2003 revised birth certificate, and it is anticipated that all states will have made the transition by 2014), national prenatal smoking trend data after 2002 are not available. In 2002, an estimated 11.5% of singleton, live-born infants were exposed to maternal smoking in utero (Dietz et al. 2010). Of these, an estimated 5.3–7.7% of preterm deliveries, 13.1–19.0% of term low birth weight deliveries, 23.2–33.6% of SIDS, and 5.0–7.3% of preterm-related deaths were attributable to prenatal smoking.

Table 9.1

Data sources for smoking prevalence during pregnancy.

The Pregnancy Risk Assessment Monitoring System (PRAMS) is another source of state- and population-based data on smoking during pregnancy. In this survey, a questionnaire is administered 2–6 months after delivery to women with a live birth. Using 2010 data from 27 PRAMS states/sites, 23% of women who delivered live infants reported smoking in the 3 months before pregnancy; 11% in the last 3 months of pregnancy; and 16% 2–6 months after delivery (Tong et al. 2013). There was large variation by state in the prevalence of smoking during the last 3 months of pregnancy, ranging from 2.3% in New York City to 30.5% in West Virginia. Demographic groups with the highest prevalence of prenatal smoking were 20–24 year olds (17.6%), American Indian/Alaska Natives (26.0%), women with less than 12 years of education (17.4%), unmarried (18.6%), and those with an annual income of less than $15,000 per year (19.0%) (Tong et al. 2013).

Underreporting of smoking among pregnant women has been documented through biochemical confirmation of self-report in clinical trials and population-based studies. In an analysis of 1999–2006 National Health and Nutrition Examination Survey data, which compared self-reported smoking status to serum cotinine, 22.9% of pregnant smokers and 9.2% of nonpregnant smokers of reproductive age did not accurately disclose their smoking status (Dietz et al. 2010). Such nondisclosure likely contributes to underreporting of prenatal smoking status on birth certificates and in self-administered surveys. It is unknown whether and to what extent nondisclosure of smoking status has changed over time. Existing surveillance systems of pregnant women do not currently gather data on noncigarette tobacco products such as little cigars/cigarillos, hookah, snus, or electronic cigarettes.

Cessation

Smoking cessation in pregnancy has been associated with improvements in outcomes including fetal growth restriction and preterm delivery (McCowan et al. 2009; Baba et al. 2012). The first study of a smoking cessation intervention for pregnant women was published in 1976 and included brief advice from a physician to quit (Baric et al. 1976). Numerous intervention trials have been conducted since then, and results have been generally positive with regard to pregnancy outcomes (Lumley et al. 2009), although the increasing importance of including biochemical validation of cessation in research protocols has also been recognized (Kendrick et al. 1995). Behavioral counseling has been shown to have a modest effect, resulting in about an additional 1 in 20 pregnant women quitting (Lumley et al. 2009), and the current best-practice guidance for prenatal smoking cessation entails psychosocial counseling delivered in the prenatal care setting (Fiore et al. 2008; American Congress of Obstetricians and Gynecologists [ACOG] 2010). However, even with universal implementation of this best-practice approach, the prevalence of smoking among pregnant women was projected to decline by no more than approximately 1% in a model of smoking among pregnant women based on 2004 U.S. data (Kim et al. 2009). Therefore, other interventions are also needed in order to have a substantial public health impact.

In addition to behavioral interventions, a number of studies have assessed the safety and efficacy of nicotine replacement therapy (NRT) for cessation during pregnancy. A 2012 meta-analysis of six randomized controlled trials (RCTs) of NRT found no significant difference for smoking cessation in later pregnancy after using NRT as an adjunct to behavioral support as compared to control (relative risk [RR] = 1.33; 95% confidence interval [CI], 0.93–1.91, 1,745 women) (Coleman 2012). Both placebo and nonplacebo controlled studies were assessed (placebo RCTs: RR = 1.20; 95% CI, 0.93–1.56, four studies, 1,524 women; nonplacebo RCTs: RR = 7.81; 95% CI, 1.51–40.35, two studies, 221 women), suggesting clinical heterogeneity and uncontrolled biases in the nonplacebo controlled trials. There was insufficient evidence to conclude that NRT had a positive or negative effect on rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, or neonatal death compared to the control groups. Nonadherence to NRT treatment was reported among the majority of participants in five of the six NRT trials (range of 7.2–29% of patients adhering to NRT treatment). A recent observational study of pregnant smokers utilizing national smoking cessation services in the United Kingdom found that use of a NRT patch along with a faster-acting form was associated with higher odds of quitting compared with no medication (odds ratio [OR] = 1.93; 95% CI, 1.13–3.29, p = 0.016), whereas use of a single form of NRT showed no benefit (OR = 1.06; 95% CI, 0.60–1.86, p = 0.84) (Brose et al. 2013). Research is needed to further assess the efficacy and safety of NRT as well as understanding the reasons for nonadherence to NRT treatments. Currently, ACOG (2010) recommends NRT only if behavioral therapy fails to achieve smoking cessation and it must be administered under the supervision of a physician.

In addition to the current clinical guidelines, section 4107 of the Patient Protection and Affordable Care Act, which took effect on October 1, 2010, requires state Medicaid programs to cover tobacco-cessation counseling and drug therapy for pregnant women without cost sharing. The update of Treating Tobacco Use and Dependence guidelines (Fiore et al. 2008) note that although the use of NRT exposes pregnant women to nicotine, smoking exposes them to nicotine plus numerous other chemicals that are injurious to the woman and fetus, and these concerns must be considered in the context of inconclusive evidence that cessation medications boost abstinence rates in pregnant smokers.

Studies of contingency management interventions, in which quitting is rewarded with financial incentives, show promise, including higher quit rates (34% of women in the intervention arm quit compared to 7.1% of women receiving standard care) and improvements in infant birth weight (Higgins et al. 2010, 2012). The effectiveness of contingency management across diverse populations and settings and the cost-benefit of implementing these interventions have not been evaluated.

Studies of the effects of interventions to prevent relapse after delivery have been mixed and limited by methodologic weaknesses; a 2009 Cochrane review found the evidence “insufficient to support the use of any specific behavioral intervention for helping smokers who have successfully quit for a short time to avoid relapse” (Hajek et al. 2009).

There is growing evidence that tobacco control policies may be effective in reducing the prevalence of prenatal smoking and improving birth outcomes. Studies conducted in Scotland and Belgium found that implementation of national smokefree air laws had a significant effect on reducing the prevalence of prenatal smoking and decreased the risk of preterm delivery (Mackay et al. 2012; Cox et al. 2013). In an analysis of 2000–2005 PRAMS data from 29 states linked to state tobacco control data, state tobacco control policies, taxes, and smokefree air laws were found to be effective in reducing maternal smoking (Adams et al. 2012). For example, a $1.00 increase in cigarette taxes and prices increased the quit rate among pregnant women from 44.1–48.9% and decreased the percentage who relapsed in the early postpartum period. Additionally, the same study found that implementing a full worksite smoking ban increased quits during pregnancy by an estimated 5%. Several studies of local ordinances in the United States have also documented reduced prevalence of smoking (Nguyen et al. 2013), and reductions in preterm births (Page et al. 2012b). Tobacco control policies are continually being implemented at local and state levels, and there is a need for evaluation of these policies and their effects on the prevalence of smoking and birth outcomes in pregnant women.

Advances in the Understanding of Tobacco and Reproductive Health

The 1964 Surgeon General's report stated that infants of smokers are more likely than those of nonsmokers to be born at less than 2,500 grams (g) (U.S. Department of Health, Education, and Welfare [USDHEW] 1964); since that time, the list of adverse reproductive health outcomes associated with maternal smoking has grown dramatically (see Table 4.4S). For many of these outcomes, however, the mechanisms through which tobacco acts to cause adverse effects are still not completely understood. As the landscape of commercial tobacco products changes and new nicotine-delivery devices are introduced into the market, gaining a better understanding of the underlying pathophysiologic mechanisms and the components responsible is of increasing urgency, as is identifying the most effective approaches to decrease the prevalence of prenatal and postnatal smoking.

Stillbirth and Perinatal Mortality

In the 1969 Surgeon General's report supplement, it was stated that prenatal smoking may be associated with stillbirth (fetal death after 28 weeks gestation) and neonatal death (death within 28 days of birth) (USDHEW 1969). In the 2001 Surgeon General's report, it was noted that cigarette smoking was consistently associated with stillbirth (USDHHS 2001), with an increased risk of 40% (Cnattingius et al. 1988) to 60% (Raymond et al. 1994). Underlying factors were attributed to IUGR, placental complications, or both. Neonatal mortality was also noted to be increased in infants of smokers by 20% (Cnattingius et al. 1988; Malloy et al. 1988). Perinatal mortality was noted to be increased by 20–30% with 3.4–8.4% of perinatal deaths attributable to smoking (DiFranza and Lew 1995).

