Life and Fitness

Cigarette Smoking, Alcohol Use and Adverse Pregnancy Outcomes: Implications for Micronutrient Supplementation1
Mary E. Cogswell,*2 Pamela Weisberg*y and Catherine Spong**
*Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, y Rollins School of Public Health, Emory University, Atlanta, GA 30322 and **Pregnancy and Perinatalogy Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
ABSTRACT This literature review examines whether smoking or alcohol use during pregnancy increases maternal micronutrient requirements and whether smoking or alcohol use interacts with micronutrient deciencies to affect pregnancy outcomes. Studies suggest that vitamin C requirements increase for pregnant smokers. Studies also indicate that b-carotene, vitamin B-12, vitamin B-6 and folate concentrations appear lower in pregnant smokers than in pregnant nonsmokers, although it is unclear whether lower serum concentrations are due to increased requirements, lower dietary or supplement intakes or other factors. Experimental animal studies suggest that iron supplementation partially ameliorates impaired fetal growth caused by cadmium, a heavy metal inhaled from cigarette smoke, but studies in humans have not substantiated cadmiums effect on fetal growth. Animal studies also suggest chronic alcohol consumption at levels of 2050% of energy intake during pregnancy may mobilize fetal vitamin A concentration from the liver and result in increases in vitamin A in fetal organs and subsequent defects. Evidence is lacking, however, on whether zinc metabolism is altered by alcohol intake during pregnancy. Health care practitioners should consider increasing nutrient levels in pregnant women who do not meet the Recommended Dietary Allowances through their diet. Future studies that examine the nutrient levels of women exposed to cigarette smoke and alcohol should control for dietary intake. In addition, randomized controlled studies of the health impact of micronutrient supplementation in pregnant women should consider stratication by exposure to cigarette smoke and alcohol use. J. Nutr. 133: 1722S1731S, 2003. KEY WORDS:  cigarette smoking  alcohol use  pregnancy  vitamins  minerals

Downloaded from jn.nutrition.org by guest on November 27, 2011

Although research studies document the adverse effects of smoking and alcohol use during pregnancy, the effects of these substances on micronutrient levels are not well dened. Imbalances in these nutrients may contribute to many of the pathological effects of smoking and alcohol use on the mother and fetus. Past reviews on the interactions between substance use and micronutrient status during pregnancy have typically focused on a specic micronutrient (1) or substance (2,3). The purpose of this review is twofold: 1) to examine whether smoking and alcohol use during pregnancy increase a womans micronutrient requirements and 2) to examine whether smoking and alcohol use interact with micronutrient deciency

to affect pregnancy outcomes. Substance use could cause micronutrient deciency, thus affecting pregnancy outcomes. It is also possible, however, that micronutrient deciency or excess may increase the risk of adverse pregnancy outcomes in women who smoke or drink alcohol. We reviewed the published literature in attempt to address these issues. We identied articles through a Medline search from 1966 through October 2001 using various search terms including micronutrients, alcohol and tobacco and pregnancy. (We will provide a full list of search terms on request.) We reviewed all abstracts and included only English language articles of original studies with information about micronutrient concentrations during pregnancy by substance exposure and about the risks of adverse pregnancy outcomes by exposure to both micronutrient deciency and substance use. Cigarette smoking during pregnancy Cigarette smoking during pregnancy is known to be harmful and can result in increased spontaneous abortions in the rst trimester, premature placenta abruption, preterm delivery, decreased birth weight and sudden infant death syndrome (4). Infants born to mothers who smoke during pregnancy weigh, on

1 Manuscript prepared for the USAID-Wellcome Trust workshop on Nutrition as a preventive strategy against adverse pregnancy outcomes, held at Merton College, Oxford, July 1819, 2002. The proceedings of this workshop are published as a supplement to The Journal of Nutrition. The workshop was sponsored by the United States Agency for International Development and The Wellcome Trust, UK. USAIDs support came through the cooperative agreement managed by the International Life Sciences Institute Research Foundation. Supplement guest editors were Zulqar A. Bhutta, Aga Khan University, Pakistan, Alan Jackson (Chair), University of Southampton, England, and Pisake Lumbiganon, Khon Kaen University, Thailand. 2 To whom correspondence should be addressed. E-mail mec0@cdc.gov.

0022-3166/03 $3.00 2003 American Society for Nutritional Sciences.

1722S

SMOKING, ALCOHOL AND MICRONUTRIENTS

1723S

average, 150300 g less than those born to mothers who do not smoke and the risk of small-for-gestational age is at least two times as high among women who smoke as among women who do not smoke (5,6). The effects of smoking during pregnancy on fetal growth and preterm delivery are greater for older women (7). Long-term smoking may increase the risk of placental complications. The data in Table 1 illustrate the fraction of low birth weight attributable to smoking and the estimated smoking prevalence in less developed and in more developed countries in the mid-1980s (5). The attributable fraction of low birth weight due to smoking varies by the prevalence of smoking between and within countries as well as the changing rates of smoking over time. Although smoking prevalence during pregnancy is difcult to quantify for most countries, in the United States it is lower than for women overall. In 1999, 15.524.4% of adult women reported smoking (8) compared with 12.3% of women who reported smoking during pregnancy (9). Maternal smoking rates have declined since 1990 but important differences remain by race and Hispanic origin (Fig. 1) (9). The mechanisms by which smoking causes adverse pregnancy outcomes are not entirely clear. Cigarette smoking is a source of oxidant stress. Carbon monoxide and nicotine both are components of cigarettes that may affect birth weight and cause preterm delivery. Carbon monoxide binds to hemoglobin to form carboxyhemoglobin, causing fetal hypoxia, which is related to sudden infant death syndrome (10). Nicotine and carbon monoxide may lead to vasoconstriction and reduced blood ow (4). Nicotine can also increase maternal blood pressure and heart rate, reducing uterine blood ow (2,4). Other components of cigarette smoke, including lead, thiocyanate and cadmium, also may damage the fetus. Cigarette smoking and micronutrients. Cigarette smoking during pregnancy may alter the micronutrient status of the pregnant woman and the fetus, leading to adverse pregnancy outcomes. Cigarette smoking decreases appetite and may decrease the amount of nutrients consumed by the pregnant woman. Cigarette smokers may be less likely to consume micronutrient supplements and more likely to consume alcohol and other substances that interact with nutrient metabolism. Cigarette smoking may decrease absorption of micronutrients in the intestine and increase the utilization of nutrients. Cigarette smoking also causes an inammatory response that can affect the serum and plasma measures of micronutrient status (11), making them difcult to interpret in smokers. If cigarette smoking increases the utilization of nutrients, nutrient requirement values should be increased for cigarette smokers. Nutrient requirement values should also be adjusted for smokers if smoking interacts with micronutrient status to affect pregnancy outcomes. Interactions might occur if placental

FIGURE 1 Percent of mothers who smoked during pregnancy by race and Hispanic origin: Selected reporting area, 1990 and 1999. Reprinted from: Matthews, T. J. (2001) Smoking during pregnancy in the 1990s. National Vital Statistics Reports, vol.49, no. 7, National Center for Health Statistics (9). NOTE: Excludes California, Indiana, New York State, and South Dakota for 1999 and California, Indiana, New York, Oklahoma, and South Dakota for 1990.

