Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
15 Reproductive and Developmental Effects moking among women of reproductive age is a critical risk factor S for reproductive health problems including fetal and infant mor- tality and impaired fetal development. Cigarette smoking has nu- merous well-documented adverse effects on pregnancy and fetal health, including low birthweight, preterm delivery, perinatal morbidity, placen- tal complications, and increased risk of sudden infant death syndrome (USDHHS, 1988, 1990). The harmful effects of cigarette smoke exposure during pregnancy have been well known for decades; nevertheless, a significant fraction of pregnant women continue to smoke and smoking continues to account for an estimated 10% of all fetal mortality (Kleinman et al., 1988). The percentage of women who smoke during pregnancy declined from 13.6% in 1996 to 12.9% in 1998 with rates being highest for non-Hispanic whites, American Indian, and Hawaiian women and for women of lower socioeconomic and educational levels (CDC, 1998, 1999, 2000). The number of cigarettes smoked per day has also steadily declined over the last decade with about a third of maternal smokers reporting smoking at least a half a pack per day in 1996 compared to more than 40% in 1990 (CDC, 1998). Among pregnant teenagers, however, the smoking rate increased from 18.8% in 1997 to 19.2% in 1998 (CDC, 2000). Trends in maternal smoking behavior, based on data from the Behav- ioral Risk Factor Surveillance System, showed a decline in overall smok- ing initiation among women aged 18-44 to a reported rate of 38.2% in 1996, with no difference between pregnant and nonpregnant women. Re- ported rates of quitting in the same population have shown little change 543
544 CLEARING THE SMOKE among pregnant and nonpregnant women, 25.2% and 14.4%, respectively in 1996 (Ebrahim et al., 2000). Even after learning that they are pregnant, 54% of women continue to smoke (Ebrahim et al., 2000). Additionally, maternal smokers who have experienced previous preterm delivery or small-for-gestational age infants do not show greater quit rates than smokers who have had uncomplicated deliveries (Cnattigius et al., 1999). According to the National Health Interview Survey (1992-1993), among female smokers in general, 72.5% reported that they wanted to quit smok- ing with 34% attempting to quit each year and 2.5% being successful. The contribution of environmental tobacco smoke (ETS), including paternal smoking, to adverse reproductive health outcomes is uncertain, but ETS exposure is widespread among women of reproductive age. Data from the third National Health and Nutrition Examination Survey report a 32.9% prevalence of ETS exposure at home or at work among non- tobacco-using females age 17 and over. FERTILITY IMPAIRMENT Smoking has been associated with increased time to conception, de- creased pregnancy rate in assisted reproduction, increased risk of ectopic pregnancy, and menstrual changes including early menopause. The risk of being unable to conceive within a year of trying is increased two- to threefold among smokers (Werler, 1997). Consistent with many previous studies, a recent cohort study of current and past smokers during assisted reproduction cycles suggested a dose-related decrease in ovarian func- tion and a 50% reduction in pregnancy rates of current smokers (Van Voorhis et al., 1996). Also, a positive relationship (odds ratio, ORâ 1.3-2.2) between cigarette smoke exposure at conception and during pregnancy and the risk of subsequent ectopic pregnancy has been documented, with mixed results regarding dose-response (Coste et al., 1991; Handler et al., 1989; Saraiya et al., 1998; Stergachis et al., 1991). Animal studies have suggested altered gonadotropin release, decrease in luteinizing hormone (LH) surge, inhibition of prolactin release, altered tubal motility, and im- pairment of blastocyst formation and implantation as possible mecha- nisms of fertility impairment among smokers (reviewed in Hughes and Brennan, 1996). Additional studies in rats have shown follicle destruction and oocyte depletion when exposed to benzo[a]pyrene (BaP), a tobacco smoke toxin (Cooper et al., 1999). Furthermore, an evaluation of the Womenâs Health Study found that current and former smokers, after ad- justing for age, race, education, marital status, number of sexual partners, frequency of intercourse, history of gonorrhea, and current method of contraception, had a significantly increased risk of pelvic inflammatory disease, possibly related to impairment of immunity and altered tubal
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 545 factors (Marchbanks et al., 1990; Scholes et al., 1992). Pelvic inflammatory disease is an independent risk factor for ectopic pregnancy and infertility. The association of altered male fertility with cigarette smoking is less consistent. Studies have shown mixed results with respect to sperm and semen quality and have not supported detrimental effects on male fertil- ity (reviewed in Hughes and Brennan, 1996). Several animal and human studies have established an increased risk of vascular erectile dysfunction associated with cigarette smoking (Juenemann et al., 1987; Shabsigh et al., 1991; U.S. DHHS, 1990), including a large survey of Vietnam-era veterans, age 31 to 49, which found a 50% increase in the risk of impotence in smokers after controlling for all other major risk factors for impotence (Mannino et al., 1994). SPONTANEOUS ABORTIONS Numerous studies suggest a positive, dose-related association be- tween smoking and spontaneous abortions, with the risk reported to be increased 20-80% (Kline et al., 1977, 1983; Ness et al., 1999). A prospective study by Ness et al. (1999) of adolescent girls and women that presented to an emergency room found a strong correlation between the risk of spontaneous abortion and the presence of cotinine (threshold concentra- tion=500 ng/ml) in the urine (OR=1.8). The association is found primarily in the second trimester and for chromosomally normal spontaneous abortions (Kline et al., 1995) thought to be associated with intrauterine growth retardation. Postulated causal mechanisms include fetal hypoxia mediated by carbon monoxide (CO) and placental and uterine vascular insufficiency or teratogenic effects mediated by nicotine (Kline et al., 1995; Ness et al., 1999). The effect is modified by alcohol consumption, caffeine use, and history of previous spontaneous abortions (Ness et al., 1999; Windham et al., 1992). Although recent large prospective study found no consistent evidence of an association between environmental tobacco smoke and spontaneous abortion (Windham et al., 1999), a few earlier studies have described such a relationship (Ahlborg and Bodin, 1991; Chatenoud et al., 1998; Windham et al., 1992). PLACENTAL COMPLICATIONS Findings have been consistent regarding the positive association of smoking with placenta previa (obstruction of the internal cervical os by the placenta), with a relative risk (RR)=1.3-2.6 and placental abruption (premature separation of the placenta from the uterus), RR=1.4-1.6 (re- viewed in Andres and Day, 2000; Castles et al., 1999). These pregnancy complications cause at least one-fifth of all prenatal deaths (Ananth et al.,