Since the 1964 Surgeon General's report, there has been significant progress in understanding the increased perinatal and infant mortality in offspring of smokers. Smoking likely increases perinatal mortality through numerous mechanisms, including abruption, placenta previa, preterm delivery, and premature and prolonged rupture of the membranes, and through physiologic responses of the fetus and newborn to stress (Meyer and Tonascia 1977). For example, an abnormal adrenal response of the fetus or neonate to hypoxia could affect cardiac function and survival (Slotkin 1998), and hypoxia from sleep apnea or airway obstruction could precipitate respiratory failure in a susceptible infant (Horne et al. 2005).

Some studies support a role for nicotine in the effects of smoking on stillbirth and perinatal mortality (see Chapter 5, “Nicotine”). Nicotinic acetylchonine receptors (nAChRs) are receptors that are ordinarily activated by endogenous acetylcholine, but that also can be stimulated by nicotine, resulting in disruption of normal cholinergic signaling (Albuquerque et al. 2009). nAChRs are expressed early in fetal development in the central, peripheral, and enteric nervous systems (reviewed by Abbott and Winzer-Serhan 2012), and transient, regional patterns of increased nAChR expression occur throughout perinatal and postnatal development. nAChRs are involved in neurogenesis, migration, differentiation, and synaptogenesis, in regulating the growth of developing neurites, guiding pathfinding of these projections, and mediating pruning of hippocampal and cortical neurons through effects on apoptosis (Dywer et al. 2008). Depending on the subunit composition, and the dose and duration of exposure, exogenous nicotine can activate or inactivate a given receptor, potentially altering fetal development. For example, animal models show that nicotine exposure in the fetus causes cell damage, and reduces cell number, and impairs synaptic activity. Receptor stimulation by nicotine leads to errors in cell development, including premature change from cell replication to differentiation and initiation of apoptosis (Slotkin et al. 1987; Slotkin 1998; Dwyer et al. 2008). Because nicotinic receptors continue to emerge after organogenesis, periods of fetal vulnerability likely extend into the second and third trimesters of pregnancy (Slotkin 1998).

Human and animal studies suggest that nAChRs in the brainstem nuclei control cardiopulmonary integration and arousal during early life (reviewed by Dwyer 2008). Gestational nicotine exposure in rat pups blunted the ventilator response to hypercapnia and hypoxia/hypercapnia in the first days of life, perhaps through effects in carotid body oxygen sensing or central processing (Huang et al. 2010). Prenatal nicotine exposure in rat pups also resulted in increased mortality in response to hypoxia (Slotkin et al. 1995), while human preterm infants of maternal smokers exhibit increased obstructive apnea and decreased arousal in response to apnea events (Sawnani et al. 2004). Additional data suggest that gestational smokeless tobacco exposure also increases the risk of apnea, of a similar magnitude to that seen with smoking (Gunnerbeck et al. 2011), further supporting a role for nicotine in underlying pathophysiologic processes.

Extensive animal research has generated plausible models to explain how nicotine could increase the risk of perinatal mortality (see Chapter 5) (Slotkin 1998). During parturition, a massive release of catecholamines from the fetal adrenal medulla protects the fetus from hypoxia and maintains blood flow to the brain and heart (Lagercrantz and Slotkin 1986). However, prenatal nicotine exposure in rat models causes immature chromaffin cells in the adrenal gland to differentiate prematurely, resulting in loss of the normal direct stimulation of the adrenal gland by hypoxia and a complete absence of catecholamine release, which in turn causes an impaired cardiac response (Slotkin 1998). This results in the loss of a critical protective response to hypoxia, which would lead to an increased risk of infant mortality (Figure 9.1) (Slotkin 1998).

Figure 9.1

Catecholamine response to hypoxia by nicotine-exposed and unexposed rats. Source: Slotkin 1998. Reprinted with permission from American Society for Pharmacology & Experimental Therapeutics, © 1998. Note: CNS = central nervous system.

Studies of stillbirth have also been conducted among smokeless tobacco users. In a study in India, researchers reported an adjusted risk for stillbirth three times higher for mothers who used smokeless tobacco than for those who do not use any tobacco. Some evidence for a dose-response relationship was found using frequency of use (Gupta and Subramoney 2006). A previous study from India also found an increased risk of stillbirth or perinatal death with use of smokeless tobacco (primarily chewing tobacco) (Krishna 1978). In a large study of Swedish women, snuff users had an increased risk of stillbirth compared with tobacco nonusers (AOR = 1.6; 95% CI, 1.1–2.3); the risk was higher for preterm stillbirth (AOR = 2.1; 95% CI, 1.3–3.4). For women smoking 1–9 cigarettes per day and smoking more than 10 cigarettes per day, the AORs for stillbirth were 1.4 (1.2–1.7) and 2.4 (2.0–3.0), respectively. When women with preeclampsia, antenatal bleeding, or small for gestational age deliveries were excluded, the smoking-related risks of stillbirth was markedly attenuated while the elevated risk for snuff users remained at the same level. These findings suggest that the mechanisms underlying the associations between smoking and stillbirth and between smokeless tobacco use and stillbirth both involve nicotine, but other factors may also contribute to increased risk in smokers (Wikström et al. 2010).

Sudden Infant Death Syndrome

SIDS is currently defined as “…sudden death of an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history” (Willinger et al. 1991, p. 681). A causal association between SIDS and smoking during and after pregnancy was established in 2004 (USDHHS 2004), more than 30 years after the landmark Collaborative Perinatal Project (CPP) first described an elevated risk of SIDS in infants of smokers. Approximated 42,000 pregnant women were enrolled, making the CPP the largest U.S.-based cohort study of pregnancy and childhood to date (reviewed by Klebanoff 2009).

Major risk factors for SIDS include prone/side sleep position, soft sleep surface, maternal smoking during pregnancy, secondhand tobacco smoke, bed sharing, and overheating (American Academy of Pediatrics [AAP] 2011). Following the release in 1992 of the recommendation that infants be placed in a nonprone position for sleep, there was a dramatic drop in the number of SIDS deaths, although this decline has plateaued. As the deaths related to prone sleeping declined, the fraction of deaths attributable to smoking increased (AAP 2011). In more recent years, the fraction of SIDS deaths attributable to smoking may be stabilizing; it is estimated that 23.2–33.6% of SIDS deaths were attributable to prenatal smoking in 2002; after extrapolating, based on trends in prenatal smoking, it was estimated that 20.2–29.3% of SIDS deaths were attributable to prenatal smoking in 2009 (Dietz et al. 2010). Guidelines for death scene investigations and autopsies are available to improve standardization of data collected and, ultimately, to improve the consistency of cause-of-death determination. However, these guidelines are not universally practiced (Camperlengo et al. 2012).

A number of hypotheses regarding the underlying causes of SIDS have been proposed. These include dysfunctional and/or immature cardiorespiratory systems; dysfunctional and/or immature arousal systems, with resulting failure to respond to stressors with normal protective responses (AAP 2011); potentiation of the laryngeal chemoreflex (Thach 2008); respiratory obstruction; bacterial toxins; thermal stress; and failure of the diaphragm with inactivation of intercostal muscles (reviewed by Harper and Kinney 2010; Goldwater 2011).

Many of these hypothesized mechanisms are unified in the triple risk model of SIDS. In this model, death from SIDS occurs in the presence of three overlapping factors: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). A number of different factors (including prenatal tobacco exposure) may make the infant vulnerable to sudden death during the critical period. SIDS then occurs only in the presence of exogenous stressors, such as bed sharing and overbundling (Figure 9.2) (Filiano and Kinney 1994).

Figure 9.2

Triple-risk model for sudden infant death syndrome (SIDS). Source: Trachtenberg et al. 2012. Reprinted with permission from American Academy of Pediatrics, © 2012.

Epidemiologic data support that a high-risk scenario as described in the triple risk model could increase the risk of SIDS. In a recent meta-analysis, the authors found that the risk of SIDS associated with bed sharing was higher for infants whose mothers smoked (combined OR = 6.27; 95% CI, 3.94–9.99), than for infants whose mothers did not smoke (combined OR = 1.66; 95% CI, 0.91–3.01) (Vennemann et al. 2012). This finding suggests that the combination of the effects of tobacco exposure on infant vulnerability and stress related to the sleep environment may combine synergistically to increase the risk of death (Alsweiler et al. 2012).

Nicotine may play an important role in increasing the risk of SIDS in infants of smokers (see Chapter 5). In animal models, exogenous nicotine administered to pregnant rats alters the expression of nAChRs in the brainstem in areas involved in autonomic function, and affects fetal autonomic activity and medullary neurotransmitter receptors (Duncan et al. 2009). In studies of human infants, prenatal tobacco exposure affects recovery from hypoxia in preterm infants (Thiriez et al. 2009); infants also display impaired arousal patterns that correspond to cotinine levels (Richardson et al. 2009). These changes in autonomic function and/or arousal could increase the risk of SIDS (reviewed by AAP 2011), although a causal pathway has not been established.