Downloaded from jn.nutrition.org by guest on November 27, 2011

TABLE 1
Proportion of low birth weight attributed to smoking by smoking prevalence
Smoking prevalence among women Less-developed countries More-developed countries Data are from reference 5. 20% 40% Proportion of low birth weight attributed to smoking 22% 36%

transfer of micronutrients is altered in smokers or if micronutrient deciency or excess increases the susceptibility of a fetus to adverse effects of cigarette smoke, for example, by increased absorption of harmful components of cigarette smoke or by increased oxidative stress. Studies that have examined the effects of smoking on micronutrient status and the interactions between micronutrient status and smoking on pregnancy outcomes are reviewed below. Cigarette smoking and vitamins. Studies have consistently shown that plasma and leukocyte vitamin C concentrations are lower in smokers than in nonsmokers (3,12). This difference may be partly attributable to lower intakes of vitamin C by smokers (1315). Pregnant smokers with vitamin C intakes similar to those of pregnant nonsmokers, however, had lower vitamin C levels in plasma, amniotic uid and breast milk (16,17) (Table 2). According to another report, plasma vitamin C exhibited an inverse correlation with breath content of ethane, a marker of lipid peroxidation, in pregnant smokers but not nonsmokers even though the intake of vitamin C from diet and supplements (320 mg/d) exceeded the Recommended Dietary Allowance (18). There was no correlation between alcohol use and breath ethane (18). This study implies that vitamin C utilization is increased among pregnant smokers. Researchers are uncertain whether smoking decreases the levels of other antioxidants (3). Plasma levels of vitamin E, vitamin A and b-carotene are not consistently lower in smokers than nonsmokers during pregnancy (Table 2). Two studies suggested no difference in maternal vitamin E levels in pregnant women by smoking status (19,20). One study indicated that serum retinol in cord blood did not differ by smoking status (21). Two studies indicated that carotene levels in maternal and cord blood were signicantly lower in pregnant smokers than nonsmokers (21,22). It was not clear, however, whether the lower b-carotene concentration in smokers was due to lower dietary intake. Two studies indicated that dietary intake of carotenoids was lower for smokers than nonsmokers (13,14) although in one of the studies (14) the difference was not statistically signicant. A third study indicated that dietary intake and serum and cord b-carotene concentrations were similar in smokers and nonsmokers (21). Although requirements for vitamin E, vitamin A and b-carotene may not

1724S

SUPPLEMENT

TABLE 2
Smoking status and nutrient levels among pregnant women
Results, mean 6 Nutrient Vitamin C Ref. 16 Subjects N = 16 smokers N = 41 nonsmokers N = 10 smokers N = 24 nonsmokers Biochemical data Vitamin C, mmol/L Maternal serum, 3236 wk gestation Breast milk, 1314 d postpartum Breast milk, 40 d postpartum Vitamin C, mmol/L Maternal serum, term Amniotic uid, term Vitamin E, mmol/L Maternal serum, 3236 wk gestation Breast milk, 1314 d postpartum Breast milk, 40 d postpartum Vitamin E, mmol/L Maternal serum, 1020 wk gestation Cord serum, term b-carotene, mmol/L Maternal serum, 1020 wk gestation Cord serum, term Cord serum, term: All-trans b-carotene, mmol/L Retinol, mmol/L Total carotenes, mmol/L Maternal serum, ,20 wk gestation Vitamin B-12, pmol/L Maternal serum, term Cord serum, term Vitamin B-12, pmol/L Maternal serum, ,20 wk gestation Maternal serum, 2030 wk gestation Maternal serum, .30 wk gestation Vitamin B-12, pmol/L Maternal serum, 18 wk gestation Maternal serum, 30 wk gestation Vitamin B-6, nmol/L Maternal serum, 18 wk gestation Maternal serum, 30 wk gestation Folate, nmol/L Maternal serum, 18 wk gestation Maternal serum, 30 wk gestation Total homocysteine, mmol/L Maternal serum, 18 wk gestation Maternal serum, 30 wk gestation Maternal blood at term: Serum zinc, mmol/L Red blood cell zinc, mg/dL Cord blood at term: Serum zinc, mmol/L Red blood cell zinc, ng/g Placenta: Zinc, ng/g Maternal blood at term: Serum zinc, mmol/L Polymorphonuclear cell (PMN) zinc, mmol/1010 PMN cells Mononuclear cell (MN) zinc, mmol/1010 MN cells Cord serum at term: Hemoglobin, g/L Iron, mmol/L Total iron binding capacity, mmol/L Ferritin, mg/dL Transferrin receptor (TfR), mg/L TfR/Ferritin index 139* 377 125.5 6 49.0* 119.3 6 50.1 109.4 6 48.6 319 6 99* 254 6 60* 15 6 10* 11 615 47 6 31 38 6 30* 5.2 6 2.4 5.7 6 3.4 8.8 6 1.5 1232 6 169 12.4 6 2.2 230 6 55* 12.1 6 2.7* 10.9 6 0.9 1.00 6 0.04* 2.47 6 0.11 Median 168* 24.5* 45.0 * 12.3* 9.3* 4.1* 181 435 140.8 6 52.3 124.1 6 54.5 112.1 6 43.4 379 6 139 309 6 102 24 6 23 15 6 16 54 6 38 54 6 39 5.0 6 1.6 4.9 6 1.6 8.7 6 1.5 1218 6 150 12.7 6 2.3 250 6 60 11.1 6 2.8 10.1 6 0.8 1.16 6 0.06 2.64 6 0.17 Smokers 73.3 6 84.2 233.7 6 202.9* 241.3 6 293.1* 41.9* 77.2*
SD

Nonsmokers 84.1 6 168.7 431.6 6 296.5 496.1 6 325.6 64.7 158.8

17

Vitamin E

19

N = 16 smokers N = 41 nonsmokers N = 31 smokers N = 35 nonsmokers

34.5 6 6.9 3.8 6 1.5 2.0 6 0.4* 20.8 6 4.3 7.4 6 2.0

34.0 6 10.2 4.4 6 1.5 2.3 6 0.8 20.5 6 3.6 7.3 6 2.0

20

Downloaded from jn.nutrition.org by guest on November 27, 2011

Vitamin A and b-carotene

20 21 22 25y

N = 31 smokers N = 35 nonsmokers N = 11 smokers N = 56 nonsmokers N = 42 smokers N = 67 nonsmokers N = 25 smokers (cord blood N = 22) N = 163 nonsmokers (cord blood N = 132) N = 89184 smokers N = 84242 nonsmokers N varies by gestation at booking N = 5765 smokers N = 122131 nonsmokers N lower at 30 wk gestation

0.2 6 0.1 0.06 6 0.04 ;1.4* ;0.45 1.8*

0.2 6 0.1 0.03 6 0.02 ;2.7 ;0.44 2.1

Vitamin B-12, vitamin B-6 and folate

26

29

Zinc

27

N = 65 smokers N = 84 non-smokers

28

N = 3235 smokers N = 2836 nonsmokers

Iron

33

N = 28 smokers N = 39 nonsmokers

157 27.0 39.0 19.0 7.6 3.4

SMOKING, ALCOHOL AND MICRONUTRIENTS

1725S

TABLE 2 (continued)
Results, mean 6 Nutrient Ref. 34 Subjects N = 25 smokers N = 23 nonsmokers N = 1236 smokers N = 112465 nonsmokers Biochemical data Cord serum at term: Iron, mmol/L Transferrin, g/L Ferritin, mg/dL Ferritin, mg/dL Maternal serum at Maternal serum at Maternal serum at Maternal serum at Maternal serum at Smokers 28.6 6 6.9 2.21 6 0.38 27.6 19 wk gestation 26 wk gestation 32 wk gestation 37 wk gestation delivery 73* 37* 22 25 28
SD

Nonsmokers 29.2 6 5.5 2.22 6 .030 27.4 37 20 19 20 28

35

* signicantly different from nonsmokers, P , 0.05. y Results shown as medians in this study.