546 CLEARING THE SMOKE 1996). Also, among smokers the perinatal death rate after placental abrup- tion is two to three times higher than among nonsmokers (Werler, 1997). There has been consistent evidence that smoking is an independent risk factor for placenta previa and placental abruption after control for poten- tial confounders including maternal age and parity, hypertension, preec- lampsia, and alcohol use. Studies have suggested a dose-dependent association between re- ported numbers of cigarettes smoked and placental complications, but the data have been inconclusive (Ananth et al., 1996; Handler et al., 1994; reviewed in Andres, 1996). Although the exact mechanism by which ma- ternal smoking causes placental complications is unknown, the placentas of smokers exhibit anatomical and histological changes that suggest hy- poxia and underperfusion (Voigt et al., 1990). The placentas of smokers have been found to be larger and heavier than those of nonsmokers (Christianson, 1979; Pfarrer et al., 1999). Pfarrer et al. (1999) found in- creased angiogenesis within the placental villi of smokers, thought to be a response to hypoxic stress caused by the components of cigarette smoke. Pfarrer and colleagues speculated that this adaptive response contributes to the large placentas of maternal smokers. Histologic studies have found necrotic and hemorrhagic changes of the decidua basalis, including calci- fication, hypertrophy, and thickening of the basement membrane (re- viewed in Voigt et al., 1990). The hypoxic and ischemic changes in placen- tal tissues are possibly due to damage of the endothelial cells of placental vessels resulting in decreased tissue perfusion and to the increase in car- boxyhemoglobin resulting in decreased oxygen delivery (Ananth et al., 1996). It has also been postulated that smokers are more prone to placen- tal inflammation and infection secondary to a smoking-related decreased immune response. PRETERM DELIVERY Preterm delivery is defined as delivery before 37 weeks gestation and is an important cause of perinatal mortality. Studies have suggested an increase in the risk of preterm delivery among maternal smokers but have been inconsistent regarding the magnitude of risk (20% to >100% in- creased risk). Evidence of a dose-response association has been demon- strated (Cnattingius, et al., 1999, reviewed in Shah and Bracken, 2000; Shiono et al., 1986). Risk of infant mortality was more pronounced for very preterm births for preterm delivery (â¤32 weeks gestation) (Kyrklund- Blomberg and Cnattingius, 1998; Windham et al., 2000) and with sponta- neous versus induced preterm births after controlling for complications of pregnancy such as placental abruption, placenta previa, premature
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 547 rupture of membranes, and hypertension (Kyrklund-Blomberg and Cnattingius, 1998). The literature has supported the reduction of risk of preterm delivery associated with smoking cessation. A large population-based cohort study of Swedish women by Cnattingius et al. (1999) found that among non- smokers with a term first delivery, those who initiated smoking after the first pregnancy had a greater risk of subsequent preterm pregnancies compared to women who did not smoke during pregnancy. Maternal smokers with an initial term delivery reduced their risk of subsequent preterm deliveries by stopping smoking prior to the second pregnancy. An earlier prospective interventional trial by Li (1993) found no improve- ment of gestational age with smoking reduction but did show a signifi- cant improvement after smoking cessation. The mechanism of smoke-attributed preterm delivery is not certain but may be related to intrauterine infections secondary to decreased im- munity, structural abnormalities especially the loss of integrity of type III collagen, or the increase in production of prostaglandin (PGE2), causing myometrial muscle contractions (Cnattigius et al., 1999). LOW BIRTHWEIGHT The detrimental effect of smoking on birthweight has been exten- sively studied and well documented. This effect has been labeled âfetal tobacco syndrome,â which is described as maternal smoking of five or more cigarettes per day during pregnancy, no evidence of maternal hy- pertension during pregnancy, symmetrical growth retardation of new- born at term, and no other explicit cause of intrauterine growth retarda- tion (Benowitz, 1991; Nieburg et al., 1985). Twelve percent of infants born to all mothers who are smokers weighed less than 2,500 grams (low birthweight) in 1998, and eleven percent of infants born to mothers who report smoking as few as one to five cigarettes per day have low birthweight (CDC, 2000). Among pregnant smokers the risk of low birthweight babies is doubled compared to nonsmokers, and about 20% of all low birthweight babies are attributable to smoking (U.S. DHHS, 1983). Infants born to mothers who smoke during pregnancy are on aver- age 200 grams lighter and 1.4 cm shorter than infants of nonsmokers (Wang et al., 1997). The effect of smoking is particularly prominent if exposure occurs after the first trimester. The association persists even after controlling for confounding factors such as maternal age, maternal nutrition, socioeconomic level, education, maternal weight gain, and alcohol consumption (reviewed in ACOG, 1997). Long-term effects of maternal smoking on growth have not been described, but small-for-