Updated Evidence Reviews

Congenital Malformations

Major structural birth defects as well as other birth defects may occur because of a malformation, disruption, or deformation of one or more parts of the body, or they can result from a chromosomal abnormality. Major birth defects can have serious adverse effects on the health, development, or functional abilities of the affected child (Centers for Disease Control and Prevention [CDC] 2008). Each year, approximately 3% of newborns in the United States are born with major birth defects, and the prevalence of all major birth defects combined has remained relatively stable in the United States from the 1970s through recent years (CDC 2008).

To date, the evidence on smoking and birth defects has been most abundant and consistent for orofacial clefts. The 2004 Surgeon General's report found the evidence to be suggestive of a causal relationship between maternal smoking and orofacial clefts. The 2010 Surgeon General's report did not include conclusions related to causality. It did provide an update of studies related to smoking and orofacial clefts, which included results of a 2004 meta-analysis that found a small but positive association with maternal smoking for cleft lip with or without cleft palate (CL/P) and for cleft palate (CP) alone (Little et al. 2004a,b; USDHHS 2010). Subsequent to that meta-analysis, eight studies have shown positive associations between periconceptional maternal smoking and orofacial clefts (Little et al. 2004a; Bille et al. 2007; Romitti et al. 2007; Johansen et al. 2009; Leite and Koifman 2009; Shaw et al. 2009; Lebby et al. 2010; Zhang et al. 2011), one of which used midpregnancy cotinine levels to more accurately ascertain prenatal smoking exposure (Shaw et al. 2009); three of these (Little et al. 2004a; Honein et al. 2007 [contains data that overlap with Romitti et al. 2007]; Shaw et al. 2009) were reviewed in the 2010 Surgeon General's report. Although the magnitude of the association between periconceptional maternal smoking and orofacial clefts is relatively modest, this remains one of the most consistent findings in etiologic research on the causes of birth defects. In addition, despite some presumed misclassification of maternal smoking given that most studies rely on self-reported exposure, methodologic research suggests the finding is quite robust and corrections for likely levels of misclassification would result in somewhat higher effect estimates (MacLehose et al. 2009).

This section summarizes the evidence for associations between maternal prenatal smoking and specific birth defects. Topics include orofacial clefts, clubfoot, gastroschisis (abdominal wall defect), congenital heart defects, craniosynostosis (premature closure of cranial sutures), and anorectal atresia. This section also summarizes the 2010 Surgeon General's report review of specific genetic risk factors for congenital malformations, and their potential interactions with tobacco exposure in the etiology of birth defects.

Biologic Basis

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 environmental factors, and 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. Tobacco smoke includes about 7,000 different compounds, many of which could have deleterious effects on a fetus during development and potentially cause major birth defects (Talbot 2008; Rogers 2009; USDHHS 2010). Specific constituents of concern include nicotine, CO, aromatic amines, and cadmium (Nelson 2001; Rogers 2009). The 2010 Surgeon General's report covered the biologic basis for injury to the fetus by maternal smoking at length.

Maternal smoking could interfere with normal organ development in offspring in several ways, including through fetal hypoxia, alterations in essential nutrients, teratogenic effects, and DNA damage. These effects could 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 the section “Smoking and Maternal and Fetal Genetic Polymorphisms” later in this chapter).

Nicotine has diverse pharmacologic and toxicologic properties, which are discussed in Chapter 5. The Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency lists nicotine as a developmental toxicant. In addition, nicotine is a vasoconstrictor and is known to cross the placenta and concentrate in the fetus at levels slightly higher than those in the mother.

CO is a by-product of combustion and thus is present in tobacco smoke and is found in higher levels in smokers than nonsmokers (USDHHS 2010). CO is a potent toxin whose primary target organ is the brain, and the fetus is more susceptible to the toxic effects of CO than is the mother. Exposure to CO from which the mother will fully recover could end in permanent neurologic damage to the fetus or even death (e.g., stillbirth) (Norman and Halton 1990; Koren et al. 1991; Rogers 2009). The fetal effects of CO are well studied in animals (Koren et al. 1991; Penney 1996) and include 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). CO-induced hypoxia appears to be related to congenital anomalies including cleft lip and CP in susceptible strains of mice (Millicovsky and Johnston 1981a,b; Bronsky et al. 1986; Bailey et al. 1995). An association with cleft lip was demonstrated in a rat model in which the medication phenytoin was administered to pregnant rats to induce embryonic hypoxia (Webster et al. 2006). Subsequent human epidemiologic studies of birth defects in relation to CO levels from air pollution early in pregnancy found associations between higher CO levels and various cardiac defects, but the findings were not consistent (Ritz et al. 2002; Gilboa et al. 2005).

Thus, the evidence suggests likely impacts of nicotine and CO on fetal development. The combination of exposure to nicotine and hypoxia could decrease the supply of nutrients and oxygen to the embryonic tissues through a vasoconstrictive impact, resulting in congenital defects (Lambers and Clark 1996).

Tobacco smoke contains heavy metals, including cadmium, which is of particular concern because of its potential teratogenic effects (Chang et al. 1980; Carmichael et al. 1982). Cadmium crosses the placenta, and in animal studies has been associated with adverse effects on fetal growth (Carmichael et al. 1982; Goyer 1991) and orofacial clefts (Mulvihill et al. 1970; Ferm 1971; Chernoff 1973), limb reduction anomalies, central nervous system defects, and some other birth defects (Ferm 1971; Barr 1973; Carmichael et al. 1982; Goyer 1991).

Reductions in serum folate levels mediated by maternal smoking have also been associated with orofacial clefts (McDonald et al. 2002; Mannino et al. 2003; Ortega et al. 2004). This is further supported by two studies that found that intake of vitamins containing folic acid was associated with a decreased risk of orofacial clefts (Itikala et al. 2001; Bailey and Berry 2005). However, one large study—the National Birth Defects Prevention Study (NBDPS), a multisite population-based case-control study in 10 sites that began in 1997, did not observe an interaction between intake of folic acid and maternal smoking in the etiology of orofacial clefts (Honein et al. 2007). This is perhaps due in part because NBDPS largely enrolled cases conceived after folic acid fortification of enriched cereal grains in the United States when folic acid intake among all women was considerably higher than before fortification. However, the lack of interaction might also be due to the lack of an association between tobacco and folic acid preventable birth defects. Smoking has not been associated consistently with neural tube defects, an outcome causally associated with decreased folate and one that has been significantly reduced by folic acid fortification (Hackshaw et al. 2011).

PAHs are products of the partial combustion of carbon-containing materials and are found in tobacco smoke (International Agency for Research on Cancer 1986, 2004; U.S. Environmental Protection Agency 1992). Studies have reported direct fetotoxic and teratogenic effects associated with PAHs, as well as adverse effects on reproduction. Other effects include immunotoxicity, endocrine effects, and toxic effects on the lungs. The toxic effects and dose-response relationships described for PAHs are primarily based on experiments in animals. Lupo and colleagues (2012) reported an association between occupational PAH exposure and gastroschisis among mothers 20 years of age or older (OR = 2.53; 95% CI, 1.27–5.04), but no association among mothers younger than 20 years of age. 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 (USDHHS 2010).

Description of the Literature Review

To update the epidemiologic literature on smoking and birth defects, a comprehensive literature search was undertaken using PubMed to capture English-language publications from 1999 through July 2012. The studies included in the review presented the outcome of either all birth defects or specific types of birth defects, and their potential association with maternal smoking, paternal smoking, or maternal exposure to secondhand smoke. Search terms included the following: (1) smoking and defect, (2) smoking and cleft, (3) smoking and heart defect, (4) smoking and gastroschisis, (5) smoking and cryptorchidism, (6) smoking and atresia, (7) smoking and congenital, (8) smoking and clubfoot, (9) smoking and renal, (10) smoking and craniosynostosis, (11) smoking and hypospadias, (12) tobacco and defect, (13) tobacco and cleft, (14) tobacco and heart defect, (15) tobacco and gastroschisis, (16) tobacco and cryptorchidism, (17) tobacco and atresia, (18) tobacco and congenital, (19) tobacco and clubfoot, (20) tobacco and renal, (21) tobacco and craniosynostosis, (22) tobacco and hypospadias, (23) smoking and malformation, and (24) tobacco and malformation. Additional articles were identified by examining the reference lists of articles identified by these searches, by searching PubMed for specific investigators, and by reviewing previous Surgeon General's reports.

Methodologic Considerations

Several methodologic challenges need to be addressed in studies of maternal smoking and congenital malformations. Case definitions can be heterogeneous across studies, but most authors attempt to remove cases associated with syndromes from the analysis. Isolated defects are sometimes studied alone, and other times they are combined with multiple defects: defined as those affected by two or more major defects in different organ systems (Rasmussen and Moore 2001). In case-control studies, periconceptional smoking status is generally obtained following delivery and after women have knowledge of their child's congenital malformation, introducing possible bias due to differential disclosure of smoking status among mothers with affected versus unaffected children. When suspected, confounding needs to be addressed through adjusted, matched, or stratified analysis. In meta-analyses, it is often difficult to fully account for confounding with the variation in treatment of confounders across studies. Finally, the selection of control groups could affect the results of case-control studies. For example, the selection of control groups with conditions also potentially associated with maternal tobacco use, such as other types of malformations, could result in bias.