be higher for smokers, lower intakes of antioxidants by smokers could lead to poorer status. To test the hypothesis that smoking-related placental calcication is moderated through dietary antioxidants, Klesges et al. (23) examined the two-way multiplicative interactions between dietary intake of antioxidants (vitamin C, a-tocopherol and b-carotene) and smoking on placental surface (in 1020 women) and villous (in 613 women) calcication. These interactions were not signicant, but the signicant independent effects of smoking and dietary antioxidants indicated an independent deleterious effect of smoking and a protective effect of dietary antioxidants on placental villous calcication. Adjustment for alcohol use (30% of the participants) and illicit drug use (8% of the participants) did not affect these associations. The ndings conrm a pathological relationship between smoking and placental calcication and suggest that dietary antioxidants and smoking may have additive effects on placental villous calcication. Studies suggest that smokers have lower blood and tissue levels of vitamin B-6, folate and vitamin B-12 than do nonsmokers (3) (Table 2). Poorer vitamin B-12 status among smokers is attributed to detoxication of cyanide inhaled from tobacco smoke (3). One study indicated that compared with pregnant smokers, pregnant nonsmokers serum concentration of B-6 were lower at 18 wk gestation, folate levels were lower at 30 wk gestation and vitamin B-12 levels were lower at both times (24). In that study, the lower folate level of the pregnant smokers during the third trimester was attributed to less adherence to iron and folate supplementation (24). Two other studies also indicated that maternal B-12 levels were signicantly lower in smokers during pregnancy (25,26). None of these studies adjusted for dietary intake, so consequently whether the differences between smokers and nonsmokers were due to diet or other factors is not known. Evidence that exposure to B vitamins and cigarette smoke interact is contradictory. McGarry and Andrews (26) suggested that maternal vitamin B-12 concentration is positively associated with infant birth weight. The association appeared stronger among smokers but it was not statistically signicant because the sample of infants with low birth weight was small (n 5 14). Contrary to these results, Frery et al. (25) suggested that increases in maternal vitamin B-12 levels are associated with decreases in infant birth weight (n 5 188). Furthermore this effect was stronger in smokers and was apparent after adjustment for folic acid concentration and alcohol consumption. An adequate explanation cannot be made to reconcile these ndings.

Cigarette smoking and minerals. Research ndings were unclear on whether women who smoked had increased requirements for zinc during pregnancy compared with women who did not smoke (Table 2). Levels of dietary zinc, plasma zinc and red blood cell zinc measured close to the time of delivery were similar in smokers and nonsmokers (27,28). Levels of cord red blood cell zinc, however, were lower in smokers (27) and levels of polymorphonuclear zinc were also lower in smokers at 2448 h postdelivery (28). Measures of plasma zinc may not be sufcient to identify differences in zinc status in pregnant women. Polymorphonuclear zinc may be a more sensitive indicator of zinc depletion than plasma zinc (11). Kuhnert et al. (29) also suggested that cadmium from cigarette smoke accumulates and binds to zinc in the placenta, lowering the amount of zinc available to the fetus. Hence placental zinc levels are higher in smokers (27,29) and the ratio of zinc to cadmium in the placenta is lower among smokers (29). How this affects the functional outcomes of the infant is unclear from current studies. In two studies, Kuhnert et al. (29,30) found that the sizes of the correlation between cord vein red blood cell zinc and birth weight were similar in smokers and nonsmokers. Goldenberg et al. (31) examined the associations between a2 macroglobulin, a carrier protein for zinc, and fetal growth retardation. They found that the association between a2 macroglobulin at 18 wk gestation and fetal growth retardation occurred predominantly in smokers. The relationship, however, did not appear to be associated with differences in serum zinc. Smoking increases hemoglobin concentration related to carbon monoxide exposure (32) as well as perhaps hemoglobin levels in the cord blood (33) and in neonates (34). The effect of smoking on other iron indices, however, is not as clear (Table 2). One study found higher mean serum ferritin levels in pregnant smokers at 19 and 26 wk gestation, but not in later gestation or at delivery (35). Another study found no difference in the mean cord levels of ferritin, transferrin or in iron of infants born to smokers or nonsmokers (34). A third study found that after delivery of term infants, mothers who smoked had lower levels in cord blood of iron, total iron binding capacity and ferritin than did nonsmoking mothers and that serum transferrin receptors and the ratio of transferrin receptors to the log of ferritin were higher among smoking mothers, suggesting poorer iron status (33). Serum ferritin concentration increases with inammation (11), making it difcult to interpret this measurement. Transferrin receptors are less affected by inammation. The authors suggested that the increase in serum transferrin receptors was related to factors that increase the fetal production of hemoglobin.

Downloaded from jn.nutrition.org by guest on November 27, 2011

1726S

SUPPLEMENT

A series of randomized control trials in mice of cadmium exposure and diets containing one of four minerals (zinc, copper, iron or selenium) indicated that iron offered partial protection against cadmium-induced fetal growth retardation, but the other minerals were ineffective (36). An additional 2 3 2 factorial randomized controlled trial in mice suggested that parenterally administered iron completely prevented cadmium-induced fetal growth retardation (37). Interestingly, cadmium caused severe anemia in the fetus but only mild anemia in the mothers suggesting that cadmium might interfere with transplacental availability of iron (37). Further randomized control trials in mice suggested that iron supplements in mice at risk of iron deciency ameliorated some of the negative effects of cadmium exposure on fetal growth (38). In support of these ndings, other groups of researchers found that maternal cadmium exposure depressed the levels of zinc, copper and iron in rats and their fetuses (39,40). In humans, however, the effects of cadmium on fetal growth are uncertain (41). An observational study in humans suggested that an interaction may exist between smoking during pregnancy and maternal anemia in their effects on sudden infant death syndrome: Anemia during the third trimester was not associated with increased risk of sudden infant death, but the risk of sudden infant death from cigarette smoking almost doubled when the prospective mothers not only smoked but were anemic (42). Two observational studies by Wu et al. (43,44) examined the interactions between supplement use and smoking status on birth outcomes (Table 3). The odds ratios for fetal death associated with smoking were modied by supplement use before pregnancy such that there was a positive association between smoking and fetal death among women who did not use supplements before pregnancy but not among those who used supplements (43). Among women giving birth to live infants, supplement intake did not appear to modify the effects of smoking status on fetal growth or preterm birth (44). These ndings were independent of alcohol consumption. However, researchers must use caution in interpreting results from these studies because the composition and dose of the supplements was unknown and information on maternal smoking and supplement use was self-reported after delivery, potentially biasing results. Conclusions. In the new Recommended Dietary Allowances published by the Institute of Medicine (12,4547),

only vitamin C requirements are increased for smokers. According to the Institute of Medicine estimates, the metabolic turnover for vitamin C is greater among smokers, and smokers require an additional 35 mg/d over that of nonsmokers to maintain adequate vitamin C status (12). Evidence indicating that smoking increases a persons requirements for other micronutrients to prevent deciency is neither as extensive nor denitive for the general population or, as indicated previously, for pregnant women. Compared with nonsmokers, smokers have lower serum concentrations of certain nutrients (i.e., b-carotene, vitamin B-12, vitamin B-6 and folic acid), but whether the lower serum concentrations are caused by lower dietary intakes or other factors unrelated to smoking is not known. For other nutrients (i.e., zinc, iron, vitamin E and vitamin A) researchers are uncertain whether smokers have lower serum concentrations than nonsmokers. Clearly, additional studies on the effects of cigarette smoking on micronutrient status need to control for dietary and supplement intake, the inammatory effects of smoking, alcohol intake and other factors. The relatively few studies that addressed interactions between exposure to cigarette smoke and micronutrient status should be interpreted with caution because of their observational nature or the difculty translating animal ndings to humans. Alcohol use during pregnancy Maternal alcohol consumption during pregnancy may lead to fetal growth retardation, malformations, developmental defects, and/or spontaneous abortion (48,49). The phrase fetal alcohol syndrome describes the simultaneous occurrence of several birth defects associated with alcohol consumption during pregnancy and consists of fetal growth restriction, central nervous system impairment and facial deformities; diagnosis requires the presence of all three defects. In one study, 3033% of women who drank 2 g alcohol/kg body weight per day gave birth to infants with fetal alcohol syndrome. Lower levels of alcohol consumption during pregnancy have also been associated with adverse outcomes. Alcohol-related morbidity among infants who do not meet the criteria for fetal alcohol syndrome is referred to as fetal alcohol effects and includes a wide variety of complications from facial anomalies to neurodevelopmental delay. The consumption of $120 g (15