548 CLEARING THE SMOKE gestational-age infants have a higher incidence of certain illnesses and disabilities into childhood and adulthood, such as cardiovascular disease, non-insulin-dependent diabetes mellitus, and hypertension (reviewed in Barker, 1997, 1999; Foresen et al., 2000). Environmental tobacco smoke has also been suggested to have a sig- nificant association with intrauterine growth retardation. A recent Swed- ish study found an OR of 2.4 for low birthweight infants among non- smoking mothers exposed to ETS and an OR of 3.6 for smoking mothers exposed to ETS (Dejin-Karlsson et al., 1998). Paternal smoking has also been shown to have an adverse effect on infant birthweight. Martinez et al. (1994) report an 88-gram average reduction in birthweight of infants whose fathers smoked more than 20 cigarettes per day. The dose-response evidence has been studied, extensively, and the findings suggest reversibility of risk with smoking reduction (Ahlsten et al., 1993; Hebel et al., 1988; Li et al., 1993; Sexton and Hebel, 1984). Li and his colleagues (1993) in a prospective intervention trial found that reduc- tion as well as cessation of smoking (defined by serum cotinine levels) resulted in significantly increased birthweights compared to women who continued to smoke. Secker-Walker et al. (1998) reported that women who stop smoking before 20 weeksâ gestation obtain maximum benefits of smoking reduction. Others have found that cessation even late in preg- nancy led to normal-weight infants (Ahlsten et al., 1993; Hebel et al., 1988). Attempts have been made to quantify the relationship of cigarette consumption and fetal growth outcomes. One such study, which evalu- ated taking the average of serial cotinine measurements over the entire pregnancy, reported that for every 1,000-ng/ml increase in urine cotinine concentration, there was an associated 59 Â± 9 gram reduction in birth- weight, an â 0.25-cm reduction in length, and an â 0.12-cm reduction in head circumference (Wang et al., 1997). Maternal serum and urine cotinine levels have been reliable markers of maternal nicotine intake and ciga- rette use and useful tools in predicting infant birthweight (Haddow et al., 1987; Li et al., 1993). Cotinine levels in infant cord blood are highly corre- lated with maternal serum and urine cotinine concentrations, r=.91 and r=.72, respectively (Wang et al., 1997). Among African Americans, a few studies have noted differences in the relationship between cigarette con- sumption and cotinine concentrations. Specifically, these studies have shown higher cotinine levels for all cigarette dose levels among African Americans (English et al., 1994). This group also reported no significant difference in birthweight reduction per 1 ng/ml maternal cotinine among black infants compared to white infants, and Li et al. (1993) found that among mothers with high baseline cotinine levels (>200 ng/ml), the birthweights of black infants were less sensitive to smoking reduction than those of white infants.
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 549 The pathogenesis of low birthweight secondary to smoking is not known but is generally thought to be multifactorial. The probable mecha- nisms involved include CO formation of carboxyhemoglobin in maternal and fetal circulation, causing decrease in oxygen delivery and resulting in tissue hypoxia and increased viscosity that may affect placental perfusion (Benowitz et al., 2000). Cyanide in tobacco smoke can decrease stores of vitamin B12, a cofactor for fetal growth (Ness et al., 1999). Additionally, smoking-related maternal and fetal nutritional deficits caused by ciga- rette smoking have been postulated as mechanisms for fetal growth retar- dation. Reduction in uteroplacental blood flow due to the vasoconstric- tive catecholamine-mediated effects of nicotine has been suggested as a possible mechanism of intrauterine growth retardation and has been stud- ied in animal models (Bassi et al., 1984). These findings have not been fully supported by measurements of placental blood flow in humans (Benowitz et al., 2000). SUDDEN INFANT DEATH SYNDROME (SIDS) It is estimated that more than 50% of the risk of SIDS may be attrib- uted to exposure to cigarette smoke (Dwyer et al., 1999). A positive asso- ciation between maternal smoking and SIDS has been consistently sup- ported in the literature (reviewed in Golding, 1997; Leach et al., 1999). Generally, the risk of SIDS increases two- to fourfold among infants of mothers who smoke during pregnancy, and the risks increase even fur- ther when combined with postnatal exposure to tobacco smoke (ACOG, 1997). However, it has been difficult to separate the effects of postnatal smoke exposure from the effects of prenatal tobacco smoke exposure (Golding, 1997; Spiers, 1999). A recent prospective study found an OR of 2-3 for the association between prenatal maternal smoking and risk of SIDS, and an OR of roughly 3 for postnatal maternal smoking; however, no significant effect was seen for smoke exposure from other household members or maternal smoking restricted to rooms without the infant (Dwyer et al., 1999). The mechanism of effect is not fully known. It has been suggested, based on animal models, that fetal nicotine exposure results in loss of the normal response of the adrenomedullary system to hypoxia (Benowitz, 1998; Slotkin et al., 1995, 1997). Furthermore, the in- creased susceptibility of infants of smoking mothers to respiratory infec- tions may play a role. CONGENITAL MALFORMATIONS Oral clefts is the most extensively studied malformation thought to be associated with maternal smoking. Research has failed to show a consis-