Epidemiologic Evidence

Tables 9.2 and 9.3S–9.8S summarize studies that examined prenatal maternal smoking as a risk factor for specific defects. Defects include orofacial clefts, clubfoot, gastroschisis, congenital heart defects, craniosynostosis, and anorectal atresia. The following sections summarize the key findings from those studies. Because Little and colleagues (2004b) completed a meta-analysis of publications through 2001, specific studies are reviewed for orofacial clefts for 2002 through July 2012 (Table 9.3S). For all other defects, the literature is reviewed from 1999 through July 2012 (Tables 9.4S–9.8S).

Table 9.2

Summary of a systematic review of maternal smoking during pregnancy and its relationship with specific congenital malformations.

Orofacial Clefts

CL/P and CP are birth defects that occur when the upper lip or the palate do not close correctly during fetal development. With a cleft lip, the tissue that makes up the lip does not join completely between the fourth and seventh week of pregnancy. With CP, the tissue that makes up the palate (roof of the mouth) does not join correctly between the sixth and ninth week of pregnancy. CL/P and CP are embryologically distinct entities, and these phenotypes have somewhat different epidemiologic characteristics. For example, CL/P is more frequent among males and CP more frequent among females; CP is less common among Hispanics than other racial/ethnic groups, but this difference is not present for CL/P (Genisca et al. 2009). Studies that assessed CL/P and CP separately for their potential association with maternal smoking found that the risk estimates for the two defect types were generally similar (Little et al. 2004a; Krapels et al. 2006; Bille et al. 2007; Honein et al. 2007).

A 2011 systematic review and meta-analysis by Hackshaw and colleagues included publications from 1959–2010. Of the 38 case-control and cohort studies, 13 showed a significant association between maternal smoking and an increased risk for CL/P, and the pooled OR was 1.28 (95% CI, 1.20–1.36). Restriction of the analysis to prospective studies did not change the findings (OR = 1.24; 95% CI not included), nor did restricting to studies with AORs (1.26; 95% CI, 1.18–1.34). The earlier meta-analysis of orofacial clefts by Little and colleagues (2004b) still contributes to this knowledge base since it included several studies that were excluded from the Hackshaw meta-analysis (Kelsey 1978; Hwang et al. 1995; Lieff 1999).

In their meta-analysis, Little and colleagues (2004b) included 24 case-control and cohort studies published between 1974–2001. The authors found a consistent association between maternal smoking and CL/P (RR = 1.34; 95% CI, 1.25–1.44) and between smoking and CP (RR = 1.22; 95% CI, 1.10–1.35). Most of the studies in this meta-analysis included consideration of confounders, such as maternal age and education; and some adjusted for partity, marital status, and race/ethnicity; and 5 addressed maternal alcohol use. Adjusted relative risks in individual studies were generally similar to crude RRs, but crude RRs were included in the meta-analysis unless only adjusted RRs were available. When the analysis was restricted to studies with isolated CL/P, or to studies that did not use controls with malformations, the findings did not change. Five of 9 studies with information about the number of cigarettes smoked per day showed evidence of a weak dose-response relationship for CL/P. Eight studies were examined for a dose-response relationship with CP; no clear evidence was observed.

Two recent studies of orofacial clefts and smoking that showed significant positive associations, and were not included in the Hackshaw meta-analysis, further strengthen the evidence for this relationship (Shaw et al. 2009; Lebby et al. 2010). One of the largest studies (Romitti et al. 2007) used NBDPS, which included data from interviews with 1,128 cases of persons with orofacial clefts. For all orofacial clefts combined, the crude OR (1.37; 95% CI, 1.20–1.57) was very similar to the ORs in both the 2004 and 2011 meta-analyses (Little et al. 2004b; Hackshaw et al. 2011), and included adjustment for folic acid, study site, prepregnancy obesity, alcohol use, gravidity, maternal age, maternal education, and maternal race/ethnicity.

As previously discussed, most studies of maternal smoking and CL/P are case-control studies, and necessarily rely on maternal self-reported smoking history obtained after delivery. This method for obtaining exposure data can result in bias if women who smoked and had adverse pregnancy outcomes are more or less likely to deny smoking than women who smoked and did not have adverse outcomes. However, in a study of the potential contributions of misclassification of maternal smoking status on studies of CL/P using Bayesian models with and without correction for reporting bias, the authors found that associations between maternal smoking and CL/P was strengthened slightly and remained significant after correction for expected levels of bias (MacLehose et al. 2009). In addition, despite other potential threats to validity, the findings on orofacial clefts and smoking have been quite consistent across study design and location.

A study in California used midpregnancy serum cotinine concentration (a metabolite of nicotine) to classify maternal smoking status (Shaw et al. 2009). Active smoking was defined as serum cotinine concentration of at least 2 ng/mL, and 11 exposed cases were identified. Maternal smoking was found to be associated with CL/P before (OR = 2.1; 95% CI, 1.0–4.4) and after adjusting for maternal age, race, and serum folate level (AOR = 2.4; 95% CI, 1.1–5.3). It is unknown to what extent the use of midpregnancy cotinine levels results in the misclassification of early pregnancy smoking; women still smoking in the middle of pregnancy were presumably also smoking in early pregnancy, but some of those smoking in early pregnancy might have stopped by the middle of pregnancy and therefore would be inappropriately included in the unexposed group, potentially attenuating the effect estimate. Although the sample size was relatively small, this key study with a biomarker for smoking exposure helps support the many consistent reports of weak associations between smoking and orofacial clefts based on self-reported smoking exposure in early pregnancy. The findings regarding a possible dose-response relationship between smoking and the risk for orofacial clefts have been mixed, with some studies finding evidence of a positive relationship (Little et al. 2004a,b; Bille et al. 2007; Honein et al. 2007) but not all (Krapels et al. 2006; Grewal et al. 2008).

The findings on exposure to secondhand smoke and orofacial clefts have been inconsistent, but there is some evidence of risk in settings where maternal smoking is relatively uncommon but exposure to secondhand smoke is high. For example, in China, the prevalence of smoking among reproductive age women is low (1.5%), while exposure to secondhand smoke is high (over 50%) (CDC 2012). Three studies conducted in China reported positive associations between maternal exposure to secondhand tobacco smoke and orofacial clefts; one included adjustment for potential confounders (occupation, flu or fever, and infant gender) (Table 9.3S) (Li et al. 2010; Jia et al. 2011; Zhang et al. 2011).

Idiopathic Talipes Equinovarus (Clubfoot)

Idiopathic talipes equinovarus or clubfoot is a serious birth defect that requires medical treatment and often surgery (Table 9.4S). There are some complexities in accurately capturing clubfoot with surveillance or research studies, and appropriately excluding those with positional foot deformities. However, despite these challenges, the findings for maternal smoking and clubfoot have been quite consistent. Six of eight studies published in 2000 or later found significant, positive associations between maternal smoking and the occurrence of congenital clubfoot (Honein et al. 2000, 2001; Skelly et al. 2002; Dickinson et al. 2008; Parker et al. 2009; Kancherla et al. 2010); three of these six studies also reported evidence of a dose-response relationship with smoking level, one did not find a dose-response relationship, and two did not assess dose.

In the study by Honein and colleagues (2000), the effect of smoking varied by self-reported family history. The OR of clubfoot associated with maternal smoking among those without a family history was 1.34 (95% CI, 1.04–1.72), but the effect estimate was much stronger, albeit imprecise (OR = 20.3; 95% CI, 7.9–52.2), for those with a positive first-degree family history. Skelly and colleagues (2002) also used self-reported smoking and found a dose-response relationship: among women who smoked 20 or more cigarettes daily, the OR for clubfoot was 3.9 (95% CI, 1.6–9.2), but among those who smoked fewer than 10 cigarettes daily it was 1.5 (95% CI, 0.9–2.5).

Dickinson and colleagues (2008) analyzed linked data from the North Carolina Birth Defects Monitoring Program and North Carolina birth certificates and health services and found a significant association between maternal smoking and clubfoot (OR = 1.40; 95% CI, 1.07–1.83), when controlling for maternal age, race/ethnicity, infant's gender, and timing of prenatal care initiation; the authors did not find a dose-response relationship. Parker and colleagues (2009) used 2001–2005 data from 10 population-based surveillance systems in the United States. Information on smoking was obtained from birth certificates and was linked to data on birth defects from surveillance systems. The ORs for clubfoot were 1.45 (95% CI, 1.32–1.60) for women who smoked 1–10 cigarettes per day and 1.88 (95% CI, 1.64–2.14) for women who smoked more than 10 cigarettes per day (Parker et al. 2009). Kancherla and colleagues (2010) analyzed population-based surveillance data from the Iowa Registry for Congenital and Inherited Disorders. The study found that maternal smoking was associated with clubfoot with an OR of 1.5 (95% CI, 1.2–1.9). It is important to note that there is a small overlap between the Parker and colleagues 2009 study (10-state analysis) and the Kancherla and colleagues 2010 study (Iowa analysis) since Iowa is 1 of 10 states included in the paper by Parker and colleagues and some of the years overlap.