Downloaded from jn.nutrition.org by guest on November 27, 2011

TABLE 3
Risk of fetal death by maternal smoking during pregnancy and regular use of multivitamin/mineral supplements before and after recognition of pregnancy, logistic regression analysis,* National Maternal and Infant Health Survey, 1988
Regular use of supplements before recognition of pregnancy Maternal smoking (cigarettes/d) 0 19 1019 $ 20 Trendy No OR (95% CI) 1.00 (referent) 1.12 (0.91, 1.36) 1.36 (1.12, 1.65) 1.59 (1.27, 2.00) p , 0.05 Yes OR (95% CI) 0.96 (0.83, 1.09) 1.00 (0.70, 1.43) 1.09 (0.75, 1.59) 0.84 (0.53, 1.33) p . 0.05 Regular use of supplements after recognition of pregnancy No OR (95% CI) 1.00 (referent) 1.04 (0.74, 1.47) 1.42 (1.01, 1.99) 1.77 (1.22, 2.55) p , 0.05 Yes OR (95% CI) 0.94 (0.82, 1.09) 1.06 (0.85, 1.33) 1.21 (0.97, 1.52) 1.22 (0.94, 1.59) p , 0.05

* Adjusted for maternal race, age, marital status at pregnancy, education, prepregnancy weight, wantedness of the pregnancy, vomiting during pregnancy, alcohol drinking during pregnancy, previous history of miscarriage and/or stillbirth, infants gender and family income during the 12 mo before delivery. y Tested by including the ordinal smoking level as a continuous variable, a dummy variable for vitamin use and a product term for smoking and vitamin use. OR, odds ratio; CI, condence interval Data are from reference 43.

SMOKING, ALCOHOL AND MICRONUTRIENTS

1727S

units) of alcohol per week has been associated with twice the risk of spontaneous abortion (odds ration [OR]3 5 2.3; 95% condence interval [CI], 1.14.5) (50). Compared with women who consumed ,1 drink/wk, women who consumed $5 drinks per week had 3 times the risk of delivering a stillborn baby (51). Taylor et al. (52) reported an 83-g decit in birth weight in infants born to mothers who consumed 12 drinks/d. It is difcult to accurately estimate the prevalence of alcohol consumption during pregnancy because self-reported data are often biased. In addition, data are limited. Alcohol use was less prevalent among pregnant than nonpregnant women in the United States (Table 4) (53): In an unplanned pregnancy, however, the fetus can be exposed to alcohol before the woman knows she is pregnant. The mechanisms underlying the teratogenic effects of alcohol are unknown. Possible mechanisms related to the effects on and interactions with micronutrient status are discussed below. Alcohol use and micronutrients. Similar to the effects of cigarette smoking, many of the effects of alcohol use during pregnancy may be mediated through micronutrients (54). Chronic alcohol intake can produce malnutrition as a result of inadequate dietary intake. Energy from alcohol may replace that from food, leading to an overall decline in nutrient intake. Alcohol intake can disturb gastrointestinal function, leading to reduced or enhanced absorption of vitamins and minerals (48). The absorption of zinc, which is a cofactor for alcohol dehydrogenase (the ethanol-metabolizing enzyme), may be impaired (55). Mobilization of vitamin A from the liver may increase with excessive alcohol consumption (56) and vitamin A toxicity can cause birth defects. Alcohol consumption increases metabolic demands, increases DNA and RNA needs for synthesis and regeneration of liver cells and impairs utilization of nutrients (48). Alcohol use may be associated with cigarette smoking and other drug use. If utilization of nutrients is impaired with alcohol use independent of dietary intake or use of other substances, nutrient requirements should be adjusted for pregnant women who use alcohol. Alcohol use and vitamins. Chronic, excessive alcohol intake appears to be related to toxicity of vitamin A, not to its deciency. In general, retinol and retinyl palmitate levels are elevated in fetal tissues of pregnant rats exposed to ethanol compared with pair-fed control rats (Table 5) (5762). Whether levels of retinoic acid or retinol binding protein differ with alcohol intake is unclear. One study suggested that alcohols effects were organ specic: vitamin A levels in the fetal liver were lower and lung and kidney vitamin A levels were higher in rats born to alcohol-exposed mothers (57). Grummer and Zachman (57) suggested that alcohol use may stimulate retinyl ester hydrolase activity in the fetus, causing mobilization of retinyl palmitate in the fetal liver. Two animal studies examined the combined effects of alcohol exposure and vitamin A toxicity during pregnancy. One study found that the reduction in fetal size and the increase in fetal deformities of rats exposed to 80,000 IU/d plus alcohol were greater than those of rats exposed to the control or to either treatment alone (63). For example, 11 of 304 fetuses whose mothers were exposed to both alcohol and vitamin A had cleft palate compared with none of the fetuses exposed to either of these factors alone (63). Similarly, the other study found that the incidence of cleft palate did not increase signicantly with alcohol intake alone, but in mice exposed to 3400 IU/d of retinyl acetate the incidence of cleft palate nearly
3

TABLE 4
Prevalence of alcohol consumption among U.S. women aged 1844 y, Behavioral Risk Factor Surveillance System, 1999
Pregnant women Any alcohol Binge Frequent Data are from reference 53. 12.8% 2.7% 3.3% Nonpregnant women 53.3% 12.3% 14.6%

doubled in mice also exposed to alcohol (64). These studies suggested that alcohol and vitamin A toxicity interacted to increase incidence of malformations. Circulating 25-hydroxyvitamin D levels in the sera and liver were decreased in rat fetuses born to mothers who consumed excessive amounts of alcohol during pregnancy, compared with pair-fed controls, despite no difference in maternal levels of 25hydroxyvitamin D (61). One possible explanation for this nding is that alcohol decreased the fetal accumulation of 25hydroxyvitamin D through diminished transfer across the placenta (61). The effects of alcohol on the metabolism of B vitamins are unclear. In one study of pregnant women, red blood cell folate concentrations at 33 wk gestation were higher and serum folate levels were the same for those who consumed $21 drinks of alcohol per week before or early in their pregnancy versus control subjects (65). The effect of heavy alcohol use persisted after adjustment for the number of cigarettes smoked daily during pregnancy. The negative correlation between the number of cigarettes smoked per day and red cell folate also persisted, suggesting the two factors had independent effects. Part of the effect of alcohol on red blood cell folate was attributed to the consumption of beer in that population (65). In beagles, maternal folate levels were not signicantly affected by ethanol or dietary protein alone, but ethanol and low dietary protein were associated with low plasma folate concentration (66), suggesting an interaction of these two nutrients with alcohol. Potential mechanisms for alterations in folate metabolism are also unclear. In two studies in non-pair-fed pregnant rats, ethanol appeared to enhance the absorption of folic acid in mothers (67) and pups (68). In pair-fed pregnant rats, exposure to ethanol in drinking water at 36% of energy decreased the placental folate receptor activity (69). Acute alcohol exposure TABLE 5
Fetal vitamin levels in animals whose mothers were exposed to alcohol during pregnancy versus controls
Animal fetal vitamin levels from mothers receiving ethanol versus control Higher Same or higher Lower or same Lower at gestational day 21 Lower Same

Downloaded from jn.nutrition.org by guest on November 27, 2011

References 5760 5860 5860 57 61 62

Indicator (fetal organ) Retinol or retinyl palmitate (heart/snout/lung/kidney/ brain) Retinol-binding protein (heart/snout/head) Retinoic acid (heart/snout/ brain) Retinyl palmitate (liver) 25hydroxyvitamin D (liver) Folate (brain/liver)

Abbreviations used: CI, condence interval; OR, odds ratio.