550 CLEARING THE SMOKE tent association, although a moderate association with cleft lip Â± cleft palate (CLP) has been described (Lieff et al., 1999). A recent study found a strong positive association between cigarette smoking and CLP, with a dose-response effect. This study found an overall 55% increase in the risk of infant CLP among all pregnant smokers, with the risk almost 80% higher for women who smoked more than a pack a day compared to nonsmoking mothers (Chung, 2000). Results have also been inconsistent regarding the interaction of maternal smoking with the rare transforming growth factor-Î± (TGF-Î±) allele and association with CLP (Christensen et al., 1999). COGNITIVE AND BEHAVIORAL DEFICITS IN CHILDHOOD Tobacco use during pregnancy has been linked to neurological dam- age that may be expressed during childhood as intellectual deficits, be- havioral problems, and poor school achievement. Studies have found sig- nificant differences in IQ scores and increased likelihood of mental retardation in children of mothers who smoked during pregnancy com- pared to children of nonsmokers (Drews et al., 1996; Olds et al., 1994). The differences are decreased but generally persist after control for environ- mental and parental factors that may influence intelligence. Attention deficit hyperactivity disorder (ADHD) has been associated with smoking during pregnancy. An OR of 2.7 has been found for the risk of children of mothers who smoked during pregnancy after controlling for socio- economic status, parental ADHD, and parental IQ. Furthermore, conduct disorder and disruptive behavior have been found to have a weak dose- related association with maternal cigarette smoking after control for con- founding social factors (Fergusson et al., 1993). Postulated mechanisms of cognitive impairment involve effects of cigarette smoking on the fetus including chronic hypoxia, decreased nu- trition, and direct toxicity to cortical tissue by toxins such as CO, nicotine, and lead in cigarette smoke. Small-for-gestational-age infants, a signifi- cant adverse effect of maternal cigarette smoking as discussed previously, have been independently linked in several studies to decreased cognitive abilities (measured by IQ scores) into childhood and adolescence, com- pared to children of normal birthweight (McCarton et al., 1996; Seidman et al., 1992; Sommerfelt et al., 2000). Animal models have linked fetal nicotine exposure to upregulation of nicotinic receptors causing hyperac- tivity in infant mice (Milberger et al., 1996). Also, fetal nicotine exposure has potentially detrimental effects on fetal brain development through premature stimulation of nicotinic cholinergic receptors in the fetal brain causing disruption of the development of cholinergic neurons, which
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 551 affects numerous other neurotransmitters and hormones, including catecholamines, serotonin, and dopamine (Benowitz et al., 2000). FETAL LUNG DEVELOPMENT Maternal smoking during pregnancy has been demonstrated to be associated with abnormal effects on fetal lung function and development, possibly contributing to increased incidence of early childhood respira- tory diseases, including bronchitis, pneumonia, and asthma (Joad, 2000; Morgan and Martinez, 1998). Based on a review by Joad (2000), in utero cigarette smoke exposure more than doubles the risk for disease of airway hyperresponsiveness in childhood, including wheezing illnesses and asthma. In a large cross-sectional study, Cunningham and colleagues (1994) found significantly lower measures of flow in pulmonary function tests among 8-12 year olds who were exposed to maternal smoking com- pared to children of nonsmokers. After controlling for prenatal exposure, no significant effect of current ETS exposure was found. This finding was further supported in a study by Tager et al. (1995) that found significantly lower expiratory flow measurements of infants up to 18 months of age among mothers who smoked during pregnancy. Lodrup Carlsen and col- leagues (1997) found supporting evidence that flow parameters were di- minished when measured within days of birth after in utero smoke expo- sure. This study also found an effect on volume measurements and a dose-response relationship to number of cigarettes smoked per day. A study of infants who were seven weeks premature (Hoo et al., 1998) sug- gests that the detrimental effects on respiratory function occur before the last trimester and further supports the predominant effects of in utero smoke exposure compared to postnatal ETS exposure. Suggested mechanisms of airway dysfunction caused by cigarette smoke exposure during pregnancy include decreased airway compliance, poor bronchial tree development, and emphysema-like changes of the alveoli (Cunningham et al., 1994; Lodrup Carlsen et al., 1997). Several animal studies have shown impaired fetal lung growth, including de- creased lung interstitium and elastic tissue (Maritz et al., 1993; Moessinger, 1989). It has been suggested that nicotine interferes with the synthesis of elastic tissue needed for stability of the alveoli and that other smoke constituents may promote protease function (Maritz et al., 1993). See Chapter 14 for further discussion of this topic. SMOKELESS TOBACCO Reproductive effects of smokeless tobacco have been less extensively studied than those of smoking. Many of the human data come from coun-
552 CLEARING THE SMOKE tries in which consumption of tobacco in other forms is more widespread among women. Animal studies have shown significant weight reduction and perinatal mortality among rat fetuses of mothers exposed to smoke- less tobacco, administered through gastric intubation of smokeless tobacco aqueous extract (Krishna, 1978; Paulson et al., 1994). Researchers in India have found a significant decrease in birthweight of infants born to moth- ers who use smokeless tobacco (Deshmukh et al., 1998; Krishnamurthy and Joshi, 1993; Verma et al., 1983). Changes in placental anatomy were also noted by Agrawal and colleagues (1983), who discovered the placenta of tobacco-chewing mothers to be on average 65.9 grams heavier than that of non-using mothers. It has been suggested that nicotine-induced vaso- constriction and decreased perfusion may be the primary mechanism leading to decreased fetal growth in mothers who use smokeless tobacco (Verma et al., 1983). CONCLUSIONS Exposure to cigarette smoking is a major cause of fetal and infant morbidity and mortality. This is particularly true for the association with low birthweight and it consequences, as well as for preterm delivery and SIDs. For several important adverse reproductive effects of maternal smoking, a decrease in smoking has been found to decrease or be associ- ated with a decrease in risks to the fetus and infant. The greatest benefit, of course, comes from smoking cessation. However, many women con- tinue to smoke during pregnancy, despite knowledge of the harmful ef- fects of smoking