Hackshaw and colleagues (2011) pooled data from 12 studies on clubfoot and smoking and found an OR of 1.28 (95% CI, 1.10–1.47) (Table 9.2). When restricted to studies that addressed potential confounders, the results were not substantially different from the pooled analysis of all studies (OR = 1.44; 95% CI, 1.20–1.71).

Gastroschisis

Gastroschisis is a congenital defect in which the abdominal contents protrude through an opening in the anterior abdominal wall. It is strongly associated with young maternal age (Rasmussen and Frias 2008). From 2000–2011, 12 studies have investigated the potential association between maternal smoking and gastroschisis and 8 reported a significant association (Table 9.5S).

A retrospective case-control study conducted from 1995–1999 in the United States and Canada examined the association of gastrochisis with maternal smoking using control infants with malformations or who were hospitalized for other reasons. The study found maternal smoking during the first 2½ months of pregnancy to be associated with gastroschisis (Werler et al. 2003), and the authors also observed evidence of a dose-response relationship. Feldkamp and colleagues (2008) used birth certificates data to assess smoking and they used birth defects surveillance data to identify cases of gastroschisis. When adjusted for maternal age and prepregnancy body mass index (BMI), the authors found a significant association between smoking during the first trimester and gastroschisis (Feldkamp et al. 2008).

Werler and colleagues (2009) compared cases and age-matched controls from NBDPS to study maternal smoking and gastroschisis. The overall AOR was 1.5 (95% CI, 1.2–1.9), and a dose-response relationship was observed. After stratification by maternal age, however, the association was present only in women who were 25 years of age or older (Werler et al. 2009). This interaction between smoking and maternal age was similar to the one described by Feldkamp and colleagues (2008). More recently, an analysis based on birth certificate data from Washington state found an association between smoking during pregnancy and gastroschisis after adjusting for birth year, maternal age, race, urban-rural residence, county of residence, paternal age, and baby's gender (Chabra et al. 2011).

Finally, Hackshaw and colleagues (2011) included 12 published studies on gastroschisis in their meta-analysis and found a significant association with maternal smoking (OR = 1.50; 95% CI, 1.28–1.76) (Table 9.2). When restricted to studies that addressed confounding, the authors found similar results (OR = 1.44; 95% CI, 1.20–1.71).

Congenital Heart Defects

Congenital heart defects are the most common type of birth defect, affecting nearly 1% of births in the United States, and including many specific types of congenital heart defects with relatively high morbidity and mortality (Reller et al. 2008). From 1999–2012, 15 published studies evaluated the association between smoking and congenital heart defects, and 9 reported significant assocations for one or more types of specific heart defects (Table 9.6S). The most consistent finding has been an associations between maternal smoking and atrial septal defects reported by 4 studies (Källén 1999a; Malik et al. 2008; Kučienė and Dulskienė 2010; Alverson et al. 2011).

Data from the Swedish Child Cardiology and Medical Birth Registries were used to assess the associations of maternal smoking with 30 categories of congenital heart defects (Källén 1999a). In this study, maternal smoking was ascertained during the first prenatal visit rather than after the pregnancy outcome was known, reducing the potential for recall bias. Significant associations were seen for transposition of the great arteries, atrial septal defects, and for patent ductus arteriosus in full-term infants. The author did not observe a dose-response relationship for the association with patent ductus arteriosus (Källén 1999a).

In the Baltimore-Washington Infant Study, the authors assessed risk factors for single ventricle defects and found ORs above unity for both maternal and paternal smoking. These findings were not significant, however, and they were not adjusted for potential confounders (Steinberger et al. 2002). A more recent analysis from the Baltimore-Washington Infant Study assessed all congenital heart defects without other birth defects and found associations between maternal smoking and secundum-type atrial septal defects, right outflow tract defects, l-transposition of the great arteries, and truncus arteriosus (Alverson et al. 2011).

Data from NBDPS was used by Malik and colleagues (2008) to study the relationship between smoking and various heart defects; the authors found that atrial septal defects were associated with smoking at all levels of exposure (1–14, 15–24, ≥25 cigarettes/day) but no dose-response relationship was observed. Other congenital heart defect phenotypes were also assessed, but did not show evidence of associations with maternal smoking. Baardman and colleagues (2012) found evidence of interactions between smoking and BMI ≥25 for all congenital heart defects (p = 0.027), septal defects (p = 0.036), conotruncal defects (p = 0.020), and for outflow tract anomalies (p = 0.024).

Hackshaw and colleagues (2011) combined all cardiovascular and congenital heart defects, but did not present results for specific phenotypes. Overall, the pooled OR from 25 published studies showed a small but significant elevation in risk for congenital heart defects (OR = 1.09; 95% CI, 1.02–1.17) (Table 9.2). When the analysis was restricted to studies that addressed confounding, the results were similar to the original analysis in both instances (OR = 1.10; 95% CI, 1.02–1.20).

Craniosynostosis

Premature fusion of one or more of the cranial suture of the skull results in craniosynostosis, a serious birth defect that usually requires surgical correction. Without timely treatment, craniosynostosis can result in serious consequences including restriction of brain growth. The critical timing of fetal exposure is unclear, but might extend beyond early pregnancy. Several publications have addressed the possible association between maternal smoking and craniosynostosis (Table 9.7S). A birth defects registry linkage study found an association between smoking and craniosynostosis among isolated cases (OR = 1.67; 95% CI, 1.27–2.19) (Källén 1999b). In addition, the author saw evidence of a dose-response relationship with smoking and differences in effects for different cranial sutures; the highest OR was observed if the sagittal suture was affected (Källén 1999b).

In the United States, maternal smoking was associated with isolated craniosynostosis in a metropolitan Atlanta, Georgia, population (OR = 1.92; 95% CI, 1.01–3.66) (Honein and Rasmussen 2000). In contrast, a case-control study using NBDPS data did not find a significant association (Carmichael et al. 2008). In the same study, for heavy smoking in the third month of pregnancy and in the second trimester, moderately increased ORs were observed (OR = 1.6; 95% CI, 0.9–2.6; and OR = 1.6; 95% CI, 0.9–2.8, respectively).

In The Netherlands, a study of infants with sagittal synostosis did not find an association with maternal smoking (Butzelaar et al. 2009). Hackshaw and colleagues (2011) analyzed five studies and found a positive association between smoking and craniosynostosis (OR = 1.33; 95% CI, 1.03–1.73) (Table 9.2). When the analysis was restricted to studies that addressed confounding, the findings did not change (OR = 1.33; 95% CI, 1.04–1.63).

Anorectal Atresia

Anorectal atresia is a defect that occurs when there is faulty separation of the rectum and urogenital system or failure of the anal membrane to rupture (Stevenson 1993). Four studies have been published since 1999 (Table 9.8S); one reported a significant association, two reported borderline/nonsignificant associations, and one found an association with paternal but not maternal smoking. Hackshaw and colleagues (2011) reviewed seven papers and reported a positive association (OR = 1.20; 95% CI, 1.06–1.36) (Table 9.2). In addition, a recent meta-analysis of risk factors for anorectal malformations reported paternal smoking as a risk factor (pooled OR = 1.53; 95% CI, 1.04–2.26) (Zwink et al. 2011).

Other Defects

There have been some studies of central nervous system defects, including neural tube defects, but case definitions have varied and most have not shown an association with maternal smoking (To and Tang 1999; Suarez et al. 2008, 2011; Van Landingham et al. 2009; Miller et al. 2010; Yin et al. 2011). Hackshaw and colleagues (2011) analyzed 17 studies and found no association between maternal smoking and anencephaly/spina bifida, but the authors found a small association with all central nervous system defects combined (pooled OR = 1.10; 95% CI, 1.01–1.19). When the analysis was restricted to studies that addressed confounding, the association was no longer signficant (OR = 1.13; 95% CI, 0.99–1.28).

Cryptorchidism or undescended testes commonly occurs with prematurity, but is typically only monitored by birth defects surveillance systems among term infants. However, it is unclear if all studies examining the potential association between cryptorchidism and smoking limited their analyses to term infants. Although a weak association between maternal smoking and cryptorchidism has been described in some studies (Akre et al. 1999; Biggs et al. 2002), other more recent studies have not reported an association (Pierik et al. 2004; Kurahashi et al. 2005a; Damgaard et al. 2008) or noted an association only among mothers who smoked heavily (Thorup et al. 2006; Jensen et al. 2007). Hackshaw and colleagues (2011) analyzed 18 studies and found a small but significant elevation in risk of cryptorchidism from maternal smoking (OR = 1.13; 95% CI, 1.02–1.25). When the analysis was restricted to studies that addressed potential confounding, the findings did not change (OR = 1.16; 95% CI, 1.08–1.25). However, the observed effect might be due at least in part to prematurity and the association between tobacco exposure and preterm birth.