1728S

SUPPLEMENT

in pregnant rats, however, appeared not to decrease folate uptake in fetoplacental tissue (62); compared with control rats, folate concentrations appeared to be similar in the brain and liver of rat fetuses (62) (Table 5) and in the sera of offspring whose mothers had been randomly assigned to receive ethanol in their water (68). The interactions of folate and ethanol on pregnancy outcomes were studied in pregnant golden hamsters (70) and rats (71). Folate exposure did not appear to protect the hamster fetus from heat- or alcohol-induced neural tube defects (70). The body weight of rat offspring whose mothers were exposed to both oral folate and alcohol during the fetal period was between that of the offspring who were exposed only to alcohol and the control group (71). No attempt was made, however, to control the energy intake of the groups. In relation to other B vitamins, in vitro studies suggested that short-term exposure to alcohol inhibited the transport of vitamin B-6 (72) but not thiamin (73) or biotin (74) in human placentas. Some evidence indicated that other B vitamins may interact with alcohol intake during pregnancy and subsequently affect maternal and fetal metabolism and outcomes. In vitamin B-6 deciency, ethanol affected fetal weight and maternal liver pyridoxal 5-phosphate activity to a greater extent than in vitamin B-6 adequacy (75). In animals exposed to alcohol with and without thiamin supplementation, the nuclear size of CA3 pyramidal cells was larger with supplementation, but thiamin administration did not suppress cell loss generated by ethanol treatment (76). Alcohol use and minerals. The relationship between excessive alcohol intake during pregnancy and zinc levels is not known with certainty. One study in humans suggested that the plasma zinc levels in 25 pregnant alcoholic women and cord concentrations of zinc were lower than values for 25 nonalcoholic women (77). Dietary intake of zinc, however, was not reported. Another human study found that the cord concentrations of both zinc and copper of 35 pregnant alcohol drinkers were lower than those in 10 pregnant nondrinkers of alcohol despite similar maternal concentrations (78), suggesting decreased placental transport. In an in vitro study, brief exposure of the human term placenta to alcohol did not inhibit placental transport of zinc (79). The animal studies that we reviewed were unclear on whether alcohol exposure during pregnancy decreased the levels of maternal and fetal zinc. Almost all of the studies were conducted in rats with adequate zinc in their diets. Three studies suggested that alcohol exposure resulted in lower levels of maternal liver concentrations of zinc (8082) but three other studies did not (8385). Although the study designs differed slightly, pair feeding, liquid or solid diet, alcohol dose and duration of exposure did not appear to explain the differences in results. Only two (86,87) of eight (8084,8688) studies suggested that zinc levels of the fetus were lower with maternal exposure to alcohol than in the control group. In one of the studies that demonstrated lower fetal levels of zinc with alcohol exposure, the placental and fetal uptake of zinc was also lower (86). Hence, most studies suggested that alcohol exposure during pregnancy in well-nourished animals did not affect fetal zinc status. This nding was conrmed by a study in primates that found that alcohol exposure during pregnancy did not affect maternal or fetal hair zinc concentrations compared with the pair-fed control primates (89). One study also examined whether zinc deciency and alcohol exposure interacted to cause lower levels of fetal zinc. According to the study results, alcohol had no effect on the zinc levels in fetal liver, kidney, muscle or bone tissue in either zinc-decient or zinc-sufcient animals (80). Results of two recent studies using metallothion-

ine-null mice exposed to alcohol and nonexposed mice as controls contradicted these ndings. Ethanol could cause zinc deciency by inducing metallothionine in the maternal liver, which could increase hepatic zinc concentration and decrease plasma zinc and the supply of zinc to the fetus. Compared with metallothionine-null pregnant mice exposed to alcohol and nonexposed control mice, zinc in metallothionine-normal mice exposed to alcohol increased in the maternal liver and decreased in maternal plasma, resulting in increased abnormalities in fetuses (90,91). This nding suggests that metallothionine may play a role in zinc metabolism in individuals exposed to alcohol. Two studies conducted by Tanaka et al. (92,93) investigated whether vitamin E or zinc supplementation ameliorated alcohols effects on fetal cerebral weight and synaptic development in mice. Both studies suggested that neither supplemental zinc nor vitamin E improved fetal synaptic development, although both vitamin E and zinc improved cerebral weight in fetal mice exposed to ethanol at lower doses (93). We found eight other studies that examined the interactions of alcohol and zinc intake on pregnancy outcomes (55,94100). Five of the studies found that the effects of excessive alcohol intake on fetal survival, fetal abnormalities or placental abnormalities were greater for animals fed zinc-decient diets (55,94,95,97,98). In the other three studies, alcohol was found to have an effect on outcome but no interaction occurred between alcohol and zinc intake (96,99,100). Differences in study design did not appear to explain the conicting results. Alcohol intake may also alter the metabolism of iron. A study of pregnant women conducted by Streissguth et al. (101) suggested that levels of ferritin, transferrin saturation and hemoglobin were similar between reported nondrinkers of alcohol and women exposed to alcohol during pregnancy except in those reporting an intake of $118 mL (4 ounces) alcohol around the time of conception. In this latter group, the rate of iron depletion (i.e., low ferritin) at the rst prenatal visit and at 32 wk gestation was higher than in the nondrinkers of alcohol. Although data were collected on smoking and drug use, no attempt was made to adjust for these exposures. Converse to these ndings, brain ferritin levels increased in ethanol-exposed rats whereas iron concentration was reduced (102). Another study suggested a rise in marrow transit time of iron and reduced plasma iron turnover in alcohol-exposed pregnant rats (103). One study examined the effects of excessive alcohol intake and iron deciency in pregnant mice on fetal weight and survival. Iron deciency and alcohol excess by themselves caused reductions in fetal weight and survival, but no apparent interaction was found between these exposures (104). The effects of alcohol exposure and iron deciency may have affected fetal weight and survival through reductions in energy intake, because the energy intake was not controlled and the pattern of maternal weight gain and energy intake also followed that of infant survival and fetal weight. Conclusions. The Institute of Medicine has indicated heavy alcohol use as a potential factor affecting the requirements of vitamin C, b-carotene, vitamin B-6 and folate as well as the toxicity of vitamin A (12,4547). The exact effects of alcohol, however, were not quantied; hence, Recommended Dietary Allowances were not adjusted for alcohol use. Similarly, we found the effects of heavy alcohol use on nutrient levels in both well-nourished and nutrientdecient pregnant animals and humans were uncertain. Although evidence exists for interactions between alcohol and micronutrients on adverse pregnancy outcomes, the

Downloaded from jn.nutrition.org by guest on November 27, 2011

SMOKING, ALCOHOL AND MICRONUTRIENTS

1729S

ndings are far from conclusive. Given the limited research in this area, future studies directed at the role of micronutrients in alcohol-induced pregnancy complications are warranted and will require an interactive evaluation. Summary The data to date on the effects of cigarette smoking and alcohol use on alterations in micronutrient levels that result in abnormal pregnancy outcome are limited. Most studies examining the effects of smoking during pregnancy on micronutrient status are observational studies in humans whereas those examining the effects of alcohol are mainly experimental studies in animals that provided 2050% of energy from alcohol. Although a few human studies examined the independent effects of exposure to cigarette smoke (or its components) and heavy alcohol use, we did not nd any study that examined the combined effects. Evidence indicates that cigarette smoking and alcohol use can alter the requirements for specic micronutrients and may play a role in the alteration in a pregnant population. Some of this alteration, however, may be related to changes in dietary or supplement intake with alcohol use, cigarette smoking or both. Therefore, consideration should be given to supplementing pregnant women who do not meet the Recommended Dietary Allowances through their diets. Further studies are needed to clarify the interactions of smoking and alcohol use with micronutrients during pregnancy and, ultimately, to determine whether pregnant women who use these substances require more micronutrients than the general population and should receive specic micronutrient supplementation. We make the following recommendations for future studies:  Studies examining the effect of smoking and alcohol use during pregnancy on micronutrient status should control for the intake of the nutrients in question as well exposure to other substances. Particular attention should be paid to including measures of micronutrient status that are not affected by the inammatory process.  Randomized control trials of the effects of micronutrient supplementation during pregnancy should, when possible, stratify randomization and results by exposure to cigarette smoke and alcohol use.