and personal experience with adverse fetal and infant conditions. Moreover, as current rates of smoking among adolescent women slowly rise, these adverse effects associated with tobacco smoke exposure while pregnant may worsen. On average, infants exposed to maternal smoking in utero are 200 grams lighter and 1.4 cm shorter than those who are unexposed. A strong dose-response has been supported in numerous studies and a decrease in dose (number of cigarettes) in controlled studies has led to increased birthweights in a predictable pattern. What is known about the mecha- nism of effect of cigarette smoke on the fetus suggests a multifactorial etiology, with CO considered to play a major role in growth retardation through increased tissue hypoxia. Nicotine has also been thought to play a role through increasing vasoconstriction and decreasing perfusion through the placenta. Although nicotine replacement products and bupropion SR are cur- rently not approved by the Food and Drug Administration for use by
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 553 pregnant women, the Agency for Healthcare Research and Qualityâs (AHCRQ) Clinical Practice Guidelines for Treating Tobacco Use and De- pendence (Fiore et al., 2000) recommend that âPharmacotherapy should be considered when a pregnant woman is otherwise unable to quit, and when the likelihood of quitting, with its potential benefits, outweighs the risks of the pharmacotherapy and potential continued smokingâ. It is generally thought that nicotine replacement therapy can reasonably be used with pregnant patients if prior behavioral modifications have failed and the patient continues to smoke at least 10-15 cigarettes per day (ACOG, 1997). There are no data regarding the efficacy of potential reduced- exposure products (PREPs) during pregnancy, but there is the presump- tion that the tobacco-related PREPs are likely to have toxic effects at some level and that, until further evidence is produced, existing guidelines concerning pharmacological PREPs still pertain. RECOMMENDATIONS Surveillance of Tobacco Use Patterns Among Pregnant Women Central to understanding exposure to tobacco products is continuous population information on patterns of tobacco use among pregnant women. This may not be attainable by general population survey methods, due to inadequate sample sizes and insufficient representation of various geo- graphic or demographic groups or of the earliest stages of pregnancy. Thus, surveys should be devoted specifically to pregnant women in all stages of gestation, irrespective of receipt of medical care. Survey content should include other known or putative causes of adverse maternal or fetal outcomes, as well as detailed product types and usage patterns as delineated in Chapter 6, in recommendations for general population sur- veillance. Biochemical and toxicological exposure measures should be a routine part of surveillance for exposure to conventional products as well as PREPs. These will be necessary to conduct more precise, coordinated toxi- cological studies and also to assess actual exposure rates more accurately. For example, dose may be measured by maternal serum and urine cotinine levels, which have shown reliable correlations with maternal and conse- quently fetal tobacco smoke exposure. Self-reported smoking data can be unreliable, since pregnant women who have been advised to quit tend to under report tobacco use because of the stigma attached to smoking (Kendrick et al., 1995). Also, self-reports do not adequately account for differences in depth and frequency of puffs among smokers.
554 CLEARING THE SMOKE Assessment of Fetal and Maternal Outcomes Associated with New Tobacco Product Exposure To practically assess the health effects of PREPs, reliable measures of health outcomes that can be utilized in a relatively short time are desired. Among the reproductive outcomes of maternal smoking, intrauterine growth retardation resulting in low birthweight babies has been exten- sively studied, and a large body of evidence has supported a causal link with cigarette smoke exposure. The committee recommends, based on currently available scientific knowledge, that fetal birthweight and in- trauterine growth retardation be used as the outcome measure in evaluat- ing the harm reduction potential of the use of PREPs. Study designs might include repeated cohort or case-control studies of pregnant women with an appropriate distribution of exposures to both PREPs and conventional products, and suitable contrast groups. Concomitant, coordinated toxico- logical studies should be performed to provide biological correlations with clinical outcomes. Such outcomes as fetal birthweight and incidence of other reproductive and developmental health outcomes (e.g., fertility outcomes, placental complications, gestational age at birth, incidence of SIDS, spontaneous abortion, etc.) should be considered primary objects of study. Findings in pregnant women exposed to PREPs may have value be- yond maternal/fetal outcomes. The nature of adverse effects from PREP exposure will likely be determined much sooner in pregnant women (several months) than findings on chronic disease outcomes such as vari- ous cancers and cardiovascular disease in nonpregnant tobacco users. Should adverse findings become apparent, there may substantial implica- tions for risk of chronic illnesses among nonpregnant adults, and coordi- nated pathogenic studies might allow conclusions on new tobacco product outcomes in advance of studies exploring longer âincubation periods.â Studies on the Component Exposures of PREPs The committee recommends that further basic research be undertaken to elucidate the components of cigarette smoke that are primarily respon- sible for adverse health outcomes. In order to evaluate the safety of many PREPs, it is important to understand the effect of smoke components, especially nicotine and CO, on the pathogenesis of intrauterine growth retardation, spontaneous abortions and other health outcomes. In addi- tion, better understanding of the risks of bupropion SR use by pregnant women (i.e., seizure risk) and the teratogenic effects of nicotine on the central nervous system, including dose-response and periods of vulner-