Hypospadias is a birth defect in boys in which the opening of the urethra is not located at the tip of the penis, and there are different degrees of hypospadias ranging from first degree (relatively minor) to second and third degree (more severe). Most of the studies to date have not found significant associations between maternal smoking and hypospadias, and a few studies have found an inverse association (Källén 2002; Pierik et al. 2004; Carmichael et al. 2005; Brouwers et al. 2007). Hackshaw and colleagues (2011) analyzed 15 studies and found a small negative association between smoking and hypospadias (OR = 0.90; 95% CI, 0.85–0.95). When the analysis was restricted to studies that addressed confounding, the findings did not change (OR = 0.89; 95% CI, 0.83–0.96).

Smoking and Maternal and Fetal Genetic Polymorphisms

Studies of the differences in the human metabolism of toxic constituents in tobacco smoke are summarized in the 2010 Surgeon General's report (Benowitz et al. 1999; Lee et al. 2000; Yang et al. 2001; USDHHS 2010). Initial investigations of the mechanisms of maternal or fetal metabolism of tobacco smoke toxins and adverse birth outcomes were conducted in studies of birth defects, and 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. The genetic polymorphisms that code for the expression inflammatory response and immune mediator enzymes and that were examined included TGF-α and TGF-β3, 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 typically measured by maternal self-reports of active smoking, exposure to secondhand smoke, and of paternal active smoking. Most of these studies examined the TGF-α genotype in neonates. In one study, genotyping was performed in both neonates and parents.

A case-control study of infants with a TGF-α *TAQ1 genotype that contained a rare allele and whose mothers had smoked during pregnancy found a significantly elevated risk for CP in offspring (Hwang et al. 1995). In a large population-based case-control study conducted by the California Birth Defects Monitoring Program registry, the risks of CP and CL with or without CP were significantly elevated among White infants with TGF-α *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 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 TGF-α genotype interactions. Zeiger and colleagues (2005) conducted a meta-analysis of data from these 5 studies and found a marginally significant interaction between maternal smoking and infant TGF-α *allele genotypes (*A2) in relation to CP (OR = 1.95; 95% CI, 1.22–3.10). A Human Genome Epidemiology review that assessed 47 published studies on the potential association between TGF-α and orofacial clefts produced somewhat inconsistent findings (Vieira 2006), but concluded that TGF-α likely had a role in modifying the risk of orofacial clefts.

Romitti and colleagues (1999) also examined the TGF-β3 genotype and maternal smoking in relation to the risk of CP or CL/P. 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 null GSTM1 genotypes in a case-control study of isolated cleft lip and CP. van Rooij and colleagues (2001) examined the association of maternal prenatal smoking and the maternal GSTT1 genotype and 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 (Kurahashi et al. 2005b). 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 CP. 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 (Lammer et al. 2004).

Evidence Synthesis

A modest but consistent association has been documented between maternal smoking during early pregnancy and orofacial clefts, and the evidence has continued to accumulate and strengthen since the 2004 Surgeon General's report. The literature is diverse and includes observations from cohort and case-control studies, and meta-analyses have produced significant pooled risk estimates even after restricting to cohort studies or studies which addressed confounding. One study with the advantage of incorporating biomarkers to objectively assess maternal smoking exposure showed a more than twofold increased risk of orofacial clefts with maternal smoking exposure. However, the results of studies examining a dose-response relationship between smoking and orofacial clefts have been mixed. Two cohort studies that both collected tobacco exposure data before delivery support the notion that a temporal relationship exists, showing an effect of maternal smoking during the time period critical for closure of the palate. Case-control studies often have significantly more power to detect risk factors for birth defects and have supported the association between maternal smoking and orofacial clefts. The plausibility of an association between maternal smoking and orofacial clefts is further supported by animal studies showing an association between cadmium and clefting and between hypoxia-inducing compounds and clefting.

The relatively weak associations described in observational studies and the lack of evidence for a dose-response relationship could reflect exposure misclassification in which some women who smoke do not disclose their smoking status, attenuating the magnitude of the effect estimate. Alternatively, a weak association could result if only certain subgroups of the population, such as those with specific genetic risk factors, are at increased risk of orofacial clefts from exposure to maternal smoke. Given the strong association with a positive family history of orofacial clefts, there are likely some genetic factors that have a major impact on risk of clefting and potentially on the association between smoking and orofacial clefts.

Although the evidence base regarding other major birth defects is growing, associations with maternal smoking are less clear. The evidence has been relatively consistent for clubfoot and gastroschisis (Tables 9.4S and 9.5S), and has been somewhat less consistent for congenital heart defects, craniosynostosis, and anorectal atresia (Tables 9.6S–9.8S). The studies have been most consistent for clubfoot, but the diagnosis of this defect and ascertainment for studies can be problematic as some positional foot deformities might be erroneously included as “clubfoot”; and there could be some selection bias in who is identified as having clubfoot rather than a less serious positional foot deformity, such as if those with better access to high-quality care are more likely to have an accurate diagnosis.

Many studies reported significant associations between maternal smoking and congenital heart defects, but the findings are not consistent across the specific phenotypes. The most consistent finding to date is for an association between atrial septal defects and maternal smoking. However, the relationships between maternal smoking and these adverse outcomes deserve further study to better understand which of these outcomes might potentially be prevented.

The published data on the role of specific genetic risk factors and their interactions with maternal smoking in the etiology of birth defects has expanded over the past decade, but there has been little consistency across studies. The literature is most extensive for orofacial clefts, but it remains unclear which genes might be most important in the causal pathways associated with smoking. At this point, there are no specific genes for which the evidence is strong enough to conclude that they clearly modify the relationship between smoking and orofacial clefts. The data on gene-environment interactions for other major birth defects is much more limited than that for orofacial clefts.

Conclusions

1. The evidence is sufficient to infer a causal relationship between maternal smoking in early pregnancy and orofacial clefts.
2. The evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking in early pregnancy and clubfoot, gastroschisis, and atrial septal heart defects.

Implications

Mothers who smoke early in pregnancy increase their risk for having an infant with an orofacial cleft. Although the attributable fraction for this exposure might be quite low, this is a completely preventable cause of a major birth defect. This risk might be greater in women with specific genetic risk factors, but research to date has not identified consistent genetic factors modifying this relationship. Efforts to reduce smoking before conception and during early pregnancy should include the provision of information on the risk of orofacial clefts.

Neurobehavorial Disorders of Childhood

This section reviews the evidence for associations between prenatal smoking and a set of neurobehavioral disorders of childhood. Previous Surgeon General's reports have considered exposure to secondhand smoke during childhood and maternal smoking during pregnancy and their effects on neurodevelopmental outcomes of children (USDHEW 1979; USDHHS 1980, 2004, 2006, 2010). However, this review goes a step further by examining prenatal exposure to tobacco smoke and these specific disorders—attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder, anxiety disorders, depression, Tourette syndrome, schizophrenia, and intellectual disability.

Biologic Basis

There are multiple biologic mechanisms through which prenatal smoke exposure could affect risk for neurobehavioral disorders in the offspring. Most research on biologic mechanisms focuses on the impact of smoking-related compounds on placental development and on nicotine's effects on the fetal brain. The effects of prenatal smoking by the mother on the placenta are described in the 2010 Surgeon General's report and include cellular and molecular abnormalities of the villous system that could lead to impaired exchange between the mother and fetus of metabolic products, oxygen, and nutrients (USDHHS 2010). A substantial body of animal research demonstrates the effects of maternal nicotine exposure on offspring neurodevelopment, including promotion of neural cell replication, initiation of a switch from cell replication to differentiation, enhancement or retardation of axonogenesis or synaptogenesis, and disruption of regulation of apoptosis (reviewed by Pauly and Slotkin 2008) (see Chapter 5). In addition, animal studies have shown associations between prenatal nicotine exposure and behavioral abnormalities also seen in children of smokers, including hyperactivity, cognitive impairment, increased anxiety, somatosensory deficits, changes in sensitivity to nicotine and other psychostimulants, and alterations in nicotine self-administration (Herrmann et al. 2008; reviewed by Pauly and Slotkin 2008). Animal studies have generally shown positive associations between prenatal exposure to nicotine and anxiogenic behavior, as well as some evidence of neurodevelopmental changes, supporting a biologic basis for this association. A 2008 review concluded that the association between prenatal nicotine exposure and anxiogenic behavior is strong in rats, but that additional research is needed to establish a link in humans (Winzer-Serhan 2008). Causal relationships between smoking and long-term cognitive and behavioral outcomes in humans are difficult to establish due to numerous potential confounding factors (Goriounova and Mansvelder 2012).

Description of the Literature Review

A systematic literature review was conducted to identify potentially relevant published research evaluating the relationship between prenatal smoking exposure and the selected neurobehavioral disorders of interest. References and abstracts were extracted from PubMed using key words for the disorders and associated MeSH terms (Table 9.9) as well as the smoking-related key words “maternal smoking.” The time period of study, 2000–2012, was chosen to cover the period following that of the previous Surgeon General's reviews on neurocognitive development, which included reference to neurobehavioral disorders (USDHHS 2004).