LITERATURE CITED
1. King, J. (2000) Determinants of maternal zinc status during pregnancy. Am. J. Clin. Nutr. 71 (Suppl.), 1334S1343S. 2. Kuhnert, B. (1991) Drug exposure to the fetus-the effect of smoking. In: Methodological issues in controlled studies on effects of prenatal exposure to drug abuse (Kilbey, M. M. & Asghar, K. eds.), pp. 117. National Institute on Drug Abuse, Rockville, MD. (Research Monograph 114). 3. Preston, A. M. (1991) Cigarette smoking-nutritional implications. Prog. Food Nutr. Sci. 15: 183217. 4. Lambers, D. S. & Clarke, K. E. (1996) The maternal and fetal physiologic effects of nicotine. Semin. Perinatol. 20: 115126. 5. Kramer, M. (1987) Determinants of low birth weight: methodological assessment and meta-analysis. Bull. World Health Organ. 65: 663737. 6. Cauleld, L., Stoltzfus, R. & Witter, F. (1998) Implications of the Institute of Medicine weight gain recommendations for preventing adverse pregnancy outcomes in black and white women. Am. J. Public Health 88: 1168 1174. 7. Wen, S. W., Goldenberg, R. L., Cutter, G. R., Hoffman, H. J., Cliver, S. P., Davis, R. O. & Dubard, M. B. (1990) Smoking, maternal age, fetal growth, and gestational age at delivery. Am. J. Obstet. Gynecol. 162: 5358. 8. Centers for Disease Control and Prevention. (2000) State-specic prevalence of current cigarette smoking among adults and the proportion of adults who work in a smoke-free environmentUnited States, 1999. MMWR. 49: 978 982. 9. Matthews, T. J. (2001) Smoking during pregnancy in the 1990s. Natl. Vital Stat. Rep. 49 (7). National Center for Health Statistics, Hyattsville, MD.

10. Haustein, K. O. (1999) Cigarette smoking, nicotine and pregnancy. Int. J. Clin. Pharmacol. Ther. 37: 417427. 11. Gibson, R. (1990) Principles of Nutritional Assessment. Oxford University Press, New York, N. Y. 12. Institute of Medicine. (2000) Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington, D. C. 13. Trygg, K., Lund-Larsen, K., Sandstand, B., Hoffman, H., Jacobsen, G. & Bakketeig, L. (1995) Do pregnant smokers eat differently from pregnant nonsmokers? Paediatr. Perinat. Epidemiol. 9: 307319. 14. Haste, F., Brooke, O., Anderson, H. & Bland, J. (1991) The effect of nutritional intake on outcome of pregnancy in smokers and non-smokers. Br. J. Nutr. 65: 347354. 15. Matthews, F., Yudkin, P., Smith, R. & Neil, A. (2000) Nutrient intakes during pregnancy: the inuence of smoking status and age. J. Epidemiol. Community Health 54: 1723. 16. Ortega, R. M., Lopez-Sobaler, A. M., Quintas, M. E., Martinez, R. M. & Andres, P. (1998) The inuence of smoking on vitamin C status during the third trimester of pregnancy and on vitamin C levels in maternal milk. J. Am. Coll. Nutr. 17: 379384. 17. Barrett, B., Gunter, E., Jenkins, J. & Wang, M. (1991) Ascorbic acid concentration in amniotic uid in late pregnancy. Biol. Neonate 60: 333335. 18. Schwarz, K., Cox, J., Sharma, S., Witter, F., Clement, L., Sehnert, S. & Risby, T. (1995) Cigarette smoking is pro-oxidant in pregnant women regardless of antioxidant nutrient intake. J. Nutr. Environ. Med. 5: 224234. 19. Ortega, R., Lopez-Sobaler, A., Martinez, R., Andres, P. & Quintaas, E. (1998) Inuence of smoking on vitamin E status during the third trimester of pregnancy and on breast-milk tocopherol concentrations in Spanish women. Am. J. Clin. Nutr. 68: 662667. 20. Kiely, M., Cogan, P., Kearney, P. & Morrissey, P. (1999) Relationship between smoking, dietary intakes and plasma levels of vitamin E and betacarotene in matched maternal-cord pairs. Int. J. Vitam. Nutr. Res. 69: 262267. 21. Moji, H., Murata, T., Morinobu, T., Manago, M., Tamai, H., Okamoto, R., Mino, M., Fujimura, M. & Takeuchi, T. (1995) Plasma levels of retinol, retinolbinding protein, all-trans beta-carotene and Cryptoxanthin in low birth weight infants. J. Nutr. Sci. Vitaminol. (Tokyo) 41: 595606. 22. Crosby, W., Metcoff, J., Costiloe, J., Mameesh, M., Sandstead, H., Jacob, R., McClain, P., Jacobson, G., Reid, W. & Burns, G. (1977) Fetal malnutrition: An appraisal of correlated factors. Am. J. Obstet. Gynecol. 128: 2231. 23. Klesges, L. M., Murray, D. M., Brown, J. E., Cliver, S. P. & Goldenberg, R. L. (1998) Relationship of cigarette smoking and dietary antioxidants with placental calicication. Am. J. Epidemiol. 147: 127135. 24. Pagan, K., Hou, J., Goldenberg, R., Cliver, S. & Tamura, T. (2001) Effect of smoking on serum concentrations of total homocysteine and B vitamins in mid-pregnancy. Clin. Chim. Acta 306: 103109. 25. Frery, N., Huel, G., Leroy, M., Moreau, T., Savard, R., Blot, P. & Lellouch, J. (1992) Vitamin B12 among parturients and their newborns and its relationship with birthweight. Eur. J. Obstet. Gynecol. Reprod. Biol. 45: 155163. 26. McGarry, J. & Andrews, J. (1972) Smoking in pregnancy and vitamin B12 metabolism. BMJ 2: 7477. 27. Kuhnert, P., Kuhnert, B., Erhard, P., Brashear, W., Groh-Wargo, S. & Webster, S. (1987) The effect of smoking on placental and fetal zinc status. Am. J. Obstet. Gynecol. 157: 12411246. 28. Simmer, K. & Thompson, R. (1985) Maternal zinc and intrauterine growth retardation. Clin. Sci. 68: 395399. 29. Kuhnert, B., Kuhnert, P. & Zarlingo, T. (1988) Association between placental cadmium and zinc and age and parity in pregnant women who smoke. Obstet. Gynecol. 71: 6770. 30. Kuhnert, B., Kuhnert, P., Debanne, S. & Williams, T. (1987) The relationship between cadmium, zinc, and birth weight in pregnant women who smoke. Am. J. Obstet. Gynecol. 157: 12471251. 31. Goldenberg, R., Tamura, T., Cliver, S., Cutter, G., Hoffman, H. & Davis, R. (1991) Maternal serum alpha2macroglobulin and fetal growth retardation. Obstet. Gynecol. 78: 594599. 32. Nordenberg, D., Yip, R. & Binkin, N. (1990) The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA 264: 15561559. 33. Sweet, D., Savage, G., Tubman, T., Lappin, T. & Halliday, H. (2001) Study of maternal inuences on fetal iron status at term using cord blood transferrin receptors. Arch. Dis. Child Fetal Neonatal Ed. 84: F40F43. 34. Meberg, A., Haga, P., Sande, H. & Foss, O. (1979) Smoking during pregnancy-hematological observation in the newborn. Acta Paediatr. Scand. 68: 731734. 35. Tamura, T., Goldenberg, R., Johnston, K. & DuBard, M. (1995) Effects of smoking on plasma ferritin concentrations in pregnant women. Clin. Chem. 41: 11901191. 36. Webster, W. S. (1979) Cadmium-induced fetal growth retardation in mice and the effects of dietary supplements of zinc, copper, iron, and selenium. J. Nutr. 109: 16461651. 37. Webster, W. S. (1978) Cadmium-induced fetal growth retardation in the mouse. Arch. Environ. Health 33: 3642. 38. Webster, W. S. (1979) Iron deciency and its role in cadmium-induced fetal growth retardation. J. Nutr. 109: 16401645. 39. Chmielnick, J. & Sowa, B. (1996) Cadmium interaction with essential metals (Zn, Cu, Fe) metabolism, and ceruloplasmin in pregnant rats and fetuses. Ecotoxicol. Environ. Saf. 35: 277281.