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 555 ability during gestation, is needed for adequate risk-benefit analysis of the harm reduction potential of these products. REFERENCES ACOG (American College of Obstetricians and Gynecologists). 1997. Educational Bulletin: Smoking and womenâs health. International Journal of Gynecology & Obstetrics 60:71-82. Agrawal P, Chansoriya M, Kaul KK. 1983. Effect of tobacco chewing by mothers on placen- tal morphology. Indian Pediatrics 20(8):561-565. Ahlborg G Jr, Bodin L. 1991. Tobacco smoke exposure and pregnancy outcome among working women. A prospective study at prenatal care centers in Orebro County, Swe- den. Am J Epidemiol 133:338-347. Ahlsten G, Cnattingius S, Lindmark G. 1993. Cessation of smoking during pregnancy im- proves fetal growth and reduces infant morbidity in the neonatal period. A popula- tion-based prospective study. Acta Paediatr 82(2):177-181. Ananth CV, Savitz DA, Luther ER. 1996. Maternal cigarette smoking as a risk factor for placental abruption, placenta previa, and uterine bleeding in pregnancy. Am J Epidemiol 144(9):881-889. Andres RL. 1996. The association of cigarette smoking with placenta previa and abruptio placentae. Semin Perinatol 20(2):154-159. Andres RL, Day MC. 2000. Perinatal complications associated with maternal tobacco use. Semin Neonatol 5(3):231-241. Barker D. 1997. Intrauterine programming of coronary heart disease and stroke. Acta Paediatr Suppl 423:178-182. Barker D. 1999. Fetal origins of cardiovascular disease. Ann Med 31(SUPP 1):3-6. Bassi JA, Rosso P, Moessinger AC, Blanc WA, James LS. 1984. Fetal growth retardation due to maternal tobacco smoke exposure in the rat. Pediatr Res 18(2):127-130. Benowitz NL. 1991. Nicotine replacement therapy during pregnancy. JAMA 266(22):3174- 3177. Benowitz NL. 1998. Nicotine Safety and Toxicity. PAF2. New York: Oxford University Press. Benowitz NL, Dempsey DA, Goldenberg RL, Hughes JR, Dolan-Mullen P, Ogburn PL, Oncken C, Orleans CT, Slotkin TA, Whiteside HP, Yaffe S. 2000. The use of pharmaco- therapies for smoking cessation during pregnancy. Tob Control 9 Suppl 3(2):III91-4. Castles A, Adams EK, Melvin CL, Kelsch C, Boulton ML. 1999. Effects of smoking during pregnancy. Five meta-analyses. Am J Prev Med 16(3):208-215. CDC (Centers for Disease Control and Prevention). 1998. Smoking during pregnancy, 1990- 96. National Vital Statistics Reports 47 (10):1-12. CDC (Centers for Disease Control and Prevention). 1999. Prevalence of selected maternal and infant characteristics, pregnancy risk assessment monitoring system (PRAMS), 1997. MMWR 48(SS05):1-37. CDC (Centers for Disease Control and Prevention). 2000. Tobacco use during pregnancy. National Vital Statistics Report 48(3):10-11. Chatenoud L, Parazzini F, di Cintio E, Zanconato G, Benzi G, Bortolus R, La Vecchia C. 1998. Paternal and maternal smoking habits before conception and during the first trimester: relation to spontaneous abortion. Ann Epidemiol 8(8):520-526. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, Murray JC. 1999. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 149(3):248-255.
556 CLEARING THE SMOKE Christianson RE. 1979. Gross differences observed in the placentas of smokers and non- smokers. Am J Epidemiol 110(2):178-187. Chung KC, Kowalski CP, Kim HM, Buchman SR. 2000. Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 105(2):485-491. Cnattingius S, Granath F, Petersson G, Harlow BL. 1999. The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries. N Engl J Med 341(13):943-948. Cooper GS, Sandler DP, Bohlig M. 1999. Active and passive smoking and the occurrence of natural menopause. Epidemiology 10(6):771-773. Coste J, Job-Spira N, Fernandez H. 1991. Increased risk of ectopic pregnancy with maternal cigarette smoking. Am J Public Health 81(2):199-201. Cunningham J, Dockery DW, Speizer FE. 1994. Maternal smoking during pregnancy as a predictor of lung function in children. Am J Epidemiol 139(12):1139-1152. Dejin-Karlsson E, Hanson BS, Ostergren PO, Sjoberg NO, Marsal K. 1998. Does passive smoking in early pregnancy increase the risk of small-for-gestational-age infants? Am J Public Health 88(10):1523-1527. Deshmukh JS, Motghare DD, Zodpey SP, Wadva SK. 1998. Low birth weight and associated maternal factors in an urban area. Indian Pediatrics 35(1):33-36. Drews CD, Murphy CC, Yeargin-allsopp M, Decoufle P. 1996. The relationship between idiopathic mental retardation and maternal smoking during pregnancy. Pediatrics 97(4):547-553. Dwyer T, Ponsonby AL, Couper D. 1999. Tobacco smoke exposure at one month of age and subsequent risk of SIDSâa prospective study. Am J Epidemiol 149(7):593-602. Ebrahim SH, Floyd RL, Merritt RK 2nd, Decoufle P, Holtzman D. 2000. Trends in preg- nancy-related smoking rates in the United States, 1987-1996. JAMA 283(3):361-366. English PB, Eskenazi B, Christianson RE. 1994. Black-white differences in serum cotinine levels among pregnant women and subsequent effects on infant birthweight. Am J Public Health 84(9):1439-1443. Fergusson DM, Horwood LJ, Lynskey MT. 1993. Maternal smoking before and after preg- nancy: effects on behavioral outcomes in middle childhood. Pediatrics 92(6):815-822. Fiore M, Bailey W, Cohen S, Dorfman S, Goldstein M, Gritz E, Heyman R, Jaen C, Kottke T, Lando H, Mecklenburg R, Mullen P, Nett L, Robinson L, Stitzer M, Tommasello A, Villejo L, Wewers M. (2000). Treating Tobacco Use and Dependence. Clinical Practice Guide- line. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service. Foresen T, Eriksson J, Tuomilheto J, Reunanen A, Osmond C, Barker D. 2000. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med 133(3):176- 182. Golding J. 1997. Sudden infant death syndrome and parental smoking-a literature review. Paediatric and Perinatal Epidemiology 11:67-77. Haddow JE, Knight GJ, Palomaki GE, Kloza EM, Wald NJ. 1987. Cigarette consumption and serum cotinine in relation to birthweight. Br J Obstet Gynaecol 94(7):678-681. Handler AS, Mason ED, Rosenberg DL, Davis FG. 1994. The relationship between exposure during pregnancy to cigarette smoking and cocaine use and placenta previa. Am J Obstet Gynecol 170(3):884-889. Handler A, Davis F, Ferre C, Yeko T. 1989. The relationship of smoking and ectopic preg- nancy. Amer J Pub Health 79(9):1239-1242. Hebel JR, Fox NL, Sexton M. 1988. Dose-response of birth weight to various measures of maternal smoking during pregnancy. J Clin Epidemiol 41(5):483-489.