Table 9.9

Key words used in the systematic literature review of prenatal smoking and neurobehavioral disorders among offspring.

Epidemiologic Evidence

Disruptive Behavioral Disorders

A large number of studies have evaluated the association between prenatal tobacco smoke exposure and disruptive behavioral disorders in children, specifically ADHD, ODD, and conduct disorder (Table 9.10S). In total, 82 studies addressing the relationship between childhood disruptive behavioral disorders, or disruptive symptoms, and prenatal tobacco smoke exposure were identified and included in the review.

In addition to the 82 studies, several systematic reviews and meta-analyses have been conducted that synthesize the large number of studies that assess the association between prenatal smoking exposure and ADHD. Langley and colleagues conducted a meta-analysis of studies published before June 2005 and ultimately included 5 case-control studies that covered a total sample of 1,265 participants; the researchers reported a pooled OR of 2.40 (95% CI, 1.61–3.52) for an ADHD diagnosis among the children of mothers who smoked during pregnancy (Langley et al. 2005). Langley and colleagues further concluded that there is a dose-response relationship between the number of cigarettes smoked and ADHD symptoms. In a later study, the authors studied offspring conceived with assisted reproductive technologies and compared those who were genetically related and unrelated to the woman who underwent the pregnancy (Thapar et al. 2009). They anticipated that the association between maternal smoking and ADHD would persist regardless of whether mother and offspring were related. They found that the magnitude of the association between prenatal smoking and parent-reported ADHD symptoms was significantly higher in the related pairs than in the unrelated pairs, suggesting that the previously observed association between maternal smoking in pregnancy and ADHD could be due to unrecognized confounding related to heritability.

Two systematic reviews concluded that there may be an association between prenatal smoking exposure and childhood ADHD (Linnet et al. 2003; Latimer et al. 2012). In 2003, Linnet and colleagues reviewed the findings of 6 case-control studies and 18 cohort studies. They concluded that there may be an association between exposure to tobacco smoke in utero and ADHD and ADHD symptoms, but that a more definite conclusion could not be made with the evidence available at the time due to methodologic issues of the reviewed studies. These issues pertained to the retrospective report of exposure information, dichotomization of exposure, selective attrition, low statistical power, poor definition of the outcome of interest (ADHD), and a failure to control for potentially relevant confounders. More recently, Latimer and colleagues (2012) reviewed literature published between 1966–2009 that evaluated the relationship between disruptive behavioral disorders and environmental risk factors, including maternal smoking. The authors noted there was a large volume of literature on ADHD, and that despite methodologic limitations (including exposure measures that are highly susceptible to recall bias and the lack of adjustment for relevant sociodemographic confounders), the literature provides some evidence of a link between prenatal smoking and the presence of disruptive behavioral disorders in children. Hence, the authors of two systematic reviews concurred that there is some evidence for an association between prenatal smoking and disruptive behaviors in offspring, such as those associated with ADHD.

Seventy studies document an association between prenatal smoking exposure and disruptive behavioral symptoms or disorders, including hyperactivity (Table 9.10S). Most controlled for potential confounding variables, but many studies suffered from the methodologic limitations listed by Linnet and colleagues (2003) and Latimer and colleagues (2012), above. Retrospective reporting of prenatal smoking exposure and failure to rigorously assess child outcomes were among the methodologic limitations of these studies. A notable exception is a nested case-control study of 3,965 Danish children that were matched on age, gender, and date of birth, which used diagnoses from medical records and assessed prenatal smoking during pregnancy (Linnet et al. 2005). Linnet and colleagues concluded that, controlling for other risk factors, prenatal smoking increased the risk for hyperkinetic disorder (the ICD equivalent of ADHD: RR = 1.9; 95% CI, 1.3–2.8).

A dose-response relationship was also reported by Koshy and colleagues (2011) in a study of 1,074 school-aged children. This study found an association between parents' retrospective reports of the number of cigarettes smoked during pregnancy and current parent-reported ADHD diagnosis among their children, although the CIs were wide (smokers: OR = 3.19; 95% CI, 1.08–9.49; heavy smoker: OR = 10.03; 95% CI, 1.62–61.99).

A number of studies have directly considered genetic factors and suggest an independent contribution of genetic factors to the association between maternal smoking and ADHD (Maugham et al. 2004; Knopik et al. 2006; D'Onofrio et al. 2008; Thapar et al. 2009; Lindblad and Hjern 2010; Obel et al. 2011; Langley et al. 2012). As reviewed earlier, Thapar and colleagues (2009) used a sample of children conceived through assisted reproductive technologies and demonstrated that the association between smoking during pregnancy and ADHD symptoms was stronger and statistically significant only among biologically related mother-child dyads. Langley and colleagues (2012) documented independent associations between ADHD in offspring and both maternal and paternal smoking, suggesting that ADHD was due to genetic or household-level confounding and not only intrauterine effects. However, researchers suggest that there is a strong likelihood of genetic and socioeconomic confounding, because parents with ADHD are more likely to fall in lower socioeconomic strata with this association strongly confounded by socioeconomic factors (Lindblad and Hjern 2010).

The evidence for maternal smoking exposure and ADHD overlaps substantially with that of the other disruptive behavioral disorders (ODD and conduct disorder) and much of the research is relevant for all three behavioral disorders, due in part to phenotypic overlap. Because the majority of studies assess the association between prenatal smoking exposure and disruptive behavioral disorders or symptoms collectively, the current epidemiologic evidence may not fully characterize the independent risks for ADHD, ODD, conduct disorder, and associated symptoms. There are several notable additions to the ADHD literature that focus on ODD and conduct disorder independent of ADHD (Wakschlag et al. 2002, 2006a,b, 2010; Nigg and Breslau 2007; Becker et al. 2008; Boden et al. 2010). For example, Boden and colleagues (2010) documented a strong association between prenatal smoking exposure and ODD and conduct disorder in a birth cohort of 926 children, evaluated for ODD and conduct disorder at 14–16 years of age and smoking exposure assessed at birth (p <0.01 for both outcomes). In a longitudinal study of 823 school-aged children, Nigg and Breslau (2007) noted that after controlling for other risks, retrospective report of prenatal smoking doubled the risk of ODD and conduct disorder; the adjusted association with ADHD was not statistically significant. In summary, the evidence shows associations with increased rates of behavior problems, including ADHD, ODD, and conduct disorders. However, concerns about unresolved confounding persist, limiting the ability to draw firm conclusions.

Anxiety and Depression

Internalizing disorders are characterized by depressed mood, anxiety, somatic, and cognitive symptoms (as opposed to externalizing disorders which are characterized by antisocial behaviors, conduct problems, and impulse-control disorders). Anxiety and depression are both considered to be internalizing conditions (American Psychiatric Association 2013). Thirteen articles were included in the review of epidemiologic evidence for an association between prenatal smoking and anxiety, depression, or internalizing symptoms in general (Table 9.11S). Of the 12 articles, 10 focused on depression or anxiety, alone or in combination with each other, or internalizing behaviors in general. One reported on anxiety and ADHD but not depression, and 1 reported on depression without anxiety. The study on anxiety and ADHD found no association between maternal smoking and anxiety among a clinic-recruited group of 275 children 5–17 years of age with ADHD (Freitag et al. 2012). The study that assessed depression without anxiety was a prospective birth cohort study and no association between prenatal smoking and depressive symptoms was observed after controlling for exposure to secondhand smoke (Maughan et al. 2001).

In 7 of the 10 studies examining depression and anxiety, the authors did not find an association between prenatal smoking and depression and/or anxiety (disorders or symptoms) among the offspring at various ages (Hill et al. 2000; Kardia et al. 2003; Whitaker et al. 2006; Gatzke-Kopp and Beauchaine 2007; Biederman et al. 2009; Lavigne et al. 2011; Liu et al. 2011). In a study of 678 preschool children (4-year-olds), a retrospective report of smoking during pregnancy was not associated with meeting diagnostic criteria for depression or anxiety on the Diagnostic Interview Schedule for Children (Lavigne et al. 2011). No association was found between prenatal exposure and symptoms of anxiety or depression in 611 offspring when they were adults in a cohort study with prospective reporting of maternal smoking; however, this study did find an association of prenatal exposure and anger temperament (Liu et al. 2011).

Finally, two studies (Whitaker et al. 2006; Gatzke-Kopp and Beauchaine 2007) that used the child behavior checklist (CBCL) to measure internalizing symptoms, including depression and anxiety, found no associations between maternal smoking and offspring outcomes. In a study of 171 children 7–15 years of age with clinical levels of psychopathology, the types of symptoms were contrasted across three levels of smoking exposure: exposure to prenatal smoking, secondhand exposure to smoking among mothers during pregnancy, and no exposure (Gatzke-Kopp and Beauchaine 2007). The researchers found no association between prenatal smoking exposure (vs. no exposure or secondhand exposure of mother during pregnancy) and symptoms of depression, dysthymia, or anxiety on the CBCL; however, there was an association with externalizing symptoms. There was also no association observed in a cohort study between maternal report of smoking at birth and internalizing symptoms at 3 years of age (Whitaker et al. 2006).