Downloaded from jn.nutrition.org by guest on November 27, 2011

1730S

SUPPLEMENT
70. Graham, J. & Fern, V. (1985) Heat- and alcohol-induced neural tube defects: interactions with folate in a golden hamster model. Pediatr. Res. 19: 247 251. 71. Cano, M., Ayaala, A., Murillo, M. & Carreras, O. (2001) Protective effect of folic acid against oxidative stress produced in 21day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period. Free Radic. Res. 34: 18. 72. Schenker, S., Johnson, R., Mahuren, D., Henderson, G. & Coburn, S. (1992) Human placental vitamin B6 (pyridoxal) transport: normal characteristics and effects of ethanol. Am. J. Physiol. 262: R966R974. 73. Schenker, S., Johnson, R., Hoyumpa, A. & Henderson, G. (1990) Thiamine-transfer by human placenta: normal transport and effects of ethanol. J. Lab. Clin. Med. 116: 106115. 74. Schenker, S., Hu, Z., Johnson, R., Yang, Y., Frosto, T., Elliott, B., Henderson, G. & Mock, D. (1993) Human placental biotin transport: normal characteristics and effect of ethanol. Alcohol. Clin. Exp. Res. 17: 566 575. 75. Lin, G. (1989) Effect of ethanol and Vitamin B6 deciency on pyridoxal 5phosphate levels and fetal growth in rat. Alcohol. Clin. Exp. Res. 13: 236 239. 76. Ba, A., Aka, K., Glin, L. & Tako, A. (1999) Comparative effects of developmental thiamine deciencies and ethanol exposure on the morphometry of the CA3 pyramidal cells. Neurotoxicol. Teratol. 21: 579586. 77. Flynn, A., Martier, S., Sokol, R., Miller, S., Golden, N. & Del Villano, B. (1981) Zinc status of pregnant alcoholic women: a determinant of fetal outcome. Lancet 1: 572574. 78. Halmesmaki, E. & Ylikorkala, O. (1985) Concentrations of zinc and copper in pregnant problem drinkers and their newborn infants. BMJ 291: 1470 1471. 79. Beer, W., Johnson, R., Guentzel, M., Lozano, J., Henderson, G. & Schenker, S. (1992) Human placental transfer of zinc: normal characteristics and role of ethanol. Alcohol. Clin. Exp. Res. 16: 98105. 80. Yeh Lee-Chuan, L. & Cerklewski, F. (1984) Interaction between ethanol and low dietary zinc during gestation and lactation in the rat. J. Nutr. 114: 20272033. 81. Dreosti, I., Manuel, S. & Buckley, R. (1982) Superoxide dismutase (EC 1.15.1.1), manganese and the effect of ethanol in adult foetal rats. Br. J. Nutr. 48: 205210. 82. Zidenberg-Cherr, S., Benak, P., Hurley, L. & Keen, C. (1988) Altered mineral metabolism: a mechanism underlying the fetal alcohol syndrome in rats. Drug Nutr. Interact. 5: 257274. 83. Greeley, S., Johnson, T., Schafer, D. & Johnson, P. (1990) Gestational alcoholism and fetal zinc accretion in long-evans rats. J. Am. Coll. Nutr. 9: 265 271. 84. Harris, J. (1990) Hepatic glutathione, metallothionein and zinc in the rat on gestational day 19 during chronic ethanol administration. J. Nutr. 120: 1080 1086. 85. Mendelson, R. & Huber, A. (1980) The effect of duration of alcohol administration on the deposition of trace elements in the fetal rat. Adv. Exp. Med. Biol. 132: 295304. 86. Ghishan, F., Patwardhan, R. & Greene, H. (1982) Fetal alcohol syndrome: inhibition of placental zinc transport as a potential mechanism for fetal growth retardation in the rat. J. Lab. Clin. Med. 100: 4552. 87. Suh, S. & Firek, A. (1982) Magnesium and zinc deciency and growth retardation in offspring of alcoholic rats. J. Am. Coll. Nutr. 1: 193198. 88. Mendelson, R. A. & Huber, A. M. (1980) The effect of duration of alcohol administration on the deposition of trace elements in the fetal rat. Adv. Exp. Med. Biol. 132: 295304. 89. Fisher, S., Alcock, N., Amirian, J. & Altshuler, H. (1988) Neonatal and maternal hair zinc levels in a nonhuman primate model of the fetal alcohol syndrome. Alcohol. Clin. Exp. Res. 12: 417421. 90. Carey, L., Coyle, P., Philcox, J. & Rofe, A. (2000) Ethanol decreases zinc transfer to the fetus in normal but not metallothionein-null mice. Alcohol. Clin. Exp. Res. 24: 12361240. 91. Carey, L. C., Coyle, P., Philcox, J. C. & Rofe, A. M. (2000) Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionine null mice. Alcohol. Clin. Exp. Res. 24: 213219. 92. Tanaka, H., Iwasaki, S., Nakazawa, K. & Inomata, K. (1988) Fetal alcohol syndrome in rats: conditions for improvement of ethanol effects on fetal cerebral development with supplementary agents. Biol. Neonate 54: 320 329. 93. Tanaka, H., Nasu, F. & Inomata, K. (1991) Fetal alcohol effects: decreased synaptic formations in the eld CA3 of fetal hippocampus. Int. J. Dev. Neurosci. 9: 509517. 94. Seyoum, G. & Persaud, T. (1995) Inuence of zinc on ethanol-induced placental changes in the rat. Histol. Histopathol. 10: 117125. 95. Ruth, R. & Goldsmith, S. (1981) Interaction between zinc deprivation and acute ethanol intoxication during pregnancy in rats. J. Nutr. 111: 20342038. 96. Ghishan, F. & Greene, H. (1983) Fetal alcohol syndrome: failure of zinc supplementation to reverse the effect of ethanol on placental transport of zinc. Pediatr. Res. 17: 529531. 97. Miller, S. (1983) Interaction of alcohol and zinc in fetal dysmorphogenesis. Pharmacol. Biochem. Behav. 18 (Suppl. 1), 311315. 98. Keppen, L., Pysher, T. & Rennert, O. (1985) Zinc deciency acts as a co-teratogen with alcohol in fetal alcohol syndrome. Pediatr. Res. 19: 944947.

40. Petering, H. G., Chowdhury, H. & Stemmer, K. L. (1979) Some effects of oral ingestion of cadmium on zinc, copper, and iron metabolism. Environ. Health Perspect. 28: 97106. 41. Jarup, L., Berglund, M., Elinder, C. G., Nordberg, G. & Vahter, M. (1998) Health effects of cadmium exposurea review of the literature and a risk estimate. Scand. J. Work Environ. Health 24 (Suppl. 1), 151. 42. Poets, C., Schlaud, M., Kleemann, W., Rudolph, A., Diekmann, U. & Sens, B. (1995) Sudden infant death and maternal cigarette smoking: results from the Lower Saxony Perinatal Working Group. Eur. J. Pediatr. 154: 326329. 43. Wu, T., Buck, G. & Mendola, P. (1998) Maternal cigarette smoking, regular use of multivitamin/mineral supplements, and risk of fetal death. Am. J. Epidemiol. 148: 215221. 44. Wu, T., Buck, G. & Mendola, P. (1998) Can regular multivitamin/ mineral supplementation modify the relation between maternal smoking and select adverse birth outcomes? Ann. Epidemiol. 8: 175183. 45. Institute of Medicine. (2000) Dietary reference intakes for thiamin, riboavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press, Washington, D. C. 46. Institute of Medicine. (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and uoride. National Academy Press, Washington, DC. 47. Institute of Medicine. (2002) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, mangenese, molybdenum, nickel, silicon, vanadium, and zinc. Prepublication Copy, Uncorrected Proofs. National Academy Press, Washington, D. C. 48. Thomson, A. (1978) Alcohol and nutrition. Clin. Endocrinol. Metab. 7: 405428. 49. Kumar, S. (1982) Fetal alcohol syndrome: mechanism of teratogenesis. Ann. Clin. Lab. Sci. 12: 254257. 50. Florey, C., Taylor, D., Bolumar, F., Kaminski, M. & Olsen, J. ed. (1992) EUROMAC. A European concerted action: maternal alcohol consumption and its relationship with the outcome of pregnancy and child development at 18 months. Int. J. Epidemiol. 21 (Suppl. 1): S38S39. 51. Ulrik, K., Kirsten, W., Sjurur Froi, O., Tine Brink, H. & Niels Jorgen, S. (2002) Moderate alcohol intake during pregnancy and the risk of still birth and death in the rst year. Am. J. Epidemiol. 155: 305331. 52. Taylor, D. (1993) Pregnancy alcohol consumption. Fetal and Maternal Medicine Review 5: 121135. 53. Centers for Disease Control and Prevention. (2002) Alcohol use among women of childbearing ageUnited States 19911999. MMWR. 51: 273276. 54. Dreotsi, I. (1993) Nutritional factors underlying the expression of the fetal alcohol syndrome. Ann. N. Y. Acad. Sci. 678: 193204. 55. Seyoum, G. & Persaud, T. (1995) Protective inuence of zinc against the deleterious effects of ethanol in postimplantation rat embryos in vivo. Exp. Toxicol. Pathol. 47: 7579. 56. Leiber, C. S. & Leo, M. A. (1986) Interaction of alcohol and nutritional factors with hepatic brosis. Prog. Liver Dis. 8: 253272. 57. Grummer, M. & Zachman, R. (1990) The effect of maternal ethanol ingestion on fetal vitamin A in the rat. Pediatr. Res. 28: 186189. 58. DeJonge, M. & Zachman, R. (1995) The effect of maternal ethanol ingestion on fetal rat heart vitamin A: a model for fetal alcohol syndrome. Pediatr. Res. 37: 418423. 59. Zachman, R. & Grummer, M. (2001) Prenatal ethanol consumption increases retinol and cellular retinol-binding protein expression in the rat fetal snout. Biol. Neonate 80: 152157. 60. Grummer, M., Langhough, R. & Zachman, R. (1993) Maternal ethanol ingestion effects on fetal rat brain vitamin A as a model for fetal alcohol syndrome. Alcohol. Clin. Exp. Res. 17: 592597. 61. Milne, M. & Baran, D. (1985) Inhibitory effect of maternal alcohol ingestion on rat pup hepatic 25Hydroxyvitamin D production. Pediatr. Res. 19: 102104. 62. Lin, G. (1981) Fetal malnutrition: a possible cause of the fetal alcohol syndrome. Prog. Biochem. Pharmacol. 18: 115121. 63. Whitby, K. E., Collins, T. F., Welsh, J. J., Black, T. N., Flynn, T., Shackelford, M., Ware, S. E., ODonnell, M. W. & Sundaresan, P. R. (1994) Developmental effects of combined exposure to ethanol and vitamin A. Food Chem. Toxicol. 32: 305320. 64. Lee, M. (1985) Potentiation of chemically induced cleft palate by ethanol ingetion during gestation in the mouse. Teratog. Carcinog. Mutagen. 5: 433440. 65. Larroque, B., Kaminski, M., Lelong, N., dHerbomez, M., Dehaene, P., Querleu, D. & Crepin, G. (1992) Folate status during pregnancy: relationship with alcohol consumption, other maternal risk factors and pregnancy outcome. Eur. J. Obstet. Gynecol. Reprod. Biol. 43: 1927. 66. Switzer, B., Anderson, J. & Pick, J. (1986) Effects of dietary protein and ethanol intake on pregnant beagles fed puried diets. J. Nutr. 116: 689697. 67. Leichter, J. & Lee, M. (1984) Intestinal folate conjugase activity and folate absorption in the ethanol-fed pregnant rat. Drug Nutr. Interact. 3: 5359. 68. Tavares, E., Gomez-Tubio, A., Murillo, M. & Carreras, O. (1999) Folic acid intestinal absorption in newborn rats at 21 day postpartum: effects of maternal ethanol consumption. Life Sci. 64: 20012010. 69. Fisher, S., Inselman, L., Duffy, L., Atkinson, M., Spencer, H. & Chang, B. (1985) Ethanol and fetal nutrition: effect of chronic ethanol exposure on rat placental growth and membrane-associated folic acid receptor binding activity. J. Pediatr. Gastroenterol. Nutr. 4: 645649.

Downloaded from jn.nutrition.org by guest on November 27, 2011

SMOKING, ALCOHOL AND MICRONUTRIENTS

99. Shetlar, C., Cogan, D., Sparkman, G., Wang, M. & Shetlar, M. (1986) Zinc and ethanol: dietary interrelationships in pregnant rats. Alcohol 3: 145152. 100. Zidenberg-Cherr, S., Rosenbaum, J. & Keen, C. (1988) Inuence of ethanol consumption on maternal-fetal transfer of zinc in pregnant rats on day 14 of pregnancy. J. Nutr. 118: 865870. 101. Streissguth, A., Barr, H., Labbe, R., Smith, J., Darby, B., Smith, N., Martin, D. & Doan, R. (1983) Alcohol use and iron status in pregnant women. Alcohol. Clin. Exp. Res. 7: 227230.

1731S

102. Miller, M., Roskams, J. & Conner, J. (1995) Iron regulation in the developing rat brain: effect of in utero ethanol exposure. J. Neurochem. 65: 373 380. 103. Sanchez, J., Casas, M. & Rama, R. (1988) Effect of chronic ethanol administration on iron metabolism in the rat. Eur. J. Haematol. 41: 321325. 104. Banna, N., Picciano, M. & Simon, J. (1983) Effects of chronic alcohol consumption and iron deciency on maternal folate status and reproductive outcome in mice. J. Nutr. 113: 21592170.

Downloaded from jn.nutrition.org by guest on November 27, 2011