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 557 Hoo AF, Henschen M, Dezateux C, Costeloe K, Stocks J. 1998. Respiratory function among preterm infants whose mothers smoked during pregnancy. Am J Respir Crit Care Med 158(3):700-705. Hughes EG, Brennan BG. 1996. Does cigarette smoking impair natural or assisted fecun- dity? Fertil Steril 66(5):679-689. Joad JP. 2000. Smoking and pediatric respiratory health. Clinics in Chest Medicine 21(1):37- 46. Jueneman K, Lue TF, Luo J, Benowitz NL, Abozeid M, Tanagho EA. 1987. The effect of cigarette smoking on penile erection. J Urology 138:438-441. Kendrick JS, Zahniser SC, Miller N, Salas N, Stine J, Gargiullo PM, Floyd RL, Spierto FW, Sexton M, Metzger RW, et al. 1995. Integrating smoking cessation into routine public prenatal care: the Smoking Cessation in Pregnancy project. Am J Public Health 85(2):217-222. Kleinman JC, Pierre MB, Madans JH, Land GH, Schramm WF. 1988. The effects of maternal smoking on fetal and infant mortality. Am J Epidemiol 127(2):274-282. Kline J, Levin B, Kinney A, Stein Z, Susser M, Warburton D. 1995. Cigarette smoking and spontaneous abortion of known karyotype. Precise data but uncertain inferences. Am J Epidemiol 141(5):417-427. Kline J, Levin B, Shrout P, Stein Z, Susser M, Warburton D. 1983. Maternal smoking and trisomy among spontaneously aborted conceptions. Am J Hum Genet 35:421-431. Kline J, Stein ZA, Susser M, Warburton D. 1977. Smoking: a risk factor for spontaneous abortion. NEJM 297(15):793-796. Krishna K. 1978. Tobacco chewing in pregnancy. Br J Obstet Gynaecol 85(10):726-728. Krishnamurthy S, Joshi S. 1993. Gender differences and low birth weight with maternal smokeless tobacco use in pregnancy. J Trop Pediatrics 39(4):253-254. Kyrklund-Blomberg NB, Cnattingius S. 1998. Preterm birth and maternal smoking: risks related to gestational age and onset of delivery. Am J Obstet Gynecol 179(4):1051-1055. Leach CE, Blair PS, Fleming PJ, Smith IJ, Platt MW, Berry PJ, Golding J. 1999. Epidemiology of SIDS and explained sudden infant deaths. CESDI SUDI Research Group. Pediatrics 104(4):e43. Li CQ, Windsor RA, Perkins L, Goldenberg RL, Lowe JB. 1993. The impact on infant birth weight and gestational age of cotinine-validated smoking reduction during pregnancy. JAMA 269(12):1519-1524. Lieff S, Olshan AF, Werler M, Strauss RP, Smith J, Mitchell A. 1999. Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns. Am J Epidemiol 150(7):683-694. Lodrup Carlsen KC, Jaakola JJK, Nafstad P, Garlsen KH. 1997. In utero exposure to ciga- rette smoking influences lung function at birth. Eur Respir J 10(8):1774-1779. Mannino DM, Klevins RM, Flanders WD. 1994. Cigarette smoking: an independent risk factor for impotence? Amer J Epidemiol 140(11):1003-1008. Marchbanks PA, Lee NC, Peterson HB. 1990. Cigarette smoking as a risk factor for pelvic inflammatory disease. Am J Obstet Gyncol 162:639-644. Maritz GS, Woolward KM, Du toit G. 1993. Maternal nicotine exposure during pregnancy and development of emphysema-like damage in the offspring. S Afr Med J 83(3):195- 198. Martinez FD, Wright AL, Taussig LM. 1994. The effect of paternal smoking on the birthweight of newborns whose mothers did not smoke. Am J Public Health 84 (9):1489- 1491. McCarton CM, Wallace IF, Divon M, Vaughan HG Jr. 1996. Cognitive and neurologic devel- opment of the premature, small for gestational age infant through age six: comparison by birth weight and gestational age. Pediatrics 98(6):1167-1178.
558 CLEARING THE SMOKE Milberger S, Biederman J, Faraone SV, Chen L, Jones J. 1996. Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry 153(9):1138-1142. Moessinger AC. 1989. Mothers who smoke and the lungs of their offspring. Ann N Y Acad Sci 562:101-104. Morgan WJ, Martinez FD. 1998. Maternal smoking and infant lung function: further evi- dence for an in utero effect. Am J Respir Crit Care Med 158(3):689-690. Ness RB, Grisso JA, Hirschinger N, Markovic N, Shaw LM, Day NL, Kline J. 1999. Cocaine and tobacco use and the risk of spontaneous abortion. N Engl J Med 340(5):333-339. Nieburg P, Marks JS, Mclaren NM, Remington PL. 1985. The fetal tobacco syndrome. JAMA 253(20):2998-2999. Olds DL, Henderson CR, Tatelbaum R. 1994. Intellectual impairment in children of women who smoke cigarettes during pregnancy. Pediatrics 93(2):221-227. Paulson RB, Shanfeld J, Mullet D, Cole J, Paulson JO. 1994. Prenatal smokeless tobacco effects on the rat fetus. J Craniofac Genet Dev Biol 14(1):16-25. Pfarrer C, Macara L, Leiser R, Kingdom J. 1999. Adaptive angiogenesis in placentas of heavy smokers. Lancet 354(9175):303. Saraiya M, Berg CJ, Kendrick JS, Strauss LT, Atrash HK, Ahn YW. 1998. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol 178(3):493-498. Scholes D, Daling JR, Stergachis AS. 1992. Current cigarette smoking and risk of acute pelvic inflammatory disease. Amer J Pub Health 82(10):1352-1355. Secker-Walker RH, Vacek PM, Flynn BS, Mead PB. 1998. Estimated gains in birth weight associated with reductions in smoking during pregnancy. J Reprod Med 43(11):967-74. Seidman DS, Laor A, Gale R, Stevenson DK, Mashiach S, Danon YL. 1992. Birth weight and intellectual performance in late adolescence. Obstet Gynecol 79(4):543-546. Sexton M, Hebel JR. 1984. A clinical trial of change in maternal smoking and its effect on birth weight. JAMA 251(7):911-915. Shabsigh R, Fishman IJ, Schum C, Dunn JK. 1991. Cigarette smoking and other vascular risk factors in vasculogenic impotence. Urology 38(3):227-231. Shah NR, Bracken MB. 2000. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet and Gynecol 182(2):465-472. Shiono PH, Klebanoff MA, Rhoads GG. 1986. Smoking and drinking during pregnancy. JAMA 255(1):82-84. Slotkin TA, Lappi SE, McCook EC, Lorber BA, Seideler FJ. 1995. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syn- drome. Brain Research Bulletin 38(1):69-75. Slotkin TA, Saleh JL, McCook EC, Seidler FJ. 1997. Impaired cardiac function during post- natal hypoxia in rats exposed to nicotine prenatally: implications for perinatal morbid- ity and mortality, and for sudden infant death syndrome. Teratology 55:177-184. Sommerfelt K, Andersson HW, Sonnander K, Ahlsten G, Ellersten B, Markestad T, Jacobsen G, Hoffman HJ, Bakketeig L. 2000. Cognitive development of term gestational age children at five years of age. Arch Dis Child 83:25-30. Spiers PS. 1999. Disentangling the separate effects of prenatal and postnatal smoking on the risk of SIDS. Am J Epidemiol 149(7):603-606, discussion 607. Stergachis A, Scholes D, Daling JR, Weiss NS, Chu J. 1991. Maternal smoking and risk of tubal pregnancy. Amer J Epidemiol 133(4):332-337. Tager IB, Ngo L, Hanrahan JP. 1995. Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 152(3):977-983.
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 559 U.S. DHHS (U.S. Department of Health and Human Services). 1983. The Health Consequences of Smoking; Cardiovascular Disease; A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Preven- tion. U.S. DHHS (U. S. Department of Health and Human Services). 1988. The Health Conse- quences of Smoking: Nicotine Addiction; A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Pre- vention. U.S. DHHS (U. S. Department of Health and Human Services). 1990. The Health Benefits of Smoking Cessation; A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Van Voorhis BJ, Dawson JD, Stovall DW, Sparks AE, Syrop CH. 1996. The effects of smok- ing on ovarian function and fertility during assisted reproduction cycles. Obstet Gynecol 88(5):785-791. Verma RC, Chansoriya M, Kaul KK. 1983. Effect of tobacco chewing by mothers on fetal outcome. Indian Pediatrics 20(2):105-111. Voigt LF, Hollenbach KA, Krohn MA, Daling JR, Hickok DE. 1990. The relationship of abruptio placentae with maternal smoking and small for gestational age infants. Obstet Gynecol 75(5):771-774. Wang X, Tager IB, Van Vunakis H, Speizer FE, Hanrahan JP. 1997. Maternal smoking dur- ing pregnancy, urine cotinine concentrations, and birth outcomes. A prospective co- hort study. Int J Epidemiol 26(5):978-988. Werler MM. 1997. Teratogen update: smoking and reproductive outcomes. Teratology 55(6):382-388. Windham GC, Hopkins B, Fenster L, Swan SH. 2000. Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight. Epidemiology 11(4):427-433. Windham GC, Swan SH, Fenster L. 1992. Parental cigarette smoking and the risk of sponta- neous abortion. Am J Epidemiol 135(12):1394-1403. Windham GC, Von Behren J, Waller K, Fenster L. 1999. Exposure to environmental and mainstream tobacco smoke and risk of spontaneous abortion. Am J Epidemiol 149(3):243- 247.