In three studies the authors did report positive associations between prenatal smoking and internalizing symptoms in children as measured by the CBCL. Two of these studies were prospective (Indredavik et al. 2007; Robinson et al. 2008). Indredavik and colleagues (2007) enrolled women by 20 weeks gestation, collected information on smoking during pregnancy at enrollment, and completed a CBCL on 84 children when they were 14 years of age. Several potential confounders were examined in the adjusted analysis, including income, parental antisocial tendencies, and birth weight. The authors estimated that 19% of the variance in externalizing behaviors was accounted for by maternal prenatal smoking, and 8.9% of internalizing behaviors. Robinson and colleagues (2008) enrolled women during pregnancy (18 weeks gestation), and assessed 1,707 offspring using the CBCL at 2 and at 5 years of age. This study reported a significant association between internalizing behaviors and maternal smoking at 2 years of age (OR = 1.26; 95% CI, 1.02–1.55); but no difference was observed at 5 years of age (Robinson et al. 2008). In a retrospective study of maternal smoking and behavior disorders in children, the authors found a significant association with internalizing behaviors (OR = 1.28; 95% CI, 1.1–1.6), but not externalizing behaviors (Teramoto et al. 2005).

In summary, three studies reported associations between exposure to prenatal smoking and internalizing symptoms, both in preschool-age children and adolescents; however, four studies examining symptoms did not find an association. Of the three studies that measured smoking prospectively, two found a positive association with internalizing symptoms (Indredavik et al. 2007; Robinson et al. 2008), and one found an association with anger temperament in adulthood, but not with symptoms of depression or anxiety (Liu et al. 2011). These findings may point to a possible nonspecific association between exposure to prenatal smoking and neurobehavioral disorders or symptoms of these disorders.

Tourette Syndrome

Two articles were identified that address maternal prenatal smoking and Tourette syndrome in offspring; neither study found a significant association (Table 9.12S). The limited evidence available for review was insufficient to permit meaningful synthesis.

Schizophrenia

There have been very few articles published after 1999 that address maternal smoking and schizophrenia in offspring. These studies are limited by small sample size, the use of surrogate markers for schizophrenia rather than the disease itself, the use of inappropriate control groups, and reliance on recall of maternal smoking status obtained many years after the pregnancy (Zammit et al. 2009; Baguelin-Pinaud et al. 2010; Hunter et al. 2011). In a meta-analysis of obstetric complications and schizophrenia published in 2002, there was no significant association observed between maternal smoking and offspring schizophrenia; however, even when the samples from only two studies were included in the analysis, the pooled sample size of cases was small (Cannon et al. 2002). Therefore, the limited evidence available for review was insufficient to permit meaningful synthesis.

Intellectual Disability

For the purposes of this review, intellectual disability was defined as having intelligence quotient (IQ) scores in health or educational records that fell at or below 70 or test scores within the intellectual disability range, as indicated on psychometric tests, such as the Wechsler Intelligence Scale for Children-Revised.

Twelve articles were identified that assessed the relationship between prenatal exposure to maternal tobacco smoke and the risk of intellectual disability in their children (Table 9.13S). Of the 12 articles, 10 demonstrated a significant association between prenatal exposure to maternal tobacco smoke and intellectual disability and/or low intellectual performance in unadjusted analyses. However, the observed associations in all 10 studies were attenuated or disappeared after adjusting for maternal education and/or maternal IQ (Fried and Watkinson 2000; Cornelius et al. 2001; Fried et al. 2003; Breslau et al. 2005; Mortensen et al. 2005; Batty et al. 2006; Huijbregts et al. 2006; Alati et al. 2008; Braun et al. 2009; Lundberg et al. 2010).

Braun and colleagues (2009) examined the association between prenatal exposure to tobacco smoke and intellectual disability in early childhood using data from a cohort of children born during 1994–1996. This study defined intellectual disability as having an IQ score below 70 points and found the risk of intellectual disability was mildly elevated among 8-year-old children whose mothers smoked during pregnancy (RR = 1.52; 95% CI, 1.27–1.83), but was no longer significant (RR = 1.12; 95% CI, 0.92–1.36) after adjustment for maternal education, maternal race, maternal age, marital status, and gender of child (Braun et al. 2009).

The association between maternal smoking during pregnancy and intellectual disability was also examined in adolescents and young adults. Kafouri and colleagues (2009) assessed the relationship between cognitive functioning in adolescent offspring 12–18 years of age and maternal cigarette smoking during pregnancy. This study used an extensive 6-hour battery of tests in which cognitive abilities were evaluated based on 33 tasks measuring verbal and visual memory, visuospatial skills, verbal abilities, processing speed, motor dexterity, and resistance to interference and found no difference between the cognitive abilities in adolescent offspring that were exposed to maternal cigarette smoking during pregnancy compared to those unexposed after adjustment for maternal education.

Lundberg and colleagues (2010) examined the association between maternal smoking during pregnancy and the risk of intellectual impairment among young adult male offspring at 18 years of age. This study found an increased risk of intellectual impairment (OR = 1.91; 95% CI, 1.81–2.00), but the effect was attenuated (OR = 1.22; 95% CI, 1.14–1.31) after adjustment for other parental factors.

In a cohort study by MacArthur and colleagues (2001), there were differences in IQ as a function of the mother's pregnancy smoking behavior, but smoking did not remain an independent predictor after accounting for confounding factors. Further, the early hazards of smoking during pregnancy seemed to resolve by later childhood, with no evidence of direct long-term effects on cognitive functioning. The authors concluded that effects observed in early childhood, which arise from smoking during pregnancy, are significantly attenuated or disappear by later childhood, with no evidence of long-term effects on cognitive functioning.

Evidence Synthesis

Although specific mechanisms linking prenatal exposure to smoking with specific behavioral conditions have not been determined, there is some evidence from human and animal studies that supports a biological basis for the association between exposure to prenatal smoking and some neurobehavioral conditions. The 2004 Surgeon General's report concluded that the evidence was inadequate to infer the presence or absence of a causal relationship between maternal smoking and either physical growth or the collective neurocognitive development of children.

Although there is consistent evidence supporting an association between prenatal smoking exposure and disruptive behavioral symptoms among children, and ADHD in particular, the magnitude of the estimated associations diminishes when family, social, and psychosocial factors are included in multivariate models. Reliance on retrospective reporting of smoking history, which is subject to recall bias, limits the ability to draw conclusions about the temporal nature of the relationship; however, select studies that did collect exposure during pregnancy corroborate the direction of findings from the retrospective studies. Much of the published literature failed to control for many potential confounders and failed to use standard criteria for the assessment of outcomes.

The literature is limited and conflicting on the relationship between prenatal smoking exposure and anxiety and depression symptoms and disorders in children. The studies reviewed here showed no consistent association between exposure to prenatal smoking and a later diagnosis of depression or anxiety.

The available evidence is quite limited and mixed on the association between prenatal smoking and both Tourette syndrome and schizophrenia among exposed children. The research on these conditions is subject to significant methodologic limitations, including small sample size, lack of an appropriate control group, low response rate, and retrospective report of smoking by mothers. Given the limited information available for these conditions, conclusions cannot be made regarding the consistency, strength, specificity, or temporal nature of the potential relationship.

Although there is evidence of an association between prenatal exposure to maternal smoke and intellectual disability, several studies suggest that this finding is substantially attenuated or eliminated when controlling for maternal education, IQ, and other sociodemographic covariates. This is similar to the pattern documented among studies of maternal smoking and disruptive behavioral disorders.

Conclusions

1. The evidence is suggestive, but not sufficient, to infer a causal relationship between maternal prenatal smoking and disruptive behavioral disorders, and attention deficit hyperactivity disorder in particular, among children.
2. The evidence is insufficient to infer the presence or absence of a causal relationship between maternal prenatal smoking and anxiety and depression in children.
3. The evidence is insufficient to infer the presence or absence of a causal relationship between maternal prenatal smoking and Tourette syndrome.
4. The evidence is insufficient to infer the presence or absence of a causal relationship between maternal prenatal smoking and schizophrenia in her offspring.
5. The evidence is insufficient to infer the presence or absence of a causal relationship between maternal prenatal smoking and intellectual disability.

Implications

There are high rates of neurobehavioral disorders among children, particularly disruptive behavioral disorders, depression, and anxiety (CDC 2010; Merikangas et al. 2010; Ghandour et al. 2012; Substance Abuse and Mental Health Services Administration 2012); these disorders have an impact on social and academic functioning, employment, and health throughout the lifespan. Additional research is needed to better understand the potential impact of exposure to prenatal smoking on neurodevelopment in general as well as on specific neurobehavioral conditions.

Chapter Conclusions

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Footnotes

